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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

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Abstract

Rationale

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.

Objectives

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.

Results

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.

Conclusions

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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References

  • Agurell S, Halldin M, Lindgren JE, Ohlsson A, Widman M, Gillepsie H, Hollister L (1986) Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev 38:21–43

    PubMed  CAS  Google Scholar 

  • Anzenbacher P, Anzenbacherová E (2001) Cytochromes P450 and metabolism of xenobiotics. Cell Mol Life Sci 58:737–747

    Article  PubMed  CAS  Google Scholar 

  • Barnett G, Chiang CW, Perez-Reyes M, Owens SM (1982) Kinetic study of smoking marijuana. J Pharmacokinet Biopharm 10:495–506

    Article  PubMed  CAS  Google Scholar 

  • Bornheim LM, Lasker JM, Raucy JL (1992) Human hepatic microsomal metabolism of Δ1-tetrahydrocannabinol. Drug Metab Depos 20:241–246

    CAS  Google Scholar 

  • El Sohly MA (2004) Quarterly report potency monitoring project #85. National Center for Natural Products Research, University of Mississippi, Oxford, USA

    Google Scholar 

  • EMCDDA (2007) Annual report from the EU drugs agency: the state of the drugs problem in Europe. Available at http://www.emcdda.europa.eu/html.cfm/index419EN.html

  • Fant RV, Heishman SJ, Bunker EB, Pickworth WB (1998) Acute and residual effects of marijuana in humans. Pharmacol Biochem Behav 60:777–784

    Article  PubMed  CAS  Google Scholar 

  • Grothenhermen F (2003) Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet 42:327–360

    Article  Google Scholar 

  • Gustafson RA, Moolchan ET, Barnes A, Levine B, Huestis MA (2003) Validated method for the simultaneous determination of Delta 9-tetrahydrocannabinol (THC), 11-hydroxy-THC and 11-nor-9-carboxy-THC in human plasma using solid phase extraction and gas chromatography-mass spectrometry with positive chemical ionization. J Chromatogr B Analyt Technol Biomed Life Sci 798:145–154

    Article  PubMed  CAS  Google Scholar 

  • Hart CL, van Gorp W, Haney M, Foltin RW, Fischman MW (2001) Effects of acute smoked marijuana on complex cognitive performance. Neuropsychopharmacology 25:757–765

    Article  PubMed  CAS  Google Scholar 

  • Huestis MA, Sampson AH, Holicky BJ, Henningfield JE, Cone EJ (1992a) Characterization of the absorption phase of marijuana smoking. Clin Pharmacol Ther 52:31–41

    PubMed  CAS  Google Scholar 

  • Huestis MA, Henningfield JE, Cone EJ (1992b) Blood cannabinoids. I. Absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana. J Anal Toxicol 16:276–282

    PubMed  CAS  Google Scholar 

  • Huestis MA, Henningfield JE, Cone EJ (1992c) Blood cannabinoids. II. Models for the prediction of time of marijuana exposure from plasma concentrations of delta 9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-delta 9-tetrahydrocannabinol (THCCOOH). J Anal Toxicol 16:283–290

    PubMed  CAS  Google Scholar 

  • Kintz P, Cirimele V (1997) Testing human blood for cannabis by GC-MS. Biomed Chromatogr 11:371–373

    Article  PubMed  CAS  Google Scholar 

  • Lane SD, Cherek DR, Tcheremssine OV, Lieving LM, Pietras CJ (2005) Acute marijuana effects on human risk taking. Neuropsychopharmacology 30:800–809

    Article  PubMed  CAS  Google Scholar 

  • Lindgren JE, Ohlsson A, Agurell S, Hollister L, Gillepsie H (1981) Clinical effects and plasma levels of delta 9-tetrahydrocannabinol (delta 9-THC) in heavy and light users of cannabis. Psychopharmacology 74:208–212

    Article  PubMed  CAS  Google Scholar 

  • Maralikova B, Weinmann W (2004) Simultaneous determination of Delta9-tetrahydrocannabinol, 11-hydroxy-Delta9-tetrahydrocannabinol and 11-nor-9-carboxy-Delta9-tetrahydrocannabinol in human plasma by high-performance liquid chromatography/tandem mass spectrometry. J Mass Spectrom 39:526–531

