Tolerance and cross-tolerance to neurocognitive effects of THC and alcohol in heavy cannabis users

Ramaekers, Johannes G.; Theunissen, Eef L.; de Brouwer, Marjolein; Toennes, Stefan W.; Moeller, Manfred R.; Kauert, Gerhold · 2010 · OpenAlex-citations

DOI: 10.1007/s00213-010-2042-1

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Summary

This study investigated whether heavy cannabis users develop tolerance to the neurocognitive impairing effects of Δ9-tetrahydrocannabinol (THC) and cross-tolerance to the effects of alcohol. While animal research suggests that chronic cannabis consumption may induce cross-tolerance to ethanol, human data supporting this claim are scarce. The researchers aimed to determine if heavy cannabis users exhibit reduced sensitivity to THC, alcohol, or their combination, and whether alcohol potentiates or mitigates THC-induced impairments. The study employed a double-blind, placebo-controlled, three-way design involving 21 heavy cannabis users (smoking more than four days per week). Participants underwent three conditions: alcohol placebo, low-dose alcohol (targeting 0.5 mg/ml blood alcohol concentration [BAC]), and high-dose alcohol (targeting 0.7 mg/ml BAC). In each condition, subjects smoked a THC cigarette (400 μg/kg) three hours after alcohol administration to maintain steady BAC levels. Neurocognitive performance was assessed repeatedly over seven hours using four tasks: critical tracking (perceptual motor control), divided attention (dual-task processing), stop-signal task (motor impulsivity), and Tower of London (executive function). Pharmacokinetic assessments monitored serum THC and BAC levels to ensure comparable intoxication across conditions. Results indicated that heavy cannabis users developed significant tolerance to the impairing effects of THC on most neurocognitive tasks. THC alone did not significantly affect performance in the critical tracking, stop-signal, or Tower of London tasks, confirming previous findings that chronic users are less sensitive to THC-induced deficits. However, alcohol significantly impaired performance in critical tracking, divided attention, and stop-signal tasks, demonstrating that heavy cannabis users did not develop cross-tolerance to alcohol. Notably, the combination of THC and alcohol produced synergistic effects on divided attention; the combined impairment was greater than that caused by alcohol alone. Specifically, THC increased control losses and reaction times in the divided-attention task only when alcohol was present, suggesting that alcohol selectively potentiated THC’s effects on this specific cognitive domain. The findings conclude that while heavy cannabis users tolerate the neurocognitive effects of THC, they remain fully susceptible to alcohol-induced impairment. Crucially, the study refutes the hypothesis of cross-tolerance between cannabis and alcohol in humans. Instead, alcohol appears to enhance the impairing effects of THC on divided attention. This has significant implications for public health and safety, particularly regarding driving under the influence, as the combined use of cannabis and alcohol may pose greater risks than either substance alone, despite the users' tolerance to cannabis.

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Topics

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• cannabis
• polydrug