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Background: Δ9-Tetrahydrocannabinol (THC) is the primary psychoactive constituent of cannabis and an active cannabinoid pharmacotherapy component. No plasma pharmacokinetic data after repeated oral THC administration are available. Methods: Six adult male daily cannabis smokers resided on a closed clinical research unit. Oral THC capsules (20 mg) were administered every 4–8 h in escalating total daily doses (40–120 mg) for 7 days. Free and glucuronidated plasma THC, 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH) were quantified by 2-dimensional GC-MS during and after dosing. Results: Free plasma THC, 11-OH-THC, and THCCOOH concentrations 19.5 h after admission (before controlled oral THC dosing) were mean 4.3 (SE 1.1), 1.3 (0.5), and 34.0 (8.4) μg/L, respectively. During oral dosing, free 11-OH-THC and THCCOOH increased steadily, whereas THC did not. Mean peak plasma free THC, 11-OH-THC, and THCCOOH concentrations were 3.8 (0.5), 3.0 (0.7), and 196.9 (39.9) μg/L, respectively, 22.5 h after the last dose. Escherichia coli β-glucuronidase hydrolysis of 264 cannabinoid specimens yielded statistically significant increases in THC, 11-OH-THC, and THCCOOH concentrations (P &amp;lt; 0.001), but conjugated concentrations were underestimated owing to incomplete enzymatic hydrolysis. Conclusions: Plasma THC concentrations remained &amp;gt;1 μg/L for at least 1 day after daily cannabis smoking and also after cessation of multiple oral THC doses. We report for the first time free plasma THC concentrations after multiple high-dose oral THC throughout the day and night, and after Escherichia coli β-glucuronidase hydrolysis. These data will aid in the interpretation of plasma THC concentrations after multiple oral doses.

Δ9-Tetrahydrocannabinol (THC), 11-Hydroxy-THC, and 11-Nor-9-carboxy-THC Plasma Pharmacokinetics during and after Continuous High-Dose Oral THC