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This document has been prepared by the Cannabis Legalization and Regulation Branch at Health Canada to provide information on the use of cannabis (marihuana) and cannabinoids for medical purposes. This document is a summary of peer-reviewed literature and international reviews concerning potential therapeutic uses and harmful effects of cannabis and cannabinoids. It is not meant to be comprehensive and should be used as a complement to other reliable sources of information. This document is not a systematic review or meta-analysis of the literature and has not rigorously evaluated the quality and weight of the available evidence nor has it graded the level of evidence. 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.
Cannabis is not an approved therapeutic product, unless a specific cannabis product has been issued a drug identification number (DIN) and a notice of compliance (NOC). The provision of this information should not be interpreted as an endorsement of the use of this product, or cannabis and cannabinoids generally, by Health Canada.
Reporting adverse reactions associated with the use of cannabis and cannabis products is important in gathering much needed information about the potential harms of cannabis and cannabis products for medical purposes. When reporting adverse reactions, please provide as much complete information as possible including the name of the licensed producer, the product brand name, the strain name, and the lot number of the product used in addition to all other information available for input in the adverse reaction reporting form. Providing Health Canada with as much complete information as possible about the adverse reaction will help Health Canada with any follow-ups or actions that may be required.
Any suspected adverse reactions associated with the use of cannabis and cannabis products (dried, oils, fresh) for medical purposes should be reported to the Canada Vigilance Program by one of the following three ways:
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:
The following bullet-point statements are meant to summarize the content found within sections 4.0 (Potential Therapeutic Uses) and 7.0 (Adverse Effects) and their respective subsections. The bullet-point statements can also be found in their respective sections and sub-sections in the body of the document itself. Note: most, but not all, clinical studies of cannabis (experimental or therapeutic) have been conducted with dried cannabis containing more THC than CBD and typically, but not always, with lower-potency THC (< 9% THC). Furthermore, the majority of the clinical studies of cannabis (experimental or therapeutic) have administered dried cannabis by smoking. Lastly, the findings from clinical studies of cannabis for therapeutic purposes may not be applicable to other chemotypes of cannabis or other cannabis products with different THC and CBD amounts and ratios.
Important Note: For the sake of completeness and for contextual purposes, the content in the following document includes information on dried cannabis and other cannabis-based products as well as selected cannabinoids. However, cannabis products and cannabinoids should not be considered equivalent even though the information on such products is presented together within the text. Cannabis and cannabis products are highly complex materials with hundreds of chemical constituents whereas cannabinoids are typically single molecules. Drawing direct comparisons between cannabis products and cannabinoids must necessarily take into account differences in the route of administration, dosage, individual pharmacological components and their potential interactions, and the different pharmacokinetic and pharmacodynamic properties of these different substances.
The endocannabinoid system (ECS) (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 bodyReference 1. The ECS has been implicated in a very broad number of physiological as well as pathophysiological processes including nervous system 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 state/moodReference 2-Reference 4. Furthermore, there is strong evidence that dysregulation of the ECS contributes to many human diseases including pain, inflammation, psychiatric disorders and neurodegenerative diseasesReference 5.
The ECS consists mainly of: the cannabinoid 1 and 2 (CB1 and CB2) receptors; the cannabinoid receptor ligands N-arachidonoylethanolamine ("anandamide") and 2-arachidonoylglycerol (2-AG); the endocannabinoid-synthesizing enzymes N-acyltransferase, phospholipase D, phospholipase C-β and diacylglycerol-lipase (DAGL); and the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) (Figure 1)Reference 2. Anandamide and 2-AG are considered the primary endogenous activators 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, virodhamine, N -homo-γ-linolenoylethanolamine and N-docosatetraenoylethanolamineReference 2Reference 6-Reference 9. Other 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)Reference 9. These fatty acyl ethanolamides 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) channelReference 10. This type of effect has been generally referred to as the so-called "entourage effect"Reference 10Reference 11. The term "entourage effect" is also used in the context of the interactions between phytocannabinoids and terpenes in a physiological system (see Section 1.1.2).
Endocannabinoids are arachidonic acid derivatives which are synthesized "on demand" (e.g. in response to an action potential in neurons or in response to another type of biological stimulus) from membrane phospholipid precursors in response to cellular requirementsReference 2Reference 12-Reference 14. Synthesis of endocannabinoids "on demand" ensures that endocannabinoid signaling is tightly controlled both spatially and temporally. Anandamide is principally, but not exclusively, produced by the transfer of arachidonic acid from phosphatidylcholine to phosphatidylethanolamine by N-acyltransferase to yield N-arachidonoylphosphatidylethanolamine (NAPE). NAPE is then hydrolyzed to form anandamide by a NAPE-specific phospholipase DReference 2Reference 15. Other synthetic routes include acyl-chain removal from NAPE by α/β-hydrolase 4 to yield glycerophospho-N-arachidonoylethanolamine followed by phosphodiester bond hydrolysis of glycerophospho-N-arachidonoylethanolamine by phosphodiesterase 1 to yield anandamideReference 16. 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 DAGLReference 2Reference 15. While anandamide and 2-AG are both derivatives of arachidonic acid, they are synthesized by pathways distinct from those used to synthesize eicosanoidsReference 17. Nevertheless, it appears that there may be a certain amount of cross talk between the eicosanoid and endocannabinoid pathwaysReference 17.
Endocannabinoids such as anandamide and 2-AG, as well as the phytocannabinoids Δ9-tetrahydrocannabinol (Δ9-THC), Δ8-THC, cannabinol (CBN) 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 cascadesReference 18Reference 19. 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 1p36Reference 20. The CNR1 coding sequence consists of one exon encoding a protein of 472 amino acidsReference 21. The CB1 receptor protein shares 97 - 99% amino acid sequence identity across species (human, rat, mouse)Reference 21. 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 lengthReference 21. 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 receptorReference 21.
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 cascadesReference 3Reference 13. Anandamide is a partial agonist at cannabinoid receptors, and binds with slightly higher affinity at CB1 compared to CB2 receptorsReference 2Reference 22. 2-AG appears to bind equally well to both cannabinoid receptors (with slightly higher affinity to CB1), but has greater potency and efficacy than anandamide at cannabinoid receptorsReference 2Reference 22.
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