The present study was designed to assess tolerance and cross-tolerance to the neurocognitive effects of THC and alcohol in heavy cannabis users. Results demonstrated that alcohol detrimentally affected performance of heavy cannabis users. THC generally did not affect performance, confirming earlier reports on tolerance to performance impairing effects of THC. Performance in the divided-attention task however was affected by both THC and alcohol, and their combination.
Alcohol was given in a low- and high-dose condition with the general aim to achieve steady BAC concentrations around 0.5 and 0.7 mg/ml, respectively, during performance testing in a 5-h time window. After 5 h, BACs were allowed to decline over time. Steady BACs were achieved by administering booster alcohol doses almost every 30 min on an as needed basis. In general, repeated alcohol dosing produced the desired BAC concentrations during performance testing in the two alcohol conditions. Performance tests were basically scheduled in three separate time windows: i.e., between 1–2.5, 3.5–5.5, and 5.5–7 h after alcohol onset. Mean BAC concentrations in the low and high alcohol-dose condition fluctuated around 0.5 and 0.7 mg/ml, respectively, during performance testing in the first and second time window. Performance testing during the third time window took place during the declining phase of BAC in both alcohol conditions. Subjective feelings of drunkenness during alcohol treatments were also comparable during the first and second time window, and gradually decreased with declining BACs in the third time window. BAC and subjective drunkenness data indicate that the levels of alcohol intoxication were comparable during performance testing in the first and second time window (i.e., prior and post-smoking THC), and declined at similar rates during performance assessments in the third time window.
The effects of alcohol in objective performance measures were consistent and straightforward. Alcohol significantly affected all performance measures in the critical tracking task, the divided-attention task, and the stop-signal task. In the critical tracking task, alcohol significantly decreased tracking performance. In the divided-attention task, alcohol increased reaction time, number of control losses, and decreased number correct signal detections and tracking. Alcohol increased stop reaction time and commission errors in the stop-signal task. The neurocognitive effects of alcohol in heavy cannabis users are comparable to those that have been reported in earlier studies in infrequent drug (including cannabis) users (Heishman et al. 1988
; Kuypers et al. 2006
; Liguori et al. 2002
; Ramaekers and Kuypers 2006
) and healthy volunteers (de Wit et al. 2000
; Vermeeren et al. 2002
). The present data strongly indicate that heavy cannabis use does not produce cross-tolerance to the impairing potential of alcohol.
Subjects smoked a cannabis cigarette every treatment condition at 3 h after onset of alcohol or alcohol placebo administrations. Subjective high was elevated to similar degrees after smoking cannabis in each treatment condition. THC concentrations were also comparable between treatments with peak THC concentrations ranging from 93 to 112 ng/ml. Together, these data suggest that THC administrations were very comparable in every treatment condition.
THC did not affect performance of heavy cannabis users in the critical tracking task, the stop-signal task, and the Tower of London. These tasks have previously been shown to be very sensitive to the impairing potential of THC when administered to infrequent cannabis (Ramaekers et al. 2006a
). The lack of THC effects on any of these tasks basically confirms previous notions that heavy cannabis users can develop tolerance to behaviorally impairing effects of THC (D'Souza et al. 2008
; Hart et al. 2001
; Jones et al. 1981
; Ramaekers et al. 2009
). However it was interesting to note that tolerance was not apparent in all performance tasks. During divided-attention task performance, THC increased the number of control losses and reaction time and decreased the number of correct signal detections. Number of times that subjects lost control over the primary task (tracking) during this dual task performance appeared particularly sensitive to the impairing effect of THC. During alcohol placebo, mean number of control losses were always low, independent of THC administration. During treatments with low and high ethanol doses, mean number of control losses increased by a factor two and five, respectively, after smoking a THC cigarette. Univariate analysis indeed revealed a significant alcohol
THC interaction for this particular parameter, supporting the notion that the combination of alcohol and THC detrimentally affected the number of control losses in a synergistic manner.
