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Cannabis (marihuana, marijuana) and the cannabinoids
Dried plant for administration by ingestion or other means
Psychoactive agent

This document has been prepared by the Controlled Substances and Tobacco Directorate at Health Canada to provide information on the use of cannabis and cannabinoids for medical purposes. Cannabis is not an approved therapeutic product and the provision of this information should not be interpreted as an endorsement of the use of this product, or cannabis generally, by Health Canada.

Despite the similarity of format, it is not a Drug Product Monograph, which is a document which would be required if the product were to receive a Notice of Compliance authorizing its sale in Canada. This document is a summary of peer-reviewed literature and international reviews concerning potential therapeutic uses and harmful effects of cannabis (marihuana) and cannabinoids. It is not meant to be comprehensive and should be used as a complement to other reliable sources of information.

This document should not be construed as expressing conclusions from Health Canada about the appropriate use of cannabis (marihuana) or cannabinoids for medical purposes.


Cannabis (marijuana, marihuana) is not an approved therapeutic substance in Canada and has not been issued a notice of compliance by Health Canada authorizing sale in Canada.

Prepared by Health Canada
Date of latest version: February 2013

(May 2013) Addendum to the Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids (February 2013 version)

Following the most recent update to this document (February 2013), a study was published in the Netherlands tracking data obtained from the Dutch medical cannabis program over the years 2003-2010. The study reported that in a population of over 5,000 Dutch patients using cannabis for medical purposes, the average daily dose of dried cannabis (various potencies) used was 0.68 grams per day (range: 0.65 - 0.82 grams per day) (Hazekamp and Heerdink 2013). In addition, information from Israel's medical marihuana program suggests that the average daily amount used by patients was approximately 1.5 grams of dried cannabis per day in 2011-2012 (Health Canada personal communication).

Hazekamp, A., and E.R. Heerdink (2013). The prevalence and incidence of medicinal cannabis on prescription in The Netherlands. Eur. J. Clin. Pharmacol. Published online April 16, 2013.

Table of Contents

List of Abbreviations

2-AG:
2-arachidonoylglycerol
5-HT:
5-hydroxytryptamine
ACEA:
arachidonyl-2-chloroethylamide
ACTH:
adrenocorticotropic hormone
AD:
Alzheimer's disease
AEA:
arachidonoylethanolamide (i.e. "anandamide")
AIDS:
acquired immune deficiency syndrome
ALS:
amyotrophic lateral sclerosis
ApoE:
apolipoprotein E
AUC:
area-under-the-curve
B.I.D.:
bis in die (i.e. twice per day)
CAMS:
Cannabis in Multiple Sclerosis
CB:
cannabinoid
CBC:
cannabichromene
CBD:
cannabidiol
CBG:
cannabigerol
CBN:
cannabinol
CNS:
central nervous system
CINV:
chemotherapy-induced nausea and vomiting
CNR1:
cannabinoid receptor gene 1
CNR2:
cannabinoid receptor gene 2
CI:
confidence interval
CRPS:
complex regional pain syndrome
CSF:
cerebrospinal fluid
CUPID:
Cannabinoid Use in Progressive Inflammatory Brain Disease
CYP:
cytochrome P450
Δ9-THC:
delta-9-tetrahydrocannabinol
DAG:
diacylglycerol
DEA:
N-docosatetraenoylethanolamine
DNBSA:
dinitrobenzene sulfonic acid
DSM-IV-TR:
diagnostic and statistical manual of mental disorders
ECS:
endocannabinoid system
FAAH:
fatty acid amide hydrolase
FEV1:
forced expiratory volume in one second
FVC:
forced vital capacity
HD:
Huntington's disease
HEA:
N-homo-γ-linolenoylethanolamine
HIV:
human immunodeficiency virus
HMO:
health maintenance organization
HSV:
herpes simplex virus
IBD:
inflammatory bowel disease
IBS:
irritable bowel syndrome
IOP:
intra-ocular pressure
I.P.:
intraperitoneal
I.V.:
intravenous
KSHV:
Kaposi's sarcoma-associated herpes virus
LDL:
low density lipoprotein
MAGL:
monoacylglycerol lipase
MDS:
macroscopic damage score
MMAR:
marihuana medical access regulations
mRNA:
messenger ribonucleic acid
MS:
multiple sclerosis
MUSEC:
MUltiple Sclerosis and Extract of Cannabis trial
NADA:
N-arachidonoyl-dopamine
NAFLD:
non-alcoholic fatty liver disease
NAPE:
N-arachidonoylphosphatidylethanolamine
NAT:
N-acyl transferase
NIDA:
National Institute on Drug Abuse
nM:
nanomolar
NNT:
number needed to treat
OA:
osteoarthritis
OEA:
oleoylethanolamide
OR:
odds ratio
PAH:
polycyclic aromatic hydrocarbon
PASAT:
paced serial addition test
PD:
Parkinson's disease
PEA:
palmitoylethanolamide
PET:
positron emission tomography
PPAR:
peroxisome proliferator- activated receptor
PTSD:
post-traumatic stress disorder
Q.I.D.:
quattuor in die (i.e. four times per day)
QOL:
quality of life
RA:
rheumatoid arthritis
RCT:
randomized controlled trial
REM:
rapid eye movement
RGC:
retinal ganglion cells
S.C.:
subcutaneous
SCI:
spinal cord injury
SNP:
single nucleotide polymorphism
SPECT:
single-photon emission computed tomography
THC:
delta-9-tetrahydrocannabinol
THCA:
tetrahydrocannabinolic acid
THCV:
tetrahydrocannabivarin
T.I.D.:
ter in die (i.e. three times per day)
TNBSA:
trinitrobenzene sulfonic acid
TRPV1:
transient receptor potential vanilloid channel 1
TS:
Tourette's syndrome
μM:
micromolar
VSV:
vesicular stomatitis virus
WHO:
World Health Organization

Author: Hanan Abramovici Ph.D.

Affiliations:
Research, Synthesis, and Dissemination Division, Office of Research and Surveillance, Controlled Substances and Tobacco Directorate, Health Canada, Ottawa, ON, Canada K1A 0K9 Email: hanan.abramovici@hc-sc.gc.ca

Acknowledgements
Health Canada would like to acknowledge and thank the following individuals for their comments and suggestions with regard to the content in this information document:

Donald I. Abrams, M.D.
Chief, Hematology-Oncology
San Francisco General Hospital
Integrative Oncology
UCSF Osher Center for Integrative Medicine
Professor of Clinical Medicine
University of California San Francisco
San Francisco, CA 94143-0874
USA

Pierre Beaulieu, Ph.D., M.D., F.R.C.A.
Professeur agrégé
Département de pharmacologie
Faculté de médecine
Université de Montréal
Bureau R-408, Pavillon Roger-Gaudry
C.P. 6128 - Succursale Centre-ville
Montréal, Québec
H3C 3J7
Canada

Paul J. Daeninck, M.D., M.Sc., F.R.C.P.C
Chair, Symptom Management Group
Room LI 101-8, O Block
CancerCare Manitoba
St. Boniface Hospital
409 Taché Ave
Winnipeg, MB
R2H 2A6
Canada

Vincenzo di Marzo, Ph.D.
Research Director
Endocannabinoid Research Group
Institute of Biomolecular Chemistry
Consiglio Nazionale delle Ricerche
Via Campi Flegrei 34
Comprensorio Olivetti
80078 Pozzuoli (NA)
Italy

Mahmoud A. ElSohly, Ph.D.
Research Professor and Professor of Pharmaceutics
National Center for Natural Products Research and Department of Pharmaceutics
School of Pharmacy
University of Mississippi
University, MS 38677
USA

Javier Fernandez-Ruiz, Ph.D.
Full Professor of Biochemistry and Molecular Biology
Department of Biochemistry and Molecular Biology
Faculty of Medicine
Complutense University
Madrid, 28040
Spain

Tony George, M.D., F.R.C.P.C.
Clinical Director, Schizophrenia Program
Endowed Chair in Addiction Psychiatry, University of Toronto
Centre for Addiction and Mental Health
250 College Street, Suite 734
Toronto, ON
M5T 1R8
Canada

Boris Gorzalka, Ph.D.
Professor
Department of Psychology
University of British Columbia
Room 1614
2136 West Mall
Vancouver, BC
V6T 1Z4
Canada

Margaret Haney, Ph.D.
Professor of Clinical Neurobiology
Columbia University
Department of Psychiatry
1051 Riverside Drive, Unit 120
New York, NY 10032
USA

Matthew N. Hill, Ph.D.
Assistant Professor
Departments of Cell Biology and Anatomy & Psychiatry
The Hotchkiss Brain Institute
University of Calgary
Calgary, AB
T2N 4N1
Canada

Harold Kalant, M.D., Ph.D., O.C.
Professor Emeritus
Department of Pharmacology and Toxicology
University of Toronto
Room 4221, Medical Sciences Building
1 King's College Circle
Toronto, ON
M5S 1A8
Canada

Aron Lichtman, Ph.D.
Professor
Department of Pharmacology & Toxicology
Molecular Medicine Research Building, Room 3042
1220 East Broad St.
P.O. Box 980613
Richmond, Virginia 23298-0613
USA

Mary Lynch, M.D., F.R.C.P.C.
Professor of Anaesthesia, Psychiatry and Pharmacology
Dalhousie University
Director, Pain Management Unit-Capital Health
Queen Elizabeth II Health Sciences Centre
4th Floor Dickson Building
5820 University Avenue
Halifax, NS
B3H 1V7
Canada

Jason McDougall, Ph.D.
Associate Professor
Departments of Pharmacology and Anaesthesia
Dalhousie University
5850 College Street
Halifax, NS
B3H 1X5
Canada

Raphael Mechoulam, Ph.D.
Professor
Institute for Drug Research, Medical Faculty
Hebrew University
Jerusalem
91120
Israel

Richard (Rik) E. Musty, Ph.D.
Professor Emeritus of Psychology
Department of Psychology
College of Arts and Sciences
University of Vermont
Burlington, VT 05405
USA

Linda Parker, Ph.D.
Professor and Canada Research Chair
Department of Psychology
University of Guelph
Guelph, Ontario
N1G 2W1
Canada

Roger G. Pertwee, MA, D.Phil. D.Sc.
Professor of Neuropharmacology
Institute of Medical Sciences
University of Aberdeen
Aberdeen
AB25 2ZD
Scotland, United Kingdom

Keith Sharkey, Ph.D.
Professor
Department of Physiology and Biophysics and Medicine
University of Calgary
HSC 1745
3330 Hospital Drive NW
Calgary, AB
T2N 4N1
Canada

Cory Toth, B.Sc., M.D., C.S.C.N., F.R.C.P.C.
Assistant Professor of Neurosciences
Hotchkiss Brain Institute
Faculty of Medicine
University of Calgary
HMRB 155
3330 Hospital Drive NW
Calgary, AB
T2N 4N1
Canada

Mark Ware, M.D., M.R.C.P., M.Sc.
Associate Director
Allan Edwards Pain Management Unit, MUHC Pain Centre
E19.145 Montreal General Hospital
1650 Cedar Avenue
Montréal, Québec
H3G 1A4
Canada

IMPORTANT NOTE: For the sake of completeness and for contextual purposes, the content in the following document includes information on dried cannabis as well as selected cannabinoids. However, cannabis and cannabinoids should not be considered equivalent even though the information on both is presented together within the text. Cannabis is a highly complex material with hundreds of chemical constituents whereas cannabinoids are single molecules. Drawing direct comparisons between cannabis and cannabinoids must necessarily take into account differences in the route of administration, dosage, and the different pharmacokinetic and pharmacodynamic properties of these different substances.


1.0 The Endocannabinoid System

The endocannabinoid system (Figure 1) is an ancient, evolutionarily conserved, and ubiquitous lipid signaling system found in all vertebrates, and which appears to have important regulatory functions throughout the human bodyFootnote 1. The endocannabinoid system has been implicated in a very broad number of physiological as well as pathophysiological processes including neural development, immune function, inflammation, appetite, metabolism and energy homeostasis, cardiovascular function, digestion, bone development and bone density, synaptic plasticity and learning, pain, reproduction, psychiatric disease, psychomotor behaviour, memory, wake/sleep cycles, and the regulation of stress and emotional stateFootnote 2,Footnote 3,Footnote 4.

Components of the endocannabinoid system

The system consists of the cannabinoid 1 and 2 (CB1 and CB2) receptors, the CB receptor ligands N-arachidonoylethanolamine (i.e. "anandamide" or AEA) and 2-arachidonoylglycerol (2-AG) as well as the endocannabinoid-synthesizing and degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) (Figure 1)Footnote 2. Anandamide and 2-AG are considered the primary endogenous mediators of cannabinoid signaling, but other endogenous molecules which exert "cannabinoid-like" effects have also been described. These other molecules include 2-arachidonoylglycerol ether (noladin ether), N-arachidonoyl dopamine (NADA), virodhamine, N-homo-γ-linolenoylethanolamine (HEA) and N-docosatetraenoylethanolamine (DEA)Footnote 2,Footnote 5,Footnote 6,Footnote 7,Footnote 8. Molecules such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) do not appear to bind to cannabinoid receptors but rather to a specific isozyme belonging to a class of nuclear receptors/transcription factors known as peroxisome proliferator-activated receptors (PPARs)Footnote 8. These endocannabinoids may, however, potentiate the effect of anandamide by competitive inhibition of FAAH, and/or through direct allosteric effects on other receptors such as the transient receptor potential vanilloid (TRPV1) channelFootnote 9. These types of effects have been generally referred to as the so-called "entourage effect"Footnote 9,Footnote 10.

Endocannabinoid synthesis

Endocannabinoids are arachidonic acid derivatives which are synthesized "on demand" from membrane phospholipid precursors in response to cellular requirementsFootnote 2,Footnote 11,Footnote 12,Footnote 13. Anandamide is principally produced by the transfer of arachidonic acid from phosphatidylcholine to phosphatidylethanolamine by N-acyltransferase (NAT) to yield N-arachidonoylphosphatidylethanolamine (NAPE). NAPE is then hydrolyzed to form anandamide by a NAPE-specific phospholipase DFootnote 2,Footnote 14. In contrast, 2-AG is principally synthesized through phospholipase C-β-mediated hydrolysis of phosphatidylinositol-4,5-bisphosphate, with arachidonic acid on the sn-2 position, to yield diacylglycerol (DAG). DAG is then hydrolyzed to 2-AG by a DAG-lipaseFootnote 2,Footnote 14. While anandamide and 2-AG are both derivatives of arachidonic acid, they are synthesized by pathways distinct from those used to synthesize eicosanoidsFootnote 15. Nevertheless, it appears that there may be a certain amount of cross-talk between the eicosanoid and endocannabinoid pathwaysFootnote 15.

Genetics and signaling through the cannabinoid receptors

Endocannabinoids such as anandamide and 2-AG, as well as the phytocannabinoids Δ9-tetrahydrocannabinol (Δ9-THC), ΔFootnote 9-THC, cannabinol and others, bind to and activate (with differing affinities and efficacies) the CB1 and CB2 receptors which are G-protein coupled receptors that activate Gi/Go-dependent signaling cascadesFootnote 16,Footnote 17. The receptors are encoded by separate genes located on separate chromosomes; in humans, the CB1 receptor gene (CNR1) locus is found on chromosome 5q15 whereas the CB2 receptor gene (CNR2) locus is located on chromosome 1p36Footnote 18. The CNR1 coding sequence consists of one exon encoding a protein of 472 amino acidsFootnote 19. The CB1 receptor protein shares 97-99% amino acid sequence identity across species (human, rat, mouse)Footnote 19. As with the CNR1 coding sequence, the CNR2 coding sequence consists of only one exon, but it encodes a shorter protein 360 amino-acids in lengthFootnote 19. The human CB2 receptor shares 48% amino acid identity with the human CB1 receptor; the mouse CB2 receptor shares 82% amino acid sequence identity with the human CB2 receptorFootnote 19.

Activation of the CB1 or CB2 Gi/o-protein coupled receptors results in inhibition of adenylyl cyclase activity, decreased formation of cyclic AMP with a corresponding decrease in protein kinase A activity, and inhibition of Ca2+ influx through various Ca2+ channels; it also results in stimulation of inwardly rectifying potassium (K+) channels and the mitogen-activated protein kinase signaling cascadesFootnote 3,Footnote 12. Anandamide is a partial agonist at CB receptors, and binds with slightly higher affinity at CB1 compared to CB2 receptorsFootnote 2,Footnote 20. 2-AG appears to bind equally well to both CB receptors (with slightly higher affinity to CB1), but has greater potency and efficacy than anandamide at CB receptorsFootnote 2,Footnote 20.

In the central nervous system (CNS), the overall effect of CB1 receptor activation is suppression of neurotransmitter release (5-hydroxytryptamine, glutamate, acetylcholine, GABA, noradrenaline, dopamine, D-aspartate, cholecystokinin) at both excitatory and inhibitory synapses with both short and long-term effectsFootnote 2,Footnote 16,Footnote 21. Inhibition of neurotransmitter release occurs through a retrograde signaling mechanism whereby endocannabinoids synthesized and released from the post-synaptic neurons diffuse backwards across the synaptic cleft and bind to CB1 receptors located on the pre-synaptic terminalsFootnote 3. This retrograde signaling mechanism permits the regulation of neurotransmission in a precise spatio-temporal mannerFootnote 3. In immune cells, activation of CB2 receptors inhibits cytokine/chemokine release and neutrophil and macrophage migration, giving rise to complex modulatory effects on immune system functionFootnote 17.

Cannabinoid receptor expression and receptor distribution

Most tissues contain a functional endocannabinoid system with the CB1 and CB2 receptors having distinct patterns of tissue expression. The CB1 receptor is one of the most abundant G-protein coupled receptors in the central and peripheral nervous systemsFootnote 17. It has been detected in the cerebral cortex, hippocampus, amygdala, basal ganglia, substantia nigra pars reticulata, internal and external segments of the globus pallidus and cerebellum (molecular layer), and at central and peripheral levels of the pain pathways including the periaqueductal gray matter, rostral ventrolateral medulla, the dorsal primary afferent spinal cord regions including the peripheral nociceptors, and the spinal interneuronsFootnote 4,Footnote 21,Footnote 22. The CB1 receptor is also expressed in many other organs and tissues including adipocytes, leukocytes, spleen, heart, lung, the gastrointestinal tract (liver, pancreas, stomach, and the small and large intestine), kidney, bladder, reproductive organs, skeletal muscle, bone, joints, and skin Footnote 23,Footnote 24,Footnote 25,Footnote 26,Footnote 27,Footnote 28,Footnote 29,Footnote 30,Footnote 31,Footnote 32,Footnote 33,Footnote 34,Footnote 35,Footnote 36,Footnote 37,Footnote 38,Footnote 39,Footnote 40,Footnote 41. CB1 receptor expression appears to be relatively sparse in the brainstem regionFootnote 4. CB2 receptors are most highly concentrated in the tissues and cells of the immune system such as the leukocytes and the spleen, but can also be found in bone and to a lesser degree in liver and in nerve cells including astrocytes, oligodendrocytes and microglia, and even some neuronal sub-populations (reviewed inFootnote 42,Footnote 43).

Other molecular targets of cannabinoids

Besides the well-known CB1 and CB2 receptors, a number of different cannabinoids are believed to bind to a number of other molecular targets. Such targets include the third putative cannabinoid receptor GPR55, the transient receptor potential (TRP) cation channel family, and a class of nuclear receptors/transcription factors known as the peroxisome proliferator-activated receptors (PPARs). For additional details on this subject please consult the following resourcesFootnote 7,Footnote 8,Footnote 20,Footnote 44. Modulation of these other cannabinoid targets adds additional layers of complexity to the known myriad effects of cannabinoids.

Signal termination

Endocannabinoid signaling is rapidly terminated by the action of two hydrolytic enzymes: fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)Footnote 3. FAAH is primarily localized post-synapticallyFootnote 45,Footnote 46 and preferentially degrades anandamideFootnote 13; MAGL is primarily localized pre-synapticallyFootnote 45,Footnote 46 and favors the catabolism of 2-AGFootnote 13.

Dysregulation of the endocannabinoid system and general therapeutic challenges of using cannabinoids

Dysregulation of the endocannabinoid system appears to be connected to a number of pathological conditions, with the changes in the functioning of the system being either protective or maladaptiveFootnote 47. Modulation of the endocannabinoid system either through the targeted inhibition of specific metabolic pathways, and/or directed agonism or antagonism of its receptors may hold therapeutic promiseFootnote 12. However, a major and consistent therapeutic challenge confronting the routine use of psychoactive cannabinoids (e.g. THC) in the clinic has remained that of achieving selective targeting of the site of disease and the sparing of other bodily regions such as the mood and cognitive centres of the brainFootnote 21,Footnote 47,Footnote 48,Footnote 49,Footnote 50.

Figure 1: The Endocannabinoid System in the Nervous System. Details are in the text following the image.

Figure 1. The Endocannabinoid System in the Nervous System

  1. Endocannabinoids are manufactured "on-demand" in the post-synaptic terminals: anandamide (AEA) is generated from phospholipase-D (PLD)-mediated hydrolysis of the membrane lipid N-arachidonoylphosphatidylethanolamine (NAPE); 2-AG from the diacylglycerol lipase (DAGL)-mediated hydrolysis of the membrane lipid diacylglycerol (DAG);
  2. These endocannabinoids (AEA and 2-AG) diffuse retrogradely towards the pre-synaptic terminals and like exogenous cannabinoids such as THC (from cannabis), dronabinol, and nabilone, they bind and activate the pre-synaptic G-protein-coupled CB1 receptors;
  3. Binding of phytocannabinoids and endocannabinoids to the CB1 receptors triggers the activation and release of the Gi/Go proteins from the CB receptors and inhibits adenylyl cyclase, thus decreasing the formation of cyclic AMP and the activity of protein kinase A;
  4. Release of the Gi/Go proteins also results in the opening of inwardly-rectifying K+ channels (depicted with a "+") causing a hyperpolarization of the pre-synaptic terminals, and the closing of Ca2+ channels (depicted with a "-"), arresting the release of stored excitatory and inhibitory neurotransmitters (e.g. glutamate, GABA, 5-hydroxytryptamine (5-HT), acetylcholine, noradrenaline, dopamine, D-aspartate and cholecystokinin) which
  5. once released, diffuse and bind to post-synaptic receptors;
  6. Anandamide and 2-AG re-enter the post- or pre-synaptic nerve terminals (possibly through the actions of a specialized transporter depicted by a "dashed" line) where they are respectively catabolized by fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) to yield either arachidonic acid (AA) and ethanolamine (ETA), or arachidonic acid and glycerol. See text for additional details. Figure adapted fromFootnote 51,Footnote 52,Footnote 53.

1.1 Cannabis

1.1.1 Chemistry and composition

Marihuana (Marijuana) is the common name for Cannabis sativa (i.e. cannabis), a hemp plant that grows throughout temperate and tropical climatesFootnote 54. The leaves and flowering tops of Cannabis plants contain at least 489 distinct compounds distributed among 18 different chemical classes, and harbor more than 70 different phytocannabinoidsFootnote 55. The principal cannabinoids appear to be delta-9-tetrahydrocannabinol (i.e. Δ9-THC, THC), cannabinol (CBN), and cannabidiol (CBD)Footnote 56,Footnote 57,Footnote 58, although the relative abundance of these and other cannabinoids can vary depending on a number of factors such as the Cannabis strain, the soil and climate conditions, and the cultivation techniquesFootnote 59,Footnote 60. Other cannabinoids found in cannabis include cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabivarin (THCV) and many othersFootnote 55. In the living plant, these phytocannabinoids exist as both inactive monocarboxylic acids (e.g. THCA) and as active decarboxylated forms (e.g. THC); however, heating (at temperatures above 120 °C) promotes decarboxylation (e.g. THCA to THC) and results in biological activationFootnote 61,Footnote 62,Footnote 63. Furthermore, pyrolysis transforms each of the hundreds of compounds in cannabis into a number of other compounds, many of which remain to be characterized both chemically and pharmacologically. Therefore, marihuana (cannabis) can be considered a very crude drug containing a very large number of chemical and pharmacological constituents, the properties of which are only slowly being understood.

Among all the chemical constituents of cannabis, and particularly among the cannabinoids, Δ9-THC is by far the best studied and is responsible for many, if not most, of the physical and psychotropic effects of cannabisFootnote 64. Other cannabinoids (such as CBD, CBC, CBG) are present in lesser amounts in the plant and have little, if any, psychotropic propertiesFootnote 64. It is reasonable to consider about 10% (range 1 - 30%) as an average for Δ9-THC content in cannabis found on the illicit market in Canada (internal communication). The dried marihuana currently provided by Health Canada is composed of the mature flowering heads of female plants and contains 12.5 ±2% total THC (Δ9-THC and Δ9-THCA), and less than 0.5% CBD, CBG, CBN, and CBCFootnote 65. The MS-17/338 production line has THC concentrations typically higher than 10%, with the mature flowering heads containing the highest concentration of THCFootnote 65. The plant is cultivated and harvested in compliance with Good Manufacturing Practices, by Prairie Plant Systems Inc. under contract to Health CanadaFootnote 66. Furthermore, the product is irradiated to ensure that users whose immune systems may be compromised are not exposed to toxic spores which may contaminate the plant material, and the finished product lot release is based on the results of bacterial, fungal, and moisture testingFootnote 65. Irradiated pouches containing the dried cannabis are kept sterile over long-term cold storage, with measures of viable microbes being below detection (Health Canada internal communication).

1.1.2 Other constituents

The large number of compounds found in cannabis span many chemical classes including cannabinoids, nitrogenous compounds, amino acids, proteins, enzymes, glycoproteins, hydrocarbons, simple alcohols, aldehydes, ketones and acids, fatty acids, simple esters and lactones, steroids, terpenes, non-cannabinoid phenols, flavonoids, vitamins, and pigmentsFootnote 55. Furthermore, differences in the presence and the relative abundance of some of these various components have been investigated, and differences have been noted between cannabis extract, vapour, and smoke, and also between cannabis varietiesFootnote 67. Of note, cannabis smoke contains many compounds not observed in either extracts or vapour, including a number which are known or suspected carcinogens or mutagensFootnote 67,Footnote 68,Footnote 69. Moreover, comparisons between cannabis smoke and tobacco smoke have shown that the former contains many of the same carcinogenic chemicals found in tobacco smokeFootnote 68,Footnote 70.

Relatively little is known about the pharmacological actions of the various other compounds found within cannabis (e.g. terpenes, flavonoids). However, it is believed that some of these compounds (e.g. terpenes) may have a broad spectrum of action (e.g. anti-oxidant, anti-anxiety, anti-inflammatory, anti-bacterial, anti-neoplastic, anti-malarial), but this information comes from a few in vitro and in vivo studies and no clinical trials exist to support these claims. Terpenes vary widely among cannabis varieties and are thought to be primarily responsible for differences in fragrance among the different Cannabis strainsFootnote 59. Furthermore, it is thought that terpenes may contribute to the distinctive smoking qualities and possibly to the character of the "high" associated with smoking cannabisFootnote 59, but again, this has not been studied in any detail. The concept that terpenes may somehow modify or enhance the physiological effects of the cannabinoidsFootnote 71,Footnote 72 is, for the moment, hypothetical as there is little, if any, pre-clinical evidence to support this hypothesis and no clinical trials on this subject have been carried out to date.

1.1.3 Stability and storage

Most of the information on the stability of marihuana/cannabis does not distinguish between Δ9-THC and its carboxylic acid (Δ9-THCA). The latter is transformed to Δ9-THC by heating during vapourization or cooking, or by pyrolysis during smoking or in the inlet of gas chromatographs used in forensic analysisFootnote 73. Heat, light, humidity, acidity and oxidation all affect the stability of cannabis and cannabinoidsFootnote 74,Footnote 75. The National Institute on Drug Abuse (NIDA) reports that retention samples of their carefully prepared and standardized cigarettes are stable for months, particularly when stored below 0 oC (-18 oC) in the dark, in tightly-closed containersFootnote 76. Even when stored at +18 oC, only a third of the THC content is lost over a five-year period with some increase in the concentration of CBN. Lower-potency cigarettes (1.15% THC) appear to lose more THC compared to higher potency cigarettes (2.87% THC)Footnote 76. Stability data for cannabis distributed by Health Canada indicate that, when stored in the refrigerator (4 °C ±1 °C) or freezer (-17 °C to -20 °C ±1°C), the finished product is stable for over 2 years without significant conversion of Δ9-THCA to Δ9-THC or any alterations in colour or aroma (Health Canada internal communication). The moisture content of the sealed, finished product is constant at 11 - 12% over a period of 12 months. When stored at room temperature (20 °C ± 2 °C), alterations in colour and aroma are detected in the finished product at 9 months, and conversion of Δ9-THCA to Δ9-THC is detected as early as 1.5 months, and increases to nearly 25% at 18 months (Health Canada internal communication). The ideal storage temperature for the finished dried cannabis product is 2 °C to 6 °C with a shelf-life of 12 months (Health Canada internal communication).

2.0 Clinical Pharmacology

2.1 Pharmacodynamics

Much of the pharmacodynamic information on cannabis refers to the effects of the major constituent Δ9-THC which acts as a partial agonist at both CB receptorsFootnote 77, has activity at non-CB receptors and other targetsFootnote 78, and is responsible for the psychoactive effects of cannabis through its actions at the CB1 receptorFootnote 79. Δ8-THC (an isomer of Δ9-THC) is found in smaller amounts in the plantFootnote 64, but like Δ9-THC, it is a partial agonist at both CB receptors and shares relatively similar efficacy and potency with Δ9-THC in in vitro assaysFootnote 77. An in vivo animal study and one clinical study suggest Δ8-THC to be a more potent anti-emetic than Δ9-THCFootnote 80,Footnote 81.

Cannabinol (CBN) is a product of Δ9-THC oxidation and has 10% of the activity of Δ9-THCFootnote 82. Its effects are not well studied but it appeared to have some possible immunosuppressive properties in a small number of in vitro studies Footnote 83. Cannabigerol (CBG) is a partial CB1/2 receptor agonist and a small number of in vitro studies suggest it may have some anti-inflammatory and analgesic propertiesFootnote 44,Footnote 82,Footnote 84,Footnote 85. It may also block 5-HT1A receptors and act as an α2-adrenoceptor agonistFootnote 86.

Cannabidiol (CBD) lacks detectable psychoactivity and does not appear to bind to either CB1 or CB2 receptors at physiologically meaningful concentrations, but it affects the activity of a significant number of other targets including ion channels, receptors, and enzymes (reviewed inFootnote 16,Footnote 82,Footnote 87). Results from pre-clinical studies suggest CBD has anti-inflammatory, analgesic, anti-nausea, anti-emetic, anti-psychotic, anti-ischemic, anxiolytic, and anti-epileptiform effects (reviewed inFootnote 82,Footnote 88).

Tetrahydrocannabivarin (THCV) acts as a CB1 receptor antagonist and CB2 receptor partial agonist in vitro and in vivo Footnote 89,Footnote 90, and pre-clinical studies suggest it may have anti-epileptiform/anti-convulsant propertiesFootnote 91.

Much of what is known about the beneficial properties of the non-psychotropic cannabinoids (e.g. CBD, THCV) is derived from in vitro and animal studies and few, if any, clinical studies of these substances exist. However, the results from these in vitro and animal studies point to potential therapeutic indications such as psychosis, epilepsy, anxiety, sleep disturbances, neurodegeneration, cerebral and myocardial ischemia, inflammation, pain and immune responses, emesis, food intake, type-1 diabetes, liver disease, osteogenesis, and cancer (reviewed inFootnote 16,Footnote 82,Footnote 92). For more in-depth information on the pharmacology of cannabinoids, the reader is invited to consult the following resourcesFootnote 20,Footnote 82,Footnote 93.

Phytocannabinoid-Phytocannabinoid Interaction and Phytocannabinoid Differences among Cannabis Strains

Despite anecdotal claims, there is limited reliable information regarding real or potential interactions, of biological or physiological significance, among phytocannabinoids, especially Δ9-THC and CBD. The limited information that exists is complex and requires further clarification through additional investigation. The following paragraphs summarize the available information on this subject.

Factors affecting the nature of the potential phytocannabinoid-phytocannabinoid interactions

Various studies have reported either potentiating, opposing, or neutral interactions between Δ9-THC and CBD Footnote 94,Footnote 95,Footnote 96,Footnote 97,Footnote 98,Footnote 99,Footnote 100,Footnote 101,Footnote 102,Footnote 103,Footnote 104,Footnote 105,Footnote 106,Footnote 107,Footnote 108,Footnote 109. The discrepancies in the nature of the interactions between Δ9-THC and CBD reported in the literature may be explained by differences in the doses and ratios of THC and CBD used in the different studies, differences in the routes of administration, dose ordering effects (CBD pretreatment vs. simultaneous co-administration), differences in the duration or chronicity of treatment (acute vs. chronic), differences in the animal species used, as well as the particular biological or physiological end-points being measured Footnote 110.

Pharmacokinetic vs. pharmacodynamic interactions

In general, there appear to be two types of mechanisms which could govern possible interactions between CBD and Δ9-THC: those of a pharmacokinetic originFootnote 102,Footnote 110, and those of a pharmacodynamic originFootnote 95,Footnote 97. Despite the limited and complex nature of the available information, it generally appears that pre-administration of CBD may potentiate some of the effects of THC (through a pharmacokinetic mechanism), whereas simultaneous co-administration of CBD and THC may result in the attenuation of some of the effects of THC (through a pharmacodynamic mechanism). Furthermore, the ratio between the two phytocannabinoids also appears to play a role in determining whether the overall effect will be of a potentiating or antagonistic nature. CBD-mediated attenuation of THC-induced effects may be observed when the ratio of CBD to THC is at least 8 : 1 (±11.1)Footnote 96,Footnote 109, whereas CBD appears to potentiate some of the effects associated with THC when the CBD to THC ratio is around 2 : 1 (±1.4)Footnote 109. Potentiation of THC effects by CBD may be caused by inhibition of THC metabolism in the liver, resulting in higher plasma levels of THC Footnote 102,Footnote 110. There is virtually no information in the peer-reviewed scientific or medical literature concerning the effects of varying CBD to THC ratios in the treatment of different medical disorders.

Psychological and physiological effects associated with varying phytocannabinoid concentrations

There are only a handful of studies examining the neurophysiological, cognitive, subjective, or behavioural effects of varying the concentrations of Δ9-THC, CBD, or other cannabinoids such as cannabichromene (CBC) in smoked cannabisFootnote 101,Footnote 111. In one study, 24 healthy men and women who had reported using cannabis at least 10 times in their lifetime were subjected to a double-blind, placebo-controlled, mixed between- and within-subject clinical trial that showed that deliberate systematic variations in the levels of either CBD or CBC in smoked cannabis were not associated with any significant differences in any of the measured subjective, physiological, or performance testsFootnote 101. In another study, the subjective effects associated with the smoked or oral administration of cannabis plant material were directly compared to those associated with smoked or oral administration of Δ9-THC (using matched doses of Δ9-THC) to normal, healthy subjectsFootnote 111. This double-blind, placebo-controlled, within-subject, crossover clinical study reported few reliable differences between the THC-only and whole-plant cannabis conditionsFootnote 111. The authors further concluded that other cannabinoids present in the cannabis plant material did not alter the subjective effects of cannabis, but they speculated that cannabis samples with higher levels of cannabinoids or different ratios of the individual cannabinoids could conceivably produce different results, although no evidence to support this claim was provided in the study. They also hypothesized that whole-plant cannabis and THC alone could differ on other outcome measures more relevant to clinical entities (e.g. spasticity or neuropathic pain). With the possible exception of one studyFootnote 112, (see section 4.6.2.3. Cancer Pain), which suggested differences between a whole-plant cannabis extract (i.e. nabiximols, marketed as Sativex®) and THC alone on cancer pain analgesia, no other clinical studies have examined this possibility. One study compared the subjective and physiological effects of oral THC to those of nabiximols in normal, healthy subjectsFootnote 107. The authors reported the absence of any modulatory effect of CBD (or other components of cannabis) at low therapeutic cannabinoid doses, with the potential exception of the subjective "high"Footnote 107. An internet-based, cross-sectional study of 1 877 individuals with a consistent history of cannabis use reported that those individuals who had indicated using cannabis with a higher CBD to THC ratio had also reported experiencing fewer psychotic experiences (an effect typically associated with exposure to higher doses of THC)Footnote 113. However, the authors noted that the effects were subtle. The study was also hampered by a number of important methodological issues suggesting that the conclusions should be interpreted with caution. In summary, further careful study is required to elucidate the influence of CBD, and other phytocannabinoids or terpenoids, on the physiological or psychological effects associated with the use of Δ9-THC, as well as on any medical disorders. There is presently insufficient scientific and clinical evidence to lend support to the anecdotal claims that one strain of cannabis may be more beneficial than another one for a particular medical condition.

Table 1 (next page), adapted from a reviewFootnote 114, notes some of the pharmacological effects of cannabis in the therapeutic dosage range. Many of the effects are biphasic, with increased activity with acute or smaller doses, and decreased activity with larger doses or chronic useFootnote 115,Footnote 116,Footnote 117. Effects differ greatly among individuals and may be greater in those who are severely ill, elderly, or those taking other drugs.

Most of the available information regarding the acute effects of smoking cannabis comes from studies conducted on recreational users, with much less information available from clinical studies of patients using cannabis for medical purposes. The acute effects of smoking or eating cannabis include euphoria (the marihuana "high") as well as cardiovascular, bronchopulmonary, ocular, psychological and psychomotor effects. Maximum euphoria typically occurs within 15 min after smoking and generally takes longer with oral administrationFootnote 64. However, some people can experience dysphoria and anxietyFootnote 118. The effects on the cardiovascular system (tachycardia, etc.) decline much faster as THC is distributed out of the circulatory system. Tachycardia is the most consistent of the acute physiological effects associated with the consumption of cannabisFootnote 117,Footnote 119,Footnote 120,Footnote 121.

The short-term psychoactive effects associated with cannabis smoking in recreational users include the above-mentioned euphoria but also relaxation, time-distortion, intensification of ordinary sensory experiences (such as eating, watching films, and listening to music), and loss of inhibitions that may result in laughterFootnote 122. This is followed by a depressant periodFootnote 123. While there is some inconsistency in reports regarding the acute effects of cannabis on memory and motor skillsFootnote 124,Footnote 125,Footnote 126, most reviews note that cannabis use is associated with impaired function on a variety of cognitive and short-term memory tasksFootnote 83,Footnote 123,Footnote 127,Footnote 128,Footnote 129,Footnote 130. The levels of Δ9-THC in the plasma after smoking appear to have a dose, time, and concentration-dependent effect on cognitive functionFootnote 131,Footnote 132,Footnote 133. Driving and operation of intricate machinery, including aircraft, may be significantly impairedFootnote 134,Footnote 135,Footnote 136,Footnote 137.

Table 1: Pharmacologic Actions of Cannabis (adapted fromFootnote 114 with additional references)
Body System/Effect Detail of Effects
Central Nervous System (CNS)
Psychological Euphoria ("high"), dysphoria, anxiety, depersonalization, precipitation or aggravation of psychosis Footnote 64,Footnote 117,Footnote 118,Footnote 138,Footnote 139,Footnote 140,Footnote 141,Footnote 142,Footnote 143,Footnote 144,Footnote 145,Footnote 146,Footnote 147,Footnote 148,Footnote 149,Footnote 150,Footnote 151,Footnote 152,Footnote 153,Footnote 154,Footnote 155,Footnote 156,Footnote 157,Footnote 158.
Perception Heightened sensory perception, distortion of space and time sense, hallucinations, misperceptionsFootnote 151,Footnote 156,Footnote 159,Footnote 160,Footnote 161,Footnote 162,Footnote 163.
Sedative Generalised CNS depression, drowsiness, somnolence; additive with other CNS depressants (opioids/alcohol)Footnote 117,Footnote 142,Footnote 157,Footnote 158,Footnote 164,Footnote 165,Footnote 166,Footnote 167,Footnote 168,Footnote 169,Footnote 170,Footnote 171,Footnote 172,Footnote 173,Footnote 174.
Cognition, psychomotor performance Fragmentation of thoughts, mental clouding, memory impairment, global impairment of performance especially in complex and demanding tasks Footnote 101,Footnote 129,Footnote 134,Footnote 135,Footnote 136,Footnote 137,Footnote 157,Footnote 174,Footnote 175,Footnote 176,Footnote 177,Footnote 178,Footnote 179,Footnote 180,Footnote 181.
Motor function Incoordination, ataxia, dysarthria, weaknessFootnote 117,Footnote 162,Footnote 168,Footnote 174,Footnote 182,Footnote 183.
Analgesic Modest effect for chronic non-cancer pain Footnote 142,Footnote 157,Footnote 158,Footnote 164,Footnote 165,Footnote 168,Footnote 172,Footnote 173,Footnote 184,Footnote 185,Footnote 186,Footnote 187,Footnote 188,Footnote 189.
Anti-nausea/anti-emetic; hyper-emetic Observed with acute dosesFootnote 88,Footnote 190,Footnote 191,Footnote 192 -- Tolerance may occur with chronic useFootnote 193. Hyperemesis may be observed with larger doses or chronic use Footnote 194,Footnote 195,Footnote 196,Footnote 197,Footnote 198,Footnote 199,Footnote 200,Footnote 201,Footnote 202,Footnote 203,Footnote 204.
Appetite Increased in normal, healthy subjects, but also in patients suffering from HIV/AIDS-associated anorexia/cachexiaFootnote 166,Footnote 167,Footnote 174,Footnote 205,Footnote 206,Footnote 207,Footnote 208,Footnote 209.
Tolerance To most behavioural and somatic effects, including the "high" (with chronic use) Footnote 210,Footnote 211,Footnote 212,Footnote 213,Footnote 214,Footnote 215,Footnote 216,Footnote 217,Footnote 218 and (see section 2.4).
Dependence, withdrawal syndrome Dependence has been produced experimentally, and observed clinically, following prolonged intoxication (Footnote 122,Footnote 156,Footnote 210,Footnote 219,Footnote 220,Footnote 221 and see section 2.4). Abstinence leads to withdrawal symptoms which can include anger, anxiety, restlessness, irritability, depressed mood, disturbed sleep, strange dreams, decreased appetite, and weight lossFootnote 156,Footnote 210,Footnote 222 and also see section 2.4).
Cardiovascular and Cerebrovascular System
Heart rate/rhythm Tachycardia with acute dosage; tolerance developing with chronic exposure Footnote 117,Footnote 119,Footnote 120,Footnote 121,Footnote 157,Footnote 158,Footnote 223,Footnote 224,Footnote 225,Footnote 226. Premature ventricular contractions, atrial fibrillation, ventricular arrhythmia also seen with acute dosesFootnote 121,Footnote 174,Footnote 227,Footnote 228,Footnote 229,Footnote 230,Footnote 231.
Peripheral circulation Vasodilatation, conjunctival redness, supine hypertension, postural hypotension Footnote 170,Footnote 174,Footnote 225,Footnote 227,Footnote 232,Footnote 233,Footnote 234.
Cardiac output Increased cardiac outputFootnote 227 and myocardial oxygen demandFootnote 232.
Cerebral blood flow Increased with acute dose, decreased with chronic use, region-dependent variationsFootnote 225,Footnote 235.
Myocardial infarction Increased risk of acute myocardial infarction within 1 h after smoking cannabis especially in individuals with existing cardiovascular diseaseFootnote 121,Footnote 232.
Stroke Increased risk of experiencing stroke after an acute episode of smoking cannabisFootnote 227,Footnote 236,Footnote 237.
Respiratory System
Carcinogenesis/mutagenesis Cannabis smoke contains many of the same chemicals as tobacco smoke, and cannabis smoke condensates are more cytotoxic and mutagenic than condensates from tobacco smokeFootnote 68,Footnote 70. Conflicting evidence linking cannabis smoking and cancerFootnote 238,Footnote 239,Footnote 240,Footnote 241.
Histopathologic changes/ inflammation Chronic cannabis smoking associated with histopathologic changes in the lung (basal cell hyperplasia, stratification, goblet cell hyperplasia, cell disorganization, inflammation, basement membrane thickening, and squamous cell metaplasia) Footnote 242. Long-term smoking associated with cough, increased production of phlegm, and wheezeFootnote 243.
Bronchodilatation Acute exposure causes dilatation; possibly reversed with chronic exposure (by smoking) Footnote 243.
Pulmonary function (FEV1; FVC) Acute, low-level exposure possibly stimulatory; long-term, heavy smoking possibly associated with increased obstruction and decreased lung functionFootnote 243,Footnote 244,Footnote 245,Footnote 246,Footnote 247.
Gastrointestinal System
General pharmacologic actions Decreased gastrointestinal motility, decreased secretion, decreased gastric/colonic emptying, anti-inflammatory actionsFootnote 31,Footnote 157,Footnote 189,Footnote 248.
Liver Increased risk of hepatic steatosis/fibrosis, especially in patients with Hepatitis C Footnote 33,Footnote 249,Footnote 250,Footnote 251. Increased Hepatitis C treatment adherence resulting in a potential sustained absence of detectable levels of Hepatitis C virusFootnote 252.
Pancreas Acute risk of pancreatitis with chronic, heavy, daily useFootnote 253,Footnote 254,Footnote 255,Footnote 256.
Musculoskeletal system
General pharmacologic actions Possible beneficial effect in chronic pain from rheumatoid arthritisFootnote 257,Footnote 258,Footnote 259 and fibromyalgiaFootnote 158,Footnote 260,Footnote 261. May attenuate spasticity from multiple sclerosisFootnote 164,Footnote 165,Footnote 188,Footnote 262. May negatively impact bone healingFootnote 263.
Eye
General pharmacologic actions Decreased intra-ocular pressureFootnote 264,Footnote 265.
Immune System
General pharmacologic actions Complex immunomodulatory effects with suppressive and/or stimulatory effects (acute and chronic dosing)Footnote 24,Footnote 266.
Reproductive System
Males With chronic administration: anti-androgenic, decreased sperm count and sperm motility, altered sperm morphology in animals (and possibly in humans) Footnote 267,Footnote 268. Tolerance to these effects may develop. Possible inhibitory effects on sexual behaviour in menFootnote 269.
Females Effects inconclusive in women (possibly due to tolerance) but changes in menstrual cycle, suppression of ovulation, and complex effects on prolactin secretion observed in female animalsFootnote 268,Footnote 270,Footnote 271. Dose-dependent stimulatory or inhibitory effects on sexual behaviour in womenFootnote 269.

2.2 Pharmacokinetics

This section is restricted to human pharmacokinetics of smoked and vapourized cannabis, oral preparations including prescription cannabinoid medicines such as dronabinol (Marinol®) and nabiximols (Sativex®), and other routes of administration (e.g. rectal, topical).

