Urinary tetrahydrocannabinol is associated with poorer working memory performance and alterations in associated brain activity.

Worldwide, cannabis is one of the most widely used psychoactive substances and cannabis use has been implicated in poorer performance in several cognitive domains, including working memory (WM). However, the neural mechanisms underlying these WM decrements are not well understood and the current study investigated the association of cannabis involvement with WM performance and associated neural activation in the Human Connectome Project (N = 1038). Multiple indicators of cannabis involvement were examined in relation to behavioral performance and brain activity in a visual N-back task using functional magnetic resonance imaging. A positive urine drug screen for tetrahydocannabinol (THC+ status), the principal psychoactive constituent in cannabis, was associated with worse WM performance and differential brain response in areas previously linked to WM performance. Furthermore, decreases in blood-activation-level-dependent (BOLD) signal in WM task-positive brain regions and increases in task-negative regions mediated the relationship between THC+ status and WM performance. In contrast, WM performance and BOLD response during the N-back task were not associated with total lifetime cannabis use, age of first use, or other indicators of involvement, suggesting that the effects of cannabis on WM were short-term residual effects, rather than long-term persistent effects. These findings elucidate differential influences of cannabis involvement on neurocognition and have significant potential implications for occupational performance in diverse settings.