____________________________________________________ Medical Marijuana and Other Cannabinoids
Cannabidiol CBD has shown exceptional therapeutic promise as a single molecular entity. It is already in clinical use as a combination product with THC and in certain cannabis strains developed to overexpress CBD. CBD produces pharmacologic actions different from, and often the opposite of, those of THC, and an increasing number of publications suggest broad therapeutic potential [103]. CBD is non-psychoactive but modulates ion channel, receptor, and enzyme targets. Preclinical studies suggest ben- eficial anti-inflammatory, analgesic, antiemetic, antipsychotic, anti-ischemic, anxiolytic, and antiepileptiform effects; human studies suggest anxiolytic efficacy [103; 104; 105]. CB2 receptor activity accounts for some anti-inflammatory and antinocicep- tive effects. CBD does not affect memory and probably curtails negative THC side effects by CB1 inverse agonist activity. The anxiolytic effects of CBD probably result from 5HT1-A recep- tor agonist activity [37]. Other mechanisms of therapeutic activity have been found. The neuroprotective properties of CBD are produced by inhibition of glutamate neurotoxicity and by antioxidant activ- ity that surpasses ascorbic acid (vitamin C) and tocopherol (vitamin E) [93]. CBD modulates endocannabinoid activity as a TRPV1 agonist and an FAAH inhibitor, and through inhibition of THC first pass hepatic metabolism into the more highly psychoactive metabolite 11-hydroxy-THC, which prolongs THC half-life and reduces the unwanted THC side effects of intoxication, panic, anxiety, and tachycardia [106]. CBD inhibits tumor necrosis factor-alpha (TNF- α ) in an animal model of rheumatoid arthritis and produces anti-inflammation and analgesia unrelated to COX-1 or COX-2 inhibition that involves promotion of adenosine receptor A2A signaling through adenosine transporter inhibition [31; 107]. Many effects of CBD follow a bell-shaped dose-response curve, sug- gesting that dose is a key factor in CBD pharmacology [104]. Outside the United States, CBD is available in equal ratio to THC in the oromucosal spray nabiximols. In Canada and the Netherlands, some cannabis strains available for medicinal use have been bred to overexpress CBD, for a 1:1 ratio of CBD to THC. Pure (>99%) isolated CBD crystals, oils, waxes, and other extracts are available from many dispensaries. In 2018, the FDA approved the first drug that contains purified CBD—a CBD oral solution for the treatment of seizures associ- ated with Lennox-Gastuat syndrome and Dravet syndrome in patients 2 years of age and older [108]. Cannabinol Cannabinol is produced by THC oxidation and is most often found in aged cannabis products. Cannabinol shares some characteristics with CBD, such as anti-convulsant and anti-inflammatory activity. Adding cannabinol to THC does not significantly increase THC effect. It is a weak CB1 and CB2 partial agonist with approximately 10% of the activity
of THC and appears to possess immunosuppressive proper- ties. Potential therapeutic applications of cannabinol include diseases characterized by cannabinoid receptor up-regulation [72; 104; 109]. Cannabigerol Cannabigerol possesses a broad mechanistic range, with activ- ity as a partial CB1 and CB2 receptor agonist, a potent TRPM8 antagonist, an agonist at TRPV1and TRPA1, and also as an anandamide reuptake inhibitor in the low micromolar range. Other mechanisms of cannabigerol include 5-HT1A receptor antagonism and α 2-adrenoceptor agonism [104; 109]. Can- nabigerol possesses anti-inflammatory and analgesic proper- ties and also demonstrates anti-proliferative and antibacterial activity [104]. Tetrahydrocannabivarin Tetrahydrocannabivarin is a CB1 receptor antagonist and CB2 receptor partial agonist. This effect is dose-dependent, as it shows THC antagonist activity at low doses while higher doses act as a CB1 agonist. Tetrahydrocannabivarin has shown anticonvulsant properties in in vitro and in vivo studies [110; 111]. Other potential benefits of tetrahydrocannabivarin include its increase of central inhibitory neurotransmission, giving it therapeutic potential in epilepsy, and CB1 antagonism suggesting clinical benefit by decreasing food intake [104]. Cannabichromene Cannabichromene, together with THC, is a major cannabinoid constituent in freshly harvested cannabis. It has activity as a potent TRPA1 agonist and weak anandamide reuptake inhibi- tor, and it is shown to exert anti-inflammatory, antimicrobial and modest analgesic activity. In preclinical animal studies, cannabichromene showed greater propensity than THC in producing adverse events, including hypothermia, sedation, and hypoactivity [104]. PHARMACOKINETICS Cannabis is inhaled or orally ingested, with substantial differ- ences between routes in the time course of absorption, distri- bution, and duration of action that explain the overwhelming preference of medical users for inhaled over orally ingested cannabis products [59]. In one study, more than 4,000 Califor- nian medical patients expressed a preference for inhaling their medication, stating the therapeutic effects from oral dronabi- nol or nabilone were more difficult to achieve and more likely to be unpleasant or excessively prolonged [112]. In contrast, inhaling cannabis provides more rapid onset of symptom relief and rapid feedback informing the patient whether titration with additional dose is needed or not [68; 113]. Absorption and Distribution The rate of drug absorption is determined by the route of administration and drug formulation. Inhalation is the pri- mary route of cannabis administration and provides rapid and efficient drug delivery from the lungs to the brain [68].
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