    Article  PubMed  CAS  Google Scholar 

  • Moeller MR, Doerr G, Warth S (1992) Simultaneous quantitation of delta-9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THC-COOH) in serum by GC/MS using deuterated internal standards and its application to a smoking study and forensic cases. J Forensic Sci 37:969–983

    PubMed  CAS  Google Scholar 

  • Niesink RJM, Rigter S, Hoek J, Goldschmidt H (2007) THC-concentraties in wiet, nederwiet en hasj in Nederlandse coffeeshops (2006–2007). Trimbos Instituut, Utrecht, The Netherlands

    Google Scholar 

  • Ohlsson A, Lindgren JE, Wahlén A, Agurell S, Hollister LE, Gillepsie HK (1982) Single dose kinetics of deuterium labelled delta 1-tetrahydrocannabinol in heavy and light cannabis users. Biomed Mass Spectrom 9:6–10

    Article  PubMed  CAS  Google Scholar 

  • Perez-Reyes M, Di Guiseppi S, Davis K, Schindler VH, Cook CE (1982) Comparison of effects of marihuana cigarettes of three different potencies. Clin Pharmacol Ther 31:617–624

    PubMed  CAS  Google Scholar 

  • Ramaekers JG, Kauert G, van Ruitenbeek P, Theunissen EL, Schneider E, Moeller MR (2006) High-potency marijuana impairs executive function and inhibitory motor control. Neuropsychopharmacology 31:2296–2303

    PubMed  CAS  Google Scholar 

  • Tanswell P, Koup J (1993) TopFit: a PC-based pharmacokinetic-pharmacodynamic data analysis program. Int J Clin Pharm Ther Toxicol 31:514–520

    CAS  Google Scholar 

  • Thomas BF, Compton DR, Martin BR (1990) Characteristization of the lipophility of natural and synthetic analogs of delta 9-tetrahydrocannabinol and its relationship to pharmacological potency. J Anal Toxicol 255:624–630

    CAS  Google Scholar 

  • Valjent E, Mitchell JM, Besson MJ, Caboche J, Maldonado R (2002) Behavioural and biochemical evidence for interactions between Delta 9-tetrahydrocannabinol and nicotine. Br J Pharmacol 135:564–578

    Article  PubMed  CAS  Google Scholar 

  • Watanabe K, Yamaori S, Funahashi T, Kimura T, Yamamoto I (2007) Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci 80:1415–1419

    Article  PubMed  CAS  Google Scholar 

  • Widman M, Agurell S, Ehrnebo M, Jones G (1974) Binding of (+)- and (−)-D1-tetracannabinols and (−)-7-hydroxy-Δ1-tetracannabinol to blood cells and plasma proteins in man. J Pharm Pharmacol 26:914–916

    PubMed  CAS  Google Scholar 

  • World Drug Report (2006) Volume 1 (analysis). United Nations Office on Drugs and Crime, United Nations Publication Sales No. E.06.XI.10

Download references

Acknowledgments

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.

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Authors and Affiliations

  1. National Institute for Public Health and the Environment, P.O. Box 1, 3720 BA, Bilthoven, The Netherlands

    Claudine C. Hunault, Tjeert T. Mensinga, Irma de Vries, Maaike Kruidenier, Marianne E. C. Leenders & Jan Meulenbelt

  2. DeltaLab, Postbus 800, 3170 DZ, Poortugaal, The Netherlands

    Hermien H. Kelholt-Dijkman & Jani Hoek

  3. Division of Perioperative and Emergency Care, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands

    Marianne E. C. Leenders

  4. Division of Intensive Care Center, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands

    Jan Meulenbelt

  5. Institute for Risk Assessment Sciences, University Utrecht, Utrecht, The Netherlands

    Jan Meulenbelt

Authors
  1. Claudine C. Hunault
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  2. Tjeert T. Mensinga
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  3. Irma de Vries
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  4. Hermien H. Kelholt-Dijkman
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  5. Jani Hoek
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  6. Maaike Kruidenier
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  7. Marianne E. C. Leenders
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  8. Jan Meulenbelt
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Corresponding author

Correspondence to Claudine C. Hunault.

Additional information

Trial registration: ClinicalTrials.gov identifier, NCT00225407

Appendix

Appendix

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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