Medical Marijuana and Other Cannabinoids _____________________________________________________
Smoked Cannabis With smoking, the onset of effect occurs within seconds to minutes. Maximal effect is experienced after 30 minutes, and the duration of effect is 2 to 3 hours [59]. Peak plasma THC occurs within 10 minutes and decreases to roughly 60% of peak by 15 minutes and to 20% of peak by 30 minutes. This rapid onset and predictable decay allows for effective dose titration not possible with oral cannabinoids [88]. The THC dose absorbed systemically is 25% to 27% of the total avail- able THC content in a marijuana cigarette (“joint”) [68; 114]. Vaporized Cannabis A study comparing smoked and vaporized administration found higher serum THC at 30 and 60 minutes post-inhalation with vaporization and comparable serum THC levels over the remaining six-hour period [115]. Vaporization was preferred by 80% of subjects, and as with smoking, vaporization was highly conducive to self-titration. The amount of THC delivery is influenced by the amount and type of cannabis, vaporizing temperature, duration of vaporization, and the balloon volume [116; 117]. Oral Ingestion The CNS and physiologic effects with oral ingestion are sub- stantially delayed relative to inhalation, including slower onset of action, lower peak plasma levels, and longer duration of effect. With pharmaceutical cannabinoids such as dronabinol, 10% to 20% of ingested THC enters systemic circulation due to extensive first-pass metabolism. In healthy volunteers, a single 2.5-mg dose of dronabinol produces mean peak plasma THC at two hours, with a range of 30 minutes to four hours; these absorption and distribution kinetics are similar following a single 10-mg dose of dronabinol [118]. Plant cannabis can be mixed into brownies, cookies, or tea prepared from the flowering tops, but all result in unreliable absorption. In one study, oral ingestion of 20 mg THC in chocolate cookies resulted in only 4% to 12% of THC enter- ing systemic absorption and peak plasma THC at one to two hours in most subjects and six hours in others, with some subjects showing multiple plasma peaks [68]. The bioavail- ability of THC from tea made of plant cannabis is lower than with smoking due to the poor water solubility of THC and the effect of hepatic first-pass metabolism [14]. Distribution THC distribution is time-dependent and begins rapidly after absorption. In plasma, THC is 95% to 99% plasma protein bound, primarily lipoproteins. The tissue distribution of lipophilic THC and its metabolites mostly involves uptake in fatty tissues and highly perfused organs such as the brain, heart, lung, and liver [59; 68]. Whether THC accumulates in the brain with long-term use is unknown, due to limits in THC access and accumulation imposed by the blood-brain barrier [119].
Metabolism Most cannabinoid metabolism occurs in the liver, with different metabolic byproducts predominating by route of administration. THC metabolism is complex and involves allylic oxidation, epoxidation, decarboxylation, and conjuga- tion. THC is oxidized by the cytochrome P450 (CYP450) oxidases 2C9, 2C19, and 3A4 to produce the active metabolite 11-hydroxy THC and the inactive metabolite 11-nor-9-carboxy THC [120]. The 11-hydroxy THC plasma level parallels observ- able drug action [68]. Relative to inhalation, first-pass hepatic metabolism with oral ingestion yields a greater proportion of 11-hydroxy THC [59]. Elimination Body fat is the major long-term storage site of THC and its biometabolites. Elimination occurs over several days due to the slow rediffusion of THC from body fat and other tissues. Roughly 20% to 35% of THC is eliminated in urine and 65% to 80% in feces, and by five days, 80% to 90% of THC is eliminated, although THC from a single dose can be detected in plasma up to 13 days later in chronic smokers as a result of extensive storage and release from body fat [59; 121]. Adverse Drug-Drug Interactions Most patients in the RCTs discussed in this course were maintained on their pre-study medications for neuropathic pain, cancer pain, fibromyalgia, or multiple sclerosis. In these and other RCTs, patients smoked or ingested cannabis while taking their prescribed opioids, NSAIDs, muscle relaxants, ket- amine, anticonvulsants, antidepressants, and benzodiazepines. Cannabis use with these other agents was well tolerated, and observed side effects did not differ from those expected with cannabis [14]. In theory, ingesting cannabis with drugs that alter its metabolic pathway should increase the risk of side effect enhancement or efficacy failure, but adverse drug-drug interactions of clinical relevance have not been reported to date. Cannabis should be used with caution by patients also using sedating substances such as alcohol or benzodiazepines [59]. Tolerance Tolerance is defined as tissue adaptation resulting from repeated drug exposure, such that one or more drug effects diminish over time. Cannabis tolerance primarily results from pharmacodynamic mechanisms, including changes in CB1 signaling ability due to receptor desensitization and down- regulation. THC tolerance varies across different brain regions, possibly explaining why tolerance develops to some cannabis effects but not to others [122]. Tolerance to most THC effects develops after a few doses and then disappears rapidly following cessation, and pharmacodynamic tolerance can be minimized by combining a low dose of cannabinoid with one or more additional therapeutic drugs [123].
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