Elsevier

Drug and Alcohol Dependence

Volume 85, Issue 2, 8 November 2006, Pages 114-122
Drug and Alcohol Dependence

Cognition and motor control as a function of Δ9-THC concentration in serum and oral fluid: Limits of impairment

https://doi.org/10.1016/j.drugalcdep.2006.03.015Get rights and content

Abstract

Cannabis use has been associated with increased risk of becoming involved in traffic accidents; however, the relation between THC concentration and driver impairment is relatively obscure. The present study was designed to define performance impairment as a function of THC in serum and oral fluid in order to provide a scientific framework to the development of per se limits for driving under the influence of cannabis. Twenty recreational users of cannabis participated in a double-blind, placebo-controlled, three-way cross-over study. Subjects were administered single doses of 0, 250 and 500 μg/kg THC by smoking. Performance tests measuring skills related to driving were conducted at regular intervals between 15 min and 6 h post smoking and included measures of perceptual-motor control (Critical tracking task), motor impulsivity (Stop signal task) and cognitive function (Tower of London). Blood and oral fluid were collected throughout testing. Results showed a strong and linear relation between THC in serum and oral fluid. Linear relations between magnitude of performance impairment and THC in oral fluid and serum, however, were low. A more promising way to define threshold levels of impairment was found by comparing the proportion of observations showing impairment or no impairment as a function of THC concentration. The proportion of observations showing impairment progressively increased as a function of serum THC in every task. Binomial tests showed an initial and significant shift toward impairment in the Critical tracking task for serum THC concentrations between 2 and 5 ng/ml. At concentrations between 5 and 10 ng/ml approximately 75–90% of the observations were indicative of significant impairment in every performance test. At THC concentrations >30 ng/ml the proportion of observations indicative of significant impairment increased to a full 100% in every performance tests. It is concluded that serum THC concentrations between 2 and 5 ng/ml establish the lower and upper range of a THC limit for impairment.

Introduction

The acute effects of Δ9-tetrahydrocannabinol (THC) on isolated cognitive functions and psychomotor skills have been repeatedly assessed in experimental studies employing within subject, double-blind, placebo-controlled designs. These have generally shown that THC in doses between 40 and 300 μg/kg causes a dose-dependant reduction in performance on laboratory tasks measuring memory, divided and sustained attention, reaction time, tracking and motor function (Ameri, 1999, Curran et al., 2002, D'Souza et al., 2004, Hall and Solowij, 1998, Hampson and Deadwyler, 1999, Leweke et al., 1998, Lichtman et al., 2002, Ramaekers et al., 2004). Performance impairment after THC was usually highest during the first hour after smoking and declined to baseline over 3–4 h after THC use. From a public health perspective, a major concern about the acute effects of cannabis is the possibility of accidents if users drive or operate machinery while intoxicated (Hall, 2001). Cannabis induced impairment of driving has been demonstrated in on-the-road driving tests (Lamers and Ramaekers, 2001, Ramaekers et al., 2000, Robbe, 1994). The effects of cannabis on driving increased with dose and were larger and more persistent in driving skills requiring sustained attention. The degree of performance impairment observed after doses up to 300 μg/kg THC were equivalent to the impairing effect of an alcohol dose producing a blood alcohol concentration (BAC) ≥0.05 g/dl, the legal limit for driving under the influence in most European countries.

There is an increasing concern across EU and US member states regarding the connection between cannabis use and road traffic accidents. From a legal point of view there is a great challenge of measurability and accuracy of interpretation because the association between levels of THC and crash risk is not fully understood. In virtually all western countries the policy regarding driving under the influence of cannabis is in whole or in part based on the detection of any amount of THC, the pharmacologically most active ingredient of cannabis, or even its inactive metabolite THC–COOH in blood or urine of the driver. Law enforcement and policy makers often call for the adoption of per se laws with a zero limit for THC or any of its metabolites. Such ‘zero-tolerance’ laws are already in place in several US states and in other countries, such as Germany. Yet, there is little scientific evidence to show that detection of THC or THC–COOH in bodily fluids can be taken as proof of impairment in any circumstance. For example, THC or its metabolite can be detected in bodily fluids for days after smoking and may thus indicate past use rather than impairment. Moreover, impairment and crash risk after recent cannabis use has been shown to increase as a function of dose; little impairment is apparent at low doses whereas serious impairment develops at high doses (Drummer et al., 2004, Menetrey et al., 2005, Ramaekers et al., 2004). Thus, a body fluid sample in a collision-involved driver that is positive for THC merely indicates that the driver is a cannabis user. Plasma concentrations of THC have been shown to vary widely between 1 and 35 ng/ml in drivers suspected of driving under the influence (Augsburger et al., 2005) and between 1 and 100 ng/ml in fatally injured drivers (Drummer et al., 2004). How varying THC levels in plasma relate to driver behavior is presently unknown but can be simulated in experimental performance studies of the pharmacodynamics and pharmacokinetics of cannabis intoxication. Such studies will contribute to a science-based foundation for government policies and law enforcement practices on cannabis and driving in analogy to the system developed for alcohol.

The present study was designed to assess the effects of a medium (i.e. 250 μg/kg) and high dose (i.e. 500 μg/kg) of THC on skills related to driving throughout 6 h post smoking. Skills related to driving were assessed at regular intervals using laboratory tasks measuring perceptual-motor control (Tracking task), motor impulsivity (Stop signal task) and cognitive function (Tower of London). Likewise, blood and oral fluid were regularly collected in order to determine the pharmacokinetic profile of THC and its main metabolites throughout performance testing. The main goals were (1) to assess the association between cannabis induced performance impairment and THC concentrations in serum and oral fluid; (2) to assess the correlation between THC concentrations in serum and oral fluid; and (3) to determine threshold THC levels in serum at which performance impairment emerges.

Section snippets

Subjects

Twenty recreational cannabis users (14 males–6 females) aged 19–29 years participated in the study. Initial screening included a questionnaire on medical history. Subjects who were pre-selected were examined by the medical supervisor who also checked vital signs and collected blood and urine samples. Standard blood chemistry, haematology and drug screen tests were conducted on these samples. Inclusion criteria were experience with the use of cannabis (at least five times in the previous 12

Results

Complete data sets (N = 20) were collected for the Critical tracking task and The Tower of London. In case of the Stop signal task data sets for nine subjects were incomplete due to technical malfunctions. All of these subjects were part of the subgroup whose oral fluid were sampled with Orasure intercept® for quantitative analysis. Consequently, no correlation between performance in the Stop signal task and THC in oral fluid was calculated due to the low number of complete data sets.

Discussion

The main findings of this study were (1) that linear, but marginal relations exist between the magnitude of performance impairment and THC levels in serum and oral fluid; (2) that THC levels in serum and oral fluid are strongly correlated; and (3) that clear cut-off levels in serum THC can be determined above which performance impairment emerges.

The pharmacodynamic and pharmacokinetic effects of THC were as expected. THC significantly impaired cognitive and motor performance in the Critical

Acknowledgements

This study was supported by grants from the German Federal Police Academy and the German Society against Alcohol Drugs and Driving (“Bund gegen Alkohol und Drogen im Straßenverkehr”). We like to thank Anita van Oers, Janneke Guyaux and Roland Otten for their contributions to study logistics and data collection. We are grateful to Elke Runow, Volker Schwarz, Werner Pogoda and Markus Duchardt for their technical assistance.

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