Rationale <p>Δ⁹-tetrahydrocannabinol (THC), the principal intoxicant in cannabis, is a highly lipophilic substance that is readily stored in fat. Preclinical research suggests that fat-stored THC can be released into circulation under lipolytic conditions, such as stress. However, compelling evidence of this phenomenon is lacking in humans.</p> Objectives <p>Here, we investigated the effects of acute stress on blood (plasma) THC (and 11-COOH-THC) concentrations as well as indices of intoxication (e.g., cognitive function, subjective drug effects) in ‘regular’ (i.e., &gt; 3 days/week) cannabis users.</p> Methods <p>Fifteen volunteers (<i>n</i> = 9 female; cannabis use: 5.0 ± 1.5 days/week) participated in a single-arm (i.e., pre-/post-intervention) trial. The intervention (stressor) was cold water immersion (CWI); specifically, 10&#xa0;min at ~ 10&#xa0;°C. Plasma cannabinoid concentrations, cognitive function and subjective drug effects were measured pre-, shortly post- and 2&#xa0;h post-intervention. Measures of stress (e.g., heart rate [HR], blood pressure [BP], subjective ratings) and lipolysis (i.e., plasma free fatty acid [FFA] and glycerol concentrations) were also obtained.</p> Results <p>CWI produced a small but significant stress response, characterised by increased HR and systolic BP and decreased subjective “calmness”. It also increased plasma FFA and glycerol concentrations, albeit modestly. However, neither plasma THC nor 11-COOH-THC concentrations increased from pre- to post-intervention. Cognitive function also remained unchanged, while subjective drug effects were negligible.</p> Conclusions <p>Stress induced via brief CWI does not appear to increase blood cannabinoid concentrations or induce intoxication in moderate cannabis users.</p>