Do cannabis users develop tolerance for the psychoactive effects of delta-9-tetrahydrocannabinol? An fMRI study

Introduction.– Cannabis can induce transient psychotic and anxiety symptoms and long-lasting disorders. The acute psychoactive effects of the main active ingredient in cannabis, (−)-trans-9-tetrahydrocannabinol (9-THC), may be modulated by previous cannabis exposure. Objectives.– To test whether modest previous cannabis exposure modulates the acute effects of 9-THC on attentional salience and emotional processing and their neurophysiological substrates. Methods.– Twenty-four healthy men participated in a double-blind, randomized, placebo-controlled, repeated-measures, within-subject, 9-THC challenge study using an fMRI paradigm. Results.– Compared to non-users (n= 12; < 5 lifetime cannabis joints smoked), abstinent modest cannabis users (n= 12; 24.5±9 lifetime cannabis joints smoked) showed less efficient attentional salience processing, also recruiting different/additional brain areas to process both attentional salient and emotional stimuli (all P≤0.01). 9-THC challenge disrupted attentional salience and emotional processing-related brain activity, also inducing transient anxiety and psychotic symptoms (all P≤0.02). However, 9-THC-induced psychotic symptoms and attentional salience behavioral impairment were more pronounced in non-users compared to users (all P≤0.04). Intriguingly, while non-users under 9-THC shifted towards recruitment of other brain areas to perform the tasks, cannabis users were less affected by the acute challenge, showing a neurophysiological pattern similar to that of non-users under placebo. Only in non-users, the 9-THC-induced psychotic symptom and cognitive impairment severity was associated with a more pronounced neurophysiological alteration (all P≤0.048). Conclusions.– Abstinent modest cannabis users display residual effects of cannabis exposure but more blunted responses to the acute symptomatic, behavioral, and neurophysiological effects of 9-THC, which are more marked in people who have never used cannabis