Predictive model accuracy in estimating last Δ9-tetrahydrocannabinol (THC) intake from plasma and whole blood cannabinoid concentrations in chronic, daily cannabis smokers administered subchronic oral THC

doi:10.1016/j.drugalcdep.2012.03.005

Drug and Alcohol Dependence

Volume 125, Issue 3, 1 October 2012, Pages 313-319

https://doi.org/10.1016/j.drugalcdep.2012.03.005 Get rights and content

Abstract

Background

Determining time since last cannabis/Δ⁹-tetrahydrocannabinol (THC) exposure is important in clinical, workplace, and forensic settings. Mathematical models calculating time of last exposure from whole blood concentrations typically employ a theoretical 0.5 whole blood-to-plasma (WB/P) ratio. No studies previously evaluated predictive models utilizing empirically-derived WB/P ratios, or whole blood cannabinoid pharmacokinetics after subchronic THC dosing.

Methods

Ten male chronic, daily cannabis smokers received escalating around-the-clock oral THC (40–120 mg daily) for 8 days. Cannabinoids were quantified in whole blood and plasma by two-dimensional gas chromatography–mass spectrometry.

Results

Maximum whole blood THC occurred 3.0 h after the first oral THC dose and 103.5 h (4.3 days) during multiple THC dosing. Median WB/P ratios were THC 0.63 (n = 196), 11-hydroxy-THC 0.60 (n = 189), and 11-nor-9-carboxy-THC (THCCOOH) 0.55 (n = 200). Predictive models utilizing these WB/P ratios accurately estimated last cannabis exposure in 96% and 100% of specimens collected within 1–5 h after a single oral THC dose and throughout multiple dosing, respectively. Models were only 60% and 12.5% accurate 12.5 and 22.5 h after the last THC dose, respectively.

Conclusions

Predictive models estimating time since last cannabis intake from whole blood and plasma cannabinoid concentrations were inaccurate during abstinence, but highly accurate during active THC dosing. THC redistribution from large cannabinoid body stores and high circulating THCCOOH concentrations create different pharmacokinetic profiles than those in less than daily cannabis smokers that were used to derive the models. Thus, the models do not accurately predict time of last THC intake in individuals consuming THC daily.

Introduction

Knowledge of the time interval since last cannabis use is important in clinical, forensic, and workplace contexts. If there is suspicion of driving under the influence of cannabis or cannabis intake prior to an occupational accident, blood, plasma or serum samples are collected to determine cannabinoid concentrations. Concentrations of Δ⁹-tetrahydrocannabinol (THC) and its acid metabolite, 11-nor-9-carboxy-THC (THCCOOH), provide insight into the time of last THC consumption. Models for estimating time of last cannabis/THC intake were developed in the author's laboratory based on plasma data collected after controlled smoked cannabis administration (Huestis et al., 2005, Huestis et al., 2006, Huestis et al., 1992), while accident investigations and postmortem analyses are primarily conducted on whole blood. Thus, implementation of predictive models, and interpretation of cannabinoid concentrations in general, requires accurate whole blood (WB) to plasma (P) ratios to enable application of plasma-derived models to whole blood data. Previous studies of predictive models utilized the generally accepted WB/P ratio of 0.5. We are not aware of any previous model evaluations that employed empirically derived WB/P ratios. This may be due, in part, to the fact that few controlled drug administration studies simultaneously analyze both whole blood and plasma specimens.

Another limitation of existing predictive models based on plasma data, whether validated with oral (Huestis et al., 2006) or multiple smoked cannabinoid administration (Huestis et al., 2005), is that they were developed in less than daily cannabis smokers. Therefore, the models’ application was recommended only for specimens from occasional or less than daily cannabis smokers. This was due to limited knowledge of cannabinoid elimination in chronic, daily cannabis smokers, and how residual THC and THCCOOH concentrations in this population might affect predictions. We recently documented measureable THC in whole blood (Karschner et al., 2009a) and plasma (Karschner et al., 2009b) for at least 7 days after cannabis cessation in chronic, daily smokers who consumed up to 10 joints/blunts per day for up to 22 years.