2.2.1 Absorption

2.2.1.1 Smoked cannabis

Smoking cannabis results in more rapid onset of action (within minutes), higher blood levels of cannabinoids, and a shorter duration of pharmacodynamic effects compared to oral administrationFootnote 62. The amount of Δ9-THC delivered from cannabis cigarettes is not uniform and is a major variable in the assessment of absorptionFootnote 62. Uncontrolled factors include the source of the plant material and the composition of the cigarette, together with the efficiency and method of smoking used by the subjectFootnote 62,Footnote 272. While it has been reported that smokers can titrate their Δ9-THC intake by adapting their smoking behaviour to obtain desired levels of Δ9-THCFootnote 273, other reasons may also explain the observed variation in smoking topographyFootnote 274. Δ9-THC absorption by inhalation is extremely rapid but quite variable, with a bioavailability of 2 - 56% through the smoking route depending on depth of inhalation, puff duration, and breathholdFootnote 275,Footnote 276. In practice, a maximum of 25 - 27% of the THC content in a cannabis cigarette is absorbed or delivered to the systemic circulation from the total available amountFootnote 117,Footnote 277.

Standardized cannabis cigarettes have been developed by the National Institute on Drug Abuse (NIDA), and the relationships among cannabis Δ9-THC content, dose administered, and resultant plasma levels have been investigated. Mean plasma Δ9-THC concentrations were 7.0 ±8.1 ng/mL and 18.1 ±12.0 ng/mL upon a single inhalation of either a 1.75% "low-dose" Δ9-THC cannabis cigarette (total available dose ~16 mg Δ9-THC), or a 3.55% Δ9-THC "high-dose" cannabis cigarette (total available dose ~34 mg Δ9-THC)Footnote 62. Smoking cannabis containing 1.64% Δ9-THC (mean available dose 13.0 mg Δ9-THC) resulted in mean peak THC plasma levels of 77 ng/mLFootnote 278. Similarly, smoking cannabis joints containing 1.8% Δ9-THC (total available dose ~14 mg Δ9-THC) resulted in mean peak plasma THC levels of approximately 75 ng/mL, whereas with 3.6% Δ9-THC (total available dose ~28.8 mg Δ9-THC), mean peak plasma Δ9-THC levels of 100 ng/mL were attainedFootnote 279. Smoking a 25 mg dose of cannabis containing 2.5, 6, or 9.4% Δ9-THC (total available doses of ~0.6, 1.5, or 2.4 mg Δ9-THC) was associated with mean peak plasma Δ9-THC concentrations of 10, 25, or 45 ng/mL Δ9-THC, respectivelyFootnote 172. Smoking one cannabis cigarette (mean weight 0.79 ±0.16 g) containing 6.8% ±0.2 THC, 0.25% ±0.08 CBD, and 0.21% ±0.02 CBN (w/w) yielding a total THC, CBD, and CBN content of 54, 2.0, and 1.7 mg of these cannabinoids per cigarette, respectively, was associated with a median whole blood THC concentration of approximately 60 ng/mL Δ9-THC (range 13 - 63 ng/mL)Footnote 280.

2.2.1.2 Vapourized cannabis

Vapourization of cannabis has been explored as an alternative to smoking. The potential advantages of vapourization include the formation of a smaller quantity of toxic by-products such as carbon monoxide, polycyclic aromatic hydrocarbons (PAHs), and tar, as well as a more efficient extraction of Δ9-THC from the cannabis materialFootnote 273,Footnote 281,Footnote 282,Footnote 283,Footnote 284. The subjective effects and plasma concentrations of Δ9-THC obtained by vapourization of cannabis are comparable to those obtained by smoking cannabis, with absorption being somewhat faster with the vapourizer compared to smoking, according to one studyFootnote 273. In addition, the study reported that the vapourizer was well tolerated with no reported adverse effects, and was preferred over smoking by the test subjectsFootnote 273. While vapourization has been reported to be amenable to self-titration (as has been claimed for smoking)Footnote 273,Footnote 283, the proper use of the vapourizer for optimal administration of cannabis for therapeutic purposes needs to be established in more detailFootnote 284. The amount and type of cannabis placed in the vapourizer, the vapourizing temperature and duration of vapourization, and the balloon volume are some of the parameters that can affect the delivery of Δ9-THCFootnote 283. Bioequivalence of vapourization compared to smoking has not been thoroughly established. Inhalation of vapourized cannabis (0.9 g of 3.56% Δ9-THC; total available dose of 32 mg of Δ9-THC) in a group of patients taking stable doses of sustained-release morphine or oxycodone resulted in mean plasma Δ9-THC levels of 126.1 ng/mL within 3 min after starting cannabis inhalation, rapidly declining to 33.7 ng/mL Δ9-THC at 10 min, and reaching 6.4 ng/mL Δ9-THC at 60 minFootnote 187. Peak Δ9-THC concentration was achieved at 3 min in all study participantsFootnote 187. Maximal subjective "high" ratings occurred at 60 min following beginning of inhalation, with a stronger and more sustained subjective "high" score for individuals taking oxycodone compared to those taking morphineFootnote 187. No statistically significant changes were reported for the AUC12 for either morphine or oxycodone, but there appeared to be a statistically significant decrease in the maximum concentration (Cmax) of morphine sulfate, and a delay in the time needed to reach Cmax for morphine during cannabis exposureFootnote 187.

2.2.1.3 Oral

Whereas the central nervous system and physiological effects occur within minutes by the smoking route or by vapourizationFootnote 129,Footnote 285, these effects proceed on a time scale of hours in the case of oral ingestionFootnote 285,Footnote 286. Oral administration results in a slower onset of action, lower peak blood levels of cannabinoids, and a longer duration of pharmacodynamic effects compared to smokingFootnote 62. The psychotropic effect or "high" occurs much more quickly by the smoking than by the oral route, which is the reason why smoking appears to be the preferred route of administration by many, especially recreational usersFootnote 287.

For orally administered prescription cannabinoid medicines such as synthetic Δ9-THC (dronabinol, marketed as Marinol®), only 10 - 20% of the administered dose enters the systemic circulation indicating extensive first-pass metabolismFootnote 174. Administration of a single 2.5 mg dose of dronabinol in healthy volunteers was associated with a mean plasma Δ9-THC Cmax of 0.7 ng/mL (range: 0.3 - 1 ng/mL), and a mean time to peak plasma Δ9-THC concentration of 2 h (range: 30 min - 4 h)Footnote 174. A single 5 mg dose of dronabinol gave a reported mean plasma Δ9-THC Cmax of 1.8 ng/mL (range: 0.4 - 3.3 ng/mL), whereas a single 10 mg dose yielded a mean plasma Δ9-THC Cmax of 6.2 ng/mL (range: 3.5 - 9 ng/mL)Footnote 174. Again, the mean time to peak plasma Δ9-THC concentration ranged from 30 min - 3 h. Twice daily dosing of dronabinol (individual doses of 2.5 mg, 5 mg, 10 mg, b.i.d.) in healthy volunteers yielded plasma Δ9-THC Cmax values of 1.3 ng/mL (range: 0.7 - 1.9 ng/mL), 2.9 ng/mL (range: 1.2 - 4.7 ng/mL), and 7.9 ng/mL (range: 3.3 - 12.4 ng/mL), respectively, with a time to peak plasma Δ9-THC concentration ranging between 30 min and 4 h after oral administrationFootnote 174. Continuous dosing for seven days with 20 mg doses of dronabinol (total daily doses of 40 -120 mg dronabinol) gave mean plasma Δ9-THC concentrations of ~20 ng/mLFootnote 288.

Δ9-THC can also be absorbed orally by ingestion of foods containing cannabis (e.g. butters, oils, brownies, cookies), and teas prepared from leaves and flowering tops. Absorption from an oral dose of 20 mg Δ9-THC in a chocolate cookie was described as slow and unreliableFootnote 272, with a systemic availability of only 4 - 12%Footnote 278. While most subjects displayed peak plasma Δ9-THC concentrations (6 ng/mL) between 1 - 2 h after ingestion, some of the 11 subjects in the study only peaked at 6 h, and many had more than one peakFootnote 62. Consumption of cannabis-laced brownies containing 2.8% Δ9-THC (44.8 mg total Δ9-THC) was associated with changes in behaviour, although the effects were slow to appear and variableFootnote 286. Peak effects occurred 2.5 - 3.5 h after dosing. Modest changes in pulse and blood pressure were also noted. Plasma concentrations of Δ9-THC were not measured in this study. In another study, ingestion of brownies containing a low dose of Δ9-THC (9 mg THC/brownie) was associated with mean peak plasma Δ9-THC levels of 5 ng/mL Δ9-THCFootnote 111. Ingestion of brownies containing a high dose of Δ9-THC (~13 mg Δ9-THC/brownie) was associated with mean peak plasma Δ9-THC levels of 6 or 9 ng/mL Δ9-THC depending on whether the THC in the brownie came from plant material or was added as pure THCFootnote 111. Using equivalent amounts of Δ9-THC, inhalation by smoking cannabis yielded peak plasma levels of Δ9-THC several-fold (five to six times or more) higher than when Δ9-THC was absorbed through the oral routeFootnote 111. Tea made from dried cannabis flowering tops (19.1% Δ9-THCA (tetrahydrocannabinolic acid), 0.6% Δ9-THC) has been documented, but the bioavailability of Δ9-THC from such teas is likely to be smaller than that achieved by smoking because of the poor water solubility of Δ9-THC and the hepatic first-pass effectFootnote 289.

2.2.1.4 Oro-mucosal

Following a single oro-mucosal administration of nabiximols (Sativex®) (four sprays totalling 10.8 mg Δ9-THC and 10 mg CBD), mean peak plasma concentrations of both THC (~5.5 ng/mL) and CBD (~3 ng/mL) typically occur within 2 - 4 h, although there is wide inter-individual variation in the peak cannabinoid plasma concentrations and in the time to onset and peak of effectsFootnote 290. When administered oro-mucosally, blood levels of Δ9-THC and other cannabinoids are lower than those achieved by inhalation of the same dose of smoked cannabis, but Δ9-THC blood levels were comparable to those seen with oral administration of dronabinolFootnote 108,Footnote 290. Oro-mucosal administration of nabiximols is amenable to self-titrationFootnote 107,Footnote 259,Footnote 291,Footnote 292.

2.2.1.5 Rectal

While Δ9-THC itself is not absorbed through the rectal route, the pro-drug Δ9-THC-hemisuccinate is absorbed; this fact, combined with decreased first-pass metabolism through the rectal route, results in a higher bioavailability of Δ9-THC by the rectal route (52 - 61%) than by the oral routeFootnote 293,Footnote 294,Footnote 295,Footnote 296,Footnote 297. Plasma concentrations of Δ9-THC are dose and vehicle-dependent, and also vary according to the chemical structure of the THC esterFootnote 296. In humans, rectal doses of 2.5 - 5.0 mg of the hemisuccinate ester of Δ9-THC were associated with peak plasma levels of Δ9-THC ranging between 1.1 and 4.1 ng/mL within 2 - 8 h, and peak plasma levels of carboxy-Δ9-THC ranging between 6.1 - 42.0 ng/mL within 1 - 8 h after administrationFootnote 293.

2.2.1.6 Topical

Cannabinoids are highly hydrophobic, making transport across the aqueous layer of the skin the rate-limiting step in the diffusion processFootnote 62. No clinical studies exist regarding the percutaneous absorption of cannabis-containing ointments, creams, or lotions. However, some research has been carried out on transdermal delivery of synthetic and natural cannabinoids using a dermal patchFootnote 298,Footnote 299. A patch containing 8 mg of Δ8-THC yielded a mean steady-state plasma concentration of 4.4 ng/mL Δ8-THC within 1.4 h in a guinea pig model, and this concentration was maintained for at least 48 hFootnote 298. Permeation of cannabidiol (CBD) and cannabinol (CBN) was found to be 10-fold higher than for Δ8-THCFootnote 300.

2.2.2 Distribution

Distribution of Δ9-THC is time-dependent and begins immediately after absorption. It is taken up primarily by fatty tissues and highly perfused organs such as the brain, heart, lung, and liverFootnote 62. Δ9-THC has a large apparent volume of distribution, approximately 10 L/kg, because of its high lipid solubilityFootnote 301. The plasma protein binding of Δ9-THC and its metabolites is approximately 97%Footnote 302,Footnote 303. Δ9-THC is mainly bound to low-density lipoproteins, with up to 10% present in red blood cellsFootnote 304, while the metabolite, 11-hydroxy THC is strongly bound to albumin with only 1% found in the free-fractionFootnote 305.

The highest concentrations of Δ9-THC are found in the heart and in adipose tissue, with levels reaching 10 and 1000 times that of plasma, respectivelyFootnote 306. Despite the high perfusion level of the brain, the blood-brain barrier (BBB) appears to limit the access and accumulation of Δ9-THC in this organFootnote 62,Footnote 307,Footnote 308, and the delay in correlating peak plasma concentration to psychoactive effects may be attributed to the time required for Δ9-THC to traverse this barrierFootnote 272.

Δ9-THC accumulates and is retained in fatty tissue, and its release from this storage site into the blood is slowFootnote 307. It is not certain if Δ9-THC persists in the brain in the long-term; however, the presence of residual cognitive deficits in abstinent heavy cannabis users raises the possibility that Δ9-THC may be retained in the brain at least in the short-termFootnote 179,Footnote 309. One animal study suggested food deprivation or adrenocorticotropic hormone (ACTH) administration in rats accelerates lipolysis and the release of Δ9-THC from fat stores, however further research is needed to determine if these effects are associated with intoxication or behavioural/cognitive changesFootnote 310.

2.2.3 Metabolism

Most cannabinoid metabolism occurs in the liver, and different metabolites predominate depending on the route of administrationFootnote 62,Footnote 272. The complex metabolism of Δ9-THC involves allylic oxidation, epoxidation, decarboxylation, and conjugationFootnote 272. Δ9-THC is oxidized by the xenobiotic-metabolizing cytochrome P450 (CYP) mixed-function oxidases 2C9, 2C19, and 3A4Footnote 62. The major initial metabolites of Δ9-THC are the active 11-hydroxy Δ9-THC, and the non-active 11-nor-9-carboxy Δ9-THCFootnote 62. 11-hydroxy Δ9-THC is rapidly formed by the action of the above-mentioned hepatic microsomal oxidases, and plasma levels of this metabolite parallel the duration of observable drug actionFootnote 311,Footnote 312.

As would be expected, oral administration of Δ9-THC results in a greater metabolism of Δ9-THC to the 11-hydroxy metabolite compared to administration by smoking (or vapourization), resulting in similar plasma concentrations of Δ9-THC and 11-hydroxy Δ9-THC through the oral route vs. inhalationFootnote 276. Information from the dronabinol (Marinol®) product monograph suggests that single doses of 2.5 mg, 5 mg, and 10 mg of Δ9-THC in healthy volunteers result in mean plasma Cmax values of 11-hydroxy Δ9-THC of 1.19 ng/mL (range: 0.4 - 1.9 ng/mL), 2.23 ng/mL (range: 0.7 - 3.7 ng/mL), and 7.51 ng/mL (range: 2.25 - 12.8 ng/mL), respectivelyFootnote 174. Twice daily dosing of dronabinol (individual doses of 2.5 mg, 5 mg, 10 mg, b.i.d.) in healthy volunteers resulted in mean plasma Cmax values of 1.65 ng/mL (range: 0.9 - 2.4 ng/mL), 3.84 ng/mL (range: 1.5 - 6.1 ng/mL), and 7.95 ng/mL (range: 4.8 - 11.1 ng/mL) of 11-hydroxy Δ9-THC, respectivelyFootnote 174. Time to reach Cmax for 11-hydroxy Δ9-THC ranged from 30 min - 4 h, with a mean of approximately 2.5 hFootnote 174. Importantly, 11-hydroxy Δ9-THC has psychotomimetic properties equal to those of Δ9-THCFootnote 276,Footnote 313,Footnote 314. The psycho-inactive 11-nor-9-carboxy Δ9-THC is the primary acid metabolite of Δ9-THC excreted in urineFootnote 315, and it is the cannabinoid often screened for in forensic analysis of body fluidsFootnote 316,Footnote 317.

CYP isozyme polymorphisms may also affect the pharmacokinetics of THC (and 11-nor-9-carboxy Δ9-THC). For example, subjects homozygous for the CYP2C9*3 allelic variant displayed significantly higher maximum plasma concentrations of Δ9-THC, significantly higher area under the curve (AUC), and significantly decreased clearance among other measures compared to the CYP2C9*1 homozygote or the *1/*3 heterozygoteFootnote 318.

Xenobiotics are not only metabolized by CYPs but they also modulate the expression level and activity of these enzymes; CYPs are therefore a focal point in drug-drug interactions and adverse drug reactionsFootnote 319. Polyaromatic hydrocarbons found in tobacco and cannabis smoke induce the expression of CYP1A2Footnote 320, while Δ9-THC, cannabidiol (CBD), and cannabinol (CBN) inhibit the activity of the CYP1A1, 1A2, and 1B1 enzymesFootnote 58. CBD has also been shown to inhibit the formation of Δ9-THC metabolites catalyzed by CYP3A4, with less effect on CYP2C9Footnote 301, albeit sufficiently to decrease the formation of 11-hydroxy THCFootnote 102,Footnote 321.

Results from in vitro experiments also suggest that Δ9-THC inhibits CYP3A4, CYP3A5, CYP2C9, and CYP2C19, while CBD inhibits CYP2C19, CYP3A4, and CYP3A5; however, higher concentrations than those seen clinically appear to be required for inhibitionFootnote 58,Footnote 290. While few clinical studies have specifically sought to evaluate cannabis-drug interactions per se, many, if not most, studies investigating the therapeutic effects of cannabis (e.g. smoked, vapourized, or orally ingested) and cannabinoid-based medicines (e.g. dronabinol, nabilone, nabiximols) have used patients that were concomitantly taking other medications (e.g. non-steroidal anti-inflammatory agents, opioids, anti-depressants, anti-convulsants, protease inhibitors) and, in general, did not report significantly increased incidences of severe adverse effects associated with the combination of cannabis or cannabinoids and these other medications. Nevertheless, clinicians should carefully monitor patients who are concomitantly consuming cannabis/cannabinoids and other medications that are metabolized by the above-mentioned enzymes.

The Sativex® product monograph cautions against combining Sativex® with amitriptyline or fentanyl (or related opioids) which are metabolized by CYP3A4 and 2C19Footnote 290. Cannabis smoking, as well as orally administered dronabinol, may also affect the pharmacokinetics of anti-retroviral medicationsFootnote 322. In addition, and as seen with tobacco smoke, cannabis smoke has the potential to induce CYP1A2 thereby increasing the metabolism of xenobiotics biotransformed by this isozyme such as theophyllineFootnote 323 or the anti-psychotic medicationsclozapine or olanzapineFootnote 324. Further information on drug-drug interactions can be found in section 6.2.

2.2.3.1 Inhalation

Plasma values of 11-hydroxy THC appear rapidly and peak shortly after Δ9-THC, at about 15 min after the start of smokingFootnote 325. Peak plasma concentrations of 11-hydroxy THC are approximately 5% - 10% of parent THC, and the area under the curve (AUC) profile of this metabolite averages 10 - 20% of the parent THCFootnote 312. Similar results were obtained with intravenous THC administrationFootnote 326.

Peak plasma values of 11-nor-9-carboxy THC occur 1.5 - 2.5 h after smoking, and are about one third the concentration of parent THCFootnote 325. Following oxidation, the phase II metabolites of the free drug or hydroxy-THC appear to be glucuronide conjugatesFootnote 272.

2.2.3.2 Oral

After oral doses of Δ9-THC, parent THC and its active metabolite 11-hydroxy- Δ9-THC (which is similar to or possibly greater in potency than Δ9-THC) are present in approximately equal concentrations in plasmaFootnote 276,Footnote 286,Footnote 327. The plasma levels of active 11-hydroxy metabolite, achieved through oral administration, are about three times higher than those seen with smokingFootnote 312. Concentrations of both parent drug and metabolite peak between approximately 2 - 4 h after oral dosing, and decline over several days. Whole-body clearance of Δ9-THC and its hydroxy metabolite averages about 0.2 L/kg-h, but is highly variable due to the complexity of cannabinoid distributionFootnote 174.

2.2.4 Excretion

Δ9-THC levels in plasma decrease rapidly after cessation of smoking. Mean THC plasma concentrations are approximately 60% and 20% of peak plasma THC concentrations 15 and 30 min post-smokingFootnote 328, respectively, and are below 5 ng/mL THC 2 h after smokingFootnote 276. Elimination of THC and its metabolites occurs via the feces (65%) and the urine (20%)Footnote 62. After five days, 80% to 90% of the total dose is excretedFootnote 312. Nevertheless, THC from a single dose can be detected in plasma up to 13 days in chronic smokers probably due to extensive storage and release from body fatFootnote 329.

Following oral administration, THC and its metabolites are also excreted in both the feces and the urineFootnote 312,Footnote 62. Biliary excretion is the major route of elimination, with about half of a radiolabelled THC oral dose being recovered from the feces within 72 h in contrast to the 10 to 15% recovered from urineFootnote 312.

The decline of Δ9-THC levels in plasma is multi-phasic, and the estimates of the terminal half-life of Δ9-THC in humans have progressively increased as analytical methods have become more sensitiveFootnote 301. While figures for the terminal elimination half-life of Δ9-THC appear to vary, it is probably safe to say that it averages at least four days and could be considerably longerFootnote 62. The variability in terminal half-life measurements are related to the dependence of this measure on assay sensitivity, as well as on the duration and timing of blood measurements Footnote 330. Low levels of THC metabolites have been detected for more than five weeks in the urine and feces of cannabis usersFootnote 301. The degree of Δ9-THC consumption does not appear to influence the plasma half-life of Δ9-THCFootnote 272,Footnote 331.

2.3 Pharmacokinetic-pharmacodynamic relationships

Much of the information on cannabinoid pharmacokinetic-pharmacodynamic relationships (mostly on Δ9-THC) is derived from studies of recreational cannabis use rather than from studies looking at therapeutic use, but in either case, this relationship depends to some extent on the point in time at which observations are made following the administration of the cannabinoid. Furthermore, the temporal relationship between plasma concentrations of Δ9-THC and the associated clinical/therapeutic, psychotropic, cognitive and motor effects is not well established. These effects often lag behind the plasma concentrations of Δ9-THC, and tolerance is known to develop to some of the effects but not to others (Footnote 101,Footnote 151,Footnote 330 and also seeFootnote 187 and section 2.4 (Tolerance and Dependence)).

As mentioned above, the relationship between dose (and plasma concentration) versus response for possible therapeutic applications are ill-defined, except for some information obtained for oral dosing with dronabinol (synthetic Δ9-THC, marketed as Marinol®), nabiximols (a botanical cannabis extract containing approximately equal concentrations of Δ9-THC and CBD as well as other cannabinoids, terpenoids and flavonoids, marketed as Sativex®), or nabilone (synthetic Δ9-THC, analog marketed as Cesamet®) for their limited indicationsFootnote 174,Footnote 290,Footnote 332. Interpretations of the pharmacokinetics of Δ9-THC are also complicated by the presence of active metabolites, particularly the psychoactive 11-hydroxy THC, which are found in higher concentrations after oral administration than after inhalationFootnote 286,Footnote 327.

Target Δ9-THC plasma concentrations have been derived based on the subjective "high" response that may or may not be related to the potential therapeutic applications. Various pharmacodynamic models provide blood plasma concentration estimates in the range of 7 - 29 ng/mL Δ9-THC necessary for the production of a 50% maximal subjective "high" effectFootnote 330. Other studies suggest that Δ9-THC plasma concentrations associated with 50% of the maximum "high" effect range between 2 and 250 ng/mL Δ9-THC (median of 19 ng/mL; mean of 43 ng/mL Δ9-THC) for the smoked or i.v. routes, while for the oral route the values range between 1 and 8 ng/mL Δ9-THC (median and mean of 5 ng/mL Δ9-THC)Footnote 111,Footnote 333. Serum concentrations between 7 and 10 ng/mL (whole blood, approximately 3 - 5 ng/mL) have been compared to a blood-alcohol concentration of 0.05% which is associated with driver impairmentFootnote 133.

Smoked cannabis

Simulation of multiple dosing with a 1% THC cigarette containing 9 mg Δ9-THC yielded a maximal "high" lasting approximately 45 min after initial dosing, declining to 50% of peak at about 100 min following smokingFootnote 151. A dosing interval of 1 h with this dose would give a "continuous high", and the recovery time after the last dose would be 150 min (i.e. 2.5 h). The peak Δ9-THC plasma concentration during this dosage is estimated at about 70 ng/mL.

One clinical study reported a peak increase in heart rate and perceived "good drug effect" within 7 min after test subjects smoked a 1 g cannabis cigarette containing either 1.8% or 3.9% THC (mean doses of Δ9-THC being 18 mg or 39 mg, respectively)Footnote 129. Compared to the placebo, both doses yielded statistically significant differences in subjective and physiological measures; the higher dose was also significantly different from the lower dose for subjective effects, but not physiological effects such as heart rate. Pharmacokinetic-pharmacodynamic modelling of concentration-effect relationship of Δ9-THC on CNS parameters and heart rate suggests that THC-evoked effects typically lag behind THC plasma concentration, with the effects lasting significantly longer than Δ9-THC plasma concentrationsFootnote 334. The equilibration half-life estimate for heart rate was approximately 7 min, but varied between 39 and 85 min for various CNS parametersFootnote 334. According to this model, the effects on the CNS developed more slowly and lasted longer than the effect on heart rate.

The psychomotor performance, subjective, and physiological effects associated with whole-blood Δ9-THC concentrations in heavy, chronic, cannabis smokers following an acute episode of cannabis smoking has been studiedFootnote 280. Subjects reported smoking a mean of one joint per day in the previous 14 days prior to the initiation of the study (range 0.7 - 12 joints per day)Footnote 280. During the study, subjects smoked one cannabis cigarette (mean weight 0.79 ±0.16 g) containing 6.8 ±0.2% THC, 0.25 ±0.08% CBD, and 0.21 ±0.02% CBN (w/w) yielding a total THC, CBD, and CBN content of 54, 2.0, and 1.7 mg of these cannabinoids per cigaretteFootnote 280. Mean peak THC blood concentrations and peak visual analog scale scores for different subjective measures occurred 15 min after starting smokingFootnote 280. According to the authors of the study, the pharmacodynamic-pharmacokinetic relationship described a counterclockwise hysteresis (i.e. where for the same plasma concentration of a drug (e.g. THC), the pharmacological effect is greater at a later time point than at an earlier one) for all measured subjective effects (e.g. "good drug effect", "high", "stoned", "stimulated", "sedated", "anxious", and "restless"). This particular kind of relationship demonstrates a lack of correlation between blood concentrations of THC and observed effects, beginning immediately after the end of smoking and continuing during the initial distribution and elimination phasesFootnote 280. All participants reported a peak subjective "high" between 66 and 85 on the visual analog scale, with peak whole blood THC concentrations at the time of these responses ranging from 13 - 63 ng/mLFootnote 280. Following the start of cannabis smoking, heart rate increased significantly at the 30 min time point, diastolic blood pressure decreased significantly only from the 30 min to 1 h time point, and systolic blood pressure and respiratory rate were unaffected at any timeFootnote 280.

Oral and oro-mucosal cannabinoids

The subjective and physiological effects after controlled administration of nabiximols (Sativex®) or oral THC have also been comparedFootnote 107. Increases in systolic blood pressure occurred with low (5 mg) and high (15 mg) oral doses of THC, as well as low (5.4 mg Δ9-THC and 5 mg CBD) and high (16.2 mg Δ9-THC and 15 mg CBD) dose nabiximols, with the effect peaking at around 3 h after administrationFootnote 107. In contrast, diastolic blood pressure decreased between 4 and 8 h after dosing. Heart rate increased after all active treatments. A statistically significant increase in heart rate relative to placebo was observed after high-dose oral THC (15 mg Δ9-THC) and high-dose nabiximols (16.2 mg Δ9-THC and 15 mg CBD), but the authors indicated that the increases appeared to be less clinically significant than those typically seen with smoked cannabisFootnote 107. High-dose oral THC (15 mg Δ9-THC) and high-dose nabiximols (16.2 mg Δ9-THC and 15 mg CBD) were associated with significantly greater "good drug effects" compared to placebo, whereas low-dose nabiximols (5.4 mg Δ9-THC and 5 mg CBD) was associated with significantly higher "good drug effects" compared to 5 mg THCFootnote 107. A subjective feeling of a "high" was reported to be significantly greater after 15 mg oral THC compared to placebo and to 5 mg oral THC. In contrast, neither the high nor the low doses of nabiximols were reported to produce a statistically significant subjective "high" feeling. Study subjects reported being most "anxious" approximately 4 h after administration of 5 mg oral THC, 3 h after 15 mg oral THC, 5.5 h after low-dose nabiximols, and 4.5 h after high-dose nabiximolsFootnote 107. All active drug treatments induced significantly more anxiety compared to placebo. After 15 mg oral THC, the concentration of THC in plasma was observed to have a weak, but statistically significant, positive correlation with systolic and diastolic blood pressure, "good drug effect", and "high"Footnote 107. After high-dose nabiximols, positive correlations were also observed between plasma THC concentrations and "anxious", "good drug effect", "high", "stimulated", and M-scale (marihuana-scale) scoresFootnote 107. Consistent with other studies, the authors of this study reported that linear correlations between plasma THC concentrations and physiological or subjective effects were weak. Lastly, although cannabidiol did not appear to significantly modulate the effects of THC, the authors suggested it may have attenuated the degree of the subjective "high"Footnote 107.

2.4. Tolerance, dependence, and withdrawal symptoms

Tolerance

Tolerance, as defined by the Liaison Committee on Pain and Addiction (a joint committee with representatives from the American Pain Society, the American Academy of Pain Medicine, and the American Society of Addiction Medicine) is a state of adaptation in which exposure to the drug causes changes that result in a diminution of one or more of the drug's effects over timeFootnote 335.

Tolerance to the effects of cannabis or cannabinoids appears to result mostly from pharmacodynamic rather than pharmacokinetic mechanismsFootnote 211. Pre-clinical studies indicate that pharmacodynamic tolerance is mainly linked to changes in the availability of the cannabinoid receptors, principally the CB1 receptor, to signal. There are two independent but interrelated molecular mechanisms producing these changes: receptor desensitization (or uncoupling of the receptor from intra-cellular downstream signal transduction events), and receptor downregulation (resulting from the internalization and/or degradation of the receptor)Footnote 336. Furthermore, within the brain, tolerance appears to vary across different regions suggesting cellular and tissue-specific mechanisms regulating desensitization/downregulation (see review by Gonzalez et al.Footnote 211). This may also hold true for other tissues or organs, explaining why tolerance develops to some of the effects of cannabis and cannabinoids but not to other effects. In animal models, the degree and time-course of tolerance appear to depend on the species used, the type of cannabinoid ligand, the dosage and duration of the treatment, and the measures employed to determine toleranceFootnote 211. Pharmacokinetic tolerance (including changes in absorption, distribution, biotransformation and excretion) has also been documented, but apparently occurs to a lesser degree than pharmacodynamic toleranceFootnote 337. In the clinical setting, tolerance to the effects of cannabis or cannabinoids can potentially be minimized by combining lower doses of cannabis or cannabinoids along with one or more additional therapeutic drugsFootnote 338.

Tolerance to most of the effects of cannabis and cannabinoids can develop after a few doses, and it also disappears rapidly following cessation of administrationFootnote 118. In normal subjects, tolerance develops to the effects of cannabis on mood, intra-ocular pressure, EEG, psychomotor performance, nausea, as well as on the cardiovascular system Footnote 212,Footnote 213. There is also some evidence to suggest that tolerance can develop to the effects of cannabis on sleep (reviewed inFootnote 161). As mentioned above, the dynamics of tolerance vary with respect to the different effects; tolerance to some of the effects develops more readily and rapidly than to othersFootnote 214,Footnote 215. A positron emission tomography imaging study of chronic daily cannabis smokers reported reversible and regionally selective downregulation of brain cannabinoid CB1 receptorsFootnote 339. This finding could help explain the results obtained from a previously published double-blind, randomized, placebo-controlled study which showed that subjects who reported frequently using cannabis (frequently being defined in this study as a positive toxicological test result for cannabis at screening, at least 10 exposures to cannabis immediately prior to study initiation, and meeting DSM-IV criteria for cannabis use disorder) displayed blunted responses to the psychotomimetic, perceptual altering, cognitive impairing, anxiogenic, and cortisol- increasing effects of THC compared to controls, but notably not to its euphoric effectsFootnote 216. Another study reported that tolerance to some of the effects of cannabis, including tolerance to the "high", developed both when THC was administered orally (30 mg; four times per day; total daily dose 120 mg)Footnote 207 and when a roughly equivalent dose was given by smoking (3.1% THC cigarette; four times per day)Footnote 340. Interestingly, there was no diminution of the appetite-stimulating effect from either route of administration.

An uncontrolled, open-label extension study of an initial five-week randomized trial of nabiximols in patients with multiple sclerosis and central neuropathic pain reported the absence of pharmacological tolerance (measured by a change in the mean daily dosage of nabiximols), even after an almost two-year treatment period in a group of select patientsFootnote 217. Another long-term, open-label extension study of nabiximols in patients with spasticity caused by multiple sclerosis echoed these findings, also reporting the absence of pharmacological tolerance (measured by a change in the mean daily dosage of nabiximols) after almost one year of treatmentFootnote 218.

Dependence and withdrawal

Dependence can be divided into two independent, but in certain situations interrelated concepts: physical dependence and psychological dependence (i.e. addiction)Footnote 335. Physical dependence, as defined by the Liaison Committee on Pain and Addiction, is a state of adaptation manifested by a drug-class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonistFootnote 190. Psychological dependence (i.e. addiction) is a primary, chronic, neurobiological disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations, and is characterized by behaviours that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and cravingFootnote 335. In the DSM-IV-TR, the term 'dependence' is closely related to the concept of addiction which may or may not include physical dependence, and is characterized by use despite harm, and loss of control over useFootnote 341.

There is evidence that cannabis dependence (physical and psychological) occurs especially with chronic, heavy useFootnote 122,Footnote 156,Footnote 210. The endocannabinoid system has been implicated in the acquisition and maintenance of drug taking behaviour, and in various physiological and behavioural processes associated with psychological dependence or addictionFootnote 2. Physical dependence is most often manifested in the appearance of withdrawal symptoms when use is abruptly halted or discontinued. Withdrawal symptoms associated with cessation of cannabis use (oral or smoked) appear within the first one to two days following discontinuation; peak effects typically occur between days 2 and 6 and most symptoms resolve within 1 - 2 weeksFootnote 342. The most common symptoms include anger or aggression, irritability, anxiety, nightmares/strange dreams, insomnia/sleep difficulties, craving, headache, restlessness, and decreased appetite or weight lossFootnote 156,Footnote 210,Footnote 222. Other symptoms appear to include depressed mood, chills, stomach pain, shakiness and sweatingFootnote 156,Footnote 210,Footnote 222.

3.0 Dosing

General remarks

Cannabis has many variables that do not fit well with the typical medical model for drug prescribingFootnote 277. The complex pharmacology of cannabinoids, interindividual (genetic) differences in cannabinoid receptor structure and function, interindividual (genetic) differences in cannabinoid metabolism affecting cannabinoid bioavailability, prior exposure to and experience with cannabis/cannabinoids, pharmacological tolerance to cannabinoids, changes to cannabinoid receptor distribution/density and/or function as a consequence of a medical disorder, the variable potency of the cannabis plant material, and the different dosing regimens and routes of administration used in different research studies all contribute to the difficulty in reporting precise doses or establishing uniform dosing schedules for cannabis (and/or cannabinoids)Footnote 277,Footnote 328.

While precise dosages have not been established, some "rough" dosing guidelines for smoked or vapourized cannabis have been published (see below). Besides smoking and vapourization, cannabis is known to be consumed in baked goods such as cookies or brownies, or drunk as teas or infusions. However, absorption of these products by the oral route is slow and erratic, and the onset of effects is delayed with the effects lasting much longer compared to smoking (see section 2.2); furthermore, dosages for orally administered products are even less well established than for smoking/vapourizationFootnote 111,Footnote 286,Footnote 289,Footnote 343. Other forms of preparation reported in the lay literature include cannabis-based butters, oils, compresses, creams, ointments, and tincturesFootnote 64,Footnote 344,Footnote 345,Footnote 346,Footnote 347 but again, no dosing information exists here and much of the information is anecdotal in nature.

Dosing remains highly individualized and relies to a great extent on titrationFootnote 277. Patients with no prior experience with cannabis and initiating cannabis therapy for the first time are cautioned to begin at a very low dose and to stop therapy if unacceptable or undesirable side effects occur. Consumption of smoked/inhaled or oral cannabis should proceed slowly, waiting between puffs for a few minutes and waiting 30 - 60 min between bites of cannabis-based oral products (e.g. cookies, baked goods) to gauge for strength of effects or for possible overdosing.

Minimal therapeutic dose and dosing ranges

Information obtained from the monograph for Marinol® (dronabinol) indicates that a daily oral dose as low as 2.5 mg Δ9-THC is associated with a therapeutic effect (e.g. treatment of AIDS-related anorexia/cachexia). Naturally, dosing will vary according to the underlying disorder and the many other variables mentioned above. Dosing ranges for Marinol® (dronabinol) vary from 2.5 mg - 40 mg Δ9-THC/dayFootnote 174. Dosing ranges for Cesamet® (nabilone) vary from 0.2 mg - 6 mg/dayFootnote 332,Footnote 348. Dosing ranges for Sativex® (nabiximols) vary from one spray (2.7 mg Δ9-THC and 2.5 mg CBD) to 16 sprays (43.2 mg Δ9-THC to 40 mg CBD) per dayFootnote 290,Footnote 349.

Various surveys published in the peer-reviewed literature have suggested that the majority of people using smoked or orally ingested cannabis for medical purposes reported using between 10 - 20 g of cannabis per week or approximately 1 - 3 g of cannabis per dayFootnote 165,Footnote 277,Footnote 350.

Monitoring

Currently, there are no clinical guidelines on monitoring patients who are taking cannabis for medical purposes.

3.1 Smoking

According to the World Health Organization (WHO)Footnote 351, a typical joint contains between 0.5 and 1.0 g of cannabis plant matter (average weight = 750 mg) which may vary in Δ9-THC content between 7.5 and 225 mg (i.e. typically between 1 and 30%; see Table 2). The amount of other cannabinoids present, mainly cannabinol (CBN) and cannabidiol (CBD), is usually much lower. The actual amount of Δ9-THC delivered in the smoke varies widely and has been estimated at 20 - 70%, the remainder being lost through combustion or side-stream smokeFootnote 277. Furthermore, the bioavailability of Δ9-THC (the fraction of Δ9-THC in the cigarette which reaches the bloodstream) from the smoking route is variable (2 - 56%) and influenced by the smoking topography (the number, duration, and spacing of puffs, hold time and inhalation volume)Footnote 276. In addition, expectation of drug reward can also influence smoking dynamicsFootnote 352. Thus, the actual dose of Δ9-THC absorbed systemically when smoked is not easily quantified but has been approximated to be around 25% of the total available amount of Δ9-THC in a cigaretteFootnote 117,Footnote 277.

Relationship between a smoked dose and an oral dose

Little information exists regarding conversion of a "smoked dose" of THC to an equivalent oral dose, however multiplication of a "smoked dose" of Δ9-THC by a conversion factor of 2.5 (to correct for differences between the bioavailability of Δ9-THC through the smoked route (~25%) vs. the oral route (~10%)) can yield an approximately equivalent oral dose of Δ9-THCFootnote 117. The "smoked dose" can be defined as the dose, in mg, of Δ9-THC that is available in the cigarette. As an example, smoking a cigarette containing 75 mg Δ9-THC by weight (see Row 4 in Table 2 [10% Δ9-THC, 750 mg dried plant material]) would yield an estimated oral dose of 187.5 mg Δ9-THC (75 mg Δ9-THC X 2.5 = 187.5 mg Δ9-THC ). Please consult Tables 3, 4 and 5 for further information regarding converting between smoked and oral doses of Δ9-THC.

Table 2: Relationship between THC Percent in Plant Material and the Available Dose (in mg THC) in an Average Joint
% THC mg THC per 750 mg dried plant materialWHO average weight ("average joint")
  • WHO average weight
  • see text in section 3.1 for additional details
1 7.5
2.5 18.75
5 37.5
10See text in section 3.1 for additional details 75See text in section 3.1 for additional details
15 112.5
20 150
30 225

Table 3: Approximate Conversion Factors Smoked/Oral Δ9-THC
  To Smoked DoseA "smoked dose" can be defined as the total available amount of Δ9-THC To Oral DoseAn oral dose is defined as the total amount of Δ9-THC that is ingested orally.
  • A "smoked dose" can be defined as the total available amount of Δ9-THC in a cannabis cigarette (calculated by multiplying the percentage of Δ9-THC by the total gram amount of cannabis in the cigarette).
  • An oral dose is defined as the total amount of Δ9-THC that is ingested orally.
From Smoked DoseA "smoked dose" can be defined as the total available amount of Δ9-THC  

Multiply the dose of Δ9-THC (in mg) in the dried plant material to be smoked by a factor of 2.5 to obtain the estimated dose of Δ9-THC (in mg) to be ingested orally.

(Smoked dose in mg X 2.5 = Oral dose in mg)

From Oral DoseAn oral dose is defined as the total amount of Δ9-THC that is ingested orally.

Divide the dose of Δ9-THC (in mg) to be ingested orally by a factor of 2.5 to obtain the estimated dose of Δ9-THC (in mg) to be smoked.

(Oral dose in mg ÷ 2.5 = Smoked dose in mg)

 

Table 4: Quick Reference of Smoked to Estimated Oral Doses of Δ9-THC
"Smoked Dose"A "smoked dose" is defined as the total available amount of Δ9-THC in a standard cannabis cigarette
% THC in a 750 mg cannabis cigarette
(Total available mg Δ9-THC)
Estimated Oral Dose (mg Δ9-THC)An oral dose is defined as the total amount (in mg) of orally ingested Δ9-THC
  • A "smoked dose" is defined as the total available amount (in mg) of Δ9-THC in a standard cannabis cigarette (750 mg joint)
  • An oral dose is defined as the total amount (in mg) of orally ingested Δ9-THC

Numbers in the table are rounded to the nearest decimal place

1 % THC (7.5 mg) 18.8 mg
2 % THC (15 mg) 37.5 mg
2.5 % THC (18.8 mg) 46.8 mg
3 % THC (22.5 mg) 56.3 mg
5 % THC (37.5 mg) 93.8 mg
7.5 % THC (56.3 mg) 140.6 mg
10 % THC (75 mg) 187.5 mg
12.5% THC (93.8 mg) 234.4 mg
15 % THC (112.5 mg) 281.3 mg
20 % THC (150 mg) 375 mg

Table 5: Quick Reference of Oral to Estimated Smoked Doses of Δ9-THC
Oral DoseAn oral dose is defined as the total amount (in mg) of orally ingested Δ9-THC
(mg Δ9-THC)
Estimated "Smoked Dose"A "smoked dose" is defined as the total available amount of Δ9-THC in a standard cannabis cigarette
(Total available mg Δ9-THC in the dried plant material in the cigarette)
  • An oral dose is defined as the total amount (in mg) of orally ingested Δ9-THC
  • A "smoked dose" is defined as the total available amount (in mg) of Δ9-THC in a standard cannabis cigarette (750 mg joint)

Numbers in the table are rounded to the nearest decimal place

0.25 0.1
0.5 0.2
0.75 0.3
1 0.4
1.25 0.5
1.5 0.6
1.75 0.7
2 0.8
2.25 0.9
2.5 1
2.75 1.1
3 1.2
3.25 1.3
3.5 1.4
3.75 1.5
4 1.6
4.25 1.7
4.5 1.8
4.75 1.9
5 2
6 2.4
7 2.8
8 3.2
9 3.6
10 4
15 6
20 8
25 10
30 12
40 16
50 20
75 30
100 40

Table 6: Comparison between Cannabis and Prescription Cannabinoid Medications
  Cannabinoid (Generic name) Registered name Principal constituents/ Source Official status in Canada Approved indications Onset (O)/ Duration of action (D) Route of admin. Availability on provincial/ territorial formulary
  • Product has been discontinued by the manufacturer (post-market; as of February 2012; not for safety reasons)
  • For Sativex®, the following marketing authorizations apply:

    Standard marketing authorization: Adjunctive treatment for symptomatic relief of spasticity in adult patients with multiple sclerosis who have not responded adequately to other therapy and who demonstrate meaningful improvement during an initial trial of therapy.

    Marketing authorization with conditions: Adjunctive treatment for symptomatic relief of neuropathic pain in adult patients with multiple sclerosis; and adjunctive analgesic treatment in adult patients with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background pain.
Cannabinoids Rx DronabinolProduct has been discontinued by the manufacturer Marinol®Product has been discontinued by the manufacturer Synthetic Δ9-THC ApprovedProduct has been discontinued by the manufacturer AIDS-related anorexia associated with weight loss; Severe nausea and vomiting associated with cancer chemotherapy O: 30 - 60 min D: 4 - 6 h Oral MBProduct has been discontinued by the manufacturer; NBProduct has been discontinued by the manufacturer; NSProduct has been discontinued by the manufacturer; ONProduct has been discontinued by the manufacturer; PEProduct has been discontinued by the manufacturer; QCProduct has been discontinued by the manufacturer; YTProduct has been discontinued by the manufacturer
Nabilone Cesamet® Synthetic Δ9-THC analogue Approved Severe nausea and vomiting associated with cancer chemotherapy O: 60 - 90 min D: 8 - 12 h Oral AB; BC; MB; NB; NL; NS; NT; NU; ON; PE; QC; SK; YT.
Nabiximols (THC+CBD and other minor cannabinoids, terpenoids, and flavonoids) Sativex® Botanical extract from established and well-characterized C. sativa strains Approved O: 15 - 40 min D: 2 - 4 h Oro-mucosal spray NS.
Plant product Cannabis (smoked) N/A C. sativa (various) Not an approved product N/A O: 5 min D: 2 - 4 h Smoking N/A
Cannabis (vapourized) N/A C. sativa (various) Not an approved product N/A O: 5 min D: 2 - 4 h Inhalation by vapourizer N/A
Cannabis (oral edible) N/A C. sativa (various) Not an approved product N/A O: 30 - 60 min D: 8 - 12 h Oral N/A
Cannabis (topical) N/A C. sativa (various) Not an approved product N/A N/A Topical N/A

Plasma concentrations of Δ9-THC following smoking

Using a paced smoking protocol, the mean plasma concentration of Δ9-THC after a first inhalation of a cannabis cigarette containing 3.55% Δ9-THC has been reported to be 18.1 ng/mL (range: 1.8 - 37.0 ng/mL), with the mean peak plasma concentration of Δ9-THC reaching 162 ng/mL (range: 76 - 267 ng/mL) after seven puffs or almost complete smoking of the cigaretteFootnote 276,Footnote 328. Peak plasma concentrations of Δ9-THC in the range of 50 - 100 ng/mL are associated with a subjective "high" (Footnote 279 and section 2.3) and can be easily attained by smoking a single 3.55% Δ9-THC cannabis cigarette (900 mg plant material, 32 mg total available Δ9-THC)Footnote 328. If the current average "street" marihuana contains 10% THC, joints from such a source might have an available 75 mg dose of Δ9-THC and could result in rapid attainment of elevated plasma Δ9-THC concentrations ( > 100 ng/mL Δ9-THC). More potent strains of cannabis could yield even higher plasma concentrations of THC.

