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 (THC COOH) 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 < 0.001), but conjugated concentrations were underestimated owing to incomplete enzymatic hydrolysis. CONCLUSIONS Plasma THC concentrations remained >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.

AIMS-To quantify blood Δ 9 -tetrahydrocannabinol (THC) concentrations in chronic cannabis users over seven days of continuous monitored abstinence.PARTICIPANTS-Twenty-five frequent, long-term cannabis users resided on a secure clinical research unit at the U.S. National Institute on Drug Abuse under continuous medical surveillance to prevent cannabis self-administration.MEASUREMENTS-Whole blood cannabinoid concentrations were determined by twodimensional gas chromatography-mass spectrometry.FINDINGS-Nine chronic users (36%) had no measurable THC during seven days of cannabis abstinence; 16 had at least one positive THC ≥0.25 ng/mL, but not necessarily on the first day. On day 7, six full days after entering the unit, six participants still displayed detectable THC concentrations (mean ± SD, 0.3 ± 0.7 ng/mL) and all 25 had measurable carboxy-metabolite (6.2 ± 8.8 ng/mL). The highest observed THC concentrations on admission (day 1) and day 7 were 7.0 and 3.0 ng/mL, respectively. Interestingly, five participants, all female, had THC positive whole blood specimens all seven days. Body mass index did not correlate with time until last THC positive specimen (N = 16; R = −0.2; p = 0.445).CONCLUSIONS-Substantial whole blood THC concentrations persist multiple days after drug discontinuation in heavy chronic cannabis users. It is currently unknown whether neurocognitive impairment occurs with low blood THC concentrations, and whether return to normal performance, as previously documented following extended cannabis abstinence, is accompanied by removal of residual THC in brain. These findings also may impact the implementation of per se limits in driving under the influence of drugs legislation.

A two-dimensional (2D) gas chromatography/electron impact-mass spectrometry (GC/EI-MS) method for simultaneous quantification of Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC), and 11-nor-Delta(9)-tetrahydrocannabinol-9-carboxylic acid (THCCOOH) in human plasma was developed and validated. The method employs 2D capillary GC and cryofocusing for enhanced resolution and sensitivity. THC, 11-OH-THC, and THCCOOH were extracted by precipitation with acetonitrile followed by solid-phase extraction. GC separation of trimethylsilyl derivatives of analytes was accomplished with two capillary columns in series coupled via a pneumatic Deans switch system. Detection and quantification were accomplished with a bench-top single quadrupole mass spectrometer operated in electron impact-selected ion monitoring mode. Limits of quantification (LOQ) were 0.125, 0.25 and 0.125 ng/mL for THC, 11-OH-THC, and THCCOOH, respectively. Accuracy ranged from 86.0 to 113.0% for all analytes. Intra- and inter-assay precision, as percent relative standard deviation, was less than 14.1% for THC, 11-OH-THC, and THCCOOH. The method was successfully applied to quantification of THC and its 11-OH-THC and THCCOOH metabolites in plasma specimens following controlled administration of THC.

AIMS To develop and empirically validate a mathematical model for identifying new cannabis use in chronic, daily cannabis smokers. DESIGN Models were based on urinary creatinine-normalized (CN) cannabinoid excretion in chronic cannabis smokers. SETTING For model development, participants resided on a secure research unit for 30 days. For model validation, participants were abstinent with daily observed urine specimens for 28 days. PARTICIPANTS 48 (model development) and 67 (model validation) daily cannabis smokers were recruited. MEASUREMENTS All voided urine was collected and analyzed for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH) by gas chromatography-mass spectrometry (GCMS, limit of quantification 2.5 ng/mL) and creatinine (mg/mL). Urine THCCOOH was normalized to creatinine, yielding ng/mg CN-THCCOOH concentrations. Urine concentration ratios were determined from 123,513 specimen pairs collected 2–30 days apart. FINDINGS A mono-exponential model (with two parameters, initial urine specimen CN-THCCOOH concentration and time between specimens), based on the Marquardt-Levenberg algorithm, provided a reasonable data fit. Prediction intervals with varying probability levels (80, 90, 95, 99%) provide upper ratio limits for each urine specimen pair. Ratios above these limits suggest cannabis re-use. Disproportionate numbers of ratios were higher than expected for some participants, prompting development of two additional rules that avoid misidentification of re-use in participants with unusual CN-THCCOOH excretion patterns. CONCLUSIONS For the first time, a validated model is available to aid in the differentiation of new cannabis use from residual CN-THCCOOH excretion in chronic, daily cannabis users. These models are valuable for clinicians, toxicologists, drug treatment staff, and workplace, military and criminal justice drug testing programs.