People who had used cannabis before were less affected by THC than those who had never tried it

Double-blind, randomized, placebo-controlled, repeated-measures, within-subject crossover study with fMRI. Twenty-four healthy men received THC challenge: 12 non-users (<5 lifetime joints) and 12 abstinent modest users (24.5 lifetime joints). Attentional salience and emotional processing were assessed behaviorally and neurophysiologically.

This study provides neurobiological evidence for cannabis tolerance at remarkably low exposure levels. Even about 25 lifetime joints created measurable differences in how the brain responded to THC. This has implications for understanding why first-time or rare cannabis users may have more dramatic reactions, including psychotic symptoms.

The finding that even modest cannabis exposure creates tolerance-like changes challenges the binary view of cannabis users versus non-users. The neurobiological adaptations from relatively few exposures suggest that the brain begins adjusting to cannabinoid signaling quickly, with implications for both safety (first-time users are most vulnerable) and research (comparing "users" to "non-users" may miss important gradients).

The sample was small (24 participants) and exclusively male. The definition of "modest" use (about 25 joints) is arbitrary. The study cannot determine whether the blunted response in modest users represents true tolerance or selection bias (people less sensitive to THC may use more). Cross-sectional comparison of groups with different exposure histories limits causal inference.