Plasma concentrations of Δ9-THC following smoking, and therapeutic efficacy

There are a small number of efficacy studies on the amounts of cannabis required for therapeutic effects (see Table 7 for a quick overview, and information throughout this document for more detailed information). A Canadian dose-ranging study showed that a single inhalation of a 25 mg dose of smoked cannabis (Δ9-THC content 9.4%; total available dose of Δ9-THC = 2.35 mg) yielded a mean plasma Δ9-THC concentration of 45 ng/mL within 2 min after initiating smokingFootnote 172. The study reported improvements in sleep and pain relief in patients suffering from chronic neuropathic painFootnote 172. Using the above-mentioned conversion formula to translate smoked to estimated oral doses of Δ9-THC, 2.35 mg Δ9-THC in the dried plant material would correspond to an estimated oral dose of 5.9 mg Δ9-THC.

Please consult Tables 3, 4 and 5 for further information regarding converting between smoked and oral doses of Δ9-THC. Please consult Table 7 for a list of clinical trials of smoked cannabis and general details regarding those trials.

3.2 Oral

The pharmacokinetic information described in section 2.2.1.3 reports the erratic and slow absorption of Δ9-THC from the oral route, and oral doses are estimated from the information in the monograph for Marinol® (dronabinol). A 10 mg b.i.d. dose of Marinol® (20 mg total Δ9-THC per day) yielded a mean peak plasma Δ9-THC concentration of 7.88 ng/mL (range: 3.33 - 12.42 ng/mL), with a bioavailability ranging between 10 and 20%Footnote 174. By comparison, consumption of a chocolate cookie containing 20 mg Δ9-THC resulted in a mean peak plasma Δ9-THC concentration of 7.5 ng/mL (range: 4.4 - 11 ng/mL), with a bioavailability of 6%Footnote 278. Tea prepared from Cannabis flowering tops and leaves has been documented, but no data are available regarding efficacyFootnote 289. To convert an oral dose to an estimated "smoked dose", the oral dose is divided by a conversion factor of 2.5Footnote 117. Thus, an oral dose of 20 mg Δ9-THC would be approximately equivalent to a "smoked dose" of 8 mg of Δ9-THC. Please consult Tables 3, 4 and 5 for further information regarding converting oral to smoked doses of Δ9-THC.

Marinol

The Marinol® (dronabinol) product monograph suggests a mean of 5 mg Δ9-THC/day (range: 2.5 - 20 mg Δ9-THC/day) for AIDS-related anorexia associated with weight lossFootnote 174. A 2.5 mg dose may be administered before lunch, followed by a second 2.5 mg dose before supper. On the other hand, to reduce or prevent cancer chemotherapy-induced nausea or vomiting, a dosage of 5 mg t.i.d. or q.i.d. is suggestedFootnote 174. In either case, the dose should be carefully titrated to avoid the manifestation of adverse effects. Please consult the drug product monograph for more detailed instructions.

Cesamet

The Cesamet® (nabilone) product monograph suggests administration of 1 - 2 mg of the drug, twice a day, with the first dose given the night before administration of the chemotherapeutic medicationFootnote 332. A 2 mg dose of nabilone gave a mean plasma concentration of 10 ng/mL nabilone, 1 - 2 h after administrationFootnote 332. The second dose is usually administered 1 - 3 h before chemotherapy. If required, the administration of nabilone can be continued up to 24 h after the chemotherapeutic agent is given. The maximum recommended daily dose is 6 mg in divided doses. Dose adjustment (titration) may be required in order to attain the desired response, or to improve tolerability. More recent clinical trials report starting doses of nabilone of 0.5 mg at night for pain or insomnia in fibromyalgia, and for insomnia in post-traumatic stress disorderFootnote 348,Footnote 353,Footnote 354. Please consult the drug product monograph for more detailed instructions.

3.3 Oro-mucosal

Dosing with nabiximols (Sativex®) is described in the product monograph along with a titration method for proper treatment initiationFootnote 290. Briefly, dosing indications in the drug product monograph suggest that on the first day of treatment patients take one spray during the morning (anytime between waking and noon), and another in the afternoon/evening (anytime between 4 pm and bedtime). On subsequent days, the number of sprays can be increased by one spray per day, as needed and tolerated. A fifteen minute time gap should be allowed between sprays. During the initial titration, sprays should be evenly spread out over the day. If at any time unacceptable adverse reactions such as dizziness or other CNS-type reactions develop, dosing should be suspended or reduced or the dosing schedule changed to increase the time intervals between doses. According to the product monograph, the average dose of nabiximols is five sprays per day (i.e. 13 mg Δ9-THC and 12.5 mg CBD) for patients with multiple sclerosis, whereas those patients with cancer pain tend to use an average of eight sprays per day (i.e. 21.6 mg Δ9-THC and 20 mg CBD)Footnote 290. The majority of patients appear to require 12 sprays or less; dosage should be adjusted as needed and toleratedFootnote 290. Administration of four sprays to healthy volunteers (total 10.8 mg Δ9-THC and 10 mg CBD) was associated with a mean maximum plasma concentration varying between 4.90 - 6.14 ng/mL Δ9-THC and 2.50 - 3.02 ng/mL CBD depending whether the drug was administered under the tongue or inside the cheek. Please consult the product monograph for more detailed information.

3.4 Vapourization

The Dutch Office of Medicinal Cannabis has published "rough" guidelines on the use of vapourizersFootnote 289. Although the amount of cannabis used per day needs to be determined on an individual basis, the initial dosage should be low and may be increased slowly as symptoms indicate. The amount of cannabis to be placed in the vapourizer may vary depending on the type of vapourizer used. Studies using the Volcano® vapourizer have reported using up to 1 g of dried cannabis in the chamber, but 50 to 500 mg of plant material is typically usedFootnote 284; Δ9-THC concentrations up to 6.8% have been testedFootnote 273,Footnote 284. Subjects appeared to self-titrate their intake in accordance with the Δ9-THC content of the cannabisFootnote 273. Peak plasma Δ9-THC levels varied between 70 - 190 ng/mL depending on the strength of Δ9-THC. The levels of cannabinoids released into the vapour phase increased with the temperature of vapourizationFootnote 284. Vapourization temperature is typically between 180 - 195°CFootnote 289; higher temperatures (e.g. 230°C) greatly increase the amounts of cannabinoids released, but also increase the amounts of by-productsFootnote 284.

4.0 Potential Therapeutic Uses

While there are many anecdotal reports concerning the therapeutic value of cannabis, clinical studies supporting the safety and efficacy of smoked cannabis for therapeutic purposes in a variety of disorders are limited, but slowly increasing in number. There are no clinical studies on the use of cannabis edibles (e.g. cookies, baked goods) or topicals for therapeutic purposes. It has been repeatedly noted that the psychotropic side effects associated with the use of cannabinoids have been found to limit their therapeutic utilityFootnote 21,Footnote 48,Footnote 50,Footnote 185,Footnote 355. Table 7 summarizes the information on published clinical trials that have been carried out thus far using smoked/vapourized cannabis.

Dronabinol is the generic name for the oral form of synthetic Δ9-THC and is marketed in the U.S. and Canada as Marinol®. It is sold in capsules containing 2.5, 5, or 10 mg of the drug dissolved in sesame oil. It is indicated for the treatment of severe nausea and vomiting associated with cancer chemotherapy, and for AIDS-related anorexia associated with weight lossFootnote 174. The drug appears to no longer be sold in Canada (post-market discontinuation of the drug product as of February 2012; not for safety reasons).

Nabilone is the generic name for an orally administered synthetic structural analogue of Δ9-THC which is marketed in Canada as Cesamet®. It is sold as capsules (0.25, 0.5, 1 mg) and is indicated for severe nausea and vomiting associated with cancer chemotherapyFootnote 332.

Nabiximols is the generic name for a whole-plant extract of two different, but standardized, strains of Cannabis sativa giving an oro-mucosal spray product containing approximately equivalent amounts of Δ9-THC (27 mg/mL) and CBD (25 mg/mL), and other cannabinoids, terpenoids, and flavonoids per 100 μl of dispensed spray. Nabiximols is marketed as Sativex® in Canada and has received a notice of compliance for use as an adjunctive treatment for the symptomatic relief of spasticity in adult patients with multiple sclerosis who have not responded adequately to other therapy, and who demonstrate meaningful improvement during an initial trial of therapy. It is also marketed (with conditions) as an adjunctive treatment for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and (with conditions) as an adjunctive analgesic in adult patients with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background painFootnote 290.

The existing scientific and clinical evidence for cannabis and certain cannabinoids in treating various symptoms associated with various medical conditions is summarized in the following sections beginning on the next page.

Table 7: Published Clinical Trials on Smoked/Vapourized Cannabis and Associated Therapeutic Benefits
Primary medical conditions and associated secondary end-points (if any) for which benefits were observed Percent and dose of Δ9-THC (if known) Trial duration; and number of patients/participants Reference
HIV/AIDS-associated weight loss 1 cannabis cigarette (~800 mg) containing 1.8% or 3.9% THC by weight, smoked once daily (i.e. one dose per day) (~14-31 mg Δ9-THC /day) 8 sessions total
(3 sessions per week);
30 participants
Footnote 166
HIV/AIDS-associated weight loss; disease-associated mood and insomnia 1 cannabis cigarette (~800 mg) containing 2.0% or 3.9% THC by weight, smoked four times per day (i.e. 4 doses per day) (~64-125 mg of Δ9-THC /day) 4 days total;
10 participants
Footnote 167
Multiple sclerosis-associated pain and spasticity 1 cannabis cigarette (~800 mg) containing 4% THC by weight, smoked once per day (i.e. one dose per day) (~32 mg Δ9-THC /day) 3 days total;
30 patients
Footnote 188
Central and peripheral chronic neuropathic pain (various etiologies) 1 cannabis cigarette (~800 mg) containing either 3.5% or 7% THC by weight, smoked in bouts over a 3 h period (i.e. one dose per day) 1 day total;
38 patients
Footnote 168
Chronic neuropathic pain from HIV-associated sensory neuropathy 1 cannabis cigarette (~900 mg) containing 3.56% THC by weight, smoked three times daily (i.e. 3 doses per day) (~96 mg Δ9-THC /day) 5 days total;
25 patients
Footnote 142
HIV-associated chronic neuropathic pain refractory to other medications 1 cannabis cigarette (~800 mg) containing between 1 and 8% THC by weight, smoked four times daily (i.e. 4 doses per day) 5 days total;
28 patients
Footnote 186
Chronic post-traumatic or post-surgical neuropathic pain refractory to other medications and associated insomnia One 25 mg dose of cannabis containing 9.4% THC by weight, smoked three times daily (i.e. three doses per day) (~7 mg Δ9-THC /day) 5 days total;
21 patients
Footnote 172
Chronic pain of various etiologies (musculoskeletal, post-traumatic, arthritic, peripheral neuropathy, cancer, fibromyalgia, migraine, multiple sclerosis, sickle cell disease, thoracic outlet syndrome) One 0.9 g dose of vapourized cannabis containing 3.56% THC by weight administered three times per day (one dose the first day, three doses per day for next three days, one dose the last day) (~96 mg Δ9-THC /day) 5 days total;
21 patients
Footnote 187

4.1 Palliative Care

Among the goals of palliative care described by the World Health Organization (WHO) are relief from pain and other distressing symptoms, and the enhancement of quality of lifeFootnote 356. While integration of cannabis into mainstream medical use can be characterized as extremely cautious, its use appears to be gaining some ground in palliative care settings where the focus is on individual choice, patient autonomy, empowerment, comfort and especially quality of life Footnote 357. Nevertheless, establishing the effectiveness of cannabis as a viable treatment option in a palliative care context requires a careful assessment of its effects in a wide range of conditions; such evidence is not yet abundant and further research is neededFootnote 358. Furthermore, while prescription cannabinoids demonstrate an acceptable safety profile according to some studies for certain medical conditions, the use of cannabis and cannabinoids in the clinic is known to be limited by their psychotropic effectsFootnote 21,Footnote 209,Footnote 359. Certain patient populations (e.g. the elderly or those suffering from pre-existing psychiatric disease) may be also be more sensitive or susceptible to experiencing adverse psychotropic, cognitive, psychiatric or other effectsFootnote 359,Footnote 360.

The evidence thus far suggests that cannabis and prescription cannabinoids (e.g. dronabinol, nabilone, or nabiximols) may be useful in alleviating a wide variety of single or co-occurring symptoms often encountered in the palliative care setting; these symptoms include intractable nausea and vomiting associated with chemotherapy or radiotherapy, anorexia/cachexia, severe intractable pain, severe depressed mood, and insomniaFootnote 208,Footnote 209. The use of cannabinoids for palliative care may also result in a decrease in the number of medications used by this patient populationFootnote 208.

For information on the use of cannabis/cannabinoids for the control of nausea and vomiting please consult section 4.2 of this document. For additional information on the use of cannabis/cannabinoids for anorexia/cachexia associated with HIV/AIDS infection or cancer please consult sections 4.3.1 and 4.3.2, respectively. For further information on the use of cannabis/cannabinoids for chronic pain syndromes (including cancer pain) please consult sections 4.6.2.2 and 4.6.2.3. For further information on the use of cannabis/cannabinoids in the treatment of sleep disorders associated with chronic diseases please see section 4.8.5.2, and please consult section 4.8.9 for information on the use of cannabis/cannabinoids in oncology.

Quality of Life

A handful of clinical studies have used standardized quality-of-life (QoL) instruments to measure whether the use of cannabis or prescription cannabinoids (e.g. nabilone, dronabinol, or nabiximols) is associated with improvements in QoL. The available studies report mixed effects of cannabis and cannabinoids on measures of QoL for a variety of different disorders. The evidence from these studies is summarized below.

Clinical studies with dronabinol

A randomized, double-blind, placebo-controlled, crossover trial of dronabinol (maximum dose of 10 mg Δ9-THC per day, for a total of three weeks) for the treatment of central neuropathic pain in patients suffering from multiple sclerosis reported statistically significant improvements in measures of QoL (SF-36 quality of life questionnaire; measures for bodily pain and mental health)Footnote 361.

A two-centre, phase II, randomized, double-blind, placebo-controlled 22-day pilot study carried out in adult patients suffering from chemosensory alterations (i.e. changes in olfaction and gustation) and poor appetite associated with advanced cancer of various etiologies reported improved and enhanced chemosensory perception among patients treated with dronabinol (2.5 mg b.i.d.) compared to those receiving placeboFootnote 362. The majority (73%) of dronabinol-treated patients self-reported an increased overall appreciation of food compared to those receiving placebo (30%). While global scores on the Functional Assessment of Anorexia-Cachexia Therapy (FAACT) QoL instrument improved to a similar extent for dronabinol and placebo-treated groups, the FAACT sub-domain for anorexia-cachexia-related nutritional well-being improved with dronabinol compared to placeboFootnote 362. Statistically significant improvements were also noted for quality of sleep and relaxation with dronabinol treatment compared to placeboFootnote 362. According to the study authors, negative psychoactive effects were minimized by starting patients at a low dose (2.5 mg once a day for three days) followed by gradual dose escalation (up to a maximum of 7.5 mg dronabinol per day)Footnote 362.

Clinical studies with cannabis extract

A multi-centre, phase III, randomized, double-blind, placebo-controlled, three-arm, parallel study in adult patients with advanced incurable cancer and suffering from cancer-related anorexia-cachexia syndrome concluded that neither cannabis extract (2.5 mg Δ9-THC, 1 mg CBD, for six weeks) nor THC (2.5 mg Δ9-THC b.i.d., for six weeks) provided any statistically significant benefit compared to placebo on measures of QoL (EORTC QLQ- C30)Footnote 363.

Clinical studies with nabilone

A randomized, double-blind, placebo-controlled trial of nabilone in patients suffering from fibromyalgia reported that adjuvant nabilone therapy (four weeks; maximum dose in the final week of treatment: 1 mg b.i.d.) was associated with a significant improvement in measures of QoL (Visual Analogue Scale for pain, and the Fibromyalgia Impact Questionnaire)Footnote 353. An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel-assignment efficacy study of nabilone as an adjuvant in the treatment of long-standing diabetic peripheral neuropathic pain reported statistically significant improvements in measures of QoL (Composite EQ-5D Index Score) and overall patient status compared to placeboFootnote 364. Doses of nabilone ranged from 1 - 4 mg/day; treatment duration was five weeksFootnote 364.

Clinical studies with nabiximols

A ten-week, prospective, randomized, double-blind, placebo-controlled trial assessing the safety and efficacy of nabiximols (Sativex®) as an adjunctive medication in the treatment of intractable diabetic peripheral neuropathy concluded that nabiximols failed to show statistically significant improvements in measures of QoL (EuroQOL, SF-36, and the McGill Pain and QOL Questionnaire)Footnote 365. A twelve-week, double-blind, randomized, placebo-controlled, parallel-group, enriched enrolment study of nabiximols as add-on therapy for patients with refractory spasticity concluded that there was no significant difference between active treatment and placebo on measures of QoL (EQ-5D Health State Index, EQ-5D Health Status VAS, SF-36)Footnote 366. A five-week, multi-centre, randomized, double-blind, placebo-controlled, parallel-group, graded-dose study evaluated the analgesic efficacy and safety of nabiximols in three dose ranges in opioid-treated cancer patients with poorly-controlled chronic painFootnote 349. The study reported the lack of any positive treatment effects on overall QoL in this study population even at the highest doses of nabiximols (11 - 16 sprays per day)Footnote 349.

Clinical studies with smoked cannabis

A randomized, double-blind, placebo-controlled, four-period, cross-over trial of smoked cannabis in the treatment of chronic neuropathic pain (chronic post-traumatic or post-surgical etiology) concluded that inhalation of smoked cannabis (25 mg of cannabis containing 2.5, 6.0, or 9.4% Δ9-THC, t.i.d. for five days) was not associated with a statistically significant difference compared to placebo on measures of QoL (EQ-5D Health Outcomes Quality of Life instrument)Footnote 172. In contrast, a cross-sectional survey examining the benefits associated with cannabis use in patients with fibromyalgia reported a statistically significant benefit in the mental health component summary score of the SF-36 Quality of Life questionnaire in patients who used cannabis compared to non-usersFootnote 158. However, no significant differences between cannabis and non-cannabis users were found in the other SF-36 domains, in the Fibromyalgia Impact Questionnaire, or the Pittsburgh Sleep Quality IndexFootnote 158.

A preliminary observational, open-label, prospective, single-arm trial in a group of 13 patients suffering from Crohn's disease or ulcerative colitis reported that treatment with inhaled cannabis over a three-month period improved subjects' quality of life, caused a statistically significant increase in subjects' weight, and improved the clinical disease activity index in patients with Crohn's diseaseFootnote 189. Patients reported a statistically significant improvement in their perception of their general health status, their ability to perform daily activities, and their ability to maintain a social lifeFootnote 189. Patients also reported a statistically significant reduction in physical pain as well as improvement in mental distressFootnote 189.

4.2 Nausea and vomiting

Chemotherapy-induced nausea and vomiting (CINV) is one of the most distressing and common adverse events associated with cancer treatmentFootnote 367. While chemotherapy-induced vomiting generally appears to be well-controlled with current first-line therapies, the associated acute, delayed, or anticipatory nausea remain more poorly controlled and the use of cannabis/cannabinoids may provide some measure of benefit in certain casesFootnote 88,Footnote 192. It is important to note that excessive use of cannabis has been reported to paradoxically trigger a chronic cyclic vomiting syndrome (i.e. hyperemesis) (see section 7.6.1 for further details on this syndrome).

Pre-clinical studies

Patient claims that smoked cannabis relieves CINV are widely recognized, and increasing evidence suggests a role for the endocannabinoid system in the regulation of nausea and vomitingFootnote 88. Cannabinoid CB1 and CB2 receptors have been found in areas of the brainstem associated with emetogenic controlFootnote 368,Footnote 369, and results from animal studies suggest the anti-nausea and anti-emetic properties of cannabinoids (e.g. Δ9-THC, dronabinol, nabilone) are most likely related to their agonistic actions at CB1 receptorsFootnote 80,Footnote 88,Footnote 370. An in vivo animal study and one small clinical study have also suggested Δ8-THC to be a more potent anti-emetic than Δ9-THCFootnote 80,Footnote 81. In addition to its actions at CB1 receptors, an in vitro study has also shown that Δ9-THC antagonizes the 5-HT3 receptorFootnote 371, a target of standard anti-emetic drugs, raising the possibility that cannabinoids may exert their anti-emetic action through more than one mechanism. More recently, studies carried out in animal models of nausea and vomiting have shown that cannabidiol (5 mg/kg, s.c.) suppressed nicotine, lithium chloride, and cisplatin-induced vomiting in the shrew; lithium chloride-induced conditioned gaping was suppressed in rats through a yet-to-be identified, but probably indirect, activation of somatodendritic 5-HT1A autoreceptors located in the dorsal raphe nucleusFootnote 372. Another study showed that the anti-nausea/vomiting effects of cannabidiol could be reversed by pre-treatment with cannabigerol (5 mg/kg, i.p.)Footnote 373.

Clinical studies

The evidence for cannabinoids such as nabilone (Cesamet®), dronabinol (Marinol®), and levonantradol in treating CINV has been reviewedFootnote 159,Footnote 374. While cannabinoids present clear advantages over placebo in the control of CINV, the evidence from randomized clinical trials shows cannabinoids to be clinically only slightly better than conventional dopamine D2-receptor antagonist anti-emeticsFootnote 159,Footnote 374. In some cases, patients appeared to prefer the cannabinoids over these conventional therapies despite the increased incidence of adverse effects such as drowsiness, dizziness, dysphoria, depression, hallucinations, paranoia, and arterial hypotension. This may be explained in part by the notion that for certain patients a degree of sedation and euphoria may be perceived as beneficial during chemotherapy.

While no peer-reviewed clinical trials of smoked cannabis for the treatment of CINV exist, Musty and Rossi have published a review of U.S. state clinical trials on the subjectFootnote 191. Patients who smoked cannabis showed a 70 - 100% relief from nausea and vomiting, while those who used a Δ9-THC capsule experienced 76 - 88% reliefFootnote 191. Plasma levels of > 10 ng/mL Δ9-THC were associated with the greatest suppression of nausea and vomiting, although levels ranging between 5 and 10 ng/mL were also effectiveFootnote 191. In all cases, patients were admitted only after they failed treatment with standard phenothiazine anti-emetics. A small clinical trial comparing smoked cannabis (2.11% Δ9-THC, in doses of 8.4 mg or 16.9 mg Δ9-THC; 0.30% cannabinol; 0.05% cannabidiol) to ondansetron (8 mg) in ipecac-induced nausea and vomiting in healthy volunteers showed that both doses of Δ9-THC reduced subjective ratings of queasiness and objective measures of vomiting; however, the effects were very modest compared to ondansetronFootnote 192. Furthermore, only cannabis produced changes in mood and subjective state.

Few, if any, clinical trials directly comparing cannabinoids to newer anti-emetics such as 5-HT3 (Ondansetron, Granisetron) or NK-1 receptor antagonists have been reported to dateFootnote 367,Footnote 374. In one clinical study with a small sample size, ondansetron and dronabinol (2.5 mg Δ9-THC first day, 10 mg second day, 10 - 20 mg thereafter) provided equal relief of delayed CINV, and the combination of dronabinol and ondansetron did not provide added benefit beyond that observed with either agent aloneFootnote 375. However, two animal studies showed that low doses of Δ9-THC, when combined with low doses of the 5-HT3 receptor antagonists ondansetron or tropisetron, were more efficacious in reducing nausea and emesis frequency than when administered individuallyFootnote 376,Footnote 377. More research is required to determine if combination therapy provides added benefits above those observed with newer standard treatments.

The use of cannabinoids (whether administered orally or by smoking cannabis) is currently considered a fourth-line adjunctive therapy in CINV when conventional anti-emetic therapies have failedFootnote 285,Footnote 378,Footnote 379,Footnote 380,Footnote 381,Footnote 382. Nabilone (Cesamet®) and dronabinol (Marinol®) are indicated for the management of severe nausea and vomiting associated with cancer chemotherapyFootnote 174,Footnote 332. Nabilone may be administered orally every 12 h at dosages ranging from 1 - 2 mg, whereas dronabinol may be administered every 6 - 8 h orally, rectally, or sub-lingually at doses ranging from 5 - 10 mgFootnote 208,Footnote 383.

The current Marihuana Medical Access Regulations (MMAR) allow the use of dried marihuana in the context of cancer chemotherapy-associated nausea and vomiting as well as nausea and vomiting associated with HIV/AIDS infection in patients who have either not benefited from, or would not be considered to benefit from, conventional treatmentsFootnote 384.

4.3 Wasting syndrome (cachexia, e.g., from tissue injury by infection or tumour) and loss of appetite (anorexia) in AIDS and cancer patients, and anorexia nervosa

The ability of cannabis to increase appetite has been recognized anecdotally for many yearsFootnote 206. In addition, results from epidemiological studies suggest that people actively using cannabis have higher intakes of energy and nutrients than non-usersFootnote 385. Controlled laboratory studies with healthy subjects suggest exposure to cannabis, whether by inhalation or oral ingestion of Δ9-THC-containing capsules, correlates positively with an increase in food consumption, caloric intake, and body weightFootnote 205,Footnote 206. Studies showing a high concentration of CB1 receptors in brain areas associated with control of food intake and satiety lend further support to the link between cannabis consumption and appetite regulationFootnote 386,Footnote 387,Footnote 388. Furthermore, increasing evidence suggests a role for the endocannabinoid system not only in modulating appetite, food palatability, and intake, but also in energy metabolism and the modulation of both lipid and glucose metabolism (reviewed inFootnote 17,Footnote 387,Footnote 388,Footnote 389).

4.3.1 To stimulate appetite and produce weight gain in AIDS patients

The ability of cannabis to stimulate appetite and food intake has been applied to clinical situations where weight gain is deemed beneficial such as in HIV-associated muscle wasting and weight loss. One studyFootnote 166 showed that experienced HIV+ cannabis smokers with clinically significant muscle mass loss benefited from both dronabinol (four to eight times the standard 2.5 mg Δ9-THC b.i.d. dose, or 10 - 20 mg Δ9-THC daily, three times per week for a total of eight sessions) and smoked cannabis (three puffs at 40 sec intervals; ~800 mg cigarettes containing 1.8 - 3.9% THC giving an estimated total daily amount of 14.4 mg - 31.2 mg THC in the cigarette, three times per week, for a total of eight study sessions). A subsequent study employed even higher doses of dronabinol (20 - 40 mg total Δ9-THC daily, for a total of four days) and smoked cannabis (~800 mg cannabis cigarettes containing 2 and 3.0% THC, administered four times per day, giving an estimated 64 - 125 mg total Δ9-THC daily in the cigarette, for a total of four days)Footnote 167. Both drugs produced substantial and comparable increases in food intake and body weight, as well as improvements in mood and sleepFootnote 166,Footnote 167. The cannabis-associated increase in body weight appeared to result from an increase in body fat rather than lean muscle massFootnote 390,Footnote 391. On the other hand, a randomized, open-label, multi-center study to assess the safety and pharmacokinetics of dronabinol and megestrol acetate (an orexigenic), alone or in combination, found that only the high-dose megestrol acetate treatment alone (750 mg/day), but not dronabinol (2.5 mg b.i.d, 5 mg total Δ9-THC/day) alone or the combination of low-dose megestrol acetate (250 mg/day) and dronabinol (2.5 mg b.i.d, 5 mg total Δ9-THC/day), produced a significant increase in mean weight over 12 weeks of treatment in patients diagnosed with HIV-associated wasting syndromeFootnote 392. The lack of an observed clinical effect in this study could have been caused by too low a dose of dronabinol.

AIDS-related anorexia associated with weight loss is an approved indication in Canada for dronabinol (Marinol®). The Marinol® product monograph summarizes a six-week, randomized, double-blind, placebo controlled-trial in 139 patients, with the 72 patients in the treatment group initially receiving 2.5 mg dronabinol twice a day, then reducing the dose to 2.5 mg at bedtime due to side effects (feeling high, dizziness, confusion and somnolence) Footnote 393. Over the treatment period, dronabinol significantly increased appetite, with a trend towards improved bodyweight and mood and a decrease in nausea. At the end of the six-week period, patients were allowed to continue receiving dronabinol, during which appetite continued to improveFootnote 394. This secondary, open-label, 12 month follow-up study suggested that dronabinol was safe and effective for long-term use for the treatment of anorexia associated with weight loss in patients with AIDSFootnote 394. The use of higher doses of dronabinol (20 mg - 40 mg per day) has been reported both in the Marinol® product monographFootnote 174 as well as in the literatureFootnote 166,Footnote 167. However, caution should be exercised in escalating dosage because of the increased frequency of dose-related adverse effects.

The current Marihuana Medical Access Regulations (MMAR) allow the use of dried marihuana in the context of HIV/AIDS-associated anorexia, cachexia, and weight loss in patients who have either not benefited from, or would not be considered to benefit from, conventional treatmentsFootnote 384.

4.3.2 To stimulate appetite and produce weight gain in cancer patients

Anorexia is ranked as one of the more troublesome symptoms associated with cancer, with more than half of patients with advanced cancer experiencing a lack of appetite and/or weight lossFootnote 395,Footnote 396. While it is anecdotally known that smoking cannabis can stimulate appetite, the effects of smoking cannabis on appetite and weight gain in patients with cancer cachexia have not been studied. The results from trials with oral Δ9-THC (dronabinol) or oral cannabis extract are mixed and the effects, if any, appear to be modest. In two early studies, oral THC (dronabinol) improved appetite and food intake in some patients undergoing cancer chemotherapyFootnote 397,Footnote 398. An open-label study of dronabinol (2.5 mg Δ9-THC, two to three times daily, four to six weeks) in patients with unresectable or advanced cancer reported increases in appetite and food intake, but weight gain was only achieved in a few patientsFootnote 399,Footnote 400. Modest weight gain was obtained with a larger dosing regimen of dronabinol (5 mg t.i.d.), but the CNS side effects including dizziness and somnolence were limiting factorsFootnote 401. In contrast, a randomized, double-blind, placebo-controlled study involving cancer patients with related anorexia-cachexia syndrome failed to demonstrate any differences in patients' appetite across treatment categories (oral cannabis extract, Δ9-THC, or placebo)Footnote 363. Furthermore, when compared to megestrol acetate, an orexigenic medication, dronabinol was significantly less efficacious in reported appetite improvement and weight gainFootnote 402. According to a recent review of the medical management of cancer cachexia, the current level of evidence for cannabinoids (e.g. dronabinol) in the treatment of this condition is lowFootnote 403.

A two-centre, phase II, randomized, double-blind, placebo-controlled, 22-day pilot study carried out in adult patients suffering from advanced cancer reported improved and enhanced chemosensory perception among patients treated with dronabinol (2.5 mg Δ9-THC b.i.d.) compared to those receiving placeboFootnote 362. The majority (73%) of dronabinol-treated patients self-reported an increased overall appreciation of food compared to those receiving placebo (30%). Similarly, the majority of dronabinol-treated patients (64%) reported increased appetite, whereas the majority of patients receiving placebo reported either decreased appetite (50%) or no change (20%). Total caloric intake per kilogram body weight did not differ significantly between treatment groups but did increase in both groups compared to baseline. Furthermore, compared to placebo, dronabinol-treated patients reported an increase in their protein intake as a proportion of total energy. According to the study authors, negative psychoactive effects were minimized by starting patients at a low dose (2.5 mg Δ9-THC once a day, for three days) followed by gradual dose escalation (up to a maximum of 7.5 mg dronabinol per day)Footnote 362.

Cancer cachexia is not an approved indication for dronabinol either in Canada or the U.S. The current Marihuana Medical Access Regulations (MMAR) allow the use of dried marihuana in the context of anorexia, cachexia and weight loss associated with cancer in patients who have either not benefited from, or would not be considered to benefit from, conventional treatmentsFootnote 384.

4.3.3 Anorexia nervosa

The endocannabinoid system has been implicated in appetite regulation and is suspected to play a role in eating disorders such as anorexia nervosaFootnote 387,Footnote 404. However, genetic studies have thus far failed to agree on an association between genes coding for endocannabinoid system proteins and the manifestation of anorexia nervosa, in spite of epidemiological and familial studies which suggest a genetic basis for this disorderFootnote 405,Footnote 406.

Little information exists on the use of cannabinoids to treat anorexia nervosa. Inter- and intra-species differences in animals with respect to anorexia nervosa-like behaviour have to some extent hampered research on the effects of Δ9-THC in this disorder. One study in a mouse model of anorexia nervosa reported conflicting resultsFootnote 407, while another study in a rat model reported a significant attenuation in weight loss only at high doses of Δ9-THC (2.0 mg/kg/day Δ9-THC)Footnote 408. A small, randomized, crossover trial of oral THC in female anorexic patients suggested that Δ9-THC produced a weight gain equivalent to the active placebo (diazepam)Footnote 409. Δ9-THC was administered in daily doses increasing from 7.5 mg (2.5 mg, t.i.d.) to a maximum of 30 mg (10 mg, t.i.d.), 90 min before meals, for a period of two weeks. Three of the eleven patients administered Δ9-THC also reported severe dysphoric reactions, withdrawing from the study. Another small clinical study of 15 patients with dementia of the Alzheimer-type reported increases in body weight, but no change in caloric intake with dronabinol (2.5 mg Δ9-THC, b.i.d.) compared to placeboFootnote 410. However, the study suffered from a number of limitations and the results should be interpreted with caution. No studies have examined the effects of smoking cannabis on anorexia nervosa. Both the British Medical AssociationFootnote 115 and the Institute of MedicineFootnote 378 concluded that cannabis was unlikely to be effective in patients with anorexia nervosa; however, further research may be warranted.

4.4 Multiple sclerosis, amyotrophic lateral sclerosis, spinal cord injury

Anecdotal reports suggest cannabis can ameliorate spasticity in patients suffering from multiple sclerosis or spinal cord injury when other drugs fail or produce unacceptable side effectsFootnote 115,Footnote 378,Footnote 411,Footnote 412,Footnote 413.

4.4.1 Multiple sclerosis

A number of studies, both in patients suffering from multiple sclerosis (MS) and in animal models of the disease, suggest the disorder is associated with changes in endocannabinoid levels, although the findings are conflicting Footnote 414,Footnote 415,Footnote 416,Footnote 417.

Pre-clinical studies

Pre-clinical studies across different animal species suggest cannabinoids improve the signs of motor dysfunction in experimental models of MS (reviewed inFootnote 418). Lyman was one of the first to report the effects of Δ9-THC in one such modelFootnote 419. In that study, affected animals treated with Δ9-THC either had no clinical signs of the disorder or showed mild clinical signs with delayed onsetFootnote 419. The treated animals also typically had a marked reduction in central nervous system tissue inflammation compared to untreated animalsFootnote 419. Subsequent studies in murine models of MS have supported and extended these findings demonstrating that Δ9-THC, but not cannabidiol, ameliorated both tremor and spasticity and reduced the overall clinical severity of the diseaseFootnote 414,Footnote 420. Further work highlighted the importance of the CB1 receptor in controlling tremor, spasticity, and the neuroinflammatory response. In contrast, the exact function of the CB2 receptor in MS remains somewhat unclear, although it is believed to play a role in regulating the neuroinflammatory responseFootnote 420,Footnote 421,Footnote 422. Although a large body of evidence suggests cannabinoids exert immunosuppressive effects, which could be beneficial in diseases such as MS, much of this information comes from pre-clinical studies where the levels of exogenous cannabinoids given to animals would likely exceed those typically administered to patientsFootnote 422. Therefore it is believed that the beneficial effects of cannabinoids are more likely to come from their neuroprotective properties rather than their immunosuppressive characteristicsFootnote 422,Footnote 423,Footnote 424.

Historical and survey data

In humans, published reports spanning 100 years suggest that people with spasticity (one of the symptoms associated with MS) may experience relief with cannabisFootnote 425. In the UK, 43% of patients with MS reported having experimented with cannabis at some point, and 68% of this population used it to alleviate the symptoms of MSFootnote 426. In Canada, the prevalence of medicinal use of cannabis among patients seeking treatment for MS, in the year 2000, was reported to be 16% in Alberta, with 43% of study respondents stating they had used cannabis at some point in their livesFootnote 164. Fourteen percent of people with MS surveyed in the year 2002 in Nova Scotia reported using cannabis for medical purposes, with 36% reporting ever having used cannabis for any purposeFootnote 165. MS patients reported using cannabis to manage symptoms such as spasticity and chronic pain as well as anxiety and/or depressionFootnote 164,Footnote 165. MS patients also reported improvements in sleep. Reputed dosages of smoked cannabis by these patients varied from a few puffs to 1 g or more at a timeFootnote 165.

Clinical studies with orally administered cannabinoid medications (cannabis extract, oral THC, nabiximols)

The results of randomized, placebo-controlled trials with orally administered cannabinoids for the treatment of muscle spasticity in MS are encouraging, but modest.

The large, multi-centre, randomized, placebo-controlled CAMS (CAnnabis in Multiple Sclerosis) study researching the effect of cannabinoids for the treatment of spasticity and other symptoms related to MS enrolled over 600 patientsFootnote 262. The primary outcome was change in overall spasticity scores measured using the Ashworth scale. The study did not show any statistically significant improvement in the Ashworth score in patients taking either an oral cannabis extract (("Cannador") containing 2.5 mg Δ9-THC, 1.25 mg CBD, and < 5% other cannabinoids), or oral Δ9-THC, for 15 weeks. However, there was evidence of a significant treatment effect on subjective, patient-reported spasticity and pain, with improvement in spasticity using either orally administered cannabis extract (61%) (Dosing: 5 - 25 mg Δ9-THC; 5 - 15 mg CBD/day; and < 5% other cannabinoids, adjusted to body weight and titrated according to side effects) or oral Δ9-THC (60%) (Dosing: 10 - 25 mg Δ9-THC/day, adjusted to body weight and titrated according to side effects) compared to placebo (46%). Patients were concomitantly taking other medications to manage MS-associated symptoms. In contrast, a longterm (12 months), double-blind, follow-up to the CAMS study showed evidence of a small treatment effect of oral Δ9-THC (Dosing: 5 - 25 mg Δ9-THC/day, adjusted to body weight and titrated according to side effects) on muscle spasticity measured by objective methods, whereas a subjective treatment effect on muscle spasticity was observed for both oral Δ9-THC and oral cannabis extract ("Cannador")Footnote 427.

Other randomized clinical trials using standardized cannabis extract capsules (containing 2.5 mg Δ9-THC and 0.9 mg CBD per capsule)Footnote 428 or nabiximols (Sativex®)Footnote 291,Footnote 429,Footnote 430 reported similar results, in that improvements were only seen in patient self-reports of symptoms but not with objective measures (e.g. Ashworth scale). The reasons behind the apparent discrepancies between subjective and objective measures are not clear; however, a number of possible explanations may be found to account for the differences. For example, it is known that spasticity is a complex phenomenonFootnote 431 and is affected by patient symptoms, physical functioning, and psychological dispositionFootnote 427. Spasticity is also inherently difficult to measure, and has no single defining featureFootnote 430. In addition, the reliability and sensitivity of the Ashworth scale (for objectively measuring spasticity) has been called into questionFootnote 262,Footnote 430.

The efficacy, safety, and tolerability of a whole-plant cannabis extract administered in capsules (2.5 mg THC and 0.9 mg CBD/capsule) were studied in a fourteen-day, prospective, randomized, double-blind, placebo-controlled crossover trial in patients with clinically stable MS-associated spasticity and an Ashworth score greater than 2Footnote 428. Slightly more than half of the study subjects had a maintenance dose of 20 mg/day of THC or more (maximum of 30 mg THC/day). Patients were concomitantly taking anti-spasticity medications. Many study subjects had had previous experience with cannabis; a significant number of those who withdrew from the study upon starting treatment with the cannabis extract did not have previous experience with cannabis. While there were no statistically significant differences between active treatment with the cannabis extract and placebo, trends in favour of active treatment were observed for mobility, self-reported spasm frequency, and ability in getting to sleepFootnote 428. The cannabis extract was generally well tolerated with no serious adverse events during the study period. However, adverse events were slightly more frequent and more severe during the active treatment period.

A six-week, multi-centre, randomized, double-blind, placebo-controlled, parallel-group study of nabiximols (Sativex®) for the treatment of five primary symptoms associated with MS (spasticity, spasm frequency, bladder problems, tremor, and pain) reported mixed resultsFootnote 291. Patients had clinically confirmed, stable MS of any type, and were on a stable medication regimen. Approximately half of the study subjects in either the active or placebo groups had previous experience with cannabis, either recreationally or for medical purposes. While the global primary symptom score (PSS), which combined the scores for all five symptoms, was not significantly different between the active treatment group and the placebo group, patients taking cannabis extract showed statistically significant differences compared to placebo in subjective, but not objective measures of spasticity (i.e. Ashworth Score), in Guy's Neurological Disability Score (GNDS), and in quality of sleep, but not in spasm frequency, pain, tremor, or bladder problems among other outcome measuresFootnote 291. Patients self-titrated to an average daily maintenance dose of nabiximols of 40.5 mg THC and 37.5 mg CBD (i.e. ~15 sprays/day). Adverse effects associated with active treatment included dizziness, disturbance in attention, fatigue, disorientation, feeling drunk, and vertigoFootnote 291.

A long-term, open-label, follow-up study of nabiximols (Sativex®) concluded that the beneficial effect observed in the study by Wade et al. 2004Footnote 291 was maintained in patients who had initially benefited from the drugFootnote 429. The mean duration of study participation in subjects who entered the follow-up study was 434 days (range: 21 - 814 days). The average number of daily doses taken by the subjects remained constant or was slightly reduced over time. The average number of daily doses of nabiximols was 11, corresponding to a dose of 30 mg THC and 28 mg CBD/dayFootnote 429. Long-term use of nabiximols in this patient population was associated with reductions in subjective measures of spasticity, spasm frequency, pain, and bladder problemsFootnote 429. Dizziness, diarrhea, nausea, fatigue, headache, and somnolence were among the most frequently reported adverse effects associated with chronic nabiximols use in this study. A two-week withdrawal study, incorporated into the long-term follow-up study, suggested that cessation of nabiximols use was not associated with a consistent withdrawal syndrome but it was associated with withdrawal-type symptoms (e.g. interrupted sleep, hot/cold flushes, fatigue, low mood, decreased appetite, emotional lability, vivid dreams, intoxication) as well as re-emergence/worsening of some MS symptomsFootnote 429.

The efficacy, safety and tolerability of nabiximols in MS were investigated in a six-week, multi-centre, phase III, double-blind, randomized, parallel-group clinical study in patients with stable MS who had failed to gain adequate relief using standard therapeutic approachesFootnote 430. Patients had to have significant spasticity in at least two muscle groups, and an Ashworth score of 2 or more. A significant number of patients had previous experience with cannabis. Forty percent of subjects assigned treatment with nabiximols showed a ≥ 30% reduction in self-reported spasticity using an 11-point subjective numerical rating spasticity scale (NRS) compared to subjects assigned to placebo (21.9%) (difference in favour of nabiximols = 18%; 95% Confidence Interval = 4.73, 31.52; p = 0.014). Mean number of sprays per day was 9.4 ±6.4 (~25 mg THC and ~24 mg CBD)Footnote 430. Subjects on placebo or nabiximols exhibited similar incidences of adverse effects, but adverse CNS effects were more common with the nabiximols groupFootnote 430. The majority of adverse events were of mild or moderate severity (e.g. dizziness, fatigue, depressed mood, disorientation, dysgeusia, disturbance in attention, blurred vision).

Nabiximols (Sativex®), an oro-mucosal spray containing 27 mg/mL of Δ9-THC and 25 mg/mL CBD, is currently marketed in Canada as an adjunctive treatment for the symptomatic relief of spasticity in adult patients with MS who have not responded adequately to other therapy and who demonstrate meaningful improvement during an initial trial of therapy. It is also marketed (with conditions) as an adjunctive treatment for the symptomatic relief of neuropathic pain in adults with MS.

CUPID and MUSEC clinical studies

The CUPID (Cannabinoid Use in Progressive Inflammatory Brain Disease) study was a randomized, double-blind, clinical investigation designed to measure whether orally administered Δ9-THC was able to slow the progression of MS (Next link will take you to another Web site sites.pcmd.ac.uk/cnrg/cupid.php). This three-year publicly-funded trial took place at the Peninsula Medical School in the U.K. and followed the earlier, one-year long, CAMS study. A total of 493 subjects with primary or secondary progressive, but not relapse-remitting, MS had been recruited from across the U.K. in 2006 and preliminary results were recently made public (Next link will take you to another Web site sites.pcmd.ac.uk/cnrg/files/cupid/CUPID_results_press_release_web.pdf). The CUPID trial found no evidence to support an effect of Δ9-THC on MS progression, as measured by using either the Expanded Disability Status Scale or the Multiple Sclerosis Impact Scale 29 (MSIS-29). However, the authors concluded that there was some evidence to suggest a beneficial effect in participants who were at the lower end of the disability scale at the time of patient enrolment. Since the observed benefit only occurred in a small sub-group of patients, further studies would be required to more closely examine the reasons for this selective effect.

