Δ9-Tetrahydrocannabinol (THC) is the main active constituent of cannabis. In recent years, the average THC content of some cannabis cigarettes has increased up to approximately 60 mg per cigarette (20% THC cigarettes). The pharmacokinetics of THC after smoking cannabis cigarettes containing more than approximately 35 mg THC (3.55% THC cigarettes) is unknown. To be able to perform suitable exposure risk analysis, it is important to know if there is a linear relation at higher doses.
The present study aimed to characterise the pharmacokinetics of THC, the active metabolite 11-OH-THC and the inactive metabolite THC-COOH after smoking a combination of tobacco and cannabis containing high THC doses.
Materials and methods
This double-blind, placebo-controlled, four-way, cross-over study included 24 male non-daily cannabis users (two to nine joints per month). Participants were randomly assigned to smoke cannabis cigarettes containing 29.3, 49.1 and 69.4 mg THC and a placebo. Serial serum samples collected over a period of 0–8 h were analysed by liquid chromatography electrospray tandem mass spectrometry. Effects on heart rate, blood pressure and ‘high’ feeling were also measured.
Mean maximal concentrations (C max) were 135.1, 202.9 and 231.0 μg/L for THC and 9.2, 16.4 and 15.8 μg/L for 11-OH-THC after smoking a 29.3-, 49.1- and 69.4-mg THC cigarette, respectively. A large inter-individual variability in C max was observed. Heart rate and ‘high’ feeling significantly increased with increasing THC dose.
This study demonstrates that the known linear association between THC dose and THC serum concentration also applies for high THC doses.
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This study was funded by the Ministry of Health, Welfare, and Sport of the Netherlands, which had no further role in study design, data collection, analysis and interpretation of data and writing the reports. The authors declare that the study complies with the current Dutch laws, i.e. the country in which the study was performed.
Trial registration: ClinicalTrials.gov identifier, NCT00225407
Serum was cleaned by solid phase extraction on a Focus SPE cartridge (3 ml, 20 mg; Varian, USA) using 1.0-ml samples. Concentrations of THC and its metabolites 11-OH-Δ9-THC (11-OH-THC) and 11-nor-carboxy-Δ9-THC (THC-COOH) were determined with liquid chromatography electrospray tandem mass spectrometry (LC-ESI±MS/MS), using a Finnigan surveyor with quantum discovery mass spectrometer (Thermo Electron, USA). Chromatographic separation (20 μl injection volume) was achieved in 10 min over a Polaris C18-A (100 × 2.0 mm) 5 μ column (Varian, USA) using gradient elution with an aqueous mobile phase (containing 0.01% trifluoracetic acid and a organic phase using methanol and acetonitrile), at a flow rate of 0.4 mL/min. Standards for the drugs were obtained from Cerilliant, Texas, USA and diluted in drug-free human plasma at a concentration ranging between 0 and 50.0 μg/L. D3-deuterated standards for THC and THC-COOH were purchased from the same corporation and added as an internal standard at the concentration of 50 μg/L. The mass spectrometer was operated in electrospray ionisation positive ion mode, and quantitation was conducted using selected reaction monitoring. Calibration analyses were completed according to internal standard methods with the Xcalibur software (Thermo Electron) using calibration curves with linear fit identification. The LOQ for THC, 11-OH-THC and THC-COOH were 0.5, 0.5 and 1.0 μg/L, respectively.
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Hunault, C.C., Mensinga, T.T., de Vries, I. et al. Delta-9-tetrahydrocannabinol (THC) serum concentrations and pharmacological effects in males after smoking a combination of tobacco and cannabis containing up to 69 mg THC. Psychopharmacology 201, 171–181 (2008). https://doi.org/10.1007/s00213-008-1260-2
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