An integrated pharmacokinetic and pharmacodynamic study of acute marijuana use

Abstract

An integrated pharmacokinetic and pharmacodynamic study of acute marijuana use in humans was designed to characterize the onset, peak, and duration of a broad range of marijuana's physiological and behavioral effects. The study design emphasized the critical smoking period, when {dollar}\Delta{dollar}9-tetrahydro-cannabinol (THC), the major active ingredient of marijuana, was absorbed and reached active sites. Six healthy males smoked a single marijuana cigarette (placebo, 1.75% or 3.55% THC) in a double-blind, randomized, Latin square study design. Advanced technologies were used which included a continuous withdrawal blood pump for rapid, integrated blood sampling; computerization of the paced smoking protocol and presentation and collection of behavioral measures; and THC and metabolite analysis by GC/MS. Previous studies have indicated a substantial time delay between peak plasma levels of THC and drug-induced effects. This study demonstrated that some behavioral and physiologic effects appear concurrently or shortly after the rapid appearance of THC in blood. The study design incorporated measurements of subjective effects after each marijuana inhalation to monitor the rapid onset of effects. Three of six subjects reported increases in drug "liking" and "feel drug" scores after the first puff. Maximum heart rates were recorded within 4 minutes of the last inhalation after the high dose cigarette. In addition, significant drug exposure was demonstrated after a single puff of marijuana smoke. Mean blood THC concentrations were 7.0 and 18.1 ng/mL following the first marijuana inhalation of a 1.75 or 3.55% THC cigarette, respectively. In addition, integrated blood sampling throughout the smoking process clearly demonstrated that peak THC levels occurred prior to the end of smoking. Blood cannabinoid data collected in this controlled clinical study were used for development of mathematical models for the prediction of elapsed time after marijuana use from the analysis of a single blood sample for cannabinoids. Corresponding confidence intervals were derived for future predictions at the 95% confidence level. The accuracy of model prediction was evaluated by comparison of the predicted time of prior drug use to the actual time of exposure and comparison of the actual time of use to the 95% confidence limits.