A double-blind, placebo-controlled, phase III study (the MUltiple Sclerosis and Extract of Cannabis trial--i.e. "MUSEC") published by the same group of researchers that conducted the CUPID trial, reported that a twelve-week treatment with an oral cannabis extract ("Cannador") (2.5 mg Δ9-THC and 0.9 mg CBD/capsule) was associated with a statistically significant relief in patient-reported muscle stiffness, muscle spasms, and body pain as well as a statistically significant improvement in sleep compared to placebo, in patients with stable MSFootnote 432. There were no statistically significant differences between cannabis extract and placebo on functional measures such as those examining the effect of spasticity on activities of daily living, ability to walk, or on social functioningFootnote 432. The majority of the patients using cannabis extract used total daily doses of 10, 15, or 25 mg of Δ9-THC with corresponding doses of 3.6, 5.4, and 9 mg of CBD. The majority of the study subjects were concomitantly using analgesics and anti-spasticity medications, but were excluded if they were using immunomodulatory medications (e.g. interferons). Active treatment with the extract was associated with an increase in the number of adverse events, but the majority of these were considered to be mild to moderate and did not persist beyond the study periodFootnote 432. The highest number of adverse events were observed during the initial two-week titration period and appeared to decrease progressively over the course of the remaining treatment sessionsFootnote 432. The most commonly observed adverse events were those associated with disturbances in CNS function (e.g. dizziness, disturbance in attention, balance disorder, somnolence, feeling abnormal, disorientation, confusion, and falls). Disturbances in gastrointestinal function were the second most commonly occurring adverse events (e.g. nausea, dry mouth).

Clinical studies with smoked cannabis

There has only been one clinical study so far using smoked cannabis for symptoms associated with MSFootnote 188. The study, a double-blind, placebo-controlled, crossover trial reported a statistically significant reduction in patient scores on the modified Ashworth scale for measuring spasticity after patients smoked cannabis once daily for three days (each cigarette contained 800 mg of 4% Δ9-THC; total available Δ9-THC dose of 32 mg per cigarette)Footnote 188. Smoking cannabis was also associated with a statistically significant reduction in patient scores on the visual analog scale for pain, although patients reportedly had low levels of pain to begin withFootnote 188. No differences between placebo and cannabis were observed in the timed-walk task, a measure of physical performanceFootnote 188. Cognitive function, as assessed by the Paced Auditory Serial Addition Test (PASAT), appeared to be significantly decreased immediately following administration of cannabis; however, the long-term clinical significance of this finding was not examined in this studyFootnote 188. The majority of patients (70%) were on disease-modifying therapy (e.g. interferon β-1a, interferon β-1b, or glatiramer), and 60% were taking anti-spasticity agents (e.g. baclofen or tizanidine). Cannabis treatment was associated with a number of different, but commonly observed adverse effects including dizziness, headache, fatigue, nausea, feeling "too high", and throat irritationFootnote 188. Study limitations included the fact that the majority of patients had prior experience with cannabis, and that the study was unblinded since most of the patients were able to tell apart the placebo from the active treatment with cannabisFootnote 188.

The current Marihuana Medical Access Regulations (MMAR) allow the use of dried marihuana in the context of severe pain and persistent muscle spasms associated with MS in patients who have either not benefited from, or would not be considered to benefit from, conventional treatmentsFootnote 384.

Generally speaking, orally administered prescription cannabinoids (e.g. dronabinol, nabilone, nabiximols) are reported to be well tolerated in patients with MSFootnote 428,Footnote 433,Footnote 434. Clinical trials to date do not indicate serious adverse effects associated with the use of these prescription cannabinoid medications. However, there appears to be an increase in the number of non-serious adverse effects associated with the short-term use of cannabinoidsFootnote 4. The most commonly reported short-term physical adverse effects are dizziness, drowsiness, and dry mouthFootnote 262,Footnote 434. Prolonged use of ingested or inhaled cannabis was associated with poorer performance on various cognitive domains (information processing speed, working memory, executive function, and visuospatial perception) in patients with MS according to one cross-sectional studyFootnote 178. In contrast, another study concluded that nabiximols (Sativex®) treatment, in cannabis-naïve MS patients, was not associated with cognitive impairmentFootnote 434. However, the study did raise the possibility that higher dosages could precipitate changes in psychological disposition, especially in those patients with a prior history of psychosis. In any case, important information is generally lacking regarding the long-term adverse effects of chronic cannabinoid use for therapeutic purposes.

Bladder dysfunction associated with multiple sclerosis or spinal cord injury

Bladder dysfunction occurs in most patients suffering from multiple sclerosis (MS) or spinal cord injuryFootnote 435. The most common complaints are increased urinary frequency, urgency, urge, and reflex incontinenceFootnote 436. Cannabinoid receptors are expressed in human bladder detrusor and urotheliumFootnote 35,Footnote 36, and may help regulate detrusor tone and bladder contraction as well as affecting bladder nociceptive response pathways (reviewed inFootnote 36).

A survey of MS patients regularly using cannabis for symptomatic relief of urinary problems reported that over half of these patients claimed improvement in urinary urgencyFootnote 437. A sixteen-week, open-label, pilot study of cannabis-based extracts (a course of Sativex® treatment followed by maintenance with 2.5 mg Δ9-THC only) for bladder dysfunction, in 15 patients with advanced MS, reported significant decreases in urinary urgency, number and volume of incontinence episodes, frequency, and nocturiaFootnote 438. Improvements were also noted in patient self-assessments of pain and quality of sleep. A subsequent randomized controlled trial of 250 MS patients suggested a clinical effect of orally administered cannabinoids (2.5 mg Δ9-THC or 1.25 mg cannabidiol (CBD) with < 5% other cannabinoids per capsule, up to a maximum 25 mg/day) on incontinence episodesFootnote 435.

4.4.2 Amyotrophic lateral sclerosis

There is some pre-clinical evidence implicating the endocannabinoid system in the progression of an amyotrophic lateral sclerosis (ALS)-like disease in mouse models of the disorder, and under certain conditions cannabinoids have been reported to modestly delay disease progression and prolong survival in these animal models (reviewed inFootnote 439 and inFootnote 440). Anecdotal reports suggest decreased muscle cramps and fasciculations in ALS patients who smoked herbal cannabis or drank cannabis tea, with up to 10% of these patients using cannabis for symptom controlFootnote 441,Footnote 442. Only two clinical trials of cannabis for the treatment of symptoms associated with ALS exist, and the results of the studies are mixed. In one four-week, randomized, double-blind, crossover pilot study of 19 ALS patients, doses of 2.5 - 10 mg per day of dronabinol (Δ9-THC) were associated with improvements in sleep and appetite, but not cramps or fasciculationsFootnote 443. In contrast, a shorter two-week study reported no improvement in these measures in ALS patients taking 10 mg of dronabinol per dayFootnote 442. In either case, dronabinol was well tolerated with few reported side effects in this patient population at the tested dosages.

4.4.3 Spinal cord injury (or spinal cord disease)

Pre-clinical animal studies suggest that spinal cord injury triggers changes in the activity of the endocannabinoid system, and that cannabinoid receptor agonists may alleviate neuropathic pain associated with spinal cord injury Footnote 444,Footnote 445,Footnote 446. However, limited clinical information exists regarding the use of cannabinoids to treat symptoms associated with spinal cord injury such as pain, spasticity, muscle spasms, urinary incontinence, and difficulties sleeping. No clinical trials of smoked cannabis for the treatment of these symptoms have been documented, but subjective improvements have been anecdotally reported by patients smoking cannabisFootnote 378,Footnote 447. Double-blind, crossover, placebo-controlled studies of oral Δ9-THC and/or Δ9-THC : CBD extract (Sativex®) suggested modest improvements in pain, spasticity, muscle spasms, and sleep quality in patients with spinal cord injuryFootnote 378,Footnote 448,Footnote 449. A randomized, double-blind, placebo-controlled parallel study using a minimum of 15 - 20 mg Δ9-THC/day (mean daily doses of 31 mg Δ9-THC orally, or 43 mg Δ9-THC-hemisuccinate rectally) showed a statistically significant improvement in spasticity scores in patients with spinal cord injuryFootnote 450. A more recent double-blind, placebo-controlled, crossover study using nabilone (0.5 mg b.i.d.) also showed an improvement in spasticity compared to placebo in patients with spinal cord injuryFootnote 451.

The current Marihuana Medical Access Regulations (MMAR) allow the use of dried marihuana in the context of severe pain and persistent muscle spasms associated with spinal cord injury or spinal cord disease in patients who have either not benefited from, or would not be considered to benefit from, conventional treatmentsFootnote 384.

4.5 Epilepsy

Increasing evidence points to a role for the endocannabinoid system in the modulation of neuronal tone and excitability, and possibly in epilepsy. Human and animal studies suggest epileptic activity is associated with changes in the levels and distribution of CB1 receptors in the hippocampusFootnote 452,Footnote 453,Footnote 454. Reduced levels of the endocannabinoid anandamide have been detected in the cerebrospinal fluid of patients with untreated, newly diagnosed, temporal lobe epilepsyFootnote 455.

Pre-clinical studies

In vitro studies, as well as those carried out in animals, generally suggest an anti-convulsant role for cannabinoidsFootnote 91,Footnote 456,Footnote 457,Footnote 458,Footnote 459. However, a pro-convulsant role has also been describedFootnote 91,Footnote 460. CB1 receptors are located mainly pre-synaptically where they typically inhibit the release of classical neurotransmittersFootnote 461. The purported anti-epileptic effect of cannabinoids is thought to be mediated by CB1-receptor dependent pre-synaptic inhibition of glutamate releaseFootnote 453,Footnote 462; on the other hand, epileptogenic effects may be triggered by pre-synaptic inhibition of GABA releaseFootnote 456,Footnote 457,Footnote 459,Footnote 463,Footnote 464. CB1 receptor agonists therefore have the potential to trigger or suppress epileptiform activity depending upon which cannabinoid-sensitive pre-synaptic terminals are preferentially affected (i.e. glutamatergic or GABAergic)Footnote 91,Footnote 462.

Clinical studies

A review of the literature describing the effects of cannabis on epileptic symptoms in humans concluded that although cannabis use can reduce seizure frequency in some cases and provoke seizures in others, in the majority of cases it probably has no effectFootnote 465. This may be caused by the rather unspecific actions of exogenously administered cannabinoids, such as Δ9-THC, which would target both excitatory and inhibitory neuronsFootnote 91. Cannabidiol (CBD) has also been examined as a potential anti-epileptic in humans (seeFootnote 466 for full review) but these early studies have not been followed up with larger and more convincing clinical trials. A recent Cochrane Collaboration review aimed at assessing the efficacy and safety of cannabinoids as monotherapy or add-on treatment for patients with epilepsy concluded that the available evidence is not sufficient to be able to draw reliable conclusions regarding the efficacy of cannabinoids as a treatment for epilepsyFootnote 467. While a dose of 200 - 300 mg of CBD could be safely administered to a small number of patients for a short period of time, the safety of long-term cannabidiol treatment could not be reliably assessedFootnote 467.

The current Marihuana Medical Access Regulations (MMAR) allow the use of dried marihuana in the context of epilepsy in patients who experience seizures and who have either not benefited from, or would not be considered to benefit from, conventional treatmentsFootnote 384.

4.6 Pain

It is now well established that the endocannabinoid system plays an important role in the modulation of pain states and that elements of the endocannabinoid system can be found at supraspinal, spinal, and peripheral levels of pain pathwaysFootnote 22,Footnote 468. The particular distribution of cannabinoid receptors provides an anatomical basis to explain some of the analgesic effects of cannabinoids, and a number of pre-clinical studies suggest a functional role for endocannabinoids (such as anandamide and 2-arachidonoylglycerol (i.e. 2-AG)) in suppressing pain under physiological conditionsFootnote 22.

Considerations and caveats

Animal vs. human studies

Pre-clinical studies in animals predict that cannabinoids should relieve both acute and chronic pain. However, results from both experimental models of pain in human volunteers and from clinical trials of patients suffering from pain instead suggest cannabinoids may be more effective for chronic rather than acute painFootnote 469,Footnote 470,Footnote 471. A number of possible explanations can exist to account for discrepancies between animal studies and human clinical trials. Such explanations include interspecies differences, differences in experimental stimuli and protocols used in the studies, and differences in the outcomes measured in the studies. Data from animal pain models are mostly based on observations of behavioural changes and cannabinoid doses sufficient to produce relevant anti-nociception in rodents are similar to those which cause other behavioural effects such as hypomotility and catatoniaFootnote 21,Footnote 472. This pharmacological overlap can make it difficult to distinguish between cannabinoid-associated anti-nociceptive effects and behavioural effectsFootnote 21,Footnote 472.

Experimental models of pain vs. chronic pain

Translation of research findings from human experimental models of pain (i.e. acute pain) to clinical pain is also complex and not straightforwardFootnote 185. In contrast to acute pain, chronic pain is a complex condition which involves interaction between sensory, affective, and cognitive componentsFootnote 185. Unlike acute pain, chronic pain is considered a disease and generally originates from prolonged acute pain which is not managed in a timely or effective mannerFootnote 473. Chronic pain also appears to involve distinct spatiotemporal neuronal mechanisms which differ from those recruited during acute, experimental painFootnote 474. Chronic pain involves altered neural transmission and long-term plasticity changes in the peripheral and central nervous systems which generate and maintain the chronic pain stateFootnote 473,Footnote 474. As such, it is difficult to compare studies of interventions for chronic pain with studies of experimentally-induced pain because of fundamental differences in the physiological state of the subjects, differences in the stimulus conditions and experimental protocols employed in the studies, and differences in the outcomes which are measuredFootnote 185.

Placebo effect

The placebo effect is another consideration to keep in mind when considering studies of cannabis/cannabinoids for the treatment of pain. The placebo effect, a psychobiological phenomenon, is perhaps more salient in disorders which have a more significant subjective or psychological component (e.g. pain, anxiety/depression), and may be somewhat less salient in diseases which have a more objective pathophysiological component (e.g. infectious diseases, cancer) Footnote 475,Footnote 476.

Patient/study subject population

Many, if not most, of the clinical trials of cannabinoids for the treatment of pain (and even other disorders such as multiple sclerosis) have recruited patients or volunteers who have had prior exposure or experience with cannabis or cannabinoids. This has raised the issue of unblinding because any study subjects having prior experience with cannabis or cannabinoids would be more likely to be able to distinguish active treatment with these drugs from the placebo controlFootnote 364. Furthermore, a number of clinical trials of cannabis/cannabinoids for the treatment of pain (or other disorders) have also used an "open-phase" period which eliminated subjects who would have either responded poorly to cannabinoids or who would have had greater chances of experiencing adverse effectsFootnote 48. The use of individuals with prior experience with cannabis or cannabinoids or the use of an "open-phase" period would increase the proportion of patients yielding results tending to overestimate some of the potential therapeutic benefits of cannabis/cannabinoids, while also tending to underestimate the extent or degree of adverse effects among the general patient populationFootnote 48,Footnote 364.

Other considerations

It is also perhaps worth mentioning that a number of clinical studies suggest the presence of a relatively narrow therapeutic window for cannabis and prescription cannabinoids in the treatment of painFootnote 21,Footnote 48,Footnote 50,Footnote 472. The well-known psychotropic and somatic side effects effects associated with the use of cannabis and cannabinoids (e.g. dronabinol, nabilone, nabiximols) are known to limit the general therapeutic utility of these drugs; it has therefore been suggested that it may be preferable to pursue therapies which focus on manipulation of the endocannabinoid system (e.g. by inhibiting the endocannabinoid-degrading enzymes FAAH or MAGL), or to combine low doses of cannabinoids with low doses of other analgesics in order to achieve the desired therapeutic effects while minimizing the incidence, frequency, and severity of the adverse effectsFootnote 21,Footnote 50.

With the above considerations and caveats in mind, the sections below summarize the results of studies examining the analgesic potential of cannabis or cannabinoids in pre-clinical and clinical models of experimentally-induced acute pain, as well as in clinical studies of chronic pain.

4.6.1. Acute Pain

4.6.1.1 Experimentally-induced acute pain
Pre-clinical studies

A number of pre-clinical studies suggest that anandamide, THC, and certain synthetic cannabinoids block pain responses in different animal models of acute pain (reviewed inFootnote 21,Footnote 472). Cannabinergic modulation of neuronal circuits in the brain and spinal cord can inhibit nociceptive processingFootnote 477,Footnote 478,Footnote 479,Footnote 480. However, despite the results obtained in pre-clinical studies, the results of studies using cannabis or cannabinoids (e.g. nabilone) to alleviate experimentally-induced acute pain in humans are mixed.

Clinical studies with smoked cannabis

An early study by Hill of 26 healthy male cannabis smokers failed to demonstrate an analgesic effect of smoked cannabis (1.4% Δ9-THC, 12 mg available Δ9-THC) in response to transcutaneous electrical stimulationFootnote 481. The study did, however, report an increase in sensory and pain sensitivity to the applied stimulus. In contrast, Milstein showed that smoked cannabis (1.3% Δ9-THC, 7.5 mg total available Δ9-THC) increased pain tolerance to a pressure stimulus in both healthy cannabis-naïve and cannabis-experienced subjects compared to placeboFootnote 482. Another study employing healthy cannabis smokers reported that smoking cannabis cigarettes (containing 3.55% Δ9-THC, or approximately 62 mg available Δ9-THC) was associated with a mild, dose-dependent, anti-nociceptive effect to a thermal heat stimulusFootnote 184. A more recent randomized, double-blind, placebo-controlled, crossover trial examined the effects of three different doses of smoked cannabis on intra-dermal capsaicin-induced pain and hyperalgesia in 15 healthy volunteersFootnote 185. Capsaicin was administered either 5 min or 45 min after smoking cannabis. Effects appeared to be dose and time dependent. No effect was observed 5 min after smoking, but analgesia was observed 45 min after smoking, and only with the medium dose of smoked cannabis (4% Δ9-THC by weight). A low dose (2% Δ9-THC by weight) had no effect. In contrast, a high dose (8% Δ9-THC by weight) was associated with significant hyperalgesia. This study identified a so-called "narrow therapeutic window"; a medium dose provided analgesic benefit, a high dose worsened the pain and was associated with additional adverse effects, and a low dose had no effect.

Clinical studies with oral THC and cannabis extract

A randomized, placebo-controlled, double-blind, crossover study of 12 healthy cannabis-naïve volunteers administered a single oral dose of 20 mg Δ9-THC reported a lack of a significant analgesic effect following exposure to a multi-model pain test battery (pressure, heat, cold, and transcutaneous electrical stimulation) Footnote 483. In addition, significant hyperalgesia was observed in the heat pain test. Psychotropic and somatic side effects were common and included anxiety, perceptual changes, hallucinations, strange thoughts, ideas and mood, confusion and disorientation, euphoria, nausea, headache, and dizziness. Another randomized, double-blind, active placebo-controlled, crossover study in 18 healthy female volunteers reported a lack of analgesia or anti-hyperalgesia with an oral cannabis extract containing 20 mg THC and 10 mg CBD (other plant cannabinoids were less than 5%) in two different experimental pain models (intra-dermal capsaicin or sunburn)Footnote 484. Side effects (sedation, nausea, and dizziness) were frequently observed. Hyperalgesia was also observed at the highest dose as in the study conducted by Wallace (above)Footnote 185.

Clinical studies with nabilone

A randomized, double-blind, placebo-controlled, crossover study of single oral doses of nabilone (0.5 mg or 1 mg) failed to show any analgesic effects during a tonic heat pain stimulusFootnote 485. However, an anti-hyperalgesic effect was observed at the highest administered dose, but only in female subjects. The authors noted a significant placebo effect and also suggested that the lack of an analgesic effect could have been attributed to the single-dose administration of the cannabinoid; a gradual dose escalation could have potentially revealed an effectFootnote 485. Similarly, a randomized, double-blind, placebo-controlled, crossover study in subjects receiving single oral doses of nabilone (1, 2, or 3 mg) failed to show any analgesic, or primary or secondary anti-hyperalgesic effects in response to capsaicin-induced pain in healthy male volunteersFootnote 355. Adverse effects of mild to moderate intensity were noted in the majority of subjects. Severe adverse reactions (e.g. dizziness, sedation, anxiety, agitation, euphoria, and perceptual and cognitive disturbances) were reported only at the highest administered dose (3 mg) in four subjects leading to their withdrawal from the study. Dose-dependent CNS effects were observed 1.5 - 6 h after dosing, reaching a maximum between 4 and 6 h after administration. A recent review suggests that there is little convincing evidence of a significant reduction in acute pain in human experimental or clinical studies of cannabinoidsFootnote 21.

4.6.1.2 Post-operative pain

Despite the introduction of new standards, guidelines, and educational efforts, data indicate that postoperative pain continues to be under or poorly managed and many of the drugs commonly used in this setting either lack sufficient efficacy or cause unacceptable side effectsFootnote 486,Footnote 487. To date, there are only four published reports on the use of cannabinoids in post-operative painFootnote 486,Footnote 488,Footnote 489,Footnote 490. The conclusions from these studies were that cannabinoids (THC, nabilone, or an oral cannabis extract containing a 2 : 1 ratio of THC to CBD) are not ideally suited to manage post-operative pain, being either moderately effectiveFootnote 486,Footnote 488, not different from placeboFootnote 489, or even anti-analgesic at high dosesFootnote 490. However, a definitive conclusion on the role of these cannabinoids in the post-operative setting cannot yet be made because of the different drugs, dosages, routes of administration, and protocols that were used in these studiesFootnote 491.

4.6.2 Chronic Pain

Acute pain that is poorly managed can lead to chronic painFootnote 492,Footnote 493. In contrast to acute pain, chronic pain is typically considered a far more complex condition which involves physical, psychological, and psychosocial factors, and which contributes to a reduced quality of lifeFootnote 494. The information below summarizes pre-clinical studies carried out in animal models of chronic pain, clinical studies in human subjects suffering from chronic pain of various etiologies, as well as some studies of experimentally-induced pain performed on patients.

4.6.2.1 Experimentally-induced pain

The anti-nociceptive efficacy of cannabinoids has been unequivocally demonstrated in several different animal models of inflammatory and neuropathic pain (reviewed inFootnote 495 and inFootnote 496). In addition, the findings from these studies suggest that modulation of the endocannabinoid system through administration of specific cannabinoid receptor agonists, or by elevation of endocannabinoid levels, suppresses hyperalgesia and allodynia induced by diverse neuropathic states (reviewed inFootnote 496). As such, similar to the situation with acute pain, pre-clinical studies of chronic pain in animal models suggest that endocannabinoids (anandamide and 2-AG), THC, and several synthetic cannabinoids have beneficial effects (reviewed inFootnote 21,Footnote 472,Footnote 496).

With respect to cannabidiol (CBD), while chronic oral administration of cannabidiol effectively decreased hyperalgesia in a rat model of inflammatory painFootnote 497, no such parallels have been found to date in humans. A more recent study suggested that a medium or a high dose of CBD attenuates tactile allodynia and thermal hypersensitivity in a mouse model of diabetic neuropathy, when administered early in the course of the disease; on the other hand there is little, if any, restorative effect if CBD is administered at a later time point Footnote 498. In contrast, nabilone was not as efficacious as CBD if administered early on, but appeared to have a small beneficial effect when administered later in the course of the diseaseFootnote 498. CBD also appeared to attenuate microgliosis in the ventral lumbar spinal cord, but only if administered early in the course of the disease, whereas nabilone had no effectFootnote 498.

There are no studies of experimentally-induced chronic pain in humans. However, in contrast to the mixed findings in human subjects exposed to acute painful stimuli, cannabinoids appear to have a more consistent beneficial profile for patients already suffering from chronic pain.

4.6.2.2 Neuropathic pain or chronic non-cancer pain

Short-term clinical studies suggest prescription cannabinoid medications (e.g. nabiximols, dronabinol, nabilone) are moderately effective in reducing intractable central or peripheral neuropathic pain of various etiologies in individuals already receiving analgesic drugsFootnote 499. Side effects appear to be comparable to existing treatments and typically include dizziness/lightheadedness, sedation, confusion, ataxia, a feeling of intoxication, euphoria ("high"), xerostomia, dysgeusia, and hungerFootnote 499,Footnote 500. These effects may be minimized by employing low doses of cannabinoids that are gradually escalated, as required. The following summarizes the existing clinical information on the use of cannabis and cannabinoids (THC, nabilone, dronabinol and nabiximols) to treat neuropathic and chronic non-cancer pain.

Clinical studies with smoked or vapourized cannabis

A randomized, double-blind, placebo-controlled, cross-over study of cannabis-experienced patients suffering from chronic neuropathic pain of various etiologies (complex regional pain syndrome, central neuropathic pain from spinal cord injury or multiple sclerosis, or peripheral neuropathic pain from diabetes or nerve injury) reported that administration of either a low dose or a high dose of smoked cannabis (3.5% Δ9-THC, 19 mg total available Δ9-THC; or 7% Δ9-THC, 34 mg total available Δ9-THC) was associated with significant equianalgesic decreases in central and peripheral neuropathic painFootnote 168. No analgesic effect was observed in tests of experimentally-induced pain (tactile or heat stimuli). Patients were taking other pain control medications during the trial such as opioids, anti-depressants, non-steroidal anti-inflammatory drugs, or anti-convulsants. Adverse effects associated with the use of cannabis appeared to be dose-dependent and included feeling "high", sedation, confusion, and neurocognitive impairment. Cognitive changes appeared to be more pronounced with higher doses of Δ9-THCFootnote 168.

In another randomized, placebo-controlled study a greater than 30% decrease in HIV-associated sensory neuropathic pain was reported in 52% of cannabis-experienced patients smoking cannabis cigarettes containing 3.56% Δ9-THC (32 mg total available Δ9-THC per cigarette), three times per day (96 mg total daily amount of Δ9-THC) for five days, compared to a 24% decrease in pain in the placebo groupFootnote 142. The number of patients that needed to be treated (NNT) to observe a 30% reduction in pain compared to controls was 3.6 and was comparable to that reported for other analgesics in the treatment of chronic neuropathic pain. In the "experimentally-induced pain" portion of the study, smoked cannabis was not associated with a statistically significant difference in acute heat pain threshold compared to placebo. However, it did appear to reduce the area of heat and capsaicin-induced acute secondary hyperalgesiaFootnote 142. Patients were taking other pain control medications during the trial such as opioids, gabapentin or other drugs. Adverse effects of smoked cannabis in this study included sedation, dizziness, confusion, anxiety, and disorientation.

A phase II, double-blind, placebo-controlled, crossover clinical trial of smoked cannabis for HIV-associated refractory neuropathic pain reported a 30% decrease in HIV-associated, distal sensory predominant, polyneuropathic pain in 46% of patients smoking cannabis for five days (1 - 8% Δ9-THC, four times daily), compared to a decrease of 18% in the placebo groupFootnote 186. The NNT in this study was 3.5. Almost all of the subjects had prior experience with cannabis and were concomitantly taking other analgesics such as opioids, non-steroidal anti-inflammatory drugs, anti-depressants or anti-convulsants. Adverse effects associated with the use of cannabis were reported to be frequent, with a trend for moderate or severe adverse effects during the active treatment phase compared to the placebo phase.

A randomized, double-blind, placebo-controlled, four period, crossover clinical study of smoked cannabis for chronic neuropathic pain caused by trauma or surgery and refractory to conventional therapies reported that compared to placebo, a single smoked inhalation of 25 mg of cannabis containing 9.4% Δ9-THC (2.35 mg total available Δ9-THC per cigarette), three times per day (7.05 mg total Δ9-THC per day) for five days, was associated with a modest but statistically significant decrease in average daily pain intensityFootnote 172. In addition, there were statistically significant improvements in measures of sleep quality and anxiety with cannabis. The majority of subjects had previous experience with cannabis and most were concomitantly taking other analgesics such as opioids, anti-depressants, anti-convulsants, or non-steroidal anti-inflammatory drugs. Adverse effects associated with the use of cannabis included headache, dry eyes, burning sensation in the upper airways (throat), dizziness, numbness, and cough.

A clinical study of patients suffering from chronic pain (musculoskeletal, post-traumatic, arthritic, peripheral neuropathy, cancer, fibromyalgia, multiple sclerosis, sickle cell disease, and thoracic outlet syndrome) reported that inhalation of vapourized cannabis (0.9 g, 3.56% Δ9-THC), three times per day for five days, was associated with a statistically significant decrease in pain (-27%, Confidence Interval = 9 - 46)Footnote 187. Subjects were on stable doses of sustained-release morphine sulfate or oxycodone, and had prior experience with smoking cannabisFootnote 187. There was a statistically significant decrease in the maximum concentration (Cmax) of morphine sulfate, but not oxycodone, during cannabis exposure. No clinically significant adverse effects were noted, but all subjects reported experiencing a "high". The study design carried a number of important limitations including small sample size, short duration, a non-randomized subject population, and the lack of a placebo.

A double-blind, placebo-controlled, crossover study of patients suffering from neuropathic pain of various etiologies (spinal cord injury, CRPS type I, causalgia-CRPS type II, diabetic neuropathy, multiple sclerosis, post-herpetic neuralgia, idiopathic peripheral neuropathy, brachial plexopathy, lumbosacral radiculopathy, and post-stroke neuropathy) reported that inhalation of vapourized cannabis (0.8 g containing either a low dose of Δ9-THC (1.29% Δ9-THC; total available amount of Δ9-THC 10.3 mg) or a medium dose of Δ9-THC (3.53% Δ9-THC; total available amount of Δ9-THC 28.2 mg)) during three separate 6 h sessions was associated with a statistically significant reduction in pain intensityFootnote 501. Inhalation proceeded using a standardized protocol (i.e. the "Foltin procedure"): participants were verbally signaled to hold the vapourizer bag with one hand, put the vapourizer mouthpiece in their mouth, get ready, inhale (5 s), hold vapour in their lungs (10 s), and finally exhale and wait before repeating the inhalation cycle (40 s)Footnote 501. Non-significant differences were observed between placebo and active treatments with respect to pain ratings at the 60 min time point following study session initiation. Following four cued inhalations of either dose of THC at the 60 min time point, a significant treatment effect was recorded 60 min later (i.e. at the 120 min time point following trial initiation). A second cued inhalation of vapourized cannabis, at the 180 min time point following trial initiation (4 - 8 puffs, flexible dosing, 2 h after first inhalation), was associated with continued analgesia lasting another 2 hFootnote 501. Both the 1.29% and 3.53% Δ9-THC doses were equianalgesic and significantly better in achieving analgesia than placebo. The NNT to achieve a 30% pain reduction was 3.2 for the placebo vs. the low-dose, 2.9 for the placebo vs. the medium-dose, and 29 for the medium- vs. the low-doseFootnote 501. The authors suggested that the NNT for active vs. placebo conditions is in the range of two commonly used anti-convulsants used to treat neuropathic pain (pregabalin, 3.9; gabapentin, 3.8). Using a Global Impression of Change rating scale, pain relief appeared to be maximal after the second dosing at 180 min, and dropped off between 1 and 2 h later. Both active doses had equal effects on ratings of pain "sharpness", while the low-dose was more effective than either the placebo or medium-dose for pain described as "burning" or "aching". All patients had prior experience with cannabis and were concomitantly taking other medications (opioids, anti-convulsants, anti-depressants, and non-steroidal anti-inflammatory drugs)Footnote 501. Cannabis treatment was associated with a small impairment of certain cognitive functions, with the greatest effects seen in domains of learning and memoryFootnote 501. The study suffered from a number of drawbacks including a relatively small number of patients, a short study period, and the possibility of treatment unblinding.

Clinical studies with orally administered prescription cannabinoids

Nabilone

An off-label, retrospective, descriptive study of 20 adult patients suffering from chronic non-cancer pain of various etiologies (post-operative or traumatic pain, reflex sympathetic dystrophy, arthritis, Crohn's disease, neuropathic pain, interstitial cystitis, HIV-associated myopathy, post-polio syndrome, idiopathic inguinal pain, and chronic headaches) reported subjective overall improvement and reduced pain intensity with nabilone as an adjunctive pain-relief therapyFootnote 494. Furthermore, beneficial effects on sleep and nausea were the main reasons for continuing use. Patients used between 1 and 2 mg of nabilone per day. Higher doses (3 - 4 mg/day) were associated with an increased incidence of adverse effects. These included dry mouth, headaches, nausea and vomiting, fatigue, cognitive impairment, dizziness, and drowsiness. Many patients were concomitantly taking other drugs such as non-steroidal anti-inflammatory drugs, opioids, and various types of anti-depressants. Many of the subjects also reported having used cannabis in the past to manage symptoms. Limitations in study design included the lack of an appropriate control group and the small number of patients.

An enriched-enrolment, randomized-withdrawal, flexible-dose, double-blind, placebo-controlled, parallel-assignment efficacy study of nabilone as an adjuvant in the treatment of diabetic peripheral neuropathic pain reported a statistically significant decrease in pain compared to placebo, with 85% of the subjects in the nabilone group reporting a ≥ 30% reduction in pain from baseline to end point, and 31% of subjects in the nabilone group reporting a ≥ 50% reduction in pain from baseline to end pointFootnote 364. Subjects taking nabilone also reported statistically significant improvements in anxiety, sleep, quality of life, and overall patient statusFootnote 364. Doses of nabilone ranged from 1 - 4 mg/dayFootnote 364. Most subjects were concomitantly taking a variety of pain medications including non-steroidal anti-inflammatory drugs, opioids, anti-depressants, and anxiolytics. Adverse events associated with the nabilone intervention included dizziness, dry mouth, drowsiness, confusion, impaired memory, lethargy, euphoria, headache, and increased appetite although weight gain was not observedFootnote 364.

Dronabinol

A randomized, double-blind, placebo-controlled, crossover trial of patients suffering from multiple sclerosis-associated central neuropathic pain reported a decrease in central pain with 10 mg maximum daily doses of dronabinolFootnote 361. Dosing started with 2.5 mg dronabinol/day and employed gradual dose-escalation every other day; total trial duration was three weeks (range: 18 - 21 days). Pain medications, other than paracetamol, were not permitted during the trial. The NNT for 50% pain reduction was 3.5 (95% Confidence Interval = 1.9 to 24.8). Fifty-four percent of patients had a ≥ 33% reduction in pain during dronabinol treatment compared with 21% of patients during placebo. The degree of pain reduction in this study was comparable to that seen with other drugs commonly used in the treatment of neuropathic pain conditionsFootnote 361. There were no significant differences reported between the treatment group and placebo in thermal sensibility, tactile and pain detection, vibration sense, temporal summation, or mechanical or cold allodyniaFootnote 361. However, there was a statistically significant increase in the pain pressure threshold in dronabinol-treated subjects. Self-reported adverse effects were common, especially during the first week of active treatment. These included lightheadedness, dizziness, drowsiness, headache, myalgia, muscle weakness, dry mouth, palpitations, and euphoriaFootnote 361.

A phase I, randomized, single-dose, double-blind, placebo-controlled, crossover trial of 30 patients taking short- or long-acting opioids (68 mg oral morphine equivalents/day; range 7.5 - 228 mg) for intractable, chronic non-cancer pain (of various etiologies) reported that both a 10 mg and 20 mg dose of dronabinol was associated with significant pain relief compared to placebo, although no difference in pain relief was observed between the two active treatmentsFootnote 502. Pain intensity and evoked pain were also significantly reduced in subjects who received the active treatments compared to placebo. Significant pain relief compared to baseline was also reported in an open-label, phase II extension to the initial phase I trial. Subjects were instructed in a stepwise dosage schedule beginning with a 5 mg/day dose, and titrating upwards to a maximum of 20 mg t.i.d. Significant side effects were observed in the majority of patients in the single-dose trial, were consistent with those observed in other clinical trials, and occurred more frequently in subjects receiving the highest dosage of the study medicationFootnote 502. The authors reported that compared to the single-dose phase I trial, the frequency of self-reported side effects in the phase II open-label study decreased with continued use of dronabinol. Limitations in the design of the study included the small number of study subjects, the large number of subjects with a history of cannabis use, the lack of appropriate comparison groups, and the lack of an active placebo. Other limitations specific to the open-label phase-II trial included the lack of a control group or crossover armFootnote 502.

Nabiximols

A number of randomized, placebo-controlled, double-blind crossover and parallel studies have shown a significant reduction in central or peripheral neuropathic pain of various etiologies (e.g. brachial plexus avulsion, multiple sclerosis-related) following treatment with nabiximols (Sativex®)Footnote 292,Footnote 503,Footnote 504. In all three studies, patients were concomitantly using other drugs to manage their pain (anti-epileptics, tricyclic anti-depressants, opioids, non-steroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, benzodiazepines, skeletal muscle relaxants). The NNT for 30% pain reduction (deemed clinically significant) varied between 8 and 9, whereas the NNT for 50% pain reduction for central neuropathic pain was 3.7, and 8.5 for peripheral pain. In two of the three studies, the majority of subjects had prior experience with cannabis for therapeutic or recreational purposesFootnote 503,Footnote 504. Furthermore, the majority of subjects allocated to the active treatment experienced minor to moderate adverse effects compared to the placebo group. These included nausea, vomiting, constipation, dizziness, intoxication, fatigue, and dry mouth among other effects.

According to the consensus statement and clinical guidelines on the pharmacological management of chronic neuropathic pain published by the Canadian Pain Society in 2007, the Society considered cannabinoid-based therapies (e.g. dronabinol and nabiximols) to be fourth-line treatments for neuropathic pain, mostly as adjuvant analgesics for pain conditions refractory to standard drugsFootnote 505 (but also see section 4.7.3 and referenceFootnote 506 for updated clinical guidelines on the use of cannabinoids for the treatment of symptoms associated with fibromyalgia). Health Canada has approved Sativex® (with conditions) as an adjunct treatment for the symptomatic relief of neuropathic pain in multiple sclerosisFootnote 290.

A Canadian systematic review of randomized clinical trials of cannabinoids (cannabis, nabilone, dronabinol and nabiximols) for the treatment of chronic non-cancer pain (neuropathic pain, mixed chronic pain, rheumatoid arthritis, fibromyalgia) concluded that cannabinoids are modestly effective for neuropathic pain, with preliminary evidence of efficacy in rheumatoid arthritis (see section 4.7.2) and fibromyalgia (see section 4.7.3) Footnote 173. Major limitations identified in the review were short trial duration, small sample sizes, and modest effect sizes, with a need for larger trials of longer duration to better establish efficacy and safety as well as potential for abuse.

4.6.2.3 Cancer pain
Clinical studies with dronabinol

Two randomized, double-blind, placebo-controlled studies suggested oral Δ9-THC (dronabinol) provided an analgesic benefit in patients suffering from moderate to severe continuous pain due to advanced cancer. The first study was a dose-ranging study of 5, 10, 15, and 20 mg Δ9-THC, given in successive days, to 10 cancer patientsFootnote 507. Significant pain relief was found at the 15 and 20 mg dose levels, but at these higher doses patients were heavily sedated and mental clouding was common. A second, placebo-controlled study compared 10 and 20 mg oral Δ9-THC with 60 and 120 mg codeine in 36 patients with cancer painFootnote 508. While the lower and higher doses of THC were equianalgesic to the lower and higher doses of codeine, respectively, statistically significant differences in analgesia were only obtained between placebo and 20 mg Δ9-THC, and between placebo and 120 mg codeine. The 10 mg Δ9-THC dose was well tolerated, and despite its sedative effect appeared to have mild analgesic potential. The 20 mg Δ9-THC dose induced somnolence, dizziness, ataxia, and blurred vision. Extreme anxiety was also observed at the 20 mg dose in a number of patients.

Clinical studies with nabiximols

A more recent randomized, double-blind, placebo-controlled, parallel-group trial of patients suffering from intractable cancer-related pain (mixed, bone, neuropathic, visceral, somatic/incident) suggested that an orally administered THC : CBD extract (nabiximols), containing 2.7 mg of Δ9-THC and 2.5 mg CBD per dose, is an efficacious adjunctive treatment for such cancer-related pain which is not fully relieved by strong opioidsFootnote 112. Baseline median morphine equivalents/day ranged from 80 - 120 mg. Forty-three percent of patients (n = 60) taking the extract achieved a ≥ 30% improvement in their pain score, which was twice the number of patients who achieved this response in the THC (n = 58) and placebo (n = 59) groups. Both the nabiximols and the THC medications were reported to be well tolerated in this patient population, and adverse events were reported to be similar to those seen in other clinical trials of nabiximols (e.g. somnolence, dizziness, and nausea). This study was followed-up by an open-label extension study which evaluated the long-term safety and tolerability of nabiximols (as well as oro-mucosal THC spray) as an adjuvant pain treatment in patients with terminal cancer-related pain refractory to strong opioid analgesicsFootnote 509. Patients who had taken part in, fully complied with the study requirements of, had not experienced an unacceptable adverse event in the initial parent studyFootnote 112, and that were expected to receive clinical benefit from nabiximols (with acceptable tolerability) were enrolled in the extension study. The most commonly reported (50%) pain type was mixed pain (nociceptive and neuropathic), followed by neuropathic pain (37%), and bone pain (28%)Footnote 509. The median duration of treatment with nabiximols (n = 39 patients) was 25 days (range: 2 - 579 days) while the mean duration of treatment with oro-mucosal THC spray (n = 4 patients) was 151.5 days (range: 4 - 657 days). The average number of sprays/day for nabiximols during the last seven days of dosing was 5.4 ±3.28 vs. 14.5 ±16.84 for THC only. No dose escalation was noted in patients taking nabiximols beyond six months and up to one year following treatment initiationFootnote 509. Although the study was a non-comparative, open-label study with no formal hypothesis testing and mostly used descriptive statistics, a decrease from baseline in mean score on the BPI-SF (Brief Pain Inventory Short-Form) was observed for both "pain severity" and "worst pain" over the five weeks of treatmentFootnote 509. However, the authors noted that the clinical investigators considered that their patients' pain control was sub-optimal. A negative change from baseline (i.e. indicating a worsening) was also reported in the physical functioning score on the EORTC QLQ-30 (an assessment tool to measure the quality of life of patients with cancer), although some improvements in scores for sleep and pain, between baseline and week 5 of treatment, were reportedFootnote 509. Eight percent of the patients on nabiximols developed a serious nabiximols-associated adverse event. The most commonly reported adverse events for nabiximols were nausea/vomiting, dry mouth, dizziness, somnolence, and confusionFootnote 509.

In contrast to the above-mentioned studies using nabiximols, a randomized, double-blind, placebo-controlled, parallel group clinical trial of opioid-treated cancer patients with intractable chronic cancer pain (e.g. bone, mixed, neuropathic, somatic, visceral) reported no statistically significant difference between placebo and the nabiximols treatment group in the primary endpoint of 30% relief from baseline pain at study endFootnote 349. However, when using a continuous responder rate analysis as a secondary endpoint (i.e. comparing the proportion of active drug vs. placebo responders across the full spectrum of response from 0 to 100%), the study was able to report a statistically significant treatment effect in favour of nabiximols. Patients were taking median opioid equivalent doses ranging between 120 and 180 mg/day. Adverse events were dose-related, with only the highest dose group comparing unfavourably to placebo. The authors noted that the trial was a dose-ranging study, and that confirmatory studies are strongly warranted. The study design also did not permit the evaluation of a therapeutic index.

In Canada, nabiximols (Sativex®) is approved (with conditions) as an adjunctive analgesic in adults with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background painFootnote 290. Current dosing recommendations for nabiximols suggest a maximum daily dose of 12 sprays (32.4 mg THC and 30 mg CBD) over a 24 h periodFootnote 107,Footnote 112,Footnote 290, although higher numbers of sprays/day have been used or documented in clinical studiesFootnote 290,Footnote 349. It should be noted that increases in the number of sprays/day were accompanied by increases in the incidence of adverse effects.

While there are no clinical trials of smoked marihuana for the treatment of cancer pain, the current Marihuana Medical Access Regulations (MMAR) allow the use of dried marihuana in cancer patients who experience severe pain and who have either not benefited from, or would not be considered to benefit from, conventional treatmentsFootnote 384.

"Opioid-sparing" effects and cannabinoid-opioid synergy

The "opioid-sparing" effect refers to the ability of a non-opioid medication to confer adjunctive analgesia with the use of a lower dose of the opioid thereby decreasing opioid-associated side effects. While there are some pre-clinical data supporting such an effect for cannabinoids, this is less well-established in published clinical studies. The following information summarizes the results from pre-clinical and clinical studies investigating cannabinoid-opioid interactions and the potential "opioid-sparing effect" of cannabinoids.

Pre-clinical data

There is a fair amount of evidence to suggest a functional interaction between the cannabinoid and the opioid systems, although much additional research is needed to understand precisely how the two systems communicate with one another. The evidence supporting a putative interaction between the cannabinoid and opioid systems comes from a number of observations. First, it is known that cannabinoids and opioids produce similar biological effects such as hypothermia, sedation, hypotension, inhibition of gastrointestinal motility, inhibition of locomotor activity, and anti-nociceptionFootnote 510,Footnote 511,Footnote 512. Furthermore, neuroanatomical studies in animals have demonstrated overlapping tissue distribution of the cannabinoid and opioid receptors, with both receptor types found in nervous system tissues associated with the processing of painful stimuli, namely the periaqueductal gray, raphe nuclei, and central-medial thalamic nucleiFootnote 510,Footnote 511,Footnote 512. There is also some evidence that the CB1 and mu-opioid receptors can co-localize in some of the same neuronal subpopulations such as those located in the superficial dorsal horn of the spinal cordFootnote 510. This co-localization may play an important role in spinal-level modulation of peripheral nociceptive inputsFootnote 510. Both receptors also share similar signal transduction molecules and pathways, the activation of which generally results in the inhibition of neurotransmitter releaseFootnote 510,Footnote 512. The role of these receptors in inhibiting neurotransmitter release is further supported by their strategic localization on pre-synaptic membranesFootnote 510. Evidence from some pre-clinical studies also suggests that acute administration of cannabinoid receptor agonists can lead to endogenous opioid peptide release, and that chronic THC administration increases endogenous opioid precursor gene expression (e.g. preproenkephalin, prodynorphin, and proopiomelanocortin) in different spinal and supraspinal structures involved in the perception of painFootnote 510. A few studies have even demonstrated the existence of cannabinoid-opioid receptor heteromers, although the exact biological significance of such receptor heteromerization remains to be fully elucidatedFootnote 513,Footnote 514. Taken together, these findings suggest the existence of cross-talk between the cannabinoid and opioid systems. Furthermore, pre-clinical studies using a combination of different opioids (morphine, codeine) and cannabinoids (THC), at acute or sub-effective doses, have reported additive and even synergistic analgesic effectsFootnote 515,Footnote 516,Footnote 517,Footnote 518,Footnote 519,Footnote 520.

