Investigating Emotional Reactivity in Experienced Users of Psychedelics: a cross-sectional fMRI study

Classic psychedelics profoundly influence emotional states, eliciting intense acute emotional experiences followed by subtle, sustained changes in emotional reactivity lasting up to several weeks. While clinical studies with controlled participant screening, dosing, and settings provide evidence for these effects, the impact of psychedelics is highly context-dependent. Thus, it remains unclear whether naturalistic, less-controlled psychedelic use similarly modulates emotional reactivity. To address this, our preregistered, cross-sectional fMRI study compared experienced psychedelic users (≥10 lifetime experiences; N = 33) with a matched group of non-users (N = 34) on behavioral and neural responses to emotional facial expressions. Psychedelic users demonstrated faster and more accurate recognition of angry facial expressions, suggesting reduced interference from threat-related stimuli during task performance. Whole-brain fMRI analyses revealed diminished neural responses to anger in limbic and salience network regions, coupled with enhanced responses to happiness in parietal and sensorimotor areas, consistent with prior clinical findings. Additionally, users showed increased precuneus activation in response to fearful facial expressions. Region-of-interest analyses further indicated reduced differentiation of emotional categories in two default mode network regions—the frontal medial cortex and parahippocampal gyrus. In conclusion, our study provides a nuanced view of neurofunctional alterations in emotional processing associated with naturalistic psychedelic use, advancing our understanding of its potential long-term effects.