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

Classic psychedelics profoundly alter emotional states, inducing intense acute experiences lasting hours, followed by subtler, longer-lasting changes in emotional reactivity that can persist for weeks. While experimental and clinical studies document these prolonged effects, the highly context-dependent nature of psychedelic experiences leaves open the question of whether naturalistic, nonclinical use similarly modulates emotional processing. To investigate this, we conducted a preregistered, cross-sectional fMRI study comparing experienced psychedelic users (≥ 10 lifetime uses; N = 33) with closely matched nonusers (N = 34). Participants performed an emotional face recognition task, and we examined behavioral performance and neural responses to angry, happy, and fearful facial expressions. Behavioral results revealed that psychedelic users recognized angry expressions more quickly and accurately, indicating enhanced processing efficiency for threat-related stimuli. Consistent with this, whole-brain fMRI analyses showed reduced activation to anger in key limbic and salience network regions. Psychedelic users also exhibited heightened responses to happy expressions in parietal and sensorimotor cortices-aligning with prior clinical observations-as well as increased precuneus activation to fearful expressions. Region-of-interest analyses further demonstrated reduced differentiation between emotional categories in two default mode network nodes: the frontal medial cortex and parahippocampal gyrus. These findings provide a nuanced characterization of neurofunctional changes in emotional processing linked to repeated naturalistic psychedelic use. By bridging clinical and real-world contexts, this work deepens our understanding of the potential long-term consequences of psychedelics and complements existing evidence from controlled therapeutic settings.