Clinical data

A limited number of clinical trials have been carried out to date with mixed results. One double-blind, placebo-controlled, crossover study of healthy human volunteers given low doses of THC, morphine, or a combination of the two drugs failed to find any differences between subjects' ratings of sensory responses to a painful thermal stimulusFootnote 521. However, the study did report that the combination of morphine and THC was associated with a decrease in the subjects' affective response to the painful thermal stimulusFootnote 521. The authors suggested that morphine and THC could combine to yield a synergistic analgesic response to the affective aspect of an experimentally-evoked pain stimulus. One clinical studyFootnote 502 reported that patients suffering from chronic non-cancer pain and not responding to opioids experienced increased analgesia, decreased pain intensity, and decreased evoked pain when given either 10 or 20 mg dronabinol (for additional details see section 4.6.2.2, under "Clinical Studies With Orally Administered Prescription Cannabinoids"). More recently it was reported that patients suffering from chronic pain of various etiologies, unrelieved by stable doses of opioids (extended release morphine or oxycodone), experienced a statistically significant improvement in pain relief (27%, Confidence Interval = 9 - 46) following inhalation of vapourized cannabis (0.9 g, 3.56% THC, three times per day for five days)Footnote 187 (for additional details see section 4.6.2.2, under "Clinical Studies With Smoked or Vapourized Cannabis"). The findings from this study suggest that addition of cannabinoids (in this case inhaled vapourized cannabis) to existing opioid therapy for pain may serve to enhance opioid-associated analgesiaFootnote 187.

In contrast, another study did not note a statistically significant decrease in the amounts of background or breakthrough opioid medications consumed by the majority of patients suffering from intractable cancer-related pain and taking either nabiximols or THCFootnote 112. Similarly, no statistically significant changes were observed in the amounts of background or breakthrough opioid doses taken by patients suffering from intractable cancer-related pain who were administered nabiximolsFootnote 349. However, the design of the latter study did not allow proper assessment of an "opioid-sparing effect" of nabiximols.

In summary, while "cannabinoid-opioid synergy" has been proposed as a way to significantly increase the analgesic effects of opioids while avoiding, or minimizing, tolerance to the effects of opioid analgesics and circumventing, or attenuating, the well-known undesirable side effects associated with the use of either cannabinoids or opioids, the clinical results are mixed and further study is required on this topicFootnote 510,Footnote 512.

4.6.2.4 Headache and Migraine

While historical and anecdotal evidence suggest a role for cannabis in the treatment of headache and migraine Footnote 522, no controlled clinical studies of cannabis or prescription cannabinoids to treat headache or migraine have been carried out to dateFootnote 523,Footnote 524.

With regard to migraine, an endocannabinoid deficiency has been postulated to underlie the pathophysiology of this disorderFootnote 525; however, the evidence supporting this hypothesis is limited. Clinical studies suggest that the concentrations of anandamide are decreased in the cerebrospinal fluid of migraineurs, while the levels of calcitonin-gene-related-peptide and nitric oxide (normally inhibited by anandamide and implicated in triggering migraine) are increasedFootnote 526,Footnote 527. In addition, the activity of the anandamide-degrading enzyme FAAH is significantly decreased in chronic migraineurs compared to controlsFootnote 528.

In one case-report, a patient suffering from pseudotumour cerebri and chronic headache reported significant pain relief after smoking cannabisFootnote 529. In another case-report, a patient complaining of cluster headaches refractory to multiple acute and preventive medications reported improvement with smoked cannabis or dronabinol (5 mg)Footnote 530. However, these single-patient case-studies should be interpreted with caution. A recent report indicated that cannabis use was very frequent among a population of French patients with episodic or chronic cluster headache, and of those patients who used cannabis to treat their headache, the majority reported variable, uncertain, or even negative effects of cannabis smoking on cluster headache Footnote 531. It should also be noted that cannabis use has been associated with reversible cerebral vasoconstriction syndrome and severe headacheFootnote 532. In addition, headache is an observed adverse effect associated with the use of cannabis or prescription cannabinoid medicationsFootnote 172,Footnote 174,Footnote 290,Footnote 332,Footnote 430,Footnote 449, and headache is also one of the most frequently reported physical symptoms associated with cannabis withdrawalFootnote 533. It is therefore possible that using cannabis simply relieves headache caused by cannabis withdrawal.

4.7. Arthritides and Musculoskeletal Disorders

The arthritides include a broad spectrum of different disorders (e.g. osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gout, and many others) all of which have in common the fact that they target or involve the joints. Among these, osteoarthritis is by far the most common type of arthritis and is the leading cause of disability in those over the age of 65 years in developed countriesFootnote 534. Rheumatoid arthritis is a destructive, auto-immune disease that affects a smaller, but not insignificant, proportion of the adult populationFootnote 534. Also covered in this section are musculoskeletal disorders such as fibromyalgia and osteoporosis.

While scientific studies have demonstrated that joints, bone, and muscle all contain a working endocannabinoid systemFootnote 38,Footnote 39,Footnote 40, there is relatively little scientific or medical information on the use of cannabis or cannabinoids to treat either the arthritides or musculoskeletal disorders. The available information is summarized below.

4.7.1 Osteoarthritis

Pre-clinical studies

Very little information is available regarding the use of cannabis or cannabinoids to treat osteoarthritis. One study reported elevated levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (i.e. 2-AG), and the "entourage" compounds PEA and OEA in the spinal cords of rats with experimentally-induced knee joint osteoarthritisFootnote 535. While no changes were observed in the levels or the activities of the endocannabinoid catabolic enzymes FAAH or MAGL in the spinal cords of the affected rats, protein levels of the major enzymes responsible for endocannabinoid synthesis were reported to be significantly elevated in these animalsFootnote 535. Another study in rats reported that intra-articular injection of the CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA) in control animals was associated with a reduction in firing rate and suppression of nociceptive activity from pain fibers innervating the joints when the joints were subjected to either normal or noxious joint rotationFootnote 536. Similar results were obtained in animals with osteoarthritic joints. The anti-nociceptive effect was blocked by co-administration of a CB1 receptor antagonist in osteoarthritic joints, but not control jointsFootnote 536. Lastly, local administration of URB597 (a FAAH inhibitor) by intra-arterial injection proximal to an osteoarthritic joint was associated with decreased mechanosensitivity of joint afferent fibers in two different rodent models of osteoarthritisFootnote 537. Behavioural experiments carried out in these rats suggested that treatment with the inhibitor also decreased joint pain measured by a decrease in hindlimb incapacitanceFootnote 537.

Clinical studies

To date there have been no clinical studies of cannabis or cannabinoids to treat osteoarthritis. Nevertheless, the current Marihuana Medical Access Regulations (MMAR) allow the use of dried marihuana for those patients experiencing severe pain associated with severe arthritis who have either not benefited from, or would not be considered to benefit from, conventional treatmentsFootnote 384.

4.7.2 Rheumatoid Arthritis

Rheumatoid arthritis is a systemic, auto-immune, inflammatory arthritis characterized by progressive synovitis with resultant joint destruction, functional disability, significant pain, and systemic complications (e.g. cardiovascular, pulmonary, psychological, and skeletal disorders such as osteoporosis)Footnote 538,Footnote 539.

Pre-clinical studies

A pre-clinical study in a rat model of rheumatoid arthritis reported that treatment with either THC or anandamide was associated with significant anti-nociception in the paw-pressure testFootnote 258. Another study using the same animal model demonstrated a synergistic anti-nociceptive interaction between THC and morphine in both arthritic and non-arthritic rats in the paw-pressure testFootnote 257.

Clinical studies

In humans, one study found that the levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the synovial fluid of patients with osteoarthritis and rheumatoid arthritis were increased compared to non-inflamed normal controls, although the significance of these findings remains unclearFootnote 40.

A preliminary clinical study assessing the effectiveness of nabiximols (Sativex®) for pain caused by rheumatoid arthritis reported a modest but statistically significant analgesic effect on movement and at rest, as well as improvement in quality of sleepFootnote 259. Administration of nabiximols was well tolerated and no significant toxicity was observed. The mean daily dose in the final treatment week was 5.4 pump actuations (equivalent to 14.6 mg THC and 13.5 mg CBD/day, treatment duration was three weeks)Footnote 259. The differences observed were small and variable across the participants.

A recent Cochrane Collaboration review concluded that the evidence in support of the use of oro-mucosal cannabis (e.g. nabiximols) for the treatment of pain associated with rheumatoid arthritis is weak and given the significant side effect profile typically associated with the use of cannabinoids, the potential harms seem to outweigh any modest benefit achievedFootnote 538.

Nevertheless, the current Marihuana Medical Access Regulations (MMAR) allow the use of dried marihuana for those patients experiencing severe pain associated with severe arthritis who have either not benefited from, or would not be considered to benefit from, conventional treatmentsFootnote 384.

4.7.3 Fibromyalgia

Fibromyalgia is a disorder characterized by widespread pain (allodynia and hyperalgesia) and a constellation of other symptoms including sleep disorders, fatigue, and emotional or cognitive disturbancesFootnote 540. While the underlying pathophysiology of fibromyalgia remains unclear, disturbances in the recruitment or functioning of peripheral and central pain processing pathways and in the levels of several important neurotransmitters (serotonin, noradrenaline, dopamine, opioids, glutamate and substance P) have been noted in patients suffering from fibromyalgiaFootnote 541,Footnote 542,Footnote 543,Footnote 544. Co-morbid depressive symptoms have also been associated with a more pronounced deficit in pain inhibition, as well as increased pain in fibromyalgia patientsFootnote 545.

Clinical studies with smoked or orally ingested cannabis

There are no clinical trials of smoked or ingested cannabis for the treatment of fibromyalgia. However, a cross-sectional survey of patients suffering from fibromyalgia found that the patients reported using cannabis (by smoking and/or eating) to alleviate pain, sleep disturbance, stiffness, mood disorders, anxiety, headaches, tiredness, morning tiredness, and digestive disturbances associated with fibromyalgiaFootnote 158. Subjects (mostly middle-aged women who did not respond to current treatment) reported statistically significant decreases in pain and stiffness, and statistically significant increases in relaxation, somnolence, and well-being 2 h after cannabis self-administrationFootnote 158. Side effects included somnolence, dry mouth, sedation, dizziness, high, tachycardia, conjunctival irritation, and hypotensionFootnote 158. The study suffered from a number of limitations including the study design, small sample size, variability in frequency and duration of cannabis use, and a biased subject population.

Clinical studies with prescription cannabinoid medications

There are relatively few properly controlled clinical studies examining the role of cannabinoids in the treatment of fibromyalgia. The available evidence is summarized below.

Dronabinol

A non-placebo controlled pilot study examining the effect of dronabinol monotherapy (2.5 - 15 mg Δ9-THC/day; with weekly increases of 2.5 mg Δ9-THC, up to a maximum of 15 mg THC/day) on experimentally-induced pain, axon reflex flare, and pain relief in patients suffering from fibromyalgia reported that a sub-population of such patients experienced significant pain relief (reduced pain perception) with 10 and 15 mg/day Δ9-THC, but no changes were observed in axon reflex flareFootnote 260. Touch-evoked allodynia and pinprick-induced hyperalgesia were also not significantly affected by Δ9-THC. Subjects who completed a three-month course of therapy (15 mg/day Δ9-THC) reported a > 50% decrease in painFootnote 260. The study, however suffered from low power due to the high rate of patient drop-out caused by intolerable side effects of the treatment. A multi-center, retrospective study of patients suffering from fibromyalgia who were prescribed an average daily dose of 7.5 mg Δ9-THC, over an average treatment period of seven months, reported a significant decrease in pain score, a significant decrease in depression, and a reduction in the intake of concomitant pain-relief medications such as opioids, antidepressants, anti-convulsants, and non-steroidal anti-inflammatory drugs following treatment with Δ9-THCFootnote 261. It is important to note that the study had a number of considerable limitations (method of data collection, heterogeneous patient selection criteria, and high subject drop-out rate) and as such, the results should be interpreted with caution.

Nabilone

A randomized, double-blind, placebo-controlled trial of nabilone (1 mg b.i.d.) for the treatment of fibromyalgia showed statistically significant improvements in a subjective measure of pain relief and anxiety, as well as on scores on the fibromyalgia impact questionnaire, after four weeks of treatmentFootnote 353. However, no significant changes in the number of tender points or tender point pain thresholds were observed (note: the use of the "tender point" as a diagnostic criterion for fibromyalgia is no longer an absolute requirement)Footnote 546. Patients were taking concomitant pain medications such as non-steroidal anti-inflammatory drugs, opioids, anti-depressants, and muscle relaxants. Nabilone did not have any lasting benefit in subjects when treatment was discontinued. A two-week randomized, double-blind, active-control, crossover study of 29 patients suffering from fibromyalgia reported that nabilone (0.5 - 1.0 mg before bedtime) improved sleep in this patient populationFootnote 354.

The recently published Canadian Clinical Guidelines for the Diagnosis and Management of Fibromyalgia Syndrome (endorsed by the Canadian Pain Society and the Canadian Rheumatology Association) indicate that with regards to possible treatments, a trial of a prescribed pharmacologic cannabinoid may be considered in a patient with fibromyalgia, particularly in the setting of important sleep disturbance (this recommendation was based on Level 3, Grade C evidence)Footnote 506. For additional information regarding the use of cannabis/cannabinoids to alleviate sleep disorders or disturbances, please consult section 4.8.5.2.

4.7.4 Osteoporosis

Osteoporosis is a disease characterized by reduced bone mineral density and an increased risk of fragility fracturesFootnote 547. It occurs when the normal cycle of bone remodelling is perturbed, leading to a net decrease in bone deposition and a net increase in bone resorptionFootnote 548. While increasing evidence suggests a role for the endocannabinoid system in bone homeostasis, the role of cannabinoids in the treatment of osteoporosis has only been studied pre-clinically and the information remains unclear due to the complex and conflicting results among the various pre-clinical studies.

Pre-clinical studies

CB1 and CB2 receptors have been detected in mouse osteoblasts and osteoclasts, although CB1 is expressed at very low levels compared to CB2Footnote 18,Footnote 549,Footnote 550. In fact, it appears that CB1 receptors are expressed more abundantly in skeletal sympathetic nerve terminals in close proximity to osteoblastsFootnote 551. Besides the receptors, the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide have been detected in mouse trabecular bone and in cultures of mouse osteoblasts and human osteoclastsFootnote 550,Footnote 552,Footnote 553. Taken together, these findings suggest the existence of a functional endocannabinoid system in bone.

The role of the endocannabinoid system in bone physiology has been investigated using mice carrying genetic deletions of either the CB1 (CNR1) or CB2 (CNR2) receptor genes. The skeletal phenotypes of CB1 receptor knockout mice appear to vary depending on the gene targeting strategy used, the mouse strain, gender, time points at which the phenotypes were assessed, and the different experimental methodologies used to measure bone densityFootnote 18. In one CB1-deficient mouse strain, young female mice had normal trabecular bone with slight cortical expansion whereas young male mice had high bone massFootnote 549,Footnote 551. Loss of CB1 receptor function was associated with protection from ovariectomy-induced bone lossFootnote 549. In addition, antagonism of CB1 and CB2 receptors prevented ovariectomy-induced bone loss in vivoFootnote 549. A subsequent study by the same group reported that CB1 knockout mice had increased peak bone mass but eventually developed age-related osteoporosisFootnote 547. The increased peak bone mass was attributed to a reduction in osteoclast formation and activity, with preservation of normal osteoblast activity. In contrast, age-related bone loss in the knockout mice appeared to be caused by preferential formation and accumulation of adipocytes at the expense of osteoblasts within the bone-marrow space as well as decreased bone formationFootnote 547. In contrast to these studies, another study using a different gene targeting strategy and mouse strain reported that both male and female CB1 knockout mice exhibited low bone mass, increased numbers of osteoclasts, and a decrease in the rate of bone formationFootnote 551. The effects of ovariectomy in this mouse line were not examined, most likely because the baseline bone mass was too small to properly measure differences between mice subjected to ovariectomy and controls.

The skeletal phenotypes of CB2 receptor knockout mice have also been investigated. Ofek reported that CB2-deficient mice display a low bone mass phenotype as well as age-related trabecular bone lossFootnote 554. These deficits were associated with increased numbers of osteoclasts and decreased numbers of osteoblast precursorsFootnote 554. Furthermore, a selective CB2 receptor agonist was reported to increase osteoblast proliferation and activity and to decrease the formation of osteoclast-like cells in vitro, and administration of this agonist attenuated ovariectomy-induced bone loss in vivoFootnote 554. While a more recent study supported the finding of age-related bone loss, it failed to find any significant differences in peak bone mass between wild-type and knockout miceFootnote 555. Furthermore, and in contrast to the study by OfekFootnote 554, selective stimulation of the CB2 receptor was associated with an increase in osteoblast differentiation and function rather than proliferation. Another study reported no differences in peak bone mass between CB2 receptor knockout mice and wild-type mice under normal conditions Footnote 556. Age-related bone loss was not measured in this study. Genetic ablation of the CB2 receptor appeared to protect against ovariectomy-induced bone loss, an effect mimicked by administration of a CB2-selective antagonistFootnote 556. Conversely, results from in vitro studies suggested that CB2-selective agonists significantly increased osteoclast formation and osteoclast sizeFootnote 556. It may be relevant to note here that single nucleotide polymorphisms (SNPs) and SNP haplotypes located in the coding region of the CB2 receptor gene have also been associated with osteoporosis in humansFootnote 557,Footnote 558,Footnote 559.

A pre-clinical study in rats measuring the impact of cannabis smoke on bone healing around titanium implants reported that chronic exposure to cannabis smoke reduced cancellous bone healing around the implants by reducing bone filling and bone-to-implant contact inside the implant threadsFootnote 263. No such effect was observed for cortical boneFootnote 263.

4.8 Other diseases and symptoms

4.8.1 Movement disorders

The individual components of the endocannabinoid system are particularly abundant in areas of the brain which control movement, such as the basal gangliaFootnote 560. Motor effects generally arise as a consequence of changes in endocannabinoid system activity, with activation of the CB1 receptor typically resulting in inhibition of movementFootnote 560. A number of studies have reported changes in CB1 receptor levels and CB1 receptor activity in motor diseases such as Parkinson's and Huntington's diseaseFootnote 561,Footnote 562,Footnote 563,Footnote 564, and the findings from such studies suggest a role for the endocannabinoid system in the pathophysiology of these and other neurological diseases.

4.8.1.1 Dystonia
Pre-clinical data

A pre-clinical study in a hamster model of primary generalized dystonia reported a dose-dependent decrease in disease severity with administration of the synthetic CB1 and CB2 cannabinoid receptor agonist WIN 55,212-2Footnote 565. However, anti-dystonic doses of the agonist were associated with severe side effects including depression of spontaneous locomotor activity and catalepsy. In addition, this CB receptor agonist increased the anti-dystonic effect of diazepamFootnote 565. A follow-up study by the same group confirmed the anti-dystonic efficacy of WIN 55,212-2 and also showed that cannabidiol delayed the progression of dystonia, but only at a very high doseFootnote 566. A pre-clinical study of anti-psychotic-induced acute dystonia and tardive dyskinesia in monkeys showed that oral dyskinesia, but not dystonia, was dose-dependently reduced by the synthetic CB1 receptor agonist CP 55,940Footnote 567.

Clinical data

While anecdotal reports suggest cannabis may alleviate symptoms associated with dystonia in humansFootnote 568, no properly controlled clinical studies of cannabis to treat dystonia have been published. A placebo-controlled, single-dose trial with 5 mg of Δ9-THC administered to a musician with focal dystonia ("Musician's Dystonia") reported an improvement in motor control in the subject's affected hand, with tiredness and poor concentration cited as side effects associated with the use of Δ9-THCFootnote 569. The therapeutic effect persisted until 2 h after intake, with a progressive return to baseline values after 5 hFootnote 569. A six-week, open-label, pilot trial of five patients taking 100 - 600 mg/day of cannabidiol reported modest dose-related improvements in all study subjects, but a worsening of tremor and hypokinesia in two patients with co-existing Parkinson's diseaseFootnote 570. Results of a double-blind, randomized, placebo-controlled study of 15 patients taking a single 0.03 mg/kg dose of nabilone and not taking any other anti-dystonia medication showed no significant reduction in dystoniaFootnote 571.

4.8.1.2 Huntington's disease
Pre-clinical and human experimental data

Results from studies carried out in animal models of Huntington's disease (HD) as well as post-mortem studies carried out in HD patients suggest that brain CB1 receptors, especially those found in the basal ganglia, are downregulated and/or desensitized as a result of the expression of the mutant Huntingtin protein, and that this occurs early in the course of the disease and prior to the appearance of overt clinical symptomsFootnote 561,Footnote 572,Footnote 573,Footnote 574,Footnote 575,Footnote 576,Footnote 577,Footnote 578,Footnote 579,Footnote 580,Footnote 581. A recent in vivo PET study of HD patients supports these findings, demonstrating profound decreases in CB1 receptor availability throughout the gray matter of the cerebrum, cerebellum, and brainstem of HD patients even in early stages of the diseaseFootnote 582. Additional pre-clinical and post-mortem studies in HD patients indicate that the decrease in CB1 receptor levels appears to be accompanied by an increase in CB2 receptor levels in glial elements, astrocytes, and in reactive microglial cellsFootnote 577,Footnote 583. Thus, a significant amount of pre-clinical evidence and some limited clinical evidence suggests that changes in the endocannabinoid system are tightly linked to the pathophysiology of HDFootnote 577,Footnote 580,Footnote 581,Footnote 582.

One pre-clinical study in a mouse model of HD reported no beneficial effects of Δ9-THC (10 mg/kg/day) Footnote 584, while another study reported that Δ9-THC (2 mg/kg/day) was associated with decreased pathology and delayed onset of HD-like symptoms compared to untreated HD miceFootnote 579.

Clinical data

With regard to clinical studies, one double-blind, placebo-controlled, 15-week, crossover trial of 15 patients with HD taking 10 mg/kg/day of oral cannabidiol did not report improvement in symptoms associated with HDFootnote 585. A randomized, double-blind, placebo-controlled, crossover pilot study found little or no beneficial effect of nabilone over placebo in patients with HDFootnote 586. However, nabilone was well tolerated in this patient population and did not appear to exacerbate chorea or HD-associated psychosis, although some adverse effects such as drowsiness and forgetfulness were noted. Patients were concomitantly taking other HD medications. The results from single-patient case studies are mixed. In one study, daily doses of 1.5 mg nabilone increased choreatic movementsFootnote 587, while in another case improved mood and decreased chorea were noted in a patient who had smoked cannabis and who then continued on 1 mg nabilone b.i.d.Footnote 588.

4.8.1.3 Parkinson's disease

Endocannabinoid ligands, their synthesizing and degrading enzymes, and cannabinoid-activated receptors are highly abundant in the basal ganglia, the brain structures primarily affected in Parkinson's disease (PD)Footnote 560. Newly diagnosed PD patients and those undergoing PD medication washout were reported to have more than double the level of anandamide in their cerebrospinal fluid compared to controls, and these results parallel those seen in animal models of PD where dopamine cell loss is accompanied by elevations in anandamide levelsFootnote 589. In animal models of PD the levels of CB1 receptors appear to be downregulated during the early, pre-symptomatic stages of the disease, but during the intermediate and advanced phases of the disease there is an increase in CB1 receptor density and function and an increase in endocannabinoid levelsFootnote 590,Footnote 591. Together, these studies suggest a complex link between the pathophysiology of PD and changes in the endocannabinoid system.

Results from animal studies suggest cannabinoid receptor agonists induce hypokinesia and thus are reported to be unlikely as suitable first-line treatments for PDFootnote 560,Footnote 592. On the other hand, cannabinoid-induced hypokinesia could be useful in attenuating the dyskinesia observed in PD patients on long-term levodopa treatmentFootnote 592. Cannabinoids having mixed CB1 antagonist/CB2 agonist properties as well as anti-oxidant effects (such as THCV) may possibly hold some therapeutic potential, but much further research is required to determine whether the beneficial effects of THCV observed in animal models of PD can find applicability in humansFootnote 593.

Clinical data

The results of clinical trials examining the role of cannabinoids (cannabis, nabilone and a standardized oral cannabis extract) in the treatment of PD are mixed. One study involving five patients suffering from idiopathic PD found no improvement in tremor after a single episode of smoking cannabis (1 g cigarette containing 2.9% Δ9-THC, 29 mg total available Δ9-THC), whereas all subjects benefited from the administration of levodopa and apomorphineFootnote 594. A small randomized clinical trial of the synthetic cannabinoid nabilone (0.03 mg/kg) in seven patients with PD found that the treatment reduced levodopa-induced dyskinesiaFootnote 595. In contrast, a four-week, randomized double-blind, crossover study demonstrated that an oral cannabis extract (2.5 mg Δ9-THC and 1.25 mg cannabidiol per capsule, b.i.d.; maximum daily dose 0.25 mg/kg Δ9-THC) did not produce any pro- or anti-parkinsonian actionFootnote 596.

4.8.1.4 Tourette's syndrome

Anecdotal and case-reports have suggested amelioration of symptoms associated with Tourette's syndrome when smoking cannabisFootnote 597,Footnote 598. A two-day, randomized, double-blind, placebo-controlled, crossover trial of single oral doses of Δ9-THC (5, 7.5, or 10 mg) in 12 adult patients with Tourette's syndrome showed plasma concentration-related improvements in control of motor and vocal tics and obsessive-compulsive behaviour, with no serious side effects; although transient, mild side effects (e.g. headache, nausea, ataxia, fatigue, anxiety) were noted in five patientsFootnote 599. In contrast to healthy cannabis users, neither a 5 mg nor a 10 mg dose of Δ9-THC caused cognitive impairment in patients with Tourette's syndromeFootnote 599. This study was followed up by a six-week, randomized, double-blind, placebo-controlled trial by the same research group. The authors reported a significant difference in tic reduction compared to placebo in some patients, and no detrimental effects on neuropsychological performance during or after treatment with 10 mg doses of Δ9-THCFootnote 600. The major limitations of all three clinical studies were their small sample size and their relatively short duration.

A Cochrane Collaboration Review examining the efficacy and safety of cannabinoids in treating tics, premonitory urges, and obsessive compulsive symptoms in patients with Tourette's syndrome concluded that there was insufficient evidence to support the use of cannabinoids in treating tics and obsessive compulsive behaviour in persons suffering from Tourette's syndromeFootnote 601.

4.8.2 Glaucoma

Glaucoma is a multi-factorial disease characterized by the progressive degeneration of the optic nerve and the death of retinal ganglion cells (RGC) ultimately leading to irreversible blindnessFootnote 602. Increased intra-ocular pressure (IOP) has been implicated in the pathophysiology of glaucoma; however, inadequate blood supply to the optic nerve, oxidative damage, and apoptosis of RGCs are also contributing factorsFootnote 265,Footnote 602,Footnote 603,Footnote 604. An endocannabinoid system exists in a number of ocular tissues, and post-mortem studies have detected decreased levels of endocannabinoids in such tissues taken from glaucoma patientsFootnote 605.

Ocular (as well as systemic) administration of cannabinoids typically lowers IOP by up to 30% (seeFootnote 265 for a full reference list). How cannabinoids reduce IOP is unclear, but several possible mechanisms have been proposed including reduction of capillary pressure, decreased aqueous humour production, and improved aqueous humour uveoscleral outflow and outflow facilityFootnote 606,Footnote 607,Footnote 608,Footnote 609,Footnote 610.

A well-controlled pilot study of six patients with ocular hypertension or early primary open-angle glaucoma reported that single sub-lingual doses of 5 mg Δ9-THC (applied by means of an oro-mucosal spray) significantly but temporarily reduced IOP 2 h after administrationFootnote 264. A single sub-lingual dose of 20 mg cannabidiol (CBD) (containing ~ 1 mg Δ9-THC) had no effect, while a single sub-lingual dose 40 mg of CBD (containing ~ 2 mg Δ9-THC) caused a significant transient increase in IOP 4 h after administrationFootnote 264. A non-randomized, unmasked, uncontrolled clinical study reported some improvement in IOP after oral ingestion of Δ9-THC (2.5 or 5 mg q.i.d., up to a maximum of 20 mg/day; treatment duration range 3 - 36 weeks) in patients with end-stage, open-angle glaucoma not responsive to medications or surgeryFootnote 611. Some patients appeared to develop tolerance to the intra-ocular pressure-lowering effects of Δ9-THC, and almost half discontinued treatment due to Δ9-THC-associated toxicity (e.g. dizziness, dry mouth, sleepiness, depression, confusion)Footnote 611. Aside from lowering IOP, cannabinoids such as Δ9-THC and CBD may also have neuroprotective effects which could also be useful in the management of glaucomaFootnote 265,Footnote 612,Footnote 613,Footnote 614,Footnote 615,Footnote 616,Footnote 617,Footnote 618,Footnote 619,Footnote 620,Footnote 621. Results from a survey carried out among 1 516 glaucoma patients at tertiary glaucoma clinics in Toronto and Montreal suggested that approximately 13% of these patients claimed they used complementary and alternative medicines to treat glaucoma, and from among these patients 2.3% reported using cannabis to treat their glaucomaFootnote 622.

In conclusion, while smoking or eating cannabis has been shown to reduce IOPFootnote 623,Footnote 624,Footnote 625, cannabinoid-based therapy appears to be limited by the short duration of cannabinoid action (3 - 4 h) and unwanted physical and psychotropic effects.

4.8.3 Asthma

There is some historical and anecdotal evidence for cannabis as a treatment for asthmaFootnote 626. In terms of pre-clinical data, there is some evidence suggesting a role for the endocannabinoid system in regulating bronchial smooth muscle toneFootnote 627 and studies in animals with classical and synthetic cannabinoids suggest a possible role for cannabinoid-based compounds in the treatment of asthmaFootnote 628,Footnote 629,Footnote 630.

Early clinical studies demonstrated significant decreases in airway resistance and increases in specific airway conductance in healthy, habitual cannabis smokers shortly after smoking cannabisFootnote 631,Footnote 632. This effect has been largely attributed to the bronchodilatory properties of Δ9-THCFootnote 633. However, for asthmatics, the benefits of smoking cannabis are likely to be minimal. While smoking cannabis appears to decrease bronchospasm, increase bronchodilatation, and modestly improve respiratory function in some asthmatics in the short-termFootnote 634,Footnote 635,Footnote 636, cannabis smoke contains noxious gases and particulates that irritate and damage the respiratory systemFootnote 633; hence, it is not a viable long-term therapy for asthma. Nevertheless, alternate methods of Δ9-THC delivery by aerosol or oral administration have been studied. Doses of 100 and 200 µg of aerosolized Δ9-THC significantly improved ventilatory function in asthmatics and were generally well toleratedFootnote 637,Footnote 638. In another study, 5 - 20 mg of aerosolized Δ9-THC rapidly and effectively increased airway conductance in healthy subjects, but caused either bronchodilatation or bronchoconstriction in asthmaticsFootnote 639. Oral administration of 10 mg Δ9-THC or 2 mg nabilone did not produce clinically significant bronchodilatation in patients with reversible airways obstructionFootnote 626,Footnote 640,Footnote 641.

4.8.4 Hypertension

CB1 receptors are expressed on various peripheral tissues including the heart and vasculature, and cannabinoid agonists and endocannabinoids decrease arterial blood pressure and cardiac contractility (reviewed inFootnote 642). There are very few studies on the effects of cannabis or cannabinoids on hypertension. In one early study, inhalation of cannabis smoke from cigarettes containing 2.8% Δ9-THC caused a greater and longer-lasting decrease of arterial blood pressure in hypertensive subjects compared to normotensivesFootnote 643. In one case-report, a woman with longstanding idiopathic intra-cranial hypertension reported improvement in her symptoms after smoking cannabis or after treatment with dronabinol (10 mg b.i.d.initially, then 5 mg b.i.d.).

There are no reports on the use of low-dose cannabinoids as supplementary therapy in hypertension.

4.8.5 Psychiatric disorders

There are anecdotal and, in some cases, historical claims regarding the beneficial effects of cannabis and cannabinoids in the treatment of a variety of psychiatric disorders including anxiety, depression, sleep disorders, post-traumatic stress disorder, and withdrawal symptoms associated with drug abuse/addiction. The following sections provide information gathered from the scientific and medical literature regarding the use of cannabis and cannabinoids in the treatment of such disorders.

4.8.5.1 Anxiety and depression

Long-term cannabis users report reductions in anxiety, increased relaxation, and relief from tensionFootnote 147. One survey conducted among over 4 400 respondents suggested that those who consumed cannabis daily or weekly reported a decrease in depressed mood, and an increase in positive affect, compared to respondents who claimed they never consumed cannabisFootnote 644. However, the study suffered from a number of serious drawbacks and should be interpreted with this in mind.

Pre-clinical and clinical evidence indicates important roles for the endocannabinoid system in both anxiety and depression. Results from animal studies suggest low doses of CB1 receptor agonists reduce anxiety-like behaviour and increase anti-depressant-like responsesFootnote 645,Footnote 646. CB1 receptor agonists appear to enhance central serotonergic and noradrenergic neurotransmission similar to the actions of anti-depressant medicationsFootnote 647,Footnote 648. On the other hand, high-level stimulation of the CB1 receptor, or administration of CB1 receptor antagonists, reverse this response and can also trigger depressionFootnote 155,Footnote 647,Footnote 649,Footnote 650. Suppression of endocannabinoid signalling is sufficient to induce a depressive-like state both in animals and in humans (reviewed inFootnote 651). Furthermore, basal serum concentrations of both anandamide and 2-arachidonoylglycerol (2-AG) have been found to be significantly reduced in women with major depression Footnote 652. These findings suggest proper endocannabinoid tone plays an important role in regulating mood.

Clinical data for cannabis and THC

While the routine use of cannabis or prescription cannabinoid medications to treat primary anxiety or depression should be viewed with caution, and especially discouraged in patients with a history of psychotic disorders (see section 7.7.3.3), limited clinical evidence indicates that these drugs may present alternative therapeutic avenues in patients suffering from anxiety or depression secondary to certain chronic diseases. For example, in a study of HIV+ patients who reported using cannabis to manage their symptoms, 93% cited an improvement in anxiety and 86% cited an improvement in depressionFootnote 653. It is important to note that 47% of those surveyed reported deterioration in memory. In another study of HIV+ cannabis smokers, high-dose dronabinol (5 mg q.i.d., for a total daily dose of 20 mg, for two days, followed by 10 mg q.i.d., for a total daily dose of 40 mg, for 14 days) was associated with an increase in self-reported "positive affect" (feeling "content"), but no change was observed in measures of anxiety or "negative affect")Footnote 193. The dosage employed in this study was eight times the recommended starting dose for appetite stimulation (i.e. 2.5 mg b.i.d), and double the maximal daily recommended dose. Improved mood was also reported as a beneficial effect of cannabis consumption in patients suffering from multiple sclerosisFootnote 654. Improvements in anxiety or depression were equally noted in a study of patients suffering from chronic neuropathic pain who smoked cannabisFootnote 172. It may be interesting to note here that rimonabant, a CB1 receptor antagonist initially marketed as an anti-obesity medication, was withdrawn from the market because its use was associated with a significant incidence of anxiety, depression, and suicide, underscoring the role of the CB1 receptor in regulating moodFootnote 650,Footnote 655.

Cannabidiol

Increasing evidence suggests a role for cannabidiol (CBD) in decreasing anxiety, although the extent to which CBD (at the concentrations commonly found in cannabis) is able to achieve this effect remains uncertainFootnote 181,Footnote 656. Pre-clinical studies have shown that CBD and CBD-derivatives decreased anxiety-like behaviour in a rat model of anxietyFootnote 657. An early clinical study showed that CBD (1 mg/kg) attenuated, but did not completely block, the anxiogenic effects of THC (0.5 mg/kg) in eight healthy volunteers with a history of marihuana useFootnote 97. A double-blind, crossover clinical study showed that a single dose of CBD (400 mg) significantly decreased anticipatory anxiety but increased mental sedation, although the findings were deemed to be preliminary and follow-up studies were suggestedFootnote 658. Single-photon emission computed tomography (SPECT) brain imaging studies showed that in contrast to placebo, CBD decreased regional cerebral blood flow in the limbic and paralimbic cortical areas, regions implicated in the pathophysiology of anxietyFootnote 658. Furthermore, a randomized, double-blind, placebo-controlled study showed that 600 mg of CBD attenuated brain activity (blood oxygenation level-dependent response) in these cortical regions in response to anxiogenic stimuliFootnote 104. In contrast, 10 mg Δ9-THC increased anxiety at baseline or in response to anxiogenic stimuli, but the brain regions affected by Δ9-THC differed from those affected by CBDFootnote 104. A more recent double-blind, randomized, placebo-controlled clinical study showed that 600 mg of orally-administered CBD was associated with a significant reduction in anxiety, cognitive impairment, and discomfort in patients suffering from generalized social anxiety disorder subjected to a simulated public-speaking testFootnote 659. The authors caution that the study was preliminary in nature, with additional larger and well-controlled studies required to substantiate this effect. Although the precise mechanism by which CBD exerts its anxiolytic effects is not well established, it may act either by decreasing blood flow to brain regions associated with the processing of anxiety or fear-based stimuli (as mentioned above), or possibly through the modulation of serotonergic neurotransmissionFootnote 660,Footnote 661.

4.8.5.2 Sleep disorders
Pre-clinical data

There is some evidence to suggest a role for the endocannabinoid system in sleep. Subjects deprived of sleep for a 24 h period had increased levels of oleoylethanolamide (OEA), a natural analog of anandamide, in their cerebrospinal fluid but not in serum, whereas levels of anandamide were unchangedFootnote 662. In rats, both acute and sub-chronic administration of anandamide induces sleepFootnote 663. Cannabis and Δ9-THC are known to have a number of effects on sleep. In general, it appears that these substances decrease sleep latency and are associated with greater ease in getting to sleep, but they consistently reduce total rapid-eye movement (REM) sleep and REM density (reviewed inFootnote 161). Furthermore, due to the long half-life of THC, sedative effects typically persist into the day following cannabinoid administrationFootnote 161.

Clinical data

A number of clinical studies point to a potential beneficial role for smoked cannabis or prescription cannabinoids (dronabinol, nabilone, nabiximols) in the treatment of sleep difficulties or disturbances associated with chronic pain (cancer pain, chronic non-cancer pain, diabetic peripheral neuropathy), HIV-associated anorexia-cachexia, multiple sclerosis, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, fibromyalgia, inflammatory bowel disease, multiple sclerosis-associated bladder dysfunction, post-traumatic stress disorder, and chemosensory alterations and anorexia-cachexia associated with advanced cancerFootnote 157,Footnote 158,Footnote 165,Footnote 166,Footnote 167,Footnote 172,Footnote 193,Footnote 259,Footnote 348,Footnote 354,Footnote 362,Footnote 364,Footnote 378,Footnote 432,Footnote 438,Footnote 443,Footnote 448,Footnote 449,Footnote 494,Footnote 506. In most of these studies, the effect on sleep was measured as a secondary outcome. Although presented elsewhere throughout the text in the relevant sections, brief summaries of these studies are presented below.

Dronabinol

A four-week, randomized, double-blind, crossover pilot study of 19 patients suffering from amyotrophic lateral sclerosis (ALS) taking 2.5 - 10 mg per day of dronabinol reported improvements in sleepFootnote 443. Two studies reported that dronabinol (20 - 40 mg total Δ9-THC/day) and smoked cannabis (~800 mg cigarettes containing 2 or 3.9% THC, administered four times per day for four days, corresponding to an estimated daily amount of 64 - 125 mg of Δ9-THC) produced improvements in mood and sleep in patients with HIV/AIDS-associated anorexia-cachexiaFootnote 166,Footnote 167. A study of HIV+ cannabis smokers treated with dronabinol for 14 days (10 mg q.i.d., 40 mg daily) reported improvements in both objective and subjective measures of sleep, but only during the first eight days of the treatment regimenFootnote 193. A two-centre, phase II, randomized, double-blind, placebo-controlled 22-day pilot study carried out in adult patients suffering from chemosensory alterations and poor-appetite associated with advanced cancer of various etiologies reported statistically significant improvements in measures of quality of sleep and relaxation with dronabinol treatment (2.5 mg b.i.d.) compared to placeboFootnote 362.

Nabilone

An off-label, retrospective, descriptive study of 20 adult patients suffering from chronic non-cancer pain of various etiologies (post-operative or traumatic pain, reflex sympathetic dystrophy, arthritis, Crohn's disease, neuropathic pain, interstitial cystitis, HIV-associated myopathy, post-polio syndrome, idiopathic inguinal pain, chronic headaches) reported beneficial effects of nabilone (1 - 2 mg/day) on sleepFootnote 494. An enriched-enrolment, randomized-withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone (1 - 4 mg/day), as an adjuvant in the treatment of diabetic peripheral neuropathic pain, reported statistically significant improvements in sleep and overall patient statusFootnote 364. An open-label, non-placebo-controlled trial of nabilone for post-traumatic stress disorder reported that nabilone treatment was associated with an improvement in sleep time, cessation or lessening of nightmare severity, and cessation of night sweatsFootnote 348. Dosing of nabilone was 0.5 mg, 1 h prior to bedtime; effective dose range was 0.2 mg - 4 mg nightly with all doses kept below 6 mg daily. A two-week, randomized, double-blind, active-control, crossover study of 29 patients suffering from fibromyalgia reported that nabilone (0.5 - 1.0 mg before bedtime) improved sleep in this patient populationFootnote 354.

Smoked cannabis

Surveys carried out among patients suffering from multiple sclerosis reported cannabis-associated improvements in sleep in this patient populationFootnote 164,Footnote 165. Reported dosages of smoked cannabis varied from a few puffs, to 1 g or more, at a timeFootnote 165. A cross-sectional survey of patients suffering from fibromyalgia reported that subjects claimed using cannabis (by smoking and/or eating) for a variety of symptoms associated with fibromyalgia, including sleep disturbanceFootnote 158. A cross-sectional survey of 291 patients with inflammatory bowel disease (Crohn's disease or ulcerative colitis) reported that one of the reasons patients used cannabis was to improve sleepFootnote 157. A two-week, randomized, double-blind, placebo-controlled, cross-over study of patients suffering from chronic neuropathic pain reported that those who smoked 25 mg of cannabis containing 9.4% Δ9-THC, three times per day for five days (2.35 mg total available Δ9-THC per cigarette, or 7.05 mg total Δ9-THC per day), fell asleep more easily and more quickly, and experienced fewer periods of wakefulnessFootnote 172.

Orally administered prescription cannabinoid medications (Cannador and nabiximols)

A double-blind, placebo-controlled, phase III study, involving patients with stable multiple sclerosis (the MUltiple Sclerosis and Extract of Cannabis trial--i.e. "MUSEC") reported that a 12-week treatment with an oral cannabis extract ("Cannador") (2.5 mg Δ9-THC and 0.9 mg cannabidiol/dose) was associated with a statistically significant improvement in sleep compared to placeboFootnote 432. The majority of the patients using cannabis extract used total daily doses of 10, 15, or 25 mg of Δ9-THC with corresponding doses of 3.6, 5.4, and 9 mg of CBD. Results from double-blind, crossover, placebo-controlled studies of oral Δ9-THC and/or Δ9-THC : CBD extract (nabiximols, marketed as Sativex®) suggested modest improvements in pain, spasticity, muscle spasms, and sleep quality in patients with spinal cord injuryFootnote 378,Footnote 448,Footnote 449. A preliminary clinical study assessing the effectiveness of nabiximols (Sativex®) in pain caused by rheumatoid arthritis reported a modest, but statistically significant, analgesic effect and consequent improvement in quality of sleepFootnote 259. The mean daily dose in the final treatment week was 5.4 pump actuations (equivalent to 14.6 mg Δ9-THC and 13.5 mg CBD). A sixteen-week, open-label pilot study of cannabis-based extracts (a course of Sativex® treatment followed by maintenance with 2.5 mg Δ9-THC only) for bladder dysfunction in 15 patients with advanced multiple sclerosis reported significant decreases in nocturia and improvement in patient self-assessment of sleep qualityFootnote 438.

The recently published Canadian Guidelines for the Diagnosis and Management of Fibromyalgia Syndrome (endorsed by the Canadian Pain Society and the Canadian Rheumatology Association) recommend that with regards to possible treatments, a trial of a prescribed pharmacologic cannabinoid may be considered in a patient with fibromyalgia, particularly in the setting of important sleep disturbance (this recommendation was based on Level 3, Grade C evidence)Footnote 506.

Data from withdrawal studies

Heavy cannabis users (mean number of joints smoked per week = 100) who abruptly discontinue cannabis use have been shown to exhibit changes in polysomnographic sleep measures, including lower total sleep times, less slow wave sleep, longer sleep onset, shorter REM latency, and worse sleep efficiency and continuity parameters compared to controlsFootnote 664. Trouble getting to sleep, nightmares and/or strange dreams, and night sweats were frequently cited items associated with cannabis withdrawalFootnote 222. These sleep disturbances progress over the first two weeks of abstinenceFootnote 665. Furthermore, sleep disturbances resulting from abrupt discontinuation of cannabis use may trigger users to relapseFootnote 274,Footnote 665. The symptoms observed during abstinence from cannabis may alternatively reveal a pre-existing sleep disorder masked by the drug.

4.8.5.3 Post-traumatic stress disorder (PTSD)

Post-traumatic stress disorder (PTSD) refers to the development of a cluster of characteristic symptoms that follow exposure to an extreme traumatic stressor and which appears to involve aberrant memory processing and impaired adaptation to changed environmental conditionsFootnote 666. Characteristic symptoms include persistent, intrusive recollections, or a re-experiencing of the original traumatic event (through dreams, nightmares, and dissociative flashbacks), numbing and avoidance, and increased arousalFootnote 348.

Role of the endocannabinoid system in PTSD

Increasing evidence suggests an important role for the endocannabinoid system in PTSD. The endocannabinoid system has been associated with the regulation of emotional states and cognitive processes, and neuroanatomical studies have detected the presence of endocannabinoid system elements in a number of brain structures involved in learning and memory, and in structures which also play central roles in fear conditioning and response (reviewed inFootnote 666). Furthermore, similarities exist between the expression of fear and anxiety in humans suffering from phobias, PTSD, or other anxiety disorders, and the expression of conditioned fear in animals. Therefore, the use of certain animal behavioural models to study PTSD is feasible and relevantFootnote 666,Footnote 667.

Pre-clinical data

A number of pre-clinical studies demonstrate that deletion of the CB1 receptor or its inhibition by pharmacological antagonists prevent the extinction of aversive memories (i.e. learned inhibition of fear), a naturally adaptive processFootnote 667,Footnote 668,Footnote 669,Footnote 670. Conversely, in some cases, CB1 receptor agonism or increased endocannabinoid-mediated neurotransmission appear to enhance extinction to some degreeFootnote 667,Footnote 670, but further research is required to clarify and substantiate this effect. However, no studies have yet investigated the effects of Δ9-THC per se on the extinction of aversive memories. Taken together, the evidence from pre-clinical studies suggests a role for the endocannabinoid system in the extinction of aversive memories, and raises the possibility that the endocannabinoid system may be a valid therapeutic target for the treatment of diseases associated with inappropriate retention of aversive memories or inadequate responses to aversive situations, such as PTSD or phobiasFootnote 668.

