155. EXPLORING LSD MICRODOSING IN AN OPEN-LABEL PILOT FOR MAJOR DEPRESSIVE DISORDER: THE INTERPLAY OF BEHAVIORAL ACTIVATION, MOOD IMPROVEMENT, AND CONNECTEDNESS

Abstract Background Depressive disorders affect about 280 million people worldwide, with many struggling to find effective relief. Conventional antidepressants are widely prescribed but often lack efficacy and have side effects, leaving many patients dissatisfied or untreated. Concurrently, psychedelic therapies have gained momentum in both research and ‘in the wild’, with emerging evidence supporting their potential in alleviating depressive symptoms. Among these, lysergic acid diethylamide (LSD) microdosing – the practice of consuming sub-hallucinogenic doses over a period of weeks or months – presents a promising option for conditions like major depressive disorder (MDD). However, there is little qualitative investigation into the effect of LSD microdosing on depression in clinical trials. Also, few studies have explored LSD microdosing for depression with researcher-supplied, controlled doses taken in natural settings. Most research is either lab-based or relies on unregulated, self-administered doses. Aims & Objectives The aim of the present study was to gain a comprehensive understanding of the experiences of individuals who took part in an open label trial of LSD microdosing to treat their MDD. Method This research presents analysis of semi-structured interviews from an open label trial of LSD microdosing for individuals with MDD. After completing an 8-week regimen of LSD microdosing, taking 15 doses in their home and one in the clinic, 17 participants undertook semi-structured interviews. These interviews involved discussion of their experiences and any changes in symptoms. The data were analyzed using thematic analysis. Results Themes were grouped into five categories: Increased Connectedness (to self, others and world/nature), Behavioral Activation (motivated for activities, cognitive, social), Improved Mental Health (better mood, cumulative positive change), Better Coping (internal, external) and Negative Effects (no change, side effects). Discussion & Conclusions The present study underscores the importance of qualitative research in psychedelic and clinical studies. Microdosing of LSD for participants with MDD seemed to provide cumulative mental health change by increasing broad range connectedness, improving mood and increasing behavioral activation over 8 weeks. This seems to be a bidirectional positive feedback loop which each aspect effecting and improving the others leading to overall positive change. The improvement in these areas also seemed to enhance participants ability to cope with negative situations if they occurred. For some participants however the LSD caused side effects or failed to change their depressive symptoms. These findings indicate that implementing a titration protocol could help reduce side effects and enhance efficacy. With observed increases in behavioral activation contributed to mood improvements and greater connectedness, these results also suggest that encouraging individuals to incorporate psychologically beneficial activities while microdosing can maximize therapeutic benefits. Overall, this study advances our understanding of treatments for depression.