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By Robert G. Bell

Robert BellAs we mentioned back in May, the AAPS Blog will discuss and highlight the history, chemistry, pharmacology, therapeutic use, and potential for abuse of marijuana. We continue that theme by diving into Marijuana Pharmacokinetics.

Marijuana can be delivered in a variety of methods, typically by pulmonary (smoking, vaporization) and oral (food, drink, tinctures, oral solids, etc.) administration. The estimated dose of THC needed to produce effects in humans ranges from 2 to 22 mg and it is estimated that only 1 percent of the THC content of a ”joint” is found in the brain after smoking (about 2–44 ug). After smoking, THC is detectable in the plasma only seconds after the inhaling marijuana, with peak plasma level being measured three to 10 minutes after the first inhalation, reflecting the conversion of THC to its metabolites in the liver (more than 100 different metabolites of THC have been identified). The effects start almost instantaneously when smoked, reaching a peak at around 20 minutes and lasting for two to three hours. If the drug is eaten, the effects are delayed and last longer, reaching a maximum at about three to four hours after drug ingestion and lasting for six to eight hours.

A typical joint contains between 0.5 g and 1.0 g of marijuana which varies in THC content between 1 and 15 percent, or approximately between 5 mg and 150 mg per joint. The amount of THC delivered in the smoke has been estimated at 20 to 70 percent, with the rest being lost through combustion or escaping in sidestream smoke. The bioavailability of THC from marijuana joints has been reported to range between 5 percent and 24 percent. The bioavailablity of oral ingestion is much less, partly due to first pass metabolisms by the liver, and the onset of high effect is delayed but the duration of action is prolonged due to the slow absorption from the gut.

Once absorbed, THC is rapidly disturbed. Due to THC lipid solubility, cannabinoids accumulate in fatty tissues reaching peak concentrations in four to five days, and then they are slowly released back into circulation. The elimination half-life is about seven days, and complete elimination of a single dose may take up to 30 days. Cannabinoids are metabolized in the liver to over 20 different metabolites with half-lives of several days. The metabolites are partially excreted in the urine but mainly in the gut where they are reabsorbed, further prolonging their action. The major metabolite is 11-hydroxy-THC, which is possibly more potent than THC itself. Due to the deposition in the fat and the presence of active metabolites, there is no clear relationship between plasma or urine concentration and the degree of cannabinoid intoxication. There are large interindividual differences in rates of metabolism, and metabolism is likely to be slowed in the elderly and in the presence of liver disease. Cannabinoids also cross the placenta, enter the fetal circulation, and penetrate into breast milk.

The LD50 values for rats administered single oral doses of THC, or crude cannabis extract, are approximately 1,000 mg/kg. Dogs and monkeys are able to tolerate significantly higher oral doses of THC, or cannabis extract, of 3,000 mg/kg (or greater in certain cases). The estimated human lethal dose of intravenous THC is 30 mg/kg, although there has been no documented evidence of death exclusively attributable to cannabis overdose to date. Marinol maximum daily dosing for appetite stimulation or anti-emesis in adults is up to 20 mg per day.

The marijuana pharmacokinetics helped us understand some of the associated recreational and medicinal metabolic metrics. I hope the cannabis blogs have not made you numb because there’s more to come. I may be getting manic about this botanic because next up is marijuana pharmacodynamics.

Robert G. Bell, Ph.D., is president and owner of Drug and Biotechnology Development LLC, a consultancy to the pharmaceutical industry and academia for biological, drug, and device development.