Clinical data

Although anecdotal evidence suggests a role for cannabis in the management of PTSD symptoms, no properly controlled clinical trials on this topic exist. In fact the only clinical trial reported to date examining the effect of cannabinoids in PTSD is an open-label, non-placebo-controlled trial of nabilone for PTSDFootnote 348. Forty-seven patients diagnosed with PTSD (according to DSM-IV-TR criteria), having at least a two-year history of PTSD-related nightmares refractory to conventional therapies, a minimum of once weekly nightmares, and with no prior history of sensitivity to cannabinoids or evidence of psychotic reactions, were admitted into the study. Patients did not discontinue any concomitant psychotropic medications, and were started on 0.5 mg nabilone, 1 h prior to bedtime. All doses were kept below 6 mg daily. The effective dose range varied between 0.2 mg and 4 mg nightly. Seventy-two percent of patients self-reported total cessation or lessening of severity of nightmares (treatment duration 4 - 12 months or longer). Other self-reported benefits included an improvement in sleep time, a reduction in daytime flashbacks, and cessation of night sweats. Reported side effects included light-headedness, amnesia, dizziness, and headache. No tolerance to nabilone was observed in this clinical trial.

4.8.5.4 Alcohol and opioid withdrawal symptoms (drug withdrawal symptoms)
Alcohol

There is evidence to suggest complex functional interactions between ethanol and the endocannabinoid system (reviewed inFootnote 671). Acute administration of ethanol in animals is associated with brain region- specific changes in endocannabinoid levels and in the expression of endocannabinoid system components (e.g. CB1 receptor, FAAH)Footnote 671. Furthermore, modulation of endocannabinoid system components through genetic ablation of CB1 receptor or FAAH expression, or by pharmacological inhibition of CB1 receptor or FAAH activity, generally results in decreased ethanol consumption in animal models (although a few exceptions have been noted)Footnote 671. In contrast, activation of the CB1 receptor appears to mediate the reinforcing properties of ethanol, facilitates ethanol consumption, and enhances re-instatement of ethanol self-administration in animal modelsFootnote 671. In the case of chronic ethanol consumption, the available evidence suggests long-term exposure to ethanol is in some cases associated with brain region-specific decreases in CB1 receptor mRNA/protein expression and CB1 receptor activity, as well as a decrease in FAAH expression and functionFootnote 671. There is also some limited evidence gathered from animal studies that suggests the endocannabinoid system may be involved in the modulation of alcohol withdrawal symptoms, with CB1 receptor agonism exacerbating withdrawal severityFootnote 671.

Opioids

Anecdotal information and findings from some animal studies suggest that cannabinoids might be useful in treating the symptoms associated with opioid withdrawalFootnote 512,Footnote 672,Footnote 673,Footnote 674,Footnote 675, but there are no supporting clinical studies in this regard. The overlapping neuroanatomical distribution, convergent neurochemical mechanisms, and comparable functional neurobiological properties of the cannabinoid and opioid systems may help explain why cannabinoids could substitute for opioids to potentially alleviate withdrawal symptoms associated with opioid abstinenceFootnote 511. However, further research is required on this subject.

4.8.5.5 Schizophrenia and psychosis
The endocannabinoid system and psychotic disorders

There is increasing evidence implicating the endocannabinoid system in schizophrenia and psychosisFootnote 676. For example, levels of anandamide were reported to be significantly elevated in the cerebrospinal fluid and serum of patients with initial prodromal states of psychosisFootnote 677. In addition, anandamide levels were also elevated in the cerebrospinal fluid and serum of anti-psychotic-naïve patients with active schizophrenia Footnote 678,Footnote 679. Post-mortem studies investigating CB1 receptor densities in the brains of schizophrenic patients have also noted an upregulation of CB1 receptor levels in the frontal and cingulate brain regions, areas of the brain typically afflicted in schizophreniaFootnote 676. While the precise role of the endocannabinoid system in psychosis and schizophrenia remains to be fully elucidated, it appears that such psychiatric disorders are accompanied by changes in the levels of endocannabinoids such as anandamide, as well as changes in CB1 receptor expression level. Although it remains to be confirmed, one hypothesis holds that the endocannabinoid system may function as a feedback mechanism, negatively regulating dopamine release and dampening the hyperdopaminergic activity observed in the brains of schizophrenic subjectsFootnote 676,Footnote 680.

Substance use disorders and psychotic disorders

Interestingly, patients with severe mental illnesses such as schizophrenia are known to have high rates of substance use disorders, with cannabis being one of the substances most often used or misused by this populationFootnote 681,Footnote 682. Two competing hypotheses have tried to explain why patients with severe mental illnesses such as schizophrenia also have co-morbid substance abuse. The "self-medication" hypothesis, in the context of psychiatric disorders, posits that those who suffer from such disorders (e.g. schizophrenics) consume cannabis in order to alleviate specific psychopathological symptoms or alternatively to diminish the side effects resulting from the use of medicationsFootnote 682,Footnote 683. While the "self-medication" hypothesis presents a compassionate, interesting, and attractive explanation to understand why schizophrenics have co-morbid substance abuse disorders, the hypothesis appears to have fallen out of favourFootnote 684. On the other hand, the "addiction-vulnerability" hypothesis claims that substance abuse vulnerability and schizophrenic symptoms share a common neuropathologyFootnote 685. In other words, this hypothesis rests on the idea that certain pathological alterations in brain structure and function will predispose certain individuals to developing both schizophrenia and substance abuse disorders.

Cannabis/THC and psychosis

Regardless of which hypothesis is correct, there is much scientific evidence to suggest a positive association between cannabis use and the development of psychosis, especially in people susceptible to psychotic disorders but also in adolescentsFootnote 138,Footnote 139,Footnote 141,Footnote 143,Footnote 144. Furthermore, controlled clinical studies carried out in those with no history of psychotic disorders reported the manifestation of transient schizophrenia-like symptoms induced by the intravenous administration of Δ9-THCFootnote 140. Likewise, intravenous administration of Δ9-THC in schizophrenics was associated with transient exacerbation of core psychotic symptomsFootnote 139.

Genetic factors

A number of studies have investigated the influence of potential genetic factors in the development of psychosis and schizophrenia, and more specifically as a function of interaction with cannabis use. Some studies have focused on the role of genetic polymorphisms at the catechol-O-methyltransferase gene (COMT) Footnote 686,Footnote 687,Footnote 688,Footnote 689,Footnote 690, and others have focused on polymorphisms at the AKT1 geneFootnote 691,Footnote 692,Footnote 693. Taken together, the data from these studies strongly suggest that single-nucleotide polymorphisms at either the COMT or AKT1 genes interact with cannabis use to predict the age at onset, as well as the likelihood of developing psychosis or schizophrenia in vulnerable individuals. Please consult section 7.7.3 for additional information on the adverse psychiatric effects associated with the use of cannabis and psychoactive cannabinoids (such as THC), and the role of genetic predisposition on the risk of developing a psychotic disorder. The findings presented above and in section 7.7.3 suggest that cannabis use, as well as exposure to Δ9-THC alone, would not be beneficial, and in fact would actually be harmful to those who may be suffering from psychotic disorders, or who may have a genetic predisposition or family history of psychosis or schizophrenia.

Cannabidiol

A number of pre-clinical and clinical studies have suggested that, in contrast to THC, other cannabinoids such as cannabidiol (CBD) may in fact have anti-psychotic properties and may benefit psychotic patients Footnote 694,Footnote 695. For example, studies in certain rat and mouse models of psychosis suggest that CBD (at doses of 15 - 60 mg/kg) reduces psychotic-like behavioural effects in a manner comparable to that observed with atypical anti-psychotic drugsFootnote 696,Footnote 697. Furthermore, one clinical study showed that pre-treatment of a small number of human subjects with CBD (5 mg i.v.), but not placebo, diminished the emergence of psychotic symptoms 30 min after i.v. administration of Δ9-THCFootnote 105. In contrast, a naturalistic study of cannabis users failed to show any differences in the prevalence of psychotic-like symptoms between subjects who reported smoking cannabis containing "low" or "high" levels of CBD; however the authors mention a number of confounding factors, including the lack of adjustment for alcohol consumption that could help explain this apparent inconsistencyFootnote 656. An internet-based, cross-sectional study of 1 877 individuals who had a consistent history of cannabis use reported that individuals who had consumed cannabis with a higher CBD to THC ratio reported experiencing fewer psychotic episodes; however, the authors noted that the observed effects were subtleFootnote 113. Furthermore, the study was hampered by a number of important methodological issues suggesting the conclusions should be interpreted with caution. More recently, a four-week, double-blind, parallel-group, randomized, active-controlled clinical trial comparing CBD (200 mg, q.i.d., up to a total daily amount of 800 mg) to amilsupride (a dopamine D2/D3 receptor antagonist used in the treatment of schizophrenia) reported that both drugs were associated with a significant clinical improvement in symptoms with no significant difference between the two treatmentsFootnote 698. Treatment with CBD was well tolerated with significantly fewer side effects compared to those associated with anti-psychotic treatment (e.g. the presence of extra-pyramidal symptoms and lower prolactin release). In addition, CBD did not appear to significantly affect either hepatic or cardiac functionsFootnote 698. Cannabidiol treatment, but not amilsupride, was also associated with an increase in serum levels of anandamideFootnote 698.

While there is some indication for a potential therapeutic role for CBD itself in the treatment of patients with pre-existing schizophrenia or psychosis or those who develop psychotic symptoms as a result of cannabis use, the extent to which CBD (at the levels typically found in cannabis) is able to ameliorate psychotic symptoms has not been firmly established and in fact, much of the cannabis consumed typically contains relatively low levels of CBDFootnote 60. For example, the CBD content of cannabis typically varies between 0.1 and 0.5%, although CBD levels of up to 8.8% (in hashish) have been notedFootnote 113. Therefore, a 1 g joint could contain between 1 mg (0.1%) and 88 mg (8.8%) of CBD--levels which are much lower than those usually administered in clinical trials (600 - 1500 mg/day)Footnote 699.

In conclusion, consumption of cannabis or other psychoactive cannabinoids (e.g. dronabinol, nabilone) should be treated with considerable caution in this patient population as these substances are believed to trigger psychotic episodes, lower the age of onset of symptoms, and contribute to a negative long-term prognosis in vulnerable individuals. Additionally, the therapeutic potential of CBD alone in the treatment of schizophrenia/psychosis, while promising, requires further study.

4.8.6 Alzheimer's disease and dementia

While still controversial, a widely accepted theory underlying the pathophysiology of Alzheimer's disease (AD) is the deposition of amyloid-β (Aβ) protein in specific brain regions leading to localized neuroinflammatory responses and accumulation of intra-cellular neurofibrillary tangles (composed of hyperphosphorylated tau protein); these events result in neuronal cell death with accompanying loss of functional synapses and changes in neurotransmitter levelsFootnote 700. These pathological processes are thought to give rise to disease-associated symptoms such as memory deficits, and cognitive and motor impairmentsFootnote 700.

The endocannabinoid system and Alzheimer's disease

There is some evidence to suggest a role for the endocannabinoid system in the pathophysiology of ADFootnote 700,Footnote 701. One in vivo study reported elevation in the levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) in response to intra-cerebral administration of Aβ1-42 peptide in animalsFootnote 702. Another study using post-mortem brain samples from AD patients showed decreased anandamide levels with increasing Aβ1-42 levels, but no association with Aβ40 levels, amyloid plaque load, or tau protein phosphorylationFootnote 703.

Pre-clinical data

Pre-clinical studies suggest the endocannabinoid system protects against excitotoxicity, oxidative stress, and inflammation--all key pathological events associated with the development of ADFootnote 704. However, limited information exists regarding the use of cannabis or cannabinoids in the treatment of AD. Results from in silico and in vitro experiments suggest Δ9-THC could bind and competitively inhibit acetylcholinesterase (AChE), which in the context of AD functions as a molecular chaperone accelerating the formation of amyloid fibrils and forming stable complexes with AβFootnote 705. Δ9-THC blocked the amyloidogenic effect of AChE, thereby diminishing Aβ aggregationFootnote 705. Other in vitro studies suggest that cannabidiol may have neuroprotective, antioxidant, and anti-apoptotic effects, as well as preventing tau protein hyperphosphorylation in cellular models of ADFootnote 706,Footnote 707,Footnote 708. Endocannabinoids have also been shown to prevent Aβ-induced lysosomal permeabilization and subsequent neuronal apoptosis in vitroFootnote 704. In pre-clinical animal models of AD, cannabidiol dose-dependently and significantly inhibited reactive gliosis and subsequent neuroinflammatory responses in Aβ-injected mice, at doses of 2.5 mg/kg/day and 10 mg/kg/day i.p., during a seven-day course of treatmentFootnote 709. Another study using both in vitro and in vivo models of AD reported opposing roles for the CB1 and CB2 receptors in this context: CB1 receptor agonism and CB2 receptor antagonism were both associated with blunted Aβ-induced reactive astrogliosis and attenuation of neuroinflammatory marker expressionFootnote 710.

Clinical data

There are very few clinical studies of cannabis or cannabinoids for the treatment of AD. One double-blind, placebo-controlled, six-week, crossover study of 12 patients suffering from Alzheimer-type dementia reported that 5 mg of dronabinol (Δ9-THC) daily was associated with a decrease in disturbed behaviourFootnote 410. However, adverse reactions such as fatigue, somnolence, and euphoria (presumably unwanted) were reported in dronabinol-treated patients. One open-label pilot study of six patients suggested an evening dose of 2.5 mg dronabinol (Δ9-THC) reduced nocturnal motor activity and agitation in those who were severely dementedFootnote 711. In one case-report, a patient suffering from dementia of the Alzheimer-type who had been treated unsuccessfully with donepezil, memantine, gabapentin, trazodone, and citalopram was given nabilone (initially 0.5 mg at bedtime, and then twice per day) with immediate reduction in the severity of agitation and resistiveness and eventual improvement in various behavioural symptoms following six weeks of continuous treatmentFootnote 712. It is unclear if the beneficial effects observed in these three studies are related to the non-specific sedative effects of Δ9-THC or nabilone, or to a specific cannabinoid-dependent therapeutic mechanism of action. It is also worth noting that one cross-sectional study reported that prolonged use of ingested or inhaled cannabis was associated with poorer performance on various cognitive domains (e.g. information processing speed, working memory, executive function, and visuospatial perception) in patients with multiple sclerosisFootnote 178. Similar adverse effects of cannabis/cannabinoids on cognition could potentially apply in the context of Alzheimer-type dementia.

A Cochrane database systematic review of cannabinoids for the treatment of dementia concluded that there was insufficient clinical evidence to suggest cannabinoids as being effective in the improvement of disturbed behavior in dementia or in the treatment of other symptoms of dementiaFootnote 713.

4.8.7 Inflammation

The role of the endocannabinoid system in inflammation is complex as the endocannabinoid system has been implicated in both pro- and anti-inflammatory processesFootnote 701. Endocannabinoids, such as anandamide and 2-arachidonoylglycerol (2-AG), are known to be produced and released by activated immune cells and to act as immune cell chemoattractants promoting or directing the inflammatory responseFootnote 714. On the other hand, cannabinoids can also suppress the production of pro-inflammatory cytokines and chemokines and thus may have therapeutic applications in diseases with an underlying inflammatory componentFootnote 714,Footnote 715. For information on other diseases with an inflammatory component such as the arthritides or inflammatory bowel disease, please consult sections 4.7 and 4.8.8.2, respectively, of this document.

4.8.7.1 Inflammatory skin diseases (dermatitis, psoriasis, pruritus)

The skin possesses an endocannabinoid systemFootnote 41. CB1 and CB2 receptors are expressed in a number of skin cells including epidermal keratinocytes, cutaneous nerves and nerve fibres, sebaceous cells, myoepithelial cells of eccrine sweat glands, sweat gland ducts, mast cells, and macrophagesFootnote 716. The endocannabinoid system and certain associated signaling pathways (e.g. PPARγ, TRPV1) appear to regulate the balance between keratinocyte proliferation, differentiation, and apoptosis; together, these systems may play a role in cutaneous homeostasis but also in diseases such as psoriasis, which is characterized by keratinocyte proliferation and inflammationFootnote 41,Footnote 717,Footnote 718,Footnote 719.

Pre-clinical and clinical studies

The results from pre-clinical studies on the role of cannabinoids in the modulation of cutaneous allergic reactions are mixed. Some studies suggest a protective role for certain cannabinoids, while others suggest an antagonistic role (reviewed inFootnote 41). In clinical studies, experimentally-induced histamine-triggered pruritus was reduced by peripheral administration of the potent synthetic CB1/CB2 cannabinoid receptor agonist HU-210, and the accompanying increases in skin blood flow and neurogenic mediated flare responses were attenuatedFootnote 720. In another study, topically applied HU-210 significantly reduced the perception of localized pain in human subjects following locally restricted application of capsaicin to the skin, and reduced subsequent heat hyperalgesia and touch-evoked allodynia without any psychomimetic effectsFootnote 721. On the other hand, there have also been some case-reports of contact urticaria following exposure to cannabis flowers, and extreme sensitization to Δ9-THC and cannabinol has also been documented in an animal model of contact dermatitisFootnote 722,Footnote 723. Therefore, while it is possible that some cannabinoids (e.g. HU-210) may have therapeutic value in the treatment of certain inflammatory skin conditions (such as psoriasis, pruritus, and dermatitis), it is also possible for some cannabinoids to trigger adverse skin reactions. Much further research is required in this area.

4.8.8 Gastrointestinal system disorders (irritable bowel syndrome, inflammatory bowel disease, hepatitis, pancreatitis, metabolic syndrome/obesity)

Historical and anecdotal reports suggest that cannabis has been used to treat a variety of gastrointestinal disorders (e.g. diarrhea, inflammation, and pain of gastrointestinal origin)Footnote 724,Footnote 725,Footnote 726.

The endocannabinoid system and gastrointestinal disorders

The expression of both the CB1 and CB2 receptors has been detected in the enteric nervous system (enteric sensory neurons, nerve fibers and terminals), whereas the human colonic epithelium, colonic epithelial cells lines, and stomach parietal cells appear to only express the CB1 receptorFootnote 28,Footnote 29. CB2 receptor expression appears to be upregulated in sections of the colon in patients with inflammatory bowel diseaseFootnote 31. In contrast, the expression and localization of endocannabinoid synthesizing enzymes have not been well determinedFootnote 31. However, studies in animals indicate that the endocannabinoid degradative enzymes FAAH and MAGL can be found in the gastrointestinal tractFootnote 31. For example, FAAH is expressed in the stomach and in the large and small intestines, and has also been localized to the cell bodies of the myenteric plexusFootnote 31. MAGL expression has been detected in the muscle and mucosal layers of the duodenum and the ileum, as well as in the proximal and distal colon, and in the nerve cell bodies and nerve fibers of the enteric nervous systemFootnote 727. There also appears to be some regional variation in the levels of endocannabinoids in the gut; 2-arachidonoylglycerol (2-AG) appears to be more abundant in the ileum than the colon, whereas the opposite is true of anandamideFootnote 31. CB1 and CB2 receptors appear to be expressed in the pancreasFootnote 30, whereas the CB1, but not the CB2 receptor, is expressed in the liver under normal conditionsFootnote 32,Footnote 33.

Cannabinoids appear to have many functions in the digestive system including the inhibition of gastric acid production, gastrointestinal motility, and secretion and ion transport, and the attenuation of visceral sensation and inflammation (reviewed inFootnote 31). Perturbations in the levels of various components of the endocannabinoid system have been noted in experimental models of gastrointestinal disorders, as well as in clinical studies (reviewed inFootnote 31). The sections below summarize the information regarding the uses of cannabis and cannabinoids in the treatment of various disorders of the gastrointestinal system.

4.8.8.1 Irritable bowel syndrome

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder encountered in clinical medicineFootnote 728. It is a spectrum of disorders characterized by the presence of chronic abdominal pain and/or discomfort and alterations in bowel habitsFootnote 728,Footnote 729. Symptom patterns can be divided into diarrhea predominant (D-IBS), constipation predominant (C-IBS), and a mixed pattern (M-IBS)Footnote 729,Footnote 730. While the pathophysiology of IBS remains unclear, the disorder is thought to be caused by dysregulation of the 'brain-gut axis' in response to psychological or environmental stressors or to physical stressors such as infection or inflammation, and is characterized by altered gut motility and visceral hypersensitivityFootnote 728,Footnote 729. There is also some emerging evidence that suggests an association between genetic alterations in genes coding for certain endocannabinoid system proteins (e.g. FAAH and CNR1) and the pathophysiology of IBS Footnote 731,Footnote 732,Footnote 733.

Pre-clinical data

A few pre-clinical studies in animal models of IBS have been carried out to date. Two studies have employed mechanically-induced colorectal distension to trigger an acute visceral pain response in rodents as a model of IBS-associated visceral hypersensitivity. One study in rats showed that intra-peritoneal injection of different synthetic cannabinoid receptor agonists inhibited pain-related responses to experimentally-induced colorectal distension when administered prior to the experimental stimulusFootnote 734. Intravenous administration of different synthetic cannabinoid receptor agonists also appeared to inhibit the overall pain-related responses to experimentally-induced colorectal distension in rats, as well as in mice, when administered after the experimental stimulusFootnote 735. In another study, subcutaneous administration of CB1 or CB2-selective agonists was reported to reduce the enhanced small intestinal transit observed in a mouse model of post-inflammatory IBSFootnote 736.

Clinical data with dronabinol

There are only a handful of clinical studies examining the effects of cannabinoids in human experimental models of IBS and in patients with IBS.

One double-blind, randomized, placebo-controlled, parallel-group study examined the effects of dronabinol on gastrointestinal transit, gastric volume, satiation, and post-prandial symptoms in a group of healthy volunteersFootnote 737. A 5 mg dose of dronabinol was associated with a significant delay in gastric emptying in female subjects, but not male subjectsFootnote 737. No significant differences in either small bowel or colonic transit were observed between subjects administered dronabinol or placebo in any gender groupFootnote 737. The 5 mg dose of dronabinol was used because a 7.5 mg dose caused intolerable side effects in more than half of the subjectsFootnote 737. Adverse effects associated with the consumption of a 5 mg dose of dronabinol included dizziness/light-headedness, dry mouth, disturbed mental concentration, and nauseaFootnote 737.

A subsequent double-blind, randomized, placebo-controlled, parallel-group study carried out by the same group investigated the effects of dronabinol on colonic sensory and motor functions of healthy human volunteersFootnote 738. Administration of a 7.5 mg dose of dronabinol significantly increased colonic compliance, especially in females, and reduced pre- and post-prandial phasic colonic motility and pressureFootnote 738. Colonic compliance is defined as the change in distensibility of the colon in response to a change in applied intracolonic pressure and it is used as a measure of colonic viscoelastic properties and as an indicator of colonic motor/contractile activityFootnote 738,Footnote 739,Footnote 740. Decreased compliance is typically associated with urgency and diarrhea, while increased compliance is typically associated with constipationFootnote 739,Footnote 741. An increase in colonic compliance in this setting could indicate a return towards proper colonic function. In contrast to the results seen in the pre-clinical rodent studies, dronabinol increased the sensory rating of pain but did not affect the sensory rating of gas, or the thresholds for first sensation of either gas or pain during experimentally-induced random phasic distensionsFootnote 738.

A double-blind, randomized, parallel-group study investigated the effects of escalating doses of dronabinol on colonic sensory and motor functions in a population of mostly female patients diagnosed with IBS according to Rome III criteria (IBS-C, IBS-D, or IBS-A (i.e. alternating between diarrhea and constipation)) Footnote 742. Only the highest dose of dronabinol tested (5 mg) was associated with a small, but statistically significant, increase in colonic complianceFootnote 742. Furthermore, the effect on colonic compliance appeared to be more pronounced in the IBS-D/A sub-group compared to IBS-C. No significant differences were observed on fasting or post-prandial colonic tone in response to dronabinol at any dose. However, the highest dose of dronabinol (5 mg) was associated with a significant reduction in the proximal left colon motility index, with a trend towards decreased colon motility indicesFootnote 742. Treatment effects were significant on the proximal colon motility index in patients with IBS-D/A, but not in IBS-C, and only for the highest doseFootnote 742. Sensation thresholds and sensation scores for gas and pain during experimentally-induced ramp distensions did not differ significantly among the different treatment groupsFootnote 742. The effects of genotype and dronabinol dose interaction on gas and pain sensation ratings, as well as on proximal fasting and distal fasting motility indices were also investigated. The results from these preliminary pharmacogenetic studies raise the possibility that the effects of dronabinol on colonic compliance and proximal colonic motility may be influenced by genetic variations in the FAAH and CNR1 genes, but further studies are required to substantiate this hypothesisFootnote 742.

A subsequent double-blind, randomized, placebo-controlled, parallel-group study in a population of mostly female patients with IBS-D (Rome III criteria) further investigated gene-treatment interactions on colonic motility in this sub-set of IBS patientsFootnote 743. Neither the 2.5 mg b.i.d. nor the 5 mg b.i.d. doses of dronabinol had any statistically significant effects on gastric, small bowel, or colonic transitFootnote 743. The effects on colonic transit were also examined as a function of genotype-by-treatment dose interaction. While treatment with dronabinol appeared to decrease colonic transit in subjects carrying the CNR1 rs806378 CT/TT polymorphism, these effects were not statistically significant. Adverse effects were reported not to differ significantly between treatment groups.

4.8.8.2 Inflammatory bowel diseases (Crohn's disease, ulcerative colitis)

Inflammatory bowel diseases (IBD) include Crohn's disease and ulcerative colitisFootnote 744. Crohn's disease is characterized by patchy, intra-mural inflammation which may affect any part of the gastrointestinal tract Footnote 745. Symptoms include abdominal pain, diarrhea and weight loss as well as systemic symptoms of malaise, anorexia, and/or feverFootnote 745. Crohn's disease may cause intestinal obstruction due to strictures, fistulae, or abscessesFootnote 745. Ulcerative colitis is characterized by diffuse mucosal inflammation limited to the colonFootnote 745. Symptoms commonly include bloody diarrhea, colicky abdominal pain, urgency, or tenesmusFootnote 745. Both diseases are associated with an equivalent increased risk of colonic carcinomaFootnote 745.

The endocannabinoid system and IBD

Endocannabinoid system changes have been observed in the gastrointestinal tracts of experimental animal models of IBD, as well as in those of IBD patientsFootnote 31,Footnote 744. These changes include changes in the levels of endocannabinoids, cannabinoid receptors, and endocannabinoid synthesizing and degrading enzymesFootnote 28,Footnote 31,Footnote 744,Footnote 746,Footnote 747,Footnote 748.

Pre-clinical data

Pre-clinical experiments in animal models of IBD suggest cannabinoids and endocannabinoids may limit intestinal inflammation and disease severity via activation of CB receptorsFootnote 749,Footnote 750,Footnote 751,Footnote 752,Footnote 753,Footnote 754.

Acute colitis

Mice bearing a genetic deletion of the CB1 receptor had a stronger colonic inflammatory responseFootnote 749 following rectal administration of dinitrobenzene sulfonic acid (DNBSA), an established method of inducing an acute colitis-like phenotype in miceFootnote 755. In contrast to wild-type mice, histological examination of the colons of CB1 knockout mice treated with DNBSA revealed disruption of epithelial structure, with extensive hemorrhagic necrosis and neutrophil infiltration into the mucosa, and with acute inflammation extending into the sub-mucosa and muscle layerFootnote 749. Pharmacological blockade of the CB1 receptor in wild-type mice produced similar effects accompanied by thickening of the bowel wall, inflammatory infiltrates, and an increase in lymphoid-follicle size associated with adherence to surrounding tissuesFootnote 749. Furthermore, in contrast to CB1 knockout mice, wild-type mice retained a significantly greater body weight following DNBSA treatmentFootnote 749. Treatment of wild-type mice with the potent synthetic CB1 and CB2 receptor agonist HU-210, prior to and after DNBSA insult, significantly reduced the macroscopic colonic inflammatory responseFootnote 749. Mice bearing a genetic deletion of the FAAH enzyme also displayed an attenuated inflammatory response to DNBSA compared to wild-type littermatesFootnote 749.

An analogous study found that CB1 and CB2 receptor knockout mice and CB1/CB2 receptor double knockout mice showed increased extent of colonic inflammation, increased loss of crypt architecture, increased hyperemia/edema, and an increased degree of infiltration of inflammatory cells compared to wild-type mice following trinitrobenzene sulfonic acid (TNBSA)-induced acute colitisFootnote 753. All three knockout strains exhibited severe transmural colitis, with severe loss of epithelium, thickening of the bowel wall, and inflammatory infiltrates compared to wild-type miceFootnote 753. Genetic deletion of either or both CB receptors was also associated with significantly increased mRNA levels of various pro-inflammatory cytokines compared to wild-type mice in mice treated with TNBSAFootnote 753.

TNBSA-induced acute colitis in mice was associated with a significant upregulation of CB2 receptor mRNA levels in the proximal and distal colons of treated miceFootnote 756. Intra-peritoneal administration of CB2 receptor agonists, prior to and following TNBSA-induced colitis, was associated with a reduction in the macroscopic damage (e.g. reduced ulceration, reduction in colonic adhesions, and reduced colonic shortening)Footnote 756. Conversely, administration of a CB2 receptor antagonist aggravated TNBSA-induced colitisFootnote 756.

Acute colitis and cannabidiol

Intra-peritoneal injection of cannabidiol (5 - 10 mg/kg) prior to DNBSA-induced acute colitis was associated with a significant attenuation of body weight loss caused by DNBSAFootnote 757. Cannabidiol (CBD) also reduced the wet weight/colon length ratio of inflamed colonic tissue, a marker of the severity and extent of the inflammatory responseFootnote 757. Furthermore, CBD (5 - 10 mg/kg) significantly reduced macroscopic damage associated with DNBSA administration (mild edema, hyperemia, and small bowel adhesions) as well as microscopic damage (epithelium erosion, and mucosal and sub-mucosal infiltration of inflammatory cells with edema)Footnote 757. Lastly, treatment with CBD significantly attenuated the observed increases in some biological markers associated with inflammation and oxidative stress, as well as attenuating the observed increases in the colonic levels of anandamide and 2-AGFootnote 757.

Another study reported that intra-peritoneal (10 mg/kg) or intra-rectal (20 mg/kg) pre-treatment with CBD, again administered prior to induction of colitis by TNBSA, caused a significant improvement of the colitis score and a decrease in the myeloperoxidase activity (a measure of neutrophil accumulation in colonic tissue) Footnote 758. No such differences were observed for orally administered CBD. Histological examination of colonic tissue further revealed decreased destruction of the epithelial lining, a reduction in colon thickness, and less infiltration of immunocytes compared to vehicle-treated miceFootnote 758. In contrast to the study by BorrelliFootnote 757, no differences in body weight were observed between vehicle-treated and CBD-treated mice that had developed colitisFootnote 758.

The effects of intra-peritoneal injections of THC, CBD, and a combination of THC and CBD on TNBSA-induced acute colitis in rats have been investigatedFootnote 754. In one experiment, treatment with 10 mg/kg of THC alone, a combination of 5 mg/kg THC and 10 mg/kg CBD, a combination of 10 mg/kg THC and 10 mg/kg CBD, or sulfasalazine alone was associated with a statistically significant decrease in the macroscopic damage score (MDS)Footnote 754. The MDS is a linear scale measuring the extent of macroscopic damage to the colon and includes markers such as the presence or absence of hyperemia, ulceration, inflammation, adhesions, damage length, and diarrheaFootnote 754. Furthermore, treatment of rats (with experimentally-induced colitis) with CBD alone did not affect body weight. However, treatment with 5 or 20 mg/kg THC alone, or a combination of 10 mg/kg THC and 10 mg/kg CBD, resulted in a significant reduction of body weight gain in rats with experimentally-induced colitis in comparison with the vehicle groupFootnote 754. Myeloperoxidase activity, a measure of inflammation, was significantly decreased in CBD-treated rats and in rats treated with 10 or 20 mg/kg THC, or 5 mg/kg THC and 10 mg/kg CBDFootnote 754. Treatment with 10 mg/kg CBD, 10 mg/kg THC, 10 mg/kg THC and 10 mg/kg CBD, or sulfasalazine alone was also associated with decreased disturbances in colonic motility resulting from TNBSA-induced colitisFootnote 754.

In a different experimental mouse model of acute colitis, the CB1 receptor-selective agonist ACEA and the synthetic CB2 receptor-selective agonist JWH-133, when injected intra-peritoneally prior to and after colonic insult, significantly reduced colon weight gain, colon shrinkage, colon inflammatory damage score, and diarrheaFootnote 751.

Inhibition of the 2-AG degrading enzyme monoacylglycerol lipase (MAGL) in mice by intra-peritoneal administration of a MAGL inhibitor prior to induction of acute colitis by TNBSA was associated with decreased macroscopic and histological colon alterations, as well as decreased colonic expression of pro-inflammatory cytokinesFootnote 759. Inhibition of MAGL was also associated with a reduction in colitis-related systemic and central inflammation in the liver and the CNSFootnote 759. Co-administration of either CB1 or CB2 receptor-selective antagonists completely abolished the protective effect in the colon afforded by MAGL inhibition, and partially reversed the protective anti-inflammatory effects associated with MAGL inhibition in the liverFootnote 759.

Chronic colitis

Intra-peritoneal administration of the synthetic CB2 receptor-specific agonist JWH-133 significantly attenuated colitis-associated body weight loss, inflammation, leukocyte infiltration, and tissue damage in a mouse model of spontaneous chronic colitisFootnote 760. This CB2 receptor specific agonist also reduced T-cell proliferation, increased T-cell apoptosis, and increased the numbers of mucosal and systemic mast cellsFootnote 760.

Ileitis

The effect of cannabichromene on inflammation-induced hypermotility in a mouse model of intestinal ileitis has been studiedFootnote 761. Ileitis is characterized by disruption of the mucosa, infiltration of lymphocytes into the sub-mucosa, increased myeloperoxidase activity, and vascular permeabilityFootnote 761. Administration of cannabichromene (15 mg/kg i.p.) following croton oil-induced intestinal inflammation was associated with a decrease in the expression of CB1 and CB2 receptor mRNA in the jejunum, but not in the ileumFootnote 761. Cannabichromene did not affect upper gastrointestinal transit, colonic propulsion, or whole gut transit in untreated mice, but did reduce intestinal motility in croton oil-treated mice at 10 and 20 mg/kg i.p.Footnote 761. Cannabichromene also dose-dependently and significantly inhibited contractions induced by acetylcholine, as well as electrical field stimulation, in vitro in ilea isolated from control mice and croton oil-treated miceFootnote 761. The inhibitory effect of cannabichromene appeared to be cannabinoid receptor-independentFootnote 761.

Clinical studies with THC

A double-blind, randomized, placebo-controlled, crossover study examining the effects of 5 and 10 mg Δ9-THC in visceral sensitivity reported that Δ9-THC did not alter baseline rectal perception to experimentally-induced distension or sensory thresholds of discomfort after sigmoid stimulation compared to placebo, in either healthy controls or IBD patientsFootnote 762. However, the authors did note a bias in the patient selection criteria which could have explained the apparent lack of effect.

Surveys and clinical studies with cannabis

Findings from a cross-sectional survey of 291 patients with IBD (Crohn's disease or ulcerative colitis) suggested that the vast majority of those patients reported using cannabis to relieve abdominal pain and to improve appetiteFootnote 157. In contrast to patients with Crohn's disease, a greater proportion of patients with ulcerative colitis reported using cannabis to improve diarrheal symptomsFootnote 157. In general, patients reported being more likely to use cannabis for symptom relief if they had a history of abdominal surgery, chronic analgesic use, alternative/complementary medicine use, and a lower SIBDQ (short inflammatory bowel disease questionnaire) scoreFootnote 157. Both ulcerative colitis and Crohn's disease patients reported using cannabis to improve stress levels and sleepFootnote 157. The mean duration of cannabis use (current or previous) was seven years. The majority of cannabis users reported using once per month or less, but 16% reported using cannabis daily or several times per dayFootnote 157. The vast majority (77%) of users reported smoking the cannabis as a joint without tobacco, 18% of users smoked it with tobacco, 3% used a water pipe, and 1% reported oral ingestionFootnote 157. Approximately one-third of patients in this study reported significant side effects associated with the use of cannabis such as paranoia, anxiety, and palpitations. Other commonly reported side effects included feeling "high", dry mouth, drowsiness, memory loss, hallucinations, and depressionFootnote 157.

A retrospective, observational study of 30 patients with Crohn's disease examined disease activity, use of medication, need for surgery, and hospitalization before and after cannabis useFootnote 248. The average duration of disease was 11 years (range: 1 - 41 years). Twenty patients suffered from inflammation of the terminal ileum, five had inflammation of the proximal ileum, and eight had Crohn's disease of the colon. The indication for cannabis was lack of response to conventional treatment in the majority of the patients, and chronic intractable pain in most of the other patientsFootnote 248. Most patients smoked cannabis as joints (0.5 g cannabis/joint), a few inhaled the smoke through water, and one patient consumed cannabis orallyFootnote 248. Of those who smoked cannabis, most smoked between one and three joints per day. One patient smoked seven joints per day. The average duration of cannabis use was two years (range: 2 months - 9 years). All patients reported that consuming cannabis had a positive effect on their disease activityFootnote 248. The scores on the Harvey-Bradshaw index (an index of Crohn's disease activity) were significantly decreased following cannabis use, and the use of other medications (e.g. 5-ASA, corticosteroids, thiopurine, methotrexate, and TNF antagonist) also appeared to be significantly reduced following use of cannabisFootnote 248. The study was limited by design and small size.

A preliminary, observational, open-label, prospective, single-arm trial in a group of 13 patients suffering from Crohn's disease or ulcerative colitis reported that treatment with inhaled cannabis over a three-month period improved subjects' quality of life, caused a statistically significant increase in subjects' weight, and improved the clinical disease activity index in patients with Crohn's diseaseFootnote 189. Patients reported a statistically significant improvement in their perception of their general health status, their ability to perform daily activities, and their ability to maintain a social lifeFootnote 189. Patients also reported a statistically significant reduction in physical pain, as well as improvement in mental distressFootnote 189. No serious adverse events were noted. Study limitations included study design, subject selection bias, the lack of a proper control group and placebo, small number of subjects, and the inability to establish a dose-response effectFootnote 189.

Note: for sections 4.8.8.3, 4.8.8.4, and 4.8.8.5 below, no clinical studies examining the role of cannabis in the treatment of these disorders have been carried out to date.

4.8.8.3 Diseases of the liver (hepatitis, fibrosis, steatosis, ischemia-reperfusion injury, hepatic encephalopathy)

CB1 receptors are expressed at low levels in the whole liver, hepatocytes, stellate cells, and hepatic vascular endothelial cells, but increased CB1 receptor expression has been detected in the context of diseases such as hepatocellular carcinoma and primary biliary cirrhosis (reviewed inFootnote 763). CB2 receptors are undetectable in normal liver but, like the CB1 receptors, they are upregulated in pathological conditions; these include nonalcoholic fatty liver disease (NAFLD), liver fibrosis, regenerating liver, and hepatocellular carcinoma (reviewed inFootnote 763). Increases in the concentrations of the endocannabinoids anandamide and 2-AG in the liver appear to vary depending on the pathophysiological condition in questionFootnote 33.

Steatosis and fibrosis

Mounting evidence suggests an important role for the endocannabinoid system in the pathophysiology of a multitude of diseases affecting the liverFootnote 33. In general, the CB1 and CB2 receptors appear to play opposing roles in the liver: activation of the CB1 receptors is implicated in the progression and worsening of alcoholic and metabolic steatosis, liver fibrogenesis, and circulatory failure associated with cirrhosis; stimulation of the CB2 receptors, in general, appears to confer beneficial effects in alcoholic fatty liver, hepatic inflammation, liver injury, liver regeneration, and fibrosis (reviewed inFootnote 33 and see alsoFootnote 249,Footnote 250,Footnote 251,Footnote 764). Conversely, antagonism of the CB1 receptor appears to attenuate liver fibrosis in animal models by interfering with the production of several pro-fibrotic, pro-inflammatory, as well as anti-inflammatory mediators secreted in the liver during chronic liver injury and the wound healing processFootnote 249,Footnote 765.

In vitro studies indicate that CBD may also play a protective role in attenuating liver fibrosis induced by acute liver injury or by chronic alcohol exposureFootnote 766. CBD dose-dependently triggered the apoptosis of cultured, activated hepatic stellate cells isolated from the livers of rats chronically exposed to an ethanol dietFootnote 766. The activation of hepatic stellate cells in response to liver injury is considered a key cellular event underlying hepatic fibrogenesisFootnote 766. Furthermore, CBD dose-dependently promoted the selective apoptosis of activated hepatic stellate cells, but not control hepatic stellate cells or primary hepatocytes, by triggering an endoplasmic reticulum-associated cellular stress response leading to apoptosis; this effect was independent of CB receptor activationFootnote 766.

Ischemia-reperfusion injury and hepatic encephalopathy

Pre-clinical studies also indicate a protective role for CBD in hepatic ischemia/reperfusion injury, and hepatic encephalopathy, in mice and ratsFootnote 767,Footnote 768,Footnote 769. Pre-treatment of mice with 3 or 10 mg/kg body weight CBD (i.p.), 2 h before induction of ischemia-reperfusion in liver, dose-dependently attenuated serum transaminase elevations at 2 and 6 h of reperfusion compared to vehicleFootnote 767. CBD administered immediately following the induction of ischemia, or at 90 min of reperfusion, still attenuated hepatic injury measured at 6 h of reperfusion, though to a lesser extent than when administered prior to the induction of the ischemia-reperfusion injuryFootnote 767. Pre-treatment with CBD also significantly reduced the signs of coagulation necrosis observed 24 h after ischemia-reperfusion, significantly attenuated hepatic cell apoptosis, significantly decreased the expression of pro-inflammatory chemokines and cytokines, attenuated neutrophil infiltration into the injury site, and decreased the expression of markers of tissue and cellular injuryFootnote 767. Similar beneficial findings in a rat model of ischemia-reperfusion injury were reported in a different study; however, CBD (5 mg/kg, i.v.) was administered after ischemia-reperfusion injuryFootnote 768. CBD treatment resulted in significant reductions in serum transaminase levels, hepatic lipid peroxidation, and the attenuation of various markers of tissue or cellular injury associated with ischemia-reperfusionFootnote 768. Administration of Δ8-tetrahydrocannabivarin (3 or 10 mg/kg, i.p.) 2 h before induction of hepatic ischemia-reperfusion injury dose-dependently attenuated serum transaminase elevations at 2 and 6 h of reperfusion compared to vehicleFootnote 770. Administration of Δ8-tetrahydrocannabivarin post-ischemia attenuated, although to a lesser degree, the hepatic injury measured at 6 h of reperfusionFootnote 770. Pre-treatment with Δ8-tetrahydrocannabivarin also significantly reduced the extent of coagulation necrosis in the liver, attenuated neutrophil infiltration, decreased the expression of hepatic pro-inflammatory chemokines and cytokines, reduced the hepatic levels of markers of oxidative stress, and decreased the extent of hepatocyte cell death following ischemia-reperfusion injuryFootnote 770.

Intra-peritoneal administration of CBD (5 mg/kg, i.p.) improved neurological, locomotor, and cognitive functions in a mouse model of fulminant hepatic encephalopathyFootnote 769. CBD also attenuated the degree of astrogliosis, but did not affect the extent and severity of necrotic lesions in the liverFootnote 769. CBD partially restored whole brain 5-HT levels, as well as the levels of markers of liver function (ammonia, bilirubin, AST, ALT) in affected miceFootnote 769.

4.8.8.4 Metabolic syndrome, obesity, diabetes
The endocannabinoid system and energy metabolism

Increasing evidence suggests an important role for the endocannabinoid system in the regulation of energy balance; dysregulation of the system is associated with the development of metabolic syndrome and obesity, and may also increase the risk of developing atherosclerosis and type-2 diabetesFootnote 11,Footnote 17,Footnote 771. Pre-clinical studies carried out in animal models of obesity and clinical studies performed in obese humans report increased endocannabinoid tone in adipose tissue, liver, pancreas, and in the hypothalamus compared to controlsFootnote 772.

The regulation of energy balance by the endocannabinoid system appears to occur both centrally (in the CNS, particularly in the hypothalamus) and peripherally in multiple organs such as the white adipose tissue, skeletal muscle, pancreas, liver, and small intestineFootnote 11,Footnote 17,Footnote 771,Footnote 773. In general, overactivity of the endocannabinoid system is associated with increased nutrient intake, enhanced energy storage, and reduced energy expenditureFootnote 17. Endocannabinoid tone appears to be modulated by hormones and peptides including leptin, insulin, ghrelin, and corticosteroidsFootnote 17. Endocannabinoids, in turn, appear to modulate the release of neurotransmitters and neuropeptides such as opioids, serotonin, and GABA, which are known to play a role in regulating appetite mainly through central mechanismsFootnote 774.

Pre-clinical data

THC and the role of the CB1 receptor

In pre-clinical in vitro studies, THC significantly inhibited basal and catecholamine-triggered lipolysis in a differentiated mouse adipocyte cell line in a concentration-dependent manner and caused dose-dependent accumulation of lipid droplets in these cellsFootnote 23. In mice, activation of the CB1 receptor resulted in increased de novo fatty acid synthesis in the liver and increased formation and storage of triglycerides in the adipose tissueFootnote 11,Footnote 775,Footnote 776,Footnote 777. In rats, central stimulation of the CB1 receptor was associated with the development of hepatic and adipose tissue insulin resistanceFootnote 772. Mice lacking overall CB1 receptor gene expression were hypophagic and were leaner than wild-type mice regardless of diet, had lower plasma insulin levels, did not develop diet-induced insulin resistance or obesity, and had enhanced leptin sensitivityFootnote 391,Footnote 775,Footnote 778. In mice, targeted deletion of the CB1 receptor in the forebrain-projecting neurons in the hypothalamus and in the nucleus of the solitary tract, and partial deletion in sympathetic neurons were associated with a lean phenotype and resistance to diet-induced obesity and increases in plasma levels of leptin, insulin, glucose, free fatty acids, and triglycerides; these effects resulted from an increase in lipid oxidation and thermogenesis as a consequence of enhanced sympathetic tone and a decrease in energy absorptionFootnote 779. Similarly, partial targeted deletion of the CB1 receptor gene in the adult mouse hypothalamus lead to a significant decrease in body weight gain triggered by an increase in energy expenditure, rather than a decrease in food intakeFootnote 777.

