DOSE-DEPENDENT MODULATION OF FRONTOSTRIATAL CONNECTIVITY BY AYAHUASCA AND VARIABILITY IN SUBJECTIVE EFFECTS RELATED TO REWARD AND THREAT SENSITIVITY

Psychedelics have shown therapeutic potential in conditions involving dysfunctional reward processing, yet their effects on intrinsic mesocorticolimbic circuitry in humans remain poorly understood. We conducted a placebo-controlled, within-subject pharmacoimaging study to examine the effects of ayahuasca on resting-state functional connectivity (rsFC) within core reward regions and to assess the influence of individual differences in reinforcement sensitivity. Twelve healthy, experiences ayahuasca users were enrolled in a study comprising placebo and two ayahuasca doses (0.5 mg/kg and 0.8 mg/kg N, N-dimethyltryptamine), administered across three fMRI sessions separated by 1-2 month washouts. Resting-state fMRI was acquired 40 minutes post-ingestion. Subjective effects were assessed using the Hallucinogen Rating Scale, Mystical Experience Questionnaire, and Spiritual Well-Being Questionnaire, while personality traits were measured with the Reinforcement Sensitivity Theory Questionnaire. ROI-to-ROI analysis revealed a significant, linear trend indicating dose-dependent reduction in rsFC between the medial prefrontal cortex and nucleus accumbens, reaching significance at the higher dose (Figure 1). Ayahuasca increased personal well-being at both doses without clinically relevant cardiovascular adverse effects. Exploratory analyses indicated that higher Fight-Flight-Freeze and Panic traits were associated with reduced affective intensity but stronger mystical-type experiences, while higher reward reactivity predicted lower positive mood. These findings provide preliminary evidence that ayahuasca transiently modulates frontostriatal connectivity implicated in motivation and affective regulation, with interindividual variability in subjective effects partly explained by reward and threat personality traits. Such modulation may reflect a temporary reorganization of motivational circuits relevant to conditions characterized by cognitive and affective rigidity.