Pharmacokinetic and Pharmacodynamic Profile of Supratherapeutic Oral Doses of Δ⁹-THC in Cannabis Users

Oral Δ⁹-tetrahydrocannabinol (Δ⁹-THC) has been evaluated as a medication for cannabis dependence, but repeated administration of acute oral doses up to 40 mg has not been effective at reducing drug-taking behavior. Larger doses might be necessary to affect cannabis use. The purpose of the present study was therefore to determine the physiological and behavioural effects of oral Δ⁹-THC at acute doses higher than those tested previously. The pharmacokinetic and pharmacodynamic profile of oral Δ⁹-THC, administered in ascending order in 15 mg increments across separate sessions, up to a maximum of 90 mg, was determined in seven cannabis users. Five subjects received all doses and two experienced untoward side effects at lower doses. Δ⁹-THC produced a constellation of effects consistent with previous clinical studies. Low cannabinoid concentrations were associated with significant effects on drug-sensitive measures, although progressively greater levels did not lead to proportionately larger drug effects. Considerable variability in C_max and t_max was observed. Doses of oral Δ⁹-THC larger than those tested previously can be administered to individuals with a history of cannabis use, although given the pharmacokinetic variability of oral Δ⁹-THC and individual differences in sensitivity, individualized dose adjustment is needed to avoid side effects and maximize therapeutic response.