Targeted deletion of the CB1 receptor gene in mouse liver is associated with the development of diet-induced obesity, but retention of glucose, insulin and leptin sensitivity and lipid indices; targeted hepatic re-expression of the CB1 receptor gene in CB1 receptor gene knockout mice was associated with glucose intolerance and insulin resistance in response to a high-fat diet, but maintenance of proper body weight Footnote 780,Footnote 781. Studies with CB1 antagonists/inverse agonists strongly suggest that antagonism/inverse agonism at the CB1 receptor is associated with reduced caloric intake, weight loss, improvement or reversal of hepatic steatosis, and restoration of insulin and glucose sensitivity and normal lipid indices in various animal models of diet-induced obesityFootnote 391,Footnote 782,Footnote 783,Footnote 784,Footnote 785,Footnote 786,Footnote 787,Footnote 788. Clinical studies with the CB1 antagonist rimonabant have strongly supported the data gathered from animal studiesFootnote 789,Footnote 790,Footnote 791,Footnote 792,Footnote 793,Footnote 794,Footnote 795.

Taken together, the above findings suggest an important role for the CB1 receptor, both centrally and peripherally, in regulating energy balance; stimulation of the CB1 receptor promotes energy storage and lipogenesis, whereas CB1 receptor antagonism has the opposite effects. Consistent with these findings, cannabis and prescription cannabinoids (dronabinol, nabilone) are known to increase appetite and body weight and have been used clinically to treat HIV/AIDS-associated anorexia-cachexia, and possibly also cancer-associated cachexia (see sections 4.3.1 and 4.3.2, respectively). Yet curiously, despite these beneficial effects on body weight in clinical disorders, a number of studies have so far failed to find an association between overweight/obesity and consumption of cannabis in the general populationFootnote 796,Footnote 797. In fact, the prevalence of obesity appeared to be significantly lower in cannabis users than in non-users, and the proportion of obese individuals also appeared to decrease with frequency of cannabis use according to a cross-sectional analysis of two U.S. epidemiological studiesFootnote 797.

Role of the CB2 receptor

The CB2 receptor also appears to also play an important role in energy balanceFootnote 798. Pre-clinical studies in mice indicate that the CB2 receptor is expressed in epididymal adipose tissue in lean mice, and the levels of this receptor appear to increase in the non-parenchymal cell fractions of adipose tissue and liver in genetically obese mice or in wild-type mice fed a high-fat dietFootnote 798. Furthermore, systemic administration of a CB2 receptor-selective agonist to lean or obese mice, or exposure of cultured fat pads to the same agonist, was associated with upregulation of a subset of genes linked to inflammation in the adipose tissue but not the liverFootnote 798. Conversely, administration of a CB2-selective antagonist reduced inflammation both in adipose tissue and liver of obese animalsFootnote 798. Under a high-fat diet, mice lacking the CB2 receptor displayed a slower body weight progression and were more insulin sensitive than wild-type miceFootnote 798. CB2 knockout mice on a high-fat diet also exhibited minimal hepatic steatosis compared to wild-type miceFootnote 798. Mice deficient in CB2 receptor expression also exhibited increased food intake and body weight with age compared to wild-type miceFootnote 799. The CB2 receptor knockout mice did not develop insulin resistance and showed enhanced insulin-stimulated glucose uptake in skeletal muscleFootnote 799. Taken together, these results suggest an important and complex role for the CB2 receptor in energy balance and obesity, although further studies are needed to better understand its role.

Other cannabinoids

Pure Δ9-tetrahydrocannabivarin (THCV) administered i.p. (3 mg/kg, 10 mg/kg, or 30 mg/kg) in mice suppressed feeding and significantly reduced body weight gain, but this effect appeared to be blocked when a botanical extract containing both Δ9-THCV and Δ9-THC was usedFootnote 92. Inclusion of cannabidiol into the botanical extract, as a way of attenuating the proposed hyperphagic effects of THC in this study, resulted in a trend towards decreased food intake in treated mice, but the effect did not reach statistical significanceFootnote 92. Lean and obese rats injected with a cannabis extract (on alternate days, for 28 days) containing a THC : CBN : CBD ratio of 1.0 : 1.2 : 0.4 (5 mg/kg Δ9-THC) exhibited a significant reduction in weight gain during the study period, but the cannabis extract treatment was not associated with any changes in either insulin or glucose levelsFootnote 800.

4.8.8.5 Diseases of the pancreas (diabetes, pancreatitis)

Although there appears to be a general lack of consensus as well as insufficient information regarding the exact expression, distribution, and function of the various endocannabinoid system components in the pancreas among different species, the pancreas does appear to have at least some, and in certain cases many, of the individual elements of the endocannabinoid systemFootnote 774,Footnote 801,Footnote 802.

Function of the endocannabinoid system in the pancreas

Two studies using primary human islet cells suggest that the CB1 and CB2 receptors are expressed in these cells, and that stimulation of the CB1 receptor is associated with secretion of insulin and glucagon while stimulation of the CB2 receptor is associated with either increased or decreased insulin secretionFootnote 801,Footnote 803 (and also reviewed inFootnote 774). More recently, the endocannabinoid 2-arachidonoylglycerol (2-AG) has been implicated in the regulation of both insulin and glucagon secretion in human pancreasFootnote 802.

Intra-muscular administration of cannabis resin (containing 6.3% Δ9-THC, 3.2% cannabidiol, and 1.9% cannabinol) at increasing doses (Δ9-THC at 2.5, 5.0, and 10 mg/kg) to dogs was associated with a progressive increase in plasma glucose levels which reached maximum values 90 min after administration, with a return to baseline values 180 min after administrationFootnote 804. Injection of anandamide or a CB1 receptor-selective agonist in rats was associated with acute glucose intolerance, whereas administration of a CB1 receptor inverse agonist attenuated this effectFootnote 805. In humans, intravenous injection of 6 mg of Δ9-THC to healthy, non-obese male volunteers was associated with acute impairment of glucose tolerance in response to glucose challenge with no change in plasma insulin levelsFootnote 806.

Survey data

A cross-sectional study of 10 896 adults, ages 20 - 59, who were participants in the National Health and Nutrition Examination Survey III (NHANES), a nationally representative sample of the U.S. population, reported that cannabis use was independently associated with a decreased prevalence of diabetes mellitus, and that cannabis users had lower odds of developing diabetes mellitus compared to non-usersFootnote 807. The lowest prevalence of diabetes mellitus was seen in current, light cannabis users, but current heavy users and past users also had a lower prevalence of diabetes mellitus than non-cannabis usersFootnote 807. Due to limitations in study methodology (e.g. cross-sectional nature of the study, self-report bias, and inconsistent sampling methodology) as well as the possibility of additional and uncontrolled confounding factors, the authors indicate that it is not yet possible to conclude that cannabis use does not lead to diabetes mellitus, nor that cannabis should be considered a treatment for this disorderFootnote 807.

Cannabis, the endocannabinoid system, and acute and chronic pancreatitis

Acute, heavy cannabis use has been linked to the development of acute pancreatitisFootnote 253,Footnote 254,Footnote 255,Footnote 256. Acute pancreatitis is a potentially lethal disorder involving inflammation, cell death, and complex neuroimmune interactions; the management of chronic pancreatitis remains clinically challenging with no definite cure and supportive measures are the only treatment availableFootnote 808,Footnote 809. Pancreatic tissue isolated from patients with acute pancreatitis has been reported to have a marked upregulation of CB1 and CB2 receptors in the acini and ducts as well as elevated levels of the endocannabinoid anandamide but not 2-AGFootnote 808. In a subsequent study, an increase in the expression levels of CB1 and CB2 receptors, and a decrease in the levels of endocannabinoids (anandamide and 2-AG) were noted in tissue samples isolated from patients suffering from chronic pancreatitis compared to pancreatic tissues isolated from healthy subjectsFootnote 809. In addition, in contrast to the findings obtained for acute pancreatitisFootnote 808, tissues isolated from patients with chronic pancreatitis appeared to have decreased levels of anandamide and 2-AGFootnote 809. Activation of CB1 and CB2 receptors in chronic pancreatitis-derived pancreatic stellate cells was also associated with the induction of a quiescent-cell phenotype as well as the downregulation of extracellular matrix protein production and inflammatory cytokine productionFootnote 809.

Pre-clinical data and acute or chronic pancreatitis

There are only a handful of reports on the effects of cannabinoids in experimental animal models of acute or chronic pancreatitis, and the findings from these reports are conflicting. Thus, the use of cannabinoids in the treatment of acute or chronic pancreatitis remains unclear. Information gathered from pre-clinical animal studies is summarized below.

Elevations in the plasma levels of anandamide have been noted in a rat model of severe acute pancreatitis Footnote 810, and administration of the CB1 receptor antagonist AM251 after induction of pancreatitis appeared to improve the course of the diseaseFootnote 810. In another study, administration of anandamide prior to induction of pancreatic damage further aggravated the usual course of the disease, whereas pre-treatment with the CB1 receptor antagonist AM251 prevented the development of cerulein-induced pancreatitis and when administered after injury also appeared to reverse cerulein-induced pancreatic damageFootnote 811. Similarly, mice treated with the CB1 receptor antagonist rimonabant prior to cerulein-induced pancreatitis exhibited significantly decreased pancreatic damage as well as decreased production of inflammatory cytokinesFootnote 812. Subcutaneous administration of a synthetic CB1/CB2 receptor agonist, both prior to as well as after induction of acute pancreatitis in mice, attenuated the abdominal pain, inflammation, and tissue pathology associated with pancreatitisFootnote 808. In contrast, a different study reported that pre-treatment of rats with a synthetic CB1/CB2 receptor agonist before induction of experimentally-induced pancreatitis attenuated the extent of tissue damage and the release of inflammatory cytokines, whereas administration of the same agonist after the induction of pancreatitis had the opposite effects and appeared to aggravate the course of the disease Footnote 813. These contradictory findings may be due to differences in experimental methods, differences in timing of drug administration, differences in the types of agonists and antagonists that were used, differences in the route of administration, and differences in animal species.

4.8.9 Anti-neoplastic properties

A number of studies have implicated the endocannabinoid system in the pathophysiology of cancer. In general, endocannabinoids seem to have a protective effect against carcinogenesis, and proper regulation of local endocannabinoid tone is likely an important factor in controlling the malignancy of different cancersFootnote 814. When compared with healthy tissues, the levels of endocannabinoids appear to be elevated in glioblastomas, meningiomas, pituitary adenomas, prostate and colon carcinomas, and endometrial sarcomas Footnote 746,Footnote 815,Footnote 816,Footnote 817,Footnote 818,Footnote 819. The expression levels of cannabinoid receptors are also differentially regulated in normal versus malignant cells, with increased or decreased levels of these receptors varying with cancer type (reviewed inFootnote 814). Such differences in the levels of endocannabinoids and in the patterns of expression levels of cannabinoid receptors across different cancer types reflect the complex role of the endocannabinoid system in cancer and are likely to pose challenges to potential therapeutic approaches. Nonetheless, a number of pre-clinical studies have shown that endocannabinoids, certain synthetic cannabinoid agonists, and some phytocannabinoids can inhibit tumour growth and progression of numerous types of cancers through various mechanisms including promotion of apoptosis, cell-cycle arrest/growth inhibition, and prevention of metastasis through inhibition of tumour invasion, migration, and neo-angiogenesis (reviewed inFootnote 814,Footnote 820).

In general, the anti-neoplastic effects of Δ9-THC appear to be biphasic: lower doses (under 100 nM), comparable to those typically seen in clinical or therapeutic settings, are considered pro-proliferative; higher doses (above 100 nM) are thought to be anti-proliferativeFootnote 821, although exceptions have been noted. Furthermore, cannabinoid concentrations above 100 nM, that is two orders of magnitude above the average affinity of these receptors for cannabinoids, are likely to produce off-target, CB receptor-independent effectsFootnote 822. As a point of reference, single oral doses of dronabinol (Δ9-THC) of 2.5, 5, and 10 mg have been associated with mean peak Δ9-THC plasma concentrations of 0.65, 1.83, and 6.22 ng/mL, respectivelyFootnote 174. These concentrations correspond to concentrations of 0.002, 0.006, and 0.02 μM (or 2, 6, and 20 nM) Δ9-THC. Doubling of these daily oral doses is associated with mean peak Δ9-THC plasma concentrations of 1.3, 2.9, and 7.9 ng/mL Δ9-THCFootnote 174, respectively, corresponding to 0.004, 0.009, and 0.03 μM (or 4, 9, and 30 nM) Δ9-THC. Continuous dosing for seven days with 20 mg doses of dronabinol (total daily doses of 40 - 120 mg dronabinol) gave mean plasma Δ9-THC concentrations of ~20 ng/mL or ~0.06 μM (60 nM) Δ9-THCFootnote 288. Smoking a 1 g joint containing 12.5% Δ9-THC can be assumed, based on the literature, to yield peak plasma Δ9-THC concentrations between 50 and 100 ng/mL or more (see section 3.1 "Smoking", subsection "Plasma concentrations of Δ9-THC following smoking"). Such Δ9-THC plasma concentrations correspond to 0.16 and 0.32 μM (or 160 and 320 nM) Δ9-THC, respectively. Plasma concentrations of Δ9-THC are known to vary widely across individuals, and diminish more rapidly by the smoking route than by oral administration. With respect to doses expressed in mg/kg of body weight, a daily oral dose of 2.5 mg of dronabinol (Δ9-THC) can be estimated to correspond to a dose of approximately 0.04 mg/kg (assuming a body weight of 70 kg), whereas a daily oral dose of 40 mg of dronabinol would correspond to a dose of approximately 0.6 mg/kg of dronabinol. Smoking a 1 g joint containing 12.5% Δ9-THC would correspond to a hypothetical dose of 1.8 mg/kg Δ9-THC.

The following paragraphs summarize the main findings from a number of pre-clinical in vitro and in vivo studies of cannabinoids in neoplastic diseases. Clinical data are presented at the end of this section.

Pre-clinical data

In vitro studies suggest that Δ9-THC decreases cell proliferation and increases cell death in human glioblastoma multiforme cell lines, with CB receptor activation accounting for only part of the observed effectsFootnote 823. In the case of astrocytomas, higher concentrations were deemed to be clinically preferable because this would bypass CB receptor activation and induce apoptosis in all astrocytoma cell sub-populationsFootnote 824. In the case of breast cancer, Δ9-THC reduced human breast cancer cell proliferation at concentrations of 4 - 10 μM (i.e. 4 000 - 10 000 nM), with more aggressive estrogen receptor-negative tumour cells being more sensitive to the effects of THC Footnote 825. In contradistinction, another study showed that Δ9-THC (50 μM (i.e. 50 000 nM) in vitro or 50 mg/kg in vivo) enhanced breast cancer growth and metastasisFootnote 826. Furthermore, Δ9-THC, CBD, and CBN all stimulated breast cancer cell proliferation at concentrations ranging from 5 - 20 μM (i.e. 5 000 - 20 000 nM)Footnote 827, but this effect appeared to depend to some extent on the hormonal milieu (with lower estrogen levels promoting, and higher estrogen levels inhibiting growth). On the other hand, cannabinoids such as cannabigerol, cannabichromene, cannabidiolic acid, and THC acid as well as cannabinoid-based extracts enriched in either Δ9-THC or CBD inhibited cell proliferation (in the micromolar range) in a number of different breast cancer cell lines Footnote 828. In in vitro studies examining the role of cannabinoids in lung cancer, Δ9-THC (10 - 15 μM) (i.e. 10 000 - 15 000 nM) attenuated growth factor-induced migration and invasion of non-small cell lung cancer cell lines Footnote 829. In the case of colorectal cancer, Δ9-THC at concentrations of 2.5 μM (i.e. 2 500 nM) and above (range: 7.5 - 12.5 μM) (i.e. 7 500 - 12 500 nM) were associated with a decrease in colorectal cancer cell survival, whereas lower concentrations (100 nM - 1 μM) had no effectFootnote 830. Taken together, these and other in vitro studies suggest cannabinoids can have complex biological effects in the context of malignancies. Differences in experimental conditions, cancer cell type, CB-receptor expression, hormonal levels, and the existence of CB-receptor dependent and independent regulatory mechanisms all appear to affect the control of growth, proliferation, and invasion of cancer cells in response to cannabinoids. Furthermore, these findings also suggest that the effective inhibitory concentrations of Δ9-THC seen in vitro are between ~ 10 and 7 500 times higher than the concentrations of Δ9-THC seen clinically, depending on the route of administration.

A pre-clinical in vivo study in rats showed that intra-tumoural administration of Δ9-THC caused significant regression of intra-cranial malignant gliomas, and an accompanying increase in animal survival time without any neurotoxicity to healthy tissuesFootnote 831. Furthermore, no substantial change was observed in certain behavioural measures suggesting that the effect of Δ9-THC was limited to diseased neural tissuesFootnote 831. Other studies showed that peritumoural administration of 0.5 mg Δ9-THC /day, twice per week, for 90 days, significantly slowed focal breast tumour growth, blocked tumour generation, decreased total tumour burden, delayed the appearance of subsequent tumours, and impaired tumour vascularization in the ErbB2-positive metastatic breast cancer mouse modelFootnote 832. Δ9-THC, at doses of 5 mg/kg/day, administered intra-peritoneally or intra-tumourally also dramatically decreased the growth and metastasis as well as the vascularization of xenografted non-small cell lung cancer cell lines in immunodeficient miceFootnote 829. CBD (5 mg/kg) or CBD-rich extract (6.5 mg/kg) administered intra-tumourally or intra-peritoneally, twice per week, to breast-cancer-cell-xenografted athymic mice significantly decreased both tumour volume and the number of metastatic nodulesFootnote 828. Other investigators showed that intra-peritoneal administration of CBD at 1 or 5 mg/kg/day significantly reduced the growth and metastasis of an aggressive breast cancer cell line in immune-competent miceFootnote 833. Importantly, the primary tumour acquired resistance to the inhibitory properties of CBD by day 25 of treatmentFootnote 833. Taken together, these studies suggest that cannabinoids such as Δ9-THC and CBD can, under a specific set of circumstances, have anti-neoplastic effects in various animal models of cancer at certain doses or concentration ranges.

Combining cannabinoids with other chemotherapeutic agents

Pre-clinical in vitro and in vivo studies investigating the effects of combining cannabinoids with frequently used chemotherapeutic agents have also been performed. One in vitro study showed that combining sub-maximal doses of Δ9-THC (0.75 μM) with cisplatin or doxorubicin reduced the viability of an astrocytoma cell line in a synergistic mannerFootnote 834. Likewise, combining sub-maximal doses of Δ9-THC with temozolomide reduced the viability of several human glioma cell lines and primary cultures of glioma cells derived from human glioblastoma multiforme biopsies in vitroFootnote 835. Complementing these findings, an in vivo study showed that combined treatment with Δ9-THC (15 mg/kg/day) and temozolomide (5 mg/kg/day) reduced the growth of glioma tumour xenografts in mice in a synergistic mannerFootnote 835.

Clinical data

There is only one report of a clinical study of Δ9-THC to treat cancerFootnote 836. In this non-placebo controlled pilot study, nine patients with glioblastoma multiforme who had failed standard surgical and radiation therapy, had clear evidence of tumour progression, and had a minimum Karnofsky score of 60 were treated with 20 - 40 µg Δ9-THC intra-tumourally per day (with doses of up to 80 - 180 µg Δ9-THC per day). Median treatment duration was 15 daysFootnote 836. While intra-tumoural administration of Δ9-THC appeared to be well tolerated, the effect of Δ9-THC on patient survival was not significantly different from that observed in other studies using chemotherapeutic agents such as temozolomide or carmustineFootnote 837,Footnote 838. Nevertheless, in vitro, Δ9-THC inhibited the proliferation and decreased the viability of tumour cells isolated from glioblastoma biopsies, most likely through a combination of cell-cycle arrest and apoptosisFootnote 836,Footnote 839. In addition, results from a separate in vitro study suggest that CBD enhanced the inhibitory effects of Δ9-THC on human glioblastoma cell proliferation and survivalFootnote 839.

Despite the evidence presented in these and other studies, there is a general consensus that Δ9-THC would not be considered the most appropriate CB agonist in anti-tumoural strategies, especially if administered systemically, because of its high hydrophobicity, relatively low agonist potency, and its well-known psychoactive properties Footnote 814,Footnote 840,Footnote 841. Much remains to be known regarding factors such as the expression levels of the cannabinoid receptors in different cancers, the effects of different cannabinoids on different cancer cell types, the identification of factors that confer resistance to cannabinoid treatment, as well as the most efficient approaches for enhancing cannabinoid anti-tumoural activity whether alone or in combination with other therapiesFootnote 828,Footnote 840. Furthermore, the apparent biphasic effect of cannabinoids further highlights the need for more comprehensive dose-response studiesFootnote 842.

4.8.10 Emerging Potential Therapeutic Uses

There are a few pre-clinical reports which suggest that administration of a low dose of THC, a CB1 receptor antagonist, or a CB2 receptor agonist may reduce the progression of atherosclerosis in mouse models of the diseaseFootnote 843,Footnote 844,Footnote 845. Oral administration of THC (1 mg/kg/day) has been associated with significant inhibition of disease progression in the apolipoprotein E (ApoE) knockout mouse, a mouse model of atherosclerosisFootnote 843. The beneficial effect of THC in this study was mediated by the CB2 receptor, likely through its inhibitory effects on immune system cells (macrophages and T-cells) located in or near atherosclerotic lesionsFootnote 843. These findings were supported by another study which showed that intra-peritoneal administration of a synthetic CB1/CB2 receptor agonist significantly reduced aortic plaque area in the ApoE knockout mouseFootnote 845. Administration of the CB receptor agonist reduced macrophage infiltration into the atherosclerotic plaque, and reduced the expression of vascular cellular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and P-selectin in the aorta, as well as reducing macrophage adhesionFootnote 845. Again, the observed beneficial effects appeared to be mediated by activation of the CB2 receptorFootnote 845. A separate study confirmed the atheroprotective effects of selective CB2 receptor activation by demonstrating increased vascular leukocyte infiltration in atherosclerotic plaques in mice lacking both the ApoE and CB2 receptors compared to ApoE knockout mice, and decreased atherosclerotic plaque formation and reduced vascular superoxide release in ApoE knockout mice treated with a CB2 receptor selective agonistFootnote 846. In contrast to these findings, a different study showed that activation or deletion of the CB2 receptor did not modulate atherogenesis in the LDL receptor knockout mouse model of atherosclerosisFootnote 847. Another study suggested that the CB2 receptor, while not affecting the size of atherosclerotic lesions in LDL receptor knockout mice, did increase lesional macrophage accumulation and smooth muscle cell infiltration, as well as reduce lesional apoptosis and alter the extra-cellular matrix of lesions Footnote 848. The findings from this study suggested that while the CB2 receptor did not play a significant role in the initial formation of atherosclerotic lesions, it did play a role in modulating the progression of the diseaseFootnote 848. On the other hand, activation of the CB1 receptor is associated with the release of reactive oxygen species and endothelial cell deathFootnote 849, and CB1 receptor blockade by rimonabant in ApoE knockout mice was associated with a significant reduction in the relative size of aortic atherosclerotic lesionsFootnote 844. In conclusion, it appears that in the case of atherosclerosis, the CB1 and CB2 receptors play opposing roles--the CB1 receptor appears to be atherogenic, whereas the CB2 receptor appears to be anti-atherogenicFootnote 844,Footnote 846,Footnote 849,Footnote 850,Footnote 851 although some controversy still remains regarding the exact role played by the CB2 receptorFootnote 852. Cannabidiol has also been shown to potently inhibit the activity of the enzyme 15-lipoxygenase, which has been implicated in the pathophysiology of atherogenesisFootnote 850,Footnote 853. Further studies are needed in this area.

5.0 Precautions

The contraindications that apply to those considering using prescription cannabinoid-based therapies (such as nabilone (Cesamet®), nabiximols (Sativex®) or dronabinol (Marinol®)) also apply to those considering using cannabis. Currently, no clinical guidelines exist with respect to monitoring patients who are taking cannabis for therapeutic purposes.

The risk/benefit ratio of using cannabis should be carefully evaluated in patients with the following medical conditions because of individual variation in response and tolerance to its effects, as well as the difficulty in dosing noted in section 3.0:

  • Cannabis should not be used in any person under the age of 18, or in any patient who has a history of hypersensitivity to any cannabinoid or to smoke. The adverse effects of cannabis use on mental health are greater during development, particularly during adolescence, than in adulthoodFootnote 146,Footnote 686,Footnote 690 (see also section 7.7.3).
  • Cannabis should not be used in patients with severe cardio-pulmonary disease because of occasional hypotension, possible hypertension, syncope, or tachycardiaFootnote 117,Footnote 233,Footnote 234.
  • Smoked cannabis is not recommended in patients with respiratory insufficiency such as asthma or chronic obstructive pulmonary diseaseFootnote 243.
  • Cannabis should not be used in patients with severe liver or renal disease. Patients with ongoing chronic hepatitis C should be strongly advised to abstain from daily cannabis use, as this has been shown to be a predictor of steatosis severity in these individualsFootnote 32,Footnote 854.
  • Cannabis should not be used in patients with a personal history of psychiatric disorders (especially schizophrenia), or a familial history of schizophrenia.
  • Cannabis should be used with caution in patients with a history of substance abuse, including alcohol abuse, because such individuals may be more prone to abuse cannabis, which itself, is a frequently abused substanceFootnote 675,Footnote 855,Footnote 856.
  • Patients with mania or depression and using cannabis or a cannabinoid should be under careful psychiatric monitoring Footnote 139,Footnote 143,Footnote 857.
  • Cannabis should be used with caution in patients receiving concomitant therapy with sedative-hypnotics or other psychoactive drugs because of the potential for additive or synergistic CNS depressant or psychoactive effects Footnote 169,Footnote 170,Footnote 171 (also see section 7.7). Cannabis may also exacerbate the CNS depressant effects of alcohol and increase the incidence of adverse effects (see section 7.7). Patients should be advised of the negative effects of cannabis/cannabinoids on memory and to report any mental or behavioural changes that occur after using cannabis Footnote 178,Footnote 181.
  • Cannabis is not recommended in women of childbearing age not on a reliable contraceptive, as well as those planning pregnancy, those who are pregnant, or women who are breastfeeding (see sections 6.0 and 7.4).

6.0 Warnings

Cannabis is one of the most widely abused illicit drugs, and can produce physical and psychological dependence Footnote 122,Footnote 156,Footnote 210,Footnote 858,Footnote 859. The drug has complex effects in the CNS and can cause cognitive and memory impairment, changes in mood, altered perception, and decreased impulse controlFootnote 152,Footnote 180,Footnote 860,Footnote 861. Patients should be supervised when administration is initiated.

Dosing:
In the case of smoked/vapourized cannabis, the dose required to achieve therapeutic effects and avoid adverse effects is difficult to estimate and is affected by the source of the plant material, its processing, and by different smoking techniques. These techniques include depth of inhalation, duration of breath-holding and the number and frequency of puffs, as well as how much of the cigarette is smoked or how much plant material is vapourized. Smoking or vapourization should proceed slowly and cautiously in a gradual fashion and should cease if the patient begins to experience the following effects: disorientation, dizziness, ataxia, agitation, anxiety, tachycardia and orthostatic hypotension, depression, hallucinations, or psychosis. There is also insufficient information regarding oral dosing, but the patient should be made aware that the effects following oral administration only begin to be felt 30 min to 1 h or more after ingestion, and that consumption of cannabis-based products (e.g. cookies, baked goods) should proceed slowly, and that edibles should be consumed only in small amounts at a time in order to gauge the effects and to prevent overdosing.
Psychosis:
Anyone experiencing an acute psychotic reaction to cannabis or cannabinoids should promptly stop taking the drug and seek immediate medical attention. A psychotic reaction is defined as a loss of contact with reality characterized by one or more of the following: changes in thinking patterns (difficulty concentrating, memory loss, and/or disconnected thoughts), delusions (fixed false beliefs not anchored in reality), hallucinations (seeing, hearing, tasting, smelling or feeling something that does not exist in reality), changes in mood (intense bursts of emotion, absence of, or blunted emotions), very disorganized behaviour or speech, and thoughts of death and suicideFootnote 341.
Occupational hazards:
Patients using cannabis should be warned not to drive or to perform hazardous tasks, such as operating heavy machinery, because impairment of mental alertness and physical coordination resulting from the use of cannabis or cannabinoids may decrease their ability to perform such tasksFootnote 182. Depending on the dose, impairment can last for over 24 h after last use because of the long half-life of Δ9-THCFootnote 62,Footnote 131,Footnote 290,Footnote 862,Footnote 863. Furthermore, impairment may be exacerbated with co-consumption of other CNS depressants (e.g. benzodiazepines, barbiturates, opioids, anti-histamines, muscle relaxants, or ethanol)Footnote 114,Footnote 170,Footnote 174,Footnote 864,Footnote 865,Footnote 866.
Pregnancy:
Pre-clinical studies suggest that endocannabinoid tone plays a critical role in fertilization, oviductal transport, implantation, and fetal/placental development (reviewed inFootnote 867). One pilot clinical study suggested that high circulating levels of anandamide were associated with an increased incidence of miscarriageFootnote 868. Thus, there is a risk that maternal exposure to cannabis or cannabinoids could potentially adversely affect conception and/or maintenance of pregnancy. In addition, the use of cannabis during pregnancy should be avoided as there is some evidence of long-term developmental problems in children exposed to cannabis in uteroFootnote 869,Footnote 870. Men, especially those on the borderline of infertility and intending to start a family, are cautioned against using cannabis since exposure to cannabis or THC could potentially reduce the success rates of intended pregnancies (see section 7.4).
Lactation:
Cannabinoids are excreted in human milk and may be absorbed by the nursing babyFootnote 871,Footnote 872. Because of potential risks to the child, nursing mothers should not use cannabis.

6.1 Tolerance, dependence, and withdrawal symptoms

Tolerance, psychological, and physical dependence can occur with prolonged use of cannabisFootnote 118,Footnote 210. Tolerance to cardiovascular effects occurs quickly, but dependence is slower to develop and appears more likely with higher, more frequent dosingFootnote 219,Footnote 220. See section 2.4 for further information on tolerance, dependence, and withdrawal symptoms.

6.2 Drug interactions

The most clinically significant interactions may occur when cannabis is taken with other CNS depressant drugs such as sedative-hypnotics or alcoholFootnote 114,Footnote 169,Footnote 170,Footnote 171,Footnote 864,Footnote 865,Footnote 866,Footnote 873,Footnote 874. An overdose can occur if a patient is smoking/vapourizing cannabis and consuming orally administered cannabinoids, whether from prescription cannabinoid medications (e.g. dronabinol, nabilone), or from consumption of teas, baked goods or other productsFootnote 174,Footnote 290.

Xenobiotic-mediated inhibition or potentiation of cannabinoid metabolism

Δ9-THC is oxidized by the xenobiotic-metabolizing cytochrome P450 (CYP) mixed-function oxidases 2C9, 2C19, and 3A4Footnote 62. Therefore substances that inhibit these CYP isoenzymes such as certain anti-depressants (e.g. fluoxetine, fluvoxamine, and nefazodone), proton pump inhibitors (e.g. cimetidine and omeprazole), macrolides (e.g. clarithromycin and erythromycin), anti-mycotics (e.g. itraconazole, fluconazole, ketoconazole, miconazole), calcium antagonists (e.g. diltiazem, verapamil), HIV protease inhibitors (e.g. ritonavir), amiodarone, and isoniazid can potentially increase the bioavailability of Δ9-THC as well as the chance of experiencing THC-related side effects Footnote 289,Footnote 875,Footnote 876. On the other hand, drugs that accelerate Δ9-THC metabolism via 2C9 and 3A4 isozymes such as rifampicin, carbamazepine, phenobarbital, phenytoin, primidone, rifabutin, troglitazone, and Saint John's Wort may conversely decrease the bioavailability of THC and hence its effectiveness if used in a therapeutic contextFootnote 289,Footnote 876.

Cannabinoid-mediated regulation of drug metabolism and drug transport

THC, CBD, and CBN are known to inhibit CYP isozymes such as CYP1A1, 1A2, and 1B1Footnote 58. Cannabis may therefore increase the bioavailability of drugs metabolized by these enzymes. Such drugs include amitryptiline, phenacetin, theophylline, granisetron, dacarbazine, and flutamideFootnote 58. THC, carboxy- Δ9-THC, CBD, and CBN all stimulate, and in some cases even inhibit, the activity of the drug transporter P-glycoprotein in vitroFootnote 56. This suggests a potential additional role for these cannabinoids in affecting the therapeutic drug efficacy and toxicity of co-administered drugsFootnote 56. Clinicians should therefore be aware other medications that the patient is taking and carefully monitor patients using other drugs along with cannabis or cannabinoids.

Cannabinoid-opioid interaction

Patients taking fentanyl (or related opioids) and anti-psychotic medications (clozapine or olanzapine) may also be at risk of experiencing adverse effects if co-consuming cannabis/cannabinoidsFootnote 322,Footnote 323,Footnote 324,Footnote 503,Footnote 877. In one study, subjects reported an increase in the intensity and duration of the "high" when oxycodone was combined with inhalation of vapourized cannabis; this effect was not observed when morphine was combined with inhalation of vapourized cannabisFootnote 187. In that study, inhalation of vapourized cannabis was associated with a statistically significant decrease in the maximum concentration (Cmax) of sustained-release morphine sulfate, and the time to Cmax for morphine was also delayed, although the delay was not statistically significantFootnote 187. There were no changes in the AUC for morphine metabolites, or in the ratio of morphine metabolites to parent morphineFootnote 187. In contrast to the effects seen with morphine sulfate, inhalation of vapourized cannabis was not associated with any changes in oxycodone pharmacokineticsFootnote 187.

Evidence from pharmacogenetic studies

Pharmacogenetic studies have suggested that patients homozygous for the CYP2C9*3 allele appear to have impaired THC metabolism and may show greater intoxication than *1/*3 heterozygotes or *1/*1 homozygotesFootnote 318.

Data from clinical studies

A significant proportion of published clinical studies of cannabis or prescription cannabinoid medications have used patient populations that were taking concomitant medications for a variety of disorders such as neuropathic pain of various etiologiesFootnote 142,Footnote 168,Footnote 172,Footnote 186,Footnote 187,Footnote 261,Footnote 292,Footnote 364,Footnote 494,Footnote 501,Footnote 502,Footnote 503, cancer-related painFootnote 112,Footnote 349,Footnote 509, fibromyalgiaFootnote 158,Footnote 261,Footnote 353,Footnote 354, pain and spasticity associated with multiple sclerosisFootnote 188,Footnote 262,Footnote 291,Footnote 361,Footnote 428,Footnote 504, and symptoms associated with Huntington's or Parkinson's diseaseFootnote 586,Footnote 595. Examples of commonly-used medications seen in clinical trials of cannabis or prescription cannabinoid medications (e.g. dronabinol, nabilone and nabiximols) include non-steroidal anti-inflammatory drugs (e.g. acetaminophen, COX-2 inhibitors), metamizol, topical steroids, muscle relaxants, short- and long-acting opioids (e.g. codeine, morphine, hydromorphone, oxycodone, oxycontin, tramadol, fentanyl, methadone), ketamine, anti-convulsants (e.g. gabapentin, pregabalin), anti-depressants (e.g. tricyclics, selective-serotonin re-uptake inhibitors, serotonin-norepinephrine re-uptake inhibitors, serotonin-antagonist re-uptake inhibitors), and anxiolytics. According to the cited clinical studies, concomitant use of cannabis or prescription cannabinoid medications with other medications was reported to be well tolerated, and many of the observed adverse effects were those typically associated with the psychotropic effects of cannabis and cannabinoids (e.g. transient impairment of sensory and perceptual functions, abnormal thinking, disturbance in attention, dizziness, confusion, sedation, fatigue, euphoria, dysphoria, depression, paranoia, hallucinations, dry mouth, anxiety, hypotension, tachycardia, headache, throat irritation).

6.3 Drug screening tests

Because of the long half-life of elimination of cannabinoids and their metabolites, drug tests screening for cannabinoids can be positive for weeks after last cannabis/cannabinoid useFootnote 878,Footnote 879 depending on the sensitivities of the tests used.

7.0 Adverse Effects

There is generally far more information available in the medical literature on the adverse effects associated with recreational cannabis use than there is with therapeutic cannabis use. Accordingly, much of the information presented below regarding the adverse effects of cannabis use comes from studies carried out among recreational users. Much less information on the adverse effects associated with the use of cannabis for therapeutic purposes comes from clinical studies, mainly because of the small number of such studies that have been carried out to date. Furthermore, while there is some information on the short-term adverse effects associated with the use of cannabis for therapeutic purposes, much less information exists on the long-term consequences of cannabis use for therapeutic purposes because all of the available clinical studies were short-term. A Canadian systematic review of the adverse effects of prescription cannabinoid medications concluded that the rate of non-serious adverse events was almost two-fold higher among those patients using prescription cannabinoid medications compared to controlsFootnote 880. The most frequently cited adverse events associated with the use of prescription cannabinoid medications were nervous system disorders, psychiatric disorders, gastrointestinal disorders, and vascular and cardiac disordersFootnote 880. An additional consideration in the evaluation of adverse effects associated with cannabis use is the concomitant use of tobacco and alcohol as well as other drugs, whether they are non-prescription, prescription, or illicit drugsFootnote 122,Footnote 881,Footnote 882,Footnote 883,Footnote 884 (and also see section 6.2).

7.1 Carcinogenesis and mutagenesis

Qualitatively, cannabis smoke condensates have been shown to contain many of the same chemicals as tobacco smoke Footnote 70. Furthermore, a number of in vitro studies have provided strong evidence that smoke from burning cannabis is carcinogenic (reviewed inFootnote 118). More recently, the cytotoxic and mutagenic potential of cannabis smoke condensates were compared to their tobacco counterpartsFootnote 68. In contrast to tobacco smoke condensates, those derived from cannabis smoke appeared to be more cytotoxic and mutagenic, while the opposite was true with respect to cytogenetic damageFootnote 68. In addition, for either cannabis or tobacco smoke, the particulate phase was substantially more cytotoxic than the gas phase. Together, these studies suggest that cannabis smoke cannot be deemed "safer" than tobacco smoke.

Despite some persuasive in vitro data, the epidemiological evidence for a link between cannabis smoking and cancer remains inconclusive because of conflicting results from a limited number of studies. One epidemiological study in relatively young clients of a health maintenance organization (HMO) found an increased incidence of prostate cancer in those men who smoked cannabis and other non-tobacco materialsFootnote 238. No other associations were found between cannabis use and other cancers; however, the study was limited by the demographics of the HMO clientele and the very low cannabis exposure threshold employed in the study to define "users". A case-control study suggested that cannabis smoking may increase the risk of head and neck cancer (Odds Ratio = 2.6; Confidence Interval = 1.1 - 6.6), with a strong dose-response pattern compared to non-smoking controlsFootnote 239. However, the authors note a number of limitations with their study such as underreporting, inaccurate cannabis dose reporting, assay sensitivity, and low power. A large population-based case-control study, carried out in the year 2006, of 1 212 incident cancer cases and 1 040 cancer-free matched controls did not find a significant relationship between long-term cannabis smoking and cancers of the lung and upper aerodigestive tractFootnote 240. However, a smaller case-control study carried out in 2008 in young adults (≤ 55 years of age), examined 79 cases of lung cancer and 324 controls and reported that the risk of lung cancer increased by 8% (95% Confidence Interval = 2 - 15%) for each "joint-year" (defined as the smoking of one joint per day for one year) after adjusting for cigarette smokingFootnote 241. Despite the conflicting evidence surrounding the carcinogenic potential of cannabis smoke in humans, it is advisable to limit the degree to which cannabis is smoked. Further well-controlled epidemiological studies are required to better establish whether there is causality between cannabis smoking and carcinogenesis in human populations. Lastly, in the case of cancer patients, the potential risks of carcinogenesis and mutagenesis associated with smoking cannabis must be weighed against any potential therapeutic benefits for this patient population; routes of administration other than smoking (e.g. vapourization, oral administration) may warrant consideration. Because vapourization is a lower-temperature process compared with pyrolysis (i.e. smoking), vapourization appears to be associated with the formation of a smaller quantity of toxic byproducts such as carbon monoxide, polycyclic aromatic hydrocarbons (PAHs), and tar, as well as a more efficient extraction of Δ9-THC from the cannabis materialFootnote 273,Footnote 281,Footnote 282,Footnote 283,Footnote 284.

7.2 Respiratory tract

Differences in the smoking techniques used by cannabis vs. tobacco smokers are reported to result in three-fold higher levels of tar, and five-fold higher levels of carbon monoxide being retained in the lungs during cannabis smoking compared to tobacco smokingFootnote 885. A systematic comparison of the mainstream smoke composition from cannabis (Health Canada product) and tobacco cigarettes (prepared in the same way and consumed in an identical manner), under two different sets of smoking conditions ("standard" and "extreme") has been reportedFootnote 70. The "standard" condition reflects typical tobacco cigarette smoking conditions, whereas the "extreme" condition approaches that typically seen in cannabis smokingFootnote 70. Ammonia in mainstream cannabis smoke was 20-fold greater than that found in tobacco smoke, and oxides of nitrogen and hydrogen cyanide were three to five times higher in cannabis smoke vs. tobacco smoke. Carbon monoxide was significantly lower in mainstream cannabis smoke, under both smoking conditions. Tar was statistically significantly higher in mainstream cannabis smoke but only under the "extreme" smoking condition.

Mucosal biopsy specimens taken from chronic cannabis smokers, who reported smoking only cannabis, showed a number of histopathologic changes including basal cell hyperplasia, stratification, goblet cell hyperplasia, cell disorganization, inflammation, basement membrane thickening, and squamous cell metaplasiaFootnote 242. However, the study employed a small number of subjects and relied on the accuracy and integrity of the subjects' recall to establish smoking status as well as frequency and duration of smoking. Epidemiological studies have found mild changes in pulmonary function in heavy cannabis smokers, including reduction of the forced expiratory volume in 1 second (FEV1), an increase in airway resistance, and a decrease in airway conductanceFootnote 244,Footnote 245,Footnote 246. Heavy chronic cannabis smokers presented with symptoms of bronchitis, including wheezing, production of phlegm and chronic cough, and long-term cannabis smoking may be a risk factor for chronic obstructive pulmonary disease in later lifeFootnote 122,Footnote 886. All changes were most evident in heavy chronic users, defined as those who smoked more than three joints per day for 25 yearsFootnote 238,Footnote 887, although evidence of measurable respiratory symptoms (e.g. decreased FEV1 /FVC ratio) was also observed in young, cannabis-dependent individuals whose smoking behaviour was comparable to tobacco smokers consuming 1 - 10 cigarettes/dayFootnote 888. The potential risk of developing chronic obstructive respiratory disease, with long-term use and/or dependence, has been claimed to be potentially as great as among tobacco usersFootnote 888. However, a recently published longitudinal study collecting repeated measurements of pulmonary function and smoking over a period of 20 years, in a cohort of 5 115 men and women in four U.S. cities (the CARDIA study), suggested a more complex picture. The study found a non-linear association between marihuana smoking and pulmonary functionFootnote 247. By comparison, tobacco smoking (current and lifetime) was linearly associated with lower FEV1 and FVC Footnote 247. Low levels of cumulative marihuana smoking were not associated with adverse effects on pulmonary function. Instead, at this level, marihuana smoking was associated with an increase in the FEV1 and FVC valuesFootnote 247. At up to seven "joint-years" (a "joint-year" defined as smoking one joint/day, 365 days/year) of lifetime exposure there was no evidence of decreased pulmonary function. However, heavy chronic marihuana smoking ( > ~30 joint-years or > ~25 smoking episodes per month) was associated with an accelerated decline in pulmonary function (FEV1 but not FVC ) Footnote 247.

Further research is needed to clarify the complex changes in lung function found in cannabis smokers, and to determine if there is a cause and effect relationship between cannabis smoking and the development of lung disease. Smoking cannabis may also increase the risk of developing respiratory infections in chronic usersFootnote 889 through exposure to infectious organisms such as fungi and molds which can be found in the plant materialFootnote 890, or alternatively by decreasing natural host defensesFootnote 891. However, further epidemiological research is also required to establish a causal relationship between cannabis smoking and respiratory infections. Vapourization of cannabis may be considered an alternative to smoking, although research is required to determine if there are any adverse effects of vapourization on lung health/function. For additional information on vapourization please consult sections 1.1.1, 1.1.2, 2.2.1.2, 3.4, 4.6.2.3, and Table 6.

7.3 Immune system

Pre-clinical studies

Evidence from in vivo and in vitro studies suggests complex and apparently dichotomous roles for the endocannabinoid system on immune system functionFootnote 24. First, CB1 and CB2 receptors are known to be expressed in various immunocytes (B cells, monocytes, neutrophils, T lymphocytes, macrophages, mast cells), with CB2 receptor expression generally being more abundant than CB1 receptor expression; the ratio of CB2 to CB1 receptor expression ranges between 10 - 100 : 1 respectively, depending on the immune cell type in questionFootnote 24,Footnote 25. Second, immune cells also have the ability to synthesize, secrete, transport and catabolize endocannabinoidsFootnote 24. Third, while stimulation of the CB2 receptor appears to be generally associated with immunosuppressive effects, activation of the CB1 receptor appears to be associated with an opposing immunostimulatory effectFootnote 24. Fourth, whereas certain cannabinoids have been shown to modulate the release of pro- or anti-inflammatory cytokines, pro-inflammatory cytokines (such as TNF-α) have, in turn, been reported to affect the functioning of the endocannabinoid system by upregulating the expression of both CB1 and CB2 receptor mRNA and protein levelsFootnote 25. Thus, there appears to be some level of cross-talk between the endocannabinoid and immune systems. Fifth, as is the case in other situations, Δ9-THC appears to have a biphasic effect on immune system function. Low doses of Δ9-THC seem to have stimulatory or pro-inflammatory effects, while higher doses appear to have inhibitory or immunosuppressive effectsFootnote 266. Both Δ9-THC and CBD have been reported to modulate cell-mediated and humoural immunity, through CB receptor-dependent and CB receptor-independent mechanismsFootnote 266,Footnote 892,Footnote 893. Cannabinoids target various cellular signaling and transcriptional pathways resulting in the inhibition of pro-inflammatory cytokine release (e.g. IL-1β, IL-6, IFN-β), and/or stimulation of anti-inflammatory cytokine release (e.g. IL-4, IL-5, Il-10, IL-13)Footnote 25,Footnote 266. CBD also appears to induce a shift in Th1/Th2 immunobalance Footnote 892. While under certain circumstances, cannabinoids may appear to have broad anti-inflammatory and immunosuppressive functions which could be of benefit in pathological conditions having inflammatory characteristics, such beneficial functions may become problematic in the context of essential defensive responses to infectionsFootnote 24. For example, in vitro as well as in vivo experiments suggest cannabinoids have an impact on virus-host cell interactions Footnote 894: cannabinoid treatment was associated with increased viral replication of HSV-2, HIV-1, KSHV, influenza, and VSV viruses, or was associated with increases in surrogate measures of infection in these experimental models Footnote 895,Footnote 896,Footnote 897,Footnote 898,Footnote 899,Footnote 900.