THC effects on reaction time and signal detection in the divided-attention task may have also been related to concomitant alcohol use. The latter measures did not reveal an alcohol
THC interaction, but an additive effect of alcohol and THC cannot be excluded. Previous studies demonstrated that the divided-attention task is very sensitive to the effects of THC and alcohol alone when given to occasional cannabis users or healthy volunteers (Moskowitz 1984
; Ramaekers et al. 2009
; Schulte et al. 2001
). Other studies have demonstrated that low doses of THC and alcohol that do not affect psychomotor function when given alone may still impair performance when given in combination (Lamers and Ramaekers 2001
). In other words, small THC impairments that would go unnoticed in isolation still might exceed the (statistical) threshold of detection when added to the impairment produced by concurrent alcohol. Likewise, it is conceivable that negligible THC effects on divided attention as previously demonstrated in heavy cannabis users (Ramaekers et al. 2009
) may become more apparent when added to those of a social dose of alcohol. This might particularly be true for attention tasks that are known for their very high sensitivity to drug and alcohol effects (Moskowitz 1984
Data from the present study confirmed that chronic cannabis users develop tolerance to the behaviorally impairing effects of THC. However, previous notions (Marks and MacAvoy 1989
; Wright and Terry 2002
) that chronic cannabis use would also develop cross-tolerance for the impairing effects of alcohol were not confirmed. It should be noted however that previous studies never demonstrated complete tolerance to the behaviorally impairing effects of alcohol in heavy cannabis users. Generally, they showed that heavy cannabis users were less impaired after an alcohol challenge than non-drug users or infrequent cannabis users. Moreover, such demonstrations of partial tolerance were always very selective for single performance parameters (e.g., tracking accuracy), whereas other task parameters (e.g., reaction time) did not reveal cross-tolerance. Previous demonstrations of cross-tolerance were obtained after administration of single doses of alcohol. Performance testing occurred during the descending phase of the blood alcohol curve. Consequently, BACs were generally lower than those obtained in the present study after repeated alcohol dosing. For example, Wright and Terry (2002
) tested tracking performance of heavy cannabis users within 30 min after drinking while mean BACs declined from 0.28 to 0.22 mg/ml. Mean BAC levels in the present study however were two to three times as high and experimentally controlled to achieve relatively steady state levels during 5 h of repeated performance testing. Repeated alcohol challenges and high BAC levels thus may have provoked more pronounced alcohol impairments than can be observed after single administration of a low alcohol dose. Consequently, cross-tolerance or behavioral adaptation may have been lacking or insufficient to compensate for prolonged alcohol impairments as observed in the present study.
The general lack of cross-tolerance for the impairing effects of alcohol as well as the potential of ethanol to potentiate the effects of THC in the divided-attention task may have important implications for heavy cannabis users who drive under the influence of both drugs. Heavy cannabis users usually operate their vehicle on day to day basis because they believe they developed resistance against the impairing effect of THC (Ramaekers et al. 2009
). In the present study, most participants (79%) admitted to driving under the influence of cannabis and a substantial proportion (32%) also admitted to driving under the influence of cannabis and alcohol in combination. The present data however demonstrated that mean BAC concentrations up to 0.7 mg/ml produce significant performance impairment and that the presence of alcohol may potentiate detrimental effects of THC during dual task performances that are common during car driving. Additive and synergistic effects of alcohol and THC on driving performance have previously been shown in occasional cannabis users (O'Kane et al. 2002
; Ramaekers et al. 2004
; Sewell et al. 2009
). The present study demonstrates that additive and synergistic effects of THC and alcohol on performance can pertain to heavy cannabis users as well.
In conclusion, the present study generally confirms that heavy cannabis users develop tolerance to the impairing effects of THC on neurocognitive task performance. Yet, heavy cannabis users did not develop cross-tolerance to the impairing effects of alcohol, and the presence of the latter even selectively potentiated THC effects on measures of divided attention.