Medical Marijuana and Other Cannabinoids _____________________________________________________
CB2 Mechanisms As noted, CB2 receptor expression is highest in immune cells. CB2 activation mediates immunosuppressive effects, includ- ing inhibition of proinflammatory cytokine production and cytokine and chemokine release, and blockade of neutrophil and macrophage migration [36; 59; 60]. ECS and Pain Pathways Pain is the most frequent condition for which medical can- nabis is used, and the antinociceptive (analgesic) actions of cannabinoids are distinct from mechanisms that mediate psychoactive effects [10; 15]. For instance, THC enhances analgesia produced by kappa opioid receptor agonist drugs, and administration of a kappa opioid receptor antagonist blocks this analgesic effect but has no effect on the psychoactive effects of THC. Cannabinoids interact with opioid, serotonin, and N-methyl-d-aspartate (NMDA) receptors, all of which are highly relevant in pain modulation [37]. The efficacy of cannabinoids in the management of chronic neuropathic pain is partially explained by ECS modulation of the descending supraspinal inhibitory pathway, an important pain pathway functionally compromised in patients with chronic pain. Via periaqueductal grey and rostral ventrome- dial medulla inputs, cannabinoid activation of CB1 and CB2 receptors stimulates the endogenous noradrenergic pathway, which activates peripheral adrenoreceptors to induce antinoci- ception. Other mechanisms of cannabinoid analgesia include functional CB2 receptor expression in dorsal root ganglion sensory neurons, the spinal cord, and brain regions highly relevant to nociceptive integration and modulation [37; 61]. Serious gastrointestinal and cardiovascular adverse effects are associated with nonsteroidal anti-inflammatory drugs (NSAIDs), and their use is now recommended at the lowest effective dose over the shortest duration possible [62; 63; 64]. In theory, cannabis may have NSAID dose-sparing effects. Cannabinoids and cyclo-oxygenase-2 (COX-2) have indepen- dent but interacting roles in pain. During inflammatory pain, prostanoids are produced, potentiating bradykinin to sensitize pain signal-transmitting C-fibers. COX-2 metabolizes anan- damide and 2-AG to prostanoid compounds that potentiate this pain-inducing cascade, and COX-2 oxidizes 2-AG into the pro-nociceptive metabolic product prostaglandin E2 (PGE2)-G. Thus, inflammatory states with COX-2 up-regulation can nul- lify the antinociceptive effects of endogenous cannabinoids and produce pro-nociceptive byproducts from their metabolism. COX-2 inhibitors block this conversion, an effect shown in peripheral pain where anandamide release is the dominant analgesic mechanism, and in stress-induced CNS pain where 2-AG release is the dominant analgesic. Low-dose COX-2 inhibitors do not block COX-2 but block the conversion of 2-AG into pro-nociceptive PGE2-G. Acetaminophen prolongs the analgesic action of 2-AG by inhibiting its enzymatic degra- dation by FAAH [61]. These findings indicate that co-ingesting cannabinoids and COX-2 inhibitors synergistically inhibits
prostaglandin and enhances endocannabinoid activity to produce greater analgesia than monotherapy with either agent [65]. Also, tolerance is a main unwanted development with all analgesic drugs, including cannabinoids, and COX-2 inhibi- tion may prolong cannabinoid analgesia [66]. CANNABINOID PHARMACOLOGY Cannabinoids are the molecular constituents of botanical cannabis (also termed phytocannabinoids) or pharmaceutical preparations that possess ECS activity. BOTANICAL CANNABIS COMPOSITION Cannabis possesses at least 489 distinct compounds from 18 different chemical classes that include terpenoids, flavonoids, phytosterols, and at least 100 cannabinoids. This does not mean there are 100 different cannabinoid effects or interac- tions; the cannabinoids fall into 10 groups of closely related cannabinoids, and most are not believed to contribute to cannabis’s effects at their naturally occurring concentrations in the plant. THC is the primary psychoactive ingredient, and depending on the particular plant, THC or cannabidiol (CBD) is the most abundant cannabinoid. The relative concentra- tion of THC, CBD, and other cannabinoids in a given plant is influenced by cannabis strain, soil and climate conditions, and cultivation techniques [8; 67]. Pyrolysis transforms hundreds of plant cannabinoid com- pounds into additional compounds. More than 2,000 com- pounds may be produced through pyrolysis of cannabis, many of which remain to be studied. As such, smoked cannabis produces many compounds not observed with vaporized or ingested cannabis [14; 68; 69]. Phytocannabinoids are dis- cussed in detail later in this course. Terpenoids Terpenoids vary widely among Cannabis varieties, accounting for differences in fragrance among different strains and possibly contributing to the distinctive smoking qualities and character of the “high” from smoked cannabis. Preclinical studies sug- gest a broad spectrum of activity with terpenoids, including anti-oxidant, antianxiety, antibacterial, antineoplastic, and antimalarial action; however, these data await confirmation in clinical trials [70; 71]. Analgesic and anti-inflammatory activity have been found in several cannabis terpenoids [72]. Myrcene is an analgesic that inhibits inflammation via PGE2 activity. Naloxone blocks this activity, suggesting an opioid-mediated mechanism [73]. β -caryophyllene produces anti-inflammation via PGE1 inhibition comparable to phenylbutazone and also acts simultaneously as a gastric cytoprotective. It possesses selective CB2 agonist activity, and additional investigation has shown increasing promise with potentially broad clinical appli- cation [74]. Other possibly therapeutic terpenoids include the PGE1 inhibitor α -pinene and the local anesthetic linalool [71; 75]. One study examined six common terpenoids, alone and
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