Taken together, the available information suggests that differences in the observed effects of cannabinoids on immune system function (i.e. immunosuppressive vs. immunostimulatory) may be explained by differences in the routes/methods of administration (smoked, oral, or other route), the length of exposure to the cannabinoid(s), the dose and type of cannabinoid used and which receptors are preferentially targeted, but also by differences between species, the experimental protocols and outcome measures that were used, and for clinical studies the health status/medical condition of the human subjectsFootnote 266.

Clinical studies

The effects of cannabis smoking on the human immune system have been studied, but to a very limited degree. A major concern with HIV-positive cannabis smokers, or patients undergoing cancer chemotherapy, is that they might be more vulnerable than other cannabis smokers to the immunosuppressive effects of cannabis or that they risk exposure to infectious organisms associated with cannabis plant materialFootnote 378. A group of studies has partially addressed the former concern. In one study, HIV-positive patients on stable anti-retroviral therapy were randomized to smoked cannabis or oral dronabinol and showed no changes in CD4+ and CD8+ T-cell, B cell, or NK cell counts and a number of other parameters compared with placebo, over a 21-day study periodFootnote 901. A longitudinal study of 481 HIV-infected men who used cannabis and who were followed over an average five-year period found that while cannabis use was generally associated with a higher CD4+ cell count in infected men and controls, no clinically meaningful associations, adverse or otherwise, between cannabis use and T-cell counts and percentages could be establishedFootnote 902. Cannabis use was also not associated with an increased rate of progression to AIDS in HIV-infected individualsFootnote 903. In another study, smoking cannabis was associated with lower plasma concentrations of the protease inhibitors indinavir and nelfinavir; dronabinol or placebo had no effectFootnote 322. However, the decreased protease inhibitor levels were not associated with an elevated viral load, or changes in CD4+ or CD8+ cell countsFootnote 390.

In humans, smoking cannabis was also associated with poorer outcome in patients with chronic hepatitis CFootnote 882,Footnote 904. Although pre-clinical studies strongly suggest that cannabinoids have broad immunomodulatory effects, and raise the possibility that cannabinoids may affect the ability of immunosuppressed patients to successfully resist or combat infections, it is unclear at this time if the immunomodulatory effects seen both pre-clinically and clinically translate into any clinically significant adverse outcomes.

Clear predictions concerning the effects of cannabinoids in those individuals who suffer from a dysregulated immune system are difficult to make because of the relative lack of available, comprehensive information on the subject. The clinician must therefore weigh the potential benefits of using cannabis and/or cannabinoids against the possible risks of using these substances on a case-by-case basis.

A recent cross-sectional study examined the association between cannabis use status and adherence to anti-retroviral therapy as well as the association between cannabis use status, HIV symptoms, and side effects associated with anti-retroviral therapy among a sample of HIV-positive individualsFootnote 905. The study reported that those subjects who had a cannabis use disorder (according to DSM-IV criteria and a Marijuana Smoking History Questionnaire score indicating daily cannabis or use more than once per day) had a significantly lower adherence to treatment than those who reported using cannabis once per week or more, but less than daily or not at allFootnote 905. Those who had a cannabis use disorder also had a higher viral load than those who used cannabis less than daily but at least once per week, as well as those who did not use at all; absolute CD4 count was not significantly different between groupsFootnote 905. Furthermore, those subjects with a cannabis use disorder reported significantly more frequent and severe HIV symptoms and/or medication side effects than those who used cannabis less than daily (but at least once per week), or those who reported not using cannabis at allFootnote 905. One limitation to this study was its cross-sectional nature, precluding the ability to establish a cause-and-effect relationship.

7.4 Reproductive and endocrine systems

Role of the endocannabinoid system in sexual physiology

The CB1 receptor is widely expressed in various brain structures such as the striatum, hippocampus, and the cerebellum, as well as the amygdala, the midbrain, and the cerebral cortex--all structures that play various roles in regulating different aspects of sexual behaviour and functionFootnote 269. For example, CB1 receptors within the striatum and cerebellum may regulate motor activity and function; CB1 receptors located within corticolimbic structures (e.g. pre-frontal cortex, amygdala and hippocampus) may regulate stress responsivity and emotional behaviour; CB1 receptors located within the dorsal raphe and ventral tegmental area may regulate genital reflexes, sexual motivation and inhibition; and lastly, CB1 receptors expressed within the hypothalamus and the pituitary gland may modulate the functioning of the hypothalamic-pituitary-gonadal axis either directly through modulation of gonadotropin-releasing hormone or indirectly through other modulatorsFootnote 269,Footnote 270.

CB1 receptor-mediated modulation of the hypothalamic-pituitary axis results in the suppression of luteinizing hormone, thyroid stimulating hormone, growth hormone, and prolactin release from the pituitary gland, while the effects on follicle stimulating hormone are seemingly unclear but point to a probable suppression of releaseFootnote 268,Footnote 906. In animals, these effects are accompanied by changes in reproductive function and behaviour including decreases in plasma testosterone levels, degenerative changes in spermatocytes and spermatids, anovulation, and potential reduction in copulatory behaviourFootnote 268,Footnote 270. Aside from the roles of the cannabinoid receptors in the brain, the male and female reproductive systems also contain an endocannabinoid system, and increasing experimental evidence suggests important roles for the endocannabinoid system in regulating various reproductive functions such as folliculogenesis, spermatogenesis, ovulation, fertilization, oviductal transport, implantation, embryo development, pregnancy, and labour (reviewed inFootnote 37).

Effects of cannabis on human sexual behaviour

There is a relative paucity of data with regards to the effects of cannabis or cannabinoids on human sexual behaviour. One review article has summarized the few available studies on the subjectFootnote 269. It concluded that in general, the effects of cannabis on sexual functioning and behaviour appear to be dose-dependent. For women, the available information suggests beneficial effects on sexual behaviour and functioning (e.g. reported increases in sensitivity to touch and relaxation and a corresponding increase in sexual responsiveness) at low to moderate doses, and potentially opposite responses at higher dosesFootnote 269. For men, the available information suggests that cannabis intake at low to moderate doses may facilitate sexual desire and activity, but that at higher doses or with more frequent or chronic use it may inhibit sexual motivation as well as erectile functionFootnote 269. Results obtained from animal studies appear to mirror some of these findings, although exceptions have also been notedFootnote 269. Although the effects of cannabis on human sexual behaviour are still not well understood, some of its reported beneficial effects have been speculatively linked to its psychoactive properties (e.g. increase in tactile sensitivity/perception or slowing of temporal perception) or alternatively, to a loss of inhibitions and an increased state of relaxationFootnote 269.

Studies investigating the effects of cannabis consumption on testosterone levels in men have yielded conflicting results Footnote 269. While some investigators have found that acute or chronic cannabis consumption significantly lowered plasma testosterone levels in a dose-dependent manner, others have apparently failed to find similar effectsFootnote 269. Differences in the reported effects of cannabis on testosterone levels among the various studies have been, in part, attributed to differences in the experimental protocols employedFootnote 269.

Effects on sperm and testicular health

The effects of cannabis and Δ9-THC on human sperm have been investigated both in vivo and in vitroFootnote 907,Footnote 908,Footnote 909. A significant decline in sperm count, concentration and motility, and an increase in abnormal sperm morphology were observed in men who smoked cannabis (8 - 20 cigarettes/day) for four weeksFootnote 907. In an in vitro study, sperm motility and acrosome reactions were decreased in both the 90% and 45% sperm fractions, the 90% fraction being the one with the best fertilizing potential and the 45% fraction being a poorer sub-populationFootnote 909. Decreased sperm motility was observed in both fractions at Δ9-THC concentrations mimicking those attained recreationally (0.32 and 4.8 μM), and in the 45% fraction at Δ9-THC concentrations typically seen therapeutically (0.032 μM). Inhibition of the acrosome reaction was only observed at the highest Δ9-THC concentration tested (4.8 µM) in the 90% fraction, while the 45% fraction displayed decreased acrosome reactions at all three Δ9-THC concentrations tested. Such effects carry the possibility of impairing crucial sperm functions and male fertility, especially in those males already on the borderline of infertilityFootnote 909.

A recently published, population-based, case-control study reported that compared with men who never used cannabis, those who had reported ever-using had a nearly two-fold increased risk of developing testicular germ-cell tumours of any histologic type (Odds Ratio = 1.94, 95% Confidence Interval: 1.02 - 3.68) and a greater than two-fold increased risk of non-seminoma or mixed germ-cell tumours (Odds Ratio = 2.42, 95% Confidence Interval: 1.08 - 5.42)Footnote 910. Men who reported using cannabis less than once per week appeared to have an elevated risk of developing testicular germ-cell tumours compared to those men who reported using cannabis more frequently. Men who reported using cannabis for a period under 10 years were also more than twice as likely to develop such tumours as those reporting ≥ 10 years of useFootnote 910.

Effects on foetal development and child development

Results from human epidemiological studies examining short-term neonatal outcomes among women who smoked cannabis during pregnancy are equivocal; some report reduced neonatal birth weight and lengthFootnote 911,Footnote 912,Footnote 913,Footnote 914 or a slightly increased risk of sudden infant deathFootnote 915, while others report no effectFootnote 916,Footnote 917,Footnote 918. On the other hand, there appear to be some long-term effects on the development of children born to mothers who used cannabis during pregnancy. Two longitudinal investigations carried out over a time span of 20 years (reviewed inFootnote 869) suggest that such in utero exposure impacts negatively on attentional behaviour and visual analysis and hypothesis testing, but not on standardized derived IQ scores. These findings were confirmed by a third studyFootnote 870. These behavioural effects also appeared to have an adverse influence on aspects of executive function in later years.

Evidence suggests that cannabinoids accumulate in the breast milk of mothers who smoke cannabis and are transferred to newborns through breastfeedingFootnote 871,Footnote 919. In a case-control studyFootnote 920, exposure to cannabis from the mother's milk during the first month post-partum appeared to be associated with a decrease in infant motor development at one year of age.

7.5 Cardiovascular system

The most consistent acute physiological effect of smoking cannabis is dose-related tachycardiaFootnote 121,Footnote 226,Footnote 232. While this is not usually considered dangerous for healthy young users, it may be dangerous to those already suffering from cardiac disorders or anginaFootnote 118,Footnote 921. Inhalation of cannabis smoke reduces the amount of exercise required to cause an angina attack by 50%Footnote 922, and has been associated with a five-fold increased risk of myocardial infarction in the first hour following smokingFootnote 232. This may be caused by a Δ9-THC-related increase in cardiac output, myocardial oxygen demand, catecholamine levels, and carboxyhemoglobin as well as postural hypotensionFootnote 226,Footnote 227,Footnote 923. While tachycardia is observed in both occasional and chronic users, tolerance develops relatively quickly with the degree of tachycardia diminishing with use. After about 8 to 10 days of constant dosing with 10 mg of Δ9-THC per day (equivalent to 80 - 100 mg of cannabis containing 10% Δ9-THC), bradycardiaFootnote 924 with a decrease in supine blood pressure was observedFootnote 925.

Cannabis is also known to cause peripheral vasodilatation, postural hypotension, and characteristic conjunctival reddening after smokingFootnote 926.

AIDS patients may be at an increased risk of experiencing adverse cardiovascular outcomes caused by interactions between cannabis and anti-retroviral drugs, such as ritonavir, which has been associated with adverse cardiovascular eventsFootnote 927.

There have been a number of case-reports of arteritis associated with long-standing, chronic, daily cannabis smoking Footnote 928,Footnote 929,Footnote 930,Footnote 931. Case-reports have also suggested an association between chronic, daily cannabis smoking and multi-focal intracranial stenosisFootnote 932 and strokeFootnote 236,Footnote 237.

7.6 Gastrointestinal system and Liver

7.6.1 Hyperemesis

There are an increasing number of case-reports being published regarding the "cannabis hyperemesis syndrome" (CHS). CHS is a condition observed in people chronically using cannabis on a daily basis, often for years, and is characterized by severe, intractable episodes of nausea and cyclic vomiting accompanied by abdominal pain (typically epigastric or periumbilical); these symptoms are relieved by compulsive hot water bathing or showering Footnote 194,Footnote 195,Footnote 196,Footnote 197,Footnote 198,Footnote 199,Footnote 200,Footnote 201,Footnote 202,Footnote 203,Footnote 204. The pathophysiology of CHS is not well understoodFootnote 202. Treatment of patients presenting with this syndrome has been reported to include: recommending cessation of cannabis use, rehydration, and psychological counsellingFootnote 200,Footnote 202. The efficacy of anti-emetics such as metoclopramide, ondansetron, prochlorperazine, and promethazine in relieving the symptoms of nausea and vomiting in patients with CHS appears to be debatableFootnote 198,Footnote 200,Footnote 201,Footnote 204. A recent case-report suggests that lorazepam (1 mg i.v., followed by 1 mg tablets b.i.d.) may provide some benefit in alleviating the symptoms of CHS, at least in the short-termFootnote 933.

7.6.2 Liver

A number of studies have strongly implicated the endocannabinoid system in chronic liver disease Footnote 934,Footnote 935,Footnote 936,Footnote 937,Footnote 938. Studies in patients with chronic hepatitis C have found a significant association between daily cannabis smoking and moderate to severe fibrosisFootnote 904, as well as cannabis smoking being a predictor of fibrosis progressionFootnote 882. Another study showed that daily cannabis use was a predictor of steatosis severity in these individualsFootnote 854. Steatosis is an independent predictor of fibrosis progression and an established factor of poor response to anti-viral therapyFootnote 939. The authors recommend that patients with ongoing chronic hepatitis C be strongly advised to abstain from daily cannabis use.

In contrast, another study showed that modest cannabis use (defined as anything less than daily use in this study) was associated with an increase in the duration of time that patients remained on anti-retroviral treatmentFootnote 252. This effect was postulated to contribute, at least in part, to an increase in the percentage of patients demonstrating a sustained virological response (i.e. the absence of detectable levels of hepatitis C virus RNA six months after completion of therapy)Footnote 252.

7.7 Central nervous system

The most frequently reported adverse events encountered with cannabinoids involve the central nervous system (CNS). Commonly reported CNS events in controlled clinical trials with dronabinol (Marinol®) and nabiximols (Sativex®) are intoxication-like reactions including drowsiness, dizziness, and transient impairment of sensory and perceptual functionsFootnote 174,Footnote 290. A "high" (easy laughing, elation, heightened awareness), which could be unwanted or unpleasant for patients, was reported in 24% of the patients receiving Marinol® as an anti-emetic, and in 8% of patients receiving it as an appetite stimulantFootnote 174. Other adverse events occurring at a rate of > 1% for Marinol® include anxiety/nervousness, confusion, and depersonalizationFootnote 174. Dizziness, euphoria, paranoia, somnolence, abnormal thinking ranged from 3 - 10%Footnote 174. The rates of amnesia, ataxia, and hallucinations were > 10% when used as an anti-emetic at higher dosesFootnote 174. Dizziness is the most common intoxication effect with Sativex®, reported initially in 35% of patients titrating their dose; the reported incidence of this effect in long-term use is approximately 25%Footnote 940. All other intoxication-like effects are reported by less than 5% of users (with the exception of somnolence, 7%)Footnote 940. Other events reported for Sativex® include disorientation and dissociation. Many, if not all, of the above-noted CNS effects also occur with cannabis.

7.7.1 Cognition

The acute effects of cannabis use on cognition have been reviewed by LundqvistFootnote 235. Cannabis impairs cognition involving faculties such as short-term memory, attention, concentration, executive functioning and visuoperceptionFootnote 180,Footnote 941,Footnote 942. The digit span task has been used to estimate the effects of cannabis on recent memory, but results have been inconsistent. Differences may be due to the dosage used, the smoking procedure, or whether the digit span task assesses forward or backward recallFootnote 943. Cannabis intoxication significantly impairs the ability to learn and recall word lists or short storiesFootnote 944.

The long-term effects of cannabis on cognition remain controversial. Some studies report a positive association between cannabis consumption and cognitive deficitsFootnote 945,Footnote 946,Footnote 947, or suggest that cognitive deficits persist after abstinenceFootnote 180,Footnote 941,Footnote 948,Footnote 949. Other studies did not find an association between cannabis use and long-term cognitive declineFootnote 948,Footnote 949. Methodological limitations and the absence of powerful effects have contributed to difficulties in assessing the effects of chronic use, and may help explain the discrepancies among studiesFootnote 950,Footnote 951. Nonetheless, studies generally suggest that chronic cannabis users suffer varying degrees of cognitive impairment that have the potential to be long-lastingFootnote 127. Prolonged use of ingested or inhaled cannabis in patients with multiple sclerosis was associated with poorer performance on various cognitive domains (e.g. information processing speed, working memory, executive function, and visuospatial perception), according to a cross-sectional studyFootnote 178. A recently published, prospective, longitudinal study investigating the association between persistent cannabis use and neuropsychological functioning in a birth cohort of 1 037 individuals followed over a period of 20 years found that persistent cannabis use beginning in adolescence was associated with statistically significant global neuropsychological decline across a number of domains of functioningFootnote 952. Furthermore, cessation of cannabis use, for a period of one year or more, did not appear to fully restore neuropsychological functioning among adolescent-onset persistent cannabis usersFootnote 952.

7.7.2 Psychomotor performance

Although no studies have been carried out to date examining the effects of cannabis or psychoactive cannabinoid exposure on psychomotor performance in individuals using these substances solely for medical purposes, it is well known that exposure to such substances impairs psychomotor performanceFootnote 118 and patients must be warned not to drive or operate complex machinery after smoking or eating cannabis or consuming psychoactive cannabinoid medications (e.g. dronabinol, nabilone, nabiximols).

A double-blind, placebo-controlled, crossover study comparing the effects of a medium dose of dronabinol (20 mg) and of two hemp milk decoctions, containing medium (16.5 mg) or high doses (45.7 mg) of THC, reported severe impairment on several performance skills required for safe drivingFootnote 953. A "moderate" dose (21 mg of THC) was associated with impairments in motor and perceptual skills necessary for safe driving Footnote 954. In one study, performance impairment appeared to be less significant among heavy cannabis users compared to occasional users, potentially because of the development of tolerance or compensatory behaviourFootnote 169. It has been suggested that, unlike alcohol, cannabis users are aware of their level of intoxication and compensate by becoming hyper-cautious; in tasks such as driving, this kind of behaviour results in decreased speed, decreased frequency of overtaking, and an increase in following distance Footnote 955,Footnote 956. Others disagree with this assertion (Footnote 957 and also seeFootnote 176).

A recent double-blind, placebo-controlled, randomized, three-way, crossover design study suggested that administration of dronabinol dose-dependently impaired driving performance in both occasional (defined as using a cannabinoid between 5 and 36 times per year) and heavy cannabis users (defined as using 1 - 3 joints per day, > 160 times per year)Footnote 958. However, the magnitude of the impairment appeared to be less in heavy users, possibly due to toleranceFootnote 958. The authors indicate that driving impairments after dronabinol were of clinical relevance and comparable to drivers operating their vehicles at a blood-alcohol concentration of greater than 0.8 mg/mL (0.08 g%)Footnote 958. Approximately 25% of the "heavy users" demonstrated impairment equivalent to, or worse than, that reported for drivers with a blood-alcohol concentration of 0.5 mg/mL (0.05 g%). Driving impairments after dronabinol use were evident even though THC plasma concentrations were relatively low (varying between 2 and 10 ng/mL)Footnote 175,Footnote 958.

A recent case-control study estimating accident risk for a variety of substances including alcohol, medicines, and illegal drugs found that the odds ratio for accident risk for all the THC concentrations measured (1 to > 5 ng/mL) was statistically significantFootnote 959. At whole-blood concentrations of ≥ 2 ng/mL THC, the risk of having an accident was significantly increasedFootnote 959. One study found that the risk of responsibility for fatal traffic crashes, while driving under the influence of cannabis, increased with increasing blood concentrations of THC such that there was a significant dose-effect relationship between risk of responsibility for fatal traffic crashes and blood concentrations of THC. The study showed that the odds ratio of having a fatal crash increased from 2.18 if blood concentrations ranged between 0 and 1 ng/mL of THC, to 4.72 if blood THC concentrations were ≥ 5 ng/mLFootnote 960. The findings from this study further support the notion of a causal relationship between cannabis use and crashesFootnote 960. Another study suggested that drivers who were judged (by a police physician) as being impaired had higher blood THC concentrations than drivers judged not to be impaired (median: 2.5 ng/mL vs. 1.9 ng/mL)Footnote 961. Using a binary logistic regression model, the odds ratio for being judged impaired appeared to increase with increasing drug concentrations from 2.9 ng/mL onwards Footnote 961. Serum THC concentrations between 2 and 5 ng/mL have been identified as a threshold above which THC-induced impairment of skills related to driving become apparentFootnote 133,Footnote 959. Performance impairment after cannabis intake was reported to be highest during the first hour after smoking, and between 1 - 2 h after oral intake, and declining after 3 - 4 h (or longer in the case of oral ingestion)Footnote 862,Footnote 961.

A recent meta-analysis of observational studies examining acute cannabis consumption and motor vehicle collision risk reported that driving under the influence of cannabis was associated with a significantly increased risk of motor vehicle collisions compared with unimpaired driving, with an odds ratio of 1.92 (95% Confidence Interval = 1.35 - 2.73; p = 0.0003)Footnote 175. Collision risk estimates were higher in case-control studies and studies of fatal collisions, than in culpability studies and studies of non-fatal collisionsFootnote 175. It has been reported that individuals who drive within 1 h of using cannabis are nearly twice as likely to be involved in motor vehicle accidents as those who do not consume cannabisFootnote 954. For this meta-analysis, only observational studies with a control or comparison group, including cohort (historical prospective), case-control, and culpability designs were included, and experimental laboratory or simulator studies were excludedFootnote 175. Furthermore, only studies that assessed acute or recent cannabis use were examined. This meta-analysis supports the findings of other studies which suggest that cannabis use impairs the performance of the cognitive and motor tasks that are required for safe driving, thereby increasing the risk of collision Footnote 175. Although driving simulator studies have reported a dose-response effect, in which elevated concentrations of THC were associated with increased crash risk, dose-response effects could not be established in this studyFootnote 175.

A double-blind, counter-balanced, placebo-controlled driving simulator study reported that driving performance was more impaired in subjects who co-consumed alcohol and low or high doses of THC by smoking cannabis cigarettesFootnote 176. The level of THC detected in the blood was higher when cannabis was consumed along with alcohol than when consumed aloneFootnote 176. It also appeared that regular cannabis users displayed more driving errors than non-regular cannabis usersFootnote 176.

A recent systematic review and meta-analysis concluded that, after adjusting for study quality, cannabis use was associated with a seven-fold estimated risk of being involved in a fatal accident, benzodiazepine use was associated with a two-fold estimated risk of a fatal accident, and opiate use with a three-fold estimated risk of a fatal accidentFootnote 177. In contrast, cannabis use was associated with a 1.5-fold estimated risk of having an accident that only caused injury, benzodiazepine use was associated with a 0.71-fold estimated risk, whereas opiates were associated with a 21-fold estimated risk of having an accident that only caused injuryFootnote 177.

7.7.3 Psychiatric effects

7.7.3.1 Acute psychotic reactions

Cannabis and cannabinoid use has been linked to episodes of acute psychosis in both regular and drug-naïve usersFootnote 122,Footnote 145,Footnote 962. In one report, two healthy patients who had participated in a randomized controlled trial (RCT) measuring the effects of orally administered cannabinoids (including dronabinol or cannabis decoctions) on psychomotor performance displayed acute psychotic reactions following exposure to cannabisFootnote 145. The subjects had no psychiatric history or concomitant drug use, but were "occasional" regular cannabis users. In another RCT, 22 healthy subjects, also with a history of occasional cannabis use, no concomitant drug use, and with no psychiatric disorders received intravenous doses of Δ9-THC paralleling peak plasma THC levels achieved by smoking cannabis cigarettes containing 1 - 3.5% Δ9-THCFootnote 140. Drug administration was associated with a range of acute, transient, behavioural, and cognitive effects including suspiciousness, paranoid and grandiose delusions, conceptual disorganization, and illusions. Depersonalization, derealization, distorted sensory perceptions, altered bodily perceptions, feelings of unreality, and extreme slowing of time were also reported. Furthermore, blunted affect, reduced rapport, lack of spontaneity, psychomotor retardation, and emotional withdrawal were observed. Another study reported similar resultsFootnote 963.

7.7.3.2 Anxiety, Depression and Bipolar Disorder
Anxiety and depression

Cannabis is known to cause an acute and short-lasting episode of anxiety, often resembling a panic attack; this is more often encountered in naïve cannabis users and those who consume higher doses of cannabis or THC ( > 5 mg oral Δ9-THC), and also when cannabis is consumed in novel or stressful environmentsFootnote 147,Footnote 155. While clinical trials of cannabis, or oral Δ9-THC, to treat anxiety or depression show either a lack of improvement or worsening of these conditions Footnote 964,Footnote 965,Footnote 966,Footnote 967 there is some evidence that cannabis or cannabinoids may be useful in treating anxiety or depression secondary to other disorders (e.g. chronic pain, post-traumatic stress disorder). For more information on potential therapeutic uses of cannabis or cannabinoids to treat anxiety and depression, please consult section 4.8.5.1.

Research on the topic of cannabis and depression is relatively scarce and conflicting. A 2003 review reported that the co-morbidity level between heavy or problematic cannabis use and depression, in surveys of the general population, exceeds what would be expected by chanceFootnote 968. The authors also identify a modest association between early-onset regular or problematic use and later depression. However, limitations in the available research on cannabis and depression, including limitations in study design, as well as limitations in the ability to measure cannabis use, and limitations in the ability to measure depression were also highlighted. A U.S. study of adults using longitudinal national survey data (n = 8 759) found that the odds of developing depression in past-year cannabis users was 1.4 times higher than the odds of non-users developing depression Footnote 969. However, after adjusting for group differences, the association was no longer significant. In a 2008 study, the same group looked at the relationship between cannabis use and depression among youth using a longitudinal cohort of 1 494 adolescents. Similar to the adult study, the results did not support the causal relationship between adolescent-onset cannabis use problems and early adult depressionFootnote 970. In contrast, another U.S. study based on the results of the National Epidemiological Survey on Alcohol and Related Conditions (n = 43 093) found that major depression was significantly associated with lifetime cannabis disorders and dependenceFootnote 971. A 2007 study using data from the Netherlands Mental Health Survey and Incidence Study found a modest increased risk of a first depressive episode (Odds Ratio = 1.62; 1.06 - 2.48), after controlling for strong confounding factorsFootnote 972. Of greater significance in this study was the strong increased risk of bipolar disorder (Odds Ratio = 4.98; 1.80 - 13.81) with cannabis use (see below for further information on cannabis and bipolar disorder). There was a dose-response relationship associated with the risk of 'any mood disorder' for almost daily and weekly users, but not for less frequent users. A survey of 248 French high school students found that cannabis users had significantly higher rates of suicidal behaviours and depressive and anxious symptoms compared to non-usersFootnote 973. Another study suggested a putative positive association between exposure to cannabis and protracted suicidal thoughts or attempts in young people, although the study suffered from a number of limitationsFootnote 974.

Bipolar disorder

Cannabis is one of the most frequently abused drugs in people diagnosed with bipolar disorder Footnote 148,Footnote 975,Footnote 976,Footnote 977,Footnote 978. A number of studies have examined the relationship between cannabis use and bipolar disorder, its effect on disease course, and its effect on treatment compliance.

One three-year, prospective study involving 4 815 subjects attempted to determine if baseline cannabis use increased the risk for development of manic symptoms, if the association between cannabis use and mania was independent of the emergence of psychotic symptoms, and if baseline mania predicted cannabis use at follow-upFootnote 975. The authors found that cannabis use at baseline was associated with follow-up mania (Odds Ratio = 5.32, 95% Confidence Interval: 3.59, 7.89). After adjusting for confounding factors, the association persisted although it was reduced (Odds Ratio = 2.70, 95% Confidence Interval: 1.54, 4.75). The risk of developing manic symptoms appeared to increase with increased baseline frequency of cannabis useFootnote 975. The effect size was largest for those who used cannabis 3 - 4 days/week, followed by those who used daily and 1 - 2 days/week, and lastly for those who used 1 - 3 days/monthFootnote 975. The authors reported that manic symptoms at baseline did not predict cannabis use during follow-up. The results suggested that use of cannabis increased the risk of developing subsequent manic symptoms and that this effect was dose-dependentFootnote 975.

Another group of investigators conducted a five-year, prospective, cohort study examining three groups of patients: one where a cannabis use disorder preceded the onset of bipolar disorder, another where bipolar disorder preceded a cannabis use disorder, and one group with bipolar disorder onlyFootnote 976. The authors found that cannabis use was associated with more time in affective (manic or mixed) episodes and with rapid cycling, but a causal relationship between cannabis use and bipolar disorder could not be establishedFootnote 976.

A separate prospective study which followed a group of type I bipolar patients over a 10-year period, beginning from the onset of illness, concluded that there was a strong association between cannabis use and manic/hypomanic episodes or symptoms, and that substance abuse preceded or coincided with, but did not follow, exacerbations of affective illnessFootnote 979.

A two-year, prospective, observational study on the outcome of pharmacological treatment of mania (the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) study) followed 3 459 eligible in- and out-patients who were being treated for acute mania in bipolar disorder, assessing patients' current cannabis use as well as the influence of cannabis exposure on clinical and social treatment outcome measuresFootnote 148. The study concluded that during a one-year treatment period, cannabis users exhibited less treatment compliance and higher levels of overall illness severity, mania, and psychosis compared to non-usersFootnote 148. Cannabis users also reported experiencing less satisfaction with lifeFootnote 148.

A preliminary study found that patients diagnosed with bipolar disorder with psychotic features were significantly more likely to carry a functional polymorphism in the promoter region of the 5-HT transporter gene and also have a diagnosis of cannabis abuse/dependence, compared to bipolar patients who did not exhibit psychotic symptomsFootnote 978. Genetic studies have also raised the possibility of a link between allelic variants of the cannabinoid receptor gene (CNR1) and susceptibility to mood disordersFootnote 980,Footnote 981.

The influence of cannabis use on age at onset in both schizophrenia and bipolar disorder (with psychotic symptoms) has been studied using regression analysisFootnote 150. The authors of this study found that although cannabis and other substance use was more frequent in patients with schizophrenia than those diagnosed with bipolar disorder, cannabis use was nonetheless associated with a decrease in age at onset in both disordersFootnote 150. Cannabis use also preceded first hospitalization in the vast majority of cases (95.4%). Furthermore, the period of most intensive use ("several times per day") preceded first admission in 87.1% of the casesFootnote 150. In bipolar patients, cannabis use reduced age at onset by an average of nine yearsFootnote 150. In contrast, in schizophrenic patients, cannabis use reduced age at onset by an average of 1.5 yearsFootnote 150. No significant difference was noted in age at onset between male and female patients in either of the diagnostic groupsFootnote 150.

Another study investigated which factors were associated with age at onset in bipolar disorder, and also examined the sequence of the onsets of excessive substance use and bipolar disorderFootnote 982. A total of 151 patients with bipolar disorder (type I and II) receiving psychiatric treatment participated in the study. The authors found that when compared with alcohol use, excessive cannabis use (defined as either meeting DSM-IV criteria for substance use disorder, or weekly use of cannabis over a period of at least four years) was associated with an earlier age at onset in both primary and secondary bipolar disorder, even after adjusting for possible confoundersFootnote 982. In addition, the mean age at onset of excessive cannabis use preceded the age at onset of bipolar disease; this was reversed in the alcohol groupFootnote 982.

One study reported that when compared with controls, patients with bipolar disorder were almost seven times (95% Confidence Interval: 5.41 - 8.52) more likely to report a lifetime history of cannabis useFootnote 977. Furthermore, this association appeared to be gender-independent. Those patients who used cannabis after, or in tandem with, their onset of bipolar symptoms had a lower age at onset of the disorder (17.5 vs. 21.5 yrs)Footnote 977. Furthermore, those who used cannabis prior to the onset of a bipolar disease episode were 1.75 times (95% Confidence Interval: 1.05 - 2.91) more likely to report disability attributable to bipolar disorderFootnote 977.

Lastly, a retrospective analysis of a large cohort of bipolar I subjects, with or without a history of a cannabis use disorder, reported that bipolar patients with a cannabis use disorder had similar age at onset as patients without such a substance use disorderFootnote 983. However, patients with a cannabis use disorder were more likely to have experienced psychosis at some time during the course of their illness compared to patients who never met the criteria for the disorderFootnote 983.

7.7.3.3 Schizophrenia and psychosis

The endocannabinoid system has been implicated in the pathogenesis of schizophrenia and psychosis (please see section 4.8.5.5 for more information). Individuals with schizophrenia, or with a family history of this disorder, are likely to be at greater risk of suffering adverse psychiatric effects as a result of using cannabis or psychoactive cannabinoids such as Δ9-THCFootnote 152. Heavy cannabis use can aggravate psychotic symptoms and cause more relapses, and those individuals who use cannabis are at an increased risk of a poor prognosisFootnote 118,Footnote 138,Footnote 984,Footnote 985. Self-reported use of cannabis in adolescence has been associated with an increased risk of developing schizophrenia, and this risk was related to frequency of cannabis exposureFootnote 986. A cohort study of over 1 000 children followed from birth to age 26 reported a three-fold increased risk of psychotic disorders in those who used cannabis, and suggested that cannabis exposure among psychologically vulnerable adolescents should be strongly discouragedFootnote 987. The relationship between cannabis use and psychotic symptoms was also studied in a cohort of 2 437 young people (ages 14 - 24 yrs) who had greater than average pre-disposition for psychosis, and who had first used cannabis during adolescenceFootnote 146. The authors found a dose-response relationship between frequency of cannabis use and the risk of psychosis. The effect of cannabis use was also much stronger in those individuals with a pre-disposition for psychosis. A systematic review of evidence pertaining to cannabis use and the occurrence of psychotic or affective mental health outcomes reported an increased risk of any psychotic outcome in individuals who had ever used cannabis compared with non-users (Odds Ratio = 1.41)Footnote 141. Furthermore, the findings appeared to show a dose-related effect, with greater risk to individuals who used cannabis most frequently (Odds Ratio = 2.09) Footnote 149,Footnote 150.

In one study, the relationship between age at onset of psychosis and other clinical characteristics in a sample of well-characterized patients diagnosed with bipolar disorder with psychosis, schizoaffective disorder, or schizophrenia, has been investigatedFootnote 149. The study concluded that lifetime cannabis abuse/dependence was associated with a significantly earlier age at onset of psychosis (3.1 years, 95% Confidence Interval: 1.4 - 4.8)Footnote 149. Furthermore, among those patients with lifetime cannabis abuse/dependence, the age at onset of cannabis abuse/dependence preceded the onset of psychotic illness by almost another three yearsFootnote 149. However, patients who had a lifetime cannabis abuse/dependence diagnosis and a lifetime alcohol abuse/dependence diagnosis had a significantly later age at onset of psychosisFootnote 149.

Another study looked at the influence of cannabis use on age at onset in both schizophrenia and bipolar disorder (with psychotic symptoms) using regression analysisFootnote 150. The authors of this study found that although cannabis and other substance use was more frequent in patients with schizophrenia than those diagnosed with bipolar disorder, cannabis use was nonetheless associated with a decrease in age at onset in both disordersFootnote 150. Cannabis use also preceded first hospitalization in the vast majority of cases (95.4%) and furthermore, the period of most intensive use ("several times per day") preceded first admission in 87.1% of the casesFootnote 150. In bipolar patients, cannabis use reduced age at onset by an average of nine yearsFootnote 150. In contrast, in schizophrenic patients, cannabis use reduced age at onset by an average of 1.5 yearsFootnote 150. No significant difference was noted in age at onset between male and female patients in either of the diagnostic groupsFootnote 150.

Although cannabis use increases the risk of psychosis, it is only one factor in a larger constellation of contributing factorsFootnote 988.

Genetic factors

A number of studies have investigated the influence of potential genetic factors in the development of psychosis and schizophrenia, and more specifically as a function of interaction with cannabis use. Some studies have focused on the role of genetic polymorphisms at the catechol-O-methyltransferase gene (COMT)Footnote 686,Footnote 687,Footnote 688,Footnote 689,Footnote 690, while others have focused on polymorphisms at the AKT1 geneFootnote 691,Footnote 692,Footnote 693, or the brain-derived neurotrophic factor (BDNF) geneFootnote 989.

Schizophrenia and the Catechol-O-Methyltransferase gene

Catechol-O-methyltransferase (COMT) regulates the breakdown of catecholamines, including neurotransmitters such as dopamine, epinephrine, and norepinephrineFootnote 690. A missense mutation at codon 158 in the COMT gene, causing a substitution to the methionine (Met) at the positional valine (Val) (Val158Met), results in an enzyme with decreased activity and correspondingly slower dopamine catabolismFootnote 990,Footnote 991. Changes in dopaminergic tone and signaling are known to affect neurophysiological function, and these changes have been implicated in the pathophysiology of schizophreniaFootnote 992. Although a large-scale association study and meta-analysis has failed to find a strong association between the Val158Met COMT polymorphism and vulnerability to schizophreniaFootnote 993, evidence gathered from convergent functional genomic data nevertheless implicates the COMT gene (as well as the CNR1 and 2 genes) in the pathophysiology of schizophreniaFootnote 994. Caspi et al.Footnote 686 followed an epidemiological birth cohort of 1 037 children longitudinally across the first three decades of life. They concluded that the COMT Val/Val homozygous genotype interacted with adolescent-onset cannabis use, but not adult-onset use, to predict the emergence of adult psychosisFootnote 686. Subsequent studies confirmed and extended these findingsFootnote 687,Footnote 688,Footnote 689,Footnote 690,Footnote 693. Carriers of the Val allele were most sensitive to Δ9-THC-induced psychotic experiences (especially if they scored highly on a psychosis liability assessment), and were also more sensitive to the Δ9-THC-induced memory and attention impairments compared to carriers of the Met alleleFootnote 687. Homozygous carriers of the Val allele, but not subjects with the homozygous Met genotype, showed an increase in the incidence of hallucinations after cannabis exposure, but this was conditional on prior psychometric evidence of psychosis liabilityFootnote 688. Those patients who were Val/Met heterozygous also appeared to be more sensitive to the effects of cannabis than Met homozygotes, but less sensitive than Val homozygotesFootnote 688. Another study suggested that cannabis use could reduce the (protective) delay effect of the COMT Met allele in influencing the age of onset of psychosisFootnote 689. These findings were supported, and extended, by a subsequent study which showed that those who started using cannabis earlier had an earlier age at onset of psychiatric disorders, and that carriers of the Val homozygous genotype had an earlier age of onset of psychosis compared to Met carriersFootnote 690. The authors of this study concluded that gene-environment interaction (i.e. the combination of the COMT Val to Met polymorphism and cannabis use) may modulate the emergence of psychosis in adolescentsFootnote 690. Taken together, these studies also suggest the presence of a gene-dosage effect, with increasing disease risk among Val/Val homozygotes, moderate risk in Val/Met heterozygotes, and less risk among Met/Met homozygotes.

Schizophrenia and the AKT1 gene

Other studies have focused on the role of AKT1, a gene that encodes a protein kinase involved in the dopamine and cannabinoid receptor signaling cascades, and which is involved in regulating cellular metabolism, cell stress, cell-cycle regulation, and apoptosis as well as regulating neuronal cell size and survivalFootnote 691. In one study, the authors found evidence of a gene-environment interaction between a single nucleotide polymorphism in the AKT1 gene (rs2494732, C/C homozygous polymorphism) and cannabis useFootnote 692. Individuals with the C/C homozygous polymorphism had an approximately two-fold increased risk of being diagnosed with a psychotic disorder after having used cannabis either daily or weeklyFootnote 692. In contrast, C/T heterozygous individuals had only a slightly increased risk of developing cannabis-related psychosis compared to T/T homozygotes, which served as the controlsFootnote 692. In another study by the same group, individuals with the rs2494732 C/C homozygous polymorphism exhibited a deficit in sustained attention, but not in verbal memory, even in the absence of current cannabis useFootnote 691.

Schizophrenia and the Brain-Derived Neurotrophic Factor gene

One study found that cannabis use, before diagnosis of schizophrenia, was associated with a decrease in the age at onset of a psychotic disorder, decreasing the age at first admission by almost three yearsFootnote 989. Furthermore, a dose-dependent association between cannabis use and age at onset of psychotic symptoms was found, with an earlier onset of psychotic disorder in heavier users Footnote 989. A significant association between a younger age of first cannabis use and an earlier onset of psychotic disorder was also found, even after controlling for possible confoundersFootnote 989. In that study, cannabis use independently predicted age at onset of a psychotic disorder in male patients, whereas in female patients cannabis use was only associated with age at onset of psychotic disorder in those who carried a Met allele mutation in the gene for brain-derived neurotrophic factor (BDNF). Female carriers of the mutant Met allele presented with psychotic symptoms seven years earlier than female patients who did not use cannabis and who had a BDNF Val/Val genotype Footnote 989.

In conclusion, given the evidence suggesting a strong genetic component in the modulation of psychosis, and especially psychosis or schizophrenia precipitated by cannabis use, the taking of a thorough patient medical history, especially one which includes a psychiatric history/evaluation, would be very valuable in determining whether cannabis/cannabinoids represent a sensible and viable therapeutic option.

7.7.3.4 Amotivational syndrome

The term "amotivational syndrome" is generally used to qualify people who exhibit apathy, lack of motivation, social withdrawal, narrowing of interests, lethargy, impaired memory, impaired concentration, disturbed judgement, and impaired occupational achievementFootnote 995.

Some investigators suggest that heavy, chronic use of cannabis is linked to the development of such a syndromeFootnote 995; de-intoxication results in resolution of symptomsFootnote 152,Footnote 996. Other investigators have not found such a causal relationshipFootnote 995,Footnote 997.

8.0 Overdose/Toxicity

LD50 values for rats administered single oral doses of THC, or crude cannabis extract, are approximately 1000 mg/kgFootnote 998. Dogs and monkeys are able to tolerate significantly higher oral doses of THC, or cannabis extract, of 3000 mg/kg (or greater in certain cases)Footnote 998. The estimated human lethal dose of intravenous THC is 30 mg/kg (2100 mg/70 kg)Footnote 174, although there has been no documented evidence of death exclusively attributable to cannabis overdose to date. Significant CNS symptoms are observed with oral doses of 0.4 mg/kg dronabinol (Marinol®)Footnote 174. Cannabis and THC often produce unwanted physical effects, typically dizziness, sedation, intoxication, transient impairment of sensory and perceptual functions, clumsiness, dry mouth, lowered blood pressure, or increased heart rateFootnote 174,Footnote 999. These adverse effects are generally tolerable and not unlike those seen with other medicationsFootnote 118. The rare acute complications (e.g. panic attacks, psychosis, convulsions, etc.) that present to hospital Emergency Departments can be managed with conservative measures, such as reassurance in a quiet environment, and administration of benzodiazepines, if requiredFootnote 1000. As is stated in the case of overdose with Marinol®Footnote 174, the signs and symptoms observed with smoked or ingested cannabis are an extension of the psychotomimetic and physiologic effects of THC. Individuals experiencing psychotic reactions should stop using cannabis or cannabinoids immediately and seek prompt medical/psychiatric attention.

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Footnote 610

Porcella, A., Maxia, C., Gessa, G. L., and Pani, L. (2001). The synthetic cannabinoid WIN55212-2 decreases the intraocular pressure in human glaucoma resistant to conventional therapies. Eur.J.Neurosci. 13: 409-412.

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Footnote 611

Flach, A. J. (2002). Delta-9-tetrahydrocannabinol (THC) in the treatment of end-stage open-angle glaucoma. Trans.Am.Ophthalmol.Soc. 100: 215-222.

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Footnote 612

Yoles, E., Belkin, M., and Schwartz, M. (1996). HU-211, a nonpsychotropic cannabinoid, produces short- and longterm neuroprotection after optic nerve axotomy. J.Neurotrauma. 13: 49-57.

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Footnote 613

Shen, M. and Thayer, S. A. (1998). Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. Mol.Pharmacol. 54: 459-462.

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Footnote 614

Levin, L. A. (1999). Direct and indirect approaches to neuroprotective therapy of glaucomatous optic neuropathy. Surv.Ophthalmol. 43 Suppl 1: S98-101.

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Footnote 615

Jin, K. L., Mao, X. O., Goldsmith, P. C., and Greenberg, D. A. (2000). CB1 cannabinoid receptor induction in experimental stroke. Ann.Neurol. 48: 257-261.

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Footnote 616

Panikashvili, D., Simeonidou, C., Ben-Shabat, S., Hanus, L. and others. (2001). An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature. 413: 527-531.

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Footnote 617

Marsicano, G., Moosmann, B., Hermann, H., Lutz, B. and others. (2002). Neuroprotective properties of cannabinoids against oxidative stress: role of the cannabinoid receptor CB1. J.Neurochem. 80: 448-456.

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Footnote 618

Mechoulam, R., Panikashvili, D., and Shohami, E. (2002). Cannabinoids and brain injury: therapeutic implications. Trends Mol.Med. 8: 58-61.

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Footnote 619

Braida, D., Pegorini, S., Arcidiacono, M. V., Consalez, G. G. and others. (2003). Post-ischemic treatment with cannabidiol prevents electroencephalographic flattening, hyperlocomotion and neuronal injury in gerbils. Neurosci.Lett. 346: 61-64.

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Footnote 620

El-Remessy, A. B., Al-Shabrawey, M., Khalifa, Y., Tsai, N. T. and others. (2006). Neuroprotective and blood-retinal barrier-preserving effects of cannabidiol in experimental diabetes. Am.J.Pathol. 168: 235-244.

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Footnote 621

Gilbert, G. L., Kim, H. J., Waataja, J. J., and Thayer, S. A. (2007). Delta9-tetrahydrocannabinol protects hippocampal neurons from excitotoxicity. Brain Res. 1128: 61-69.