A study of spontaneous and antagonist-elicited cannabis withdrawal in chronic, daily cannabis smokers (Gorelick et al., 2011) provided an opportunity to characterize whole blood THC, 11-hydroxy-THC (11-OH-THC), and THCCOOH pharmacokinetics and WB/P cannabinoid ratios in simultaneously collected specimens. Specimens were collected for 19.5 h of abstinence from previously self-administered smoked cannabis, after a single 20-mg oral THC dose, during administration of up to 120 mg oral THC per day for eight days, and for 22.5 h after the last oral THC dose. Now, for the first time, data are available to test the accuracy of predictive models in individuals who had a large THC body burden from previously self-administered chronic, daily cannabis smoking, and who received subchronic around-the-clock oral THC while abstaining from smoked cannabis. Furthermore, for the first time predictive models utilized empirically-derived WB/P cannabinoid ratios.

Section snippets

Participants

Inclusion criteria for participants included ages 18–45 years, cannabis use history for ≥1 year, daily smoking (on average) for ≥3 months, and cannabinoid-positive urine specimen within 30 days prior to enrollment. Participants with a history of clinically significant medical or psychiatric disease, clinically significant illness within 2 weeks of study initiation, current DSM-IV axis I disorder (other than cannabis, caffeine or nicotine dependence, or simple phobia), current physical dependence

Results

Ten adult males last smoking cannabis within 24 h of admission completed the study (see Table 1 for participant characteristics). Median (range) whole blood cannabinoid concentrations on admission from previously self-administered smoked cannabis were 3.0 ng/mL (1.4–20.3), 1.7 ng/mL (0.8–7.3), and 31.0 ng/mL (12.8–86.9) for THC, 11-OH-THC, and THCCOOH, respectively (Table 1, Fig. 1). 12.5 h later, THC and 11-OH-THC concentrations decreased to 2.3 (0.9–5.9) and 0.6 (0.5–3.5) ng/mL, respectively,

Discussion

To the best of our knowledge, this is the first study to evaluate the accuracy of estimation models for time since last THC intake utilizing empirically derived (rather than theoretical) WB/P ratios in individuals administered subchronic oral THC. In addition, this is the first study to evaluate the time course of cannabinoid disposition in whole blood and plasma during around-the-clock oral THC dosing and initiation of abstinence in such a population. The models overestimated time of last

Conclusions

An accurate predictive model to determine the time of last exposure to cannabis or THC is important in clinical, workplace, and forensic contexts, although the degree of accuracy needed may vary with the context. For example, in a drug abuse treatment setting, a positive test may trigger significant consequences, regardless of the time of last exposure, whereas accuracy to within minutes may be important in the context of an accident or crime. These data reaffirm our recent research (Karschner

Role of funding sources

Funding for this study was provided by the Intramural Research Program, NIH, National Institute on Drug Abuse; NIDA Residential Research Support Services Contract HHSN271200599091CADB (D. Kelly, PI) to the Maryland Psychiatric Research Center (MPRC); and a Cooperative Research and Development Agreement between Sanofi-aventis and the National Institutes of Health. NIDA and MPRC had no further role in the study design; in the collection, analysis, and interpretation of data; in the writing of the

Acknowledgments

The authors would like to acknowledge the clinical staffs of the National Institute on Drug Abuse Intramural Research Program, including Kathie Demuth, David Darwin, Janeen Nichels, and John Etter; the Maryland Psychiatric Research Center; and the Johns Hopkins Behavioral Pharmacology Research Unit, and Tsadik Abraham, Ross Lowe, and Allan Barnes for technical assistance.

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^☆: Supplementary information for this article is available. Please see Appendix A for more information.

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Published by Elsevier Ireland Ltd.

Predictive model accuracy in estimating last Δ9-tetrahydrocannabinol (THC) intake from plasma and whole blood cannabinoid concentrations in chronic, daily cannabis smokers administered subchronic oral THC☆

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Participants

Results

Discussion

Conclusions

Role of funding sources

Acknowledgments

J. Chromatogr. A

J. Pain Symptom Manage.

Delirium following ingestion of marijuana present in chocolate cookies

CNS Spectr.

Cannabis psychosis following bhang ingestion

Br. J. Addict.

Antagonist-elicited cannabis withdrawal in humans

J. Clin. Psychopharmacol.

Medical use of cannabis in the Netherlands

Neurology

The treatment of spasticity with [Delta]9-tetrahydrocannabinol in persons with spinal cord injury

Spinal Cord

Abstinence symptoms following oral THC administration to humans

Psychopharmacologia

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.

Predictive model accuracy in estimating last Δ⁹-tetrahydrocannabinol (THC) intake from plasma and whole blood cannabinoid concentrations in chronic, daily cannabis smokers administered subchronic oral THC☆