230. LSD microdosing for depression: hype or hope? A randomised controlled trial in major depressive disorder

Abstract Background Depressive disorders affect approximately 280 million people worldwide, with many patients finding existing treatments ineffective or limited by adverse effects. Growing evidence from community microdosing reports suggests that psychedelic therapies may help alleviate depressive symptoms. Among these, lysergic acid diethylamide (LSD) microdosing has shown particular promise for Major Depressive Disorder (MDD). However, there are no data from randomised controlled trials to support this practice in clinical populations. Aims & Objectives To determine whether LSD microdosing produces greater reductions in depressive symptoms compared with an active placebo (caffeine) and to explore differences in subjective experiences between the two trial arms.

Method: Single-site, randomised, triple-masked clinical trial conducted at the University of Auckland Clinical Research Centre. Physically healthy adults with major depressive disorder (MDD) and no history of psychotic disorders were included. Participants took 16 doses over 8 weeks of lysergic-acid diethylamide (LSD) or active placebo (caffeine) at home, starting at 8 μg of LSD, titrated to 4 – 20 μg in a double-dummy design. Primary efficacy was depression severity measured by the Montgomery-Åsberg Depression Rating Scale at eight weeks. Following the dosing period, participants also completed semi-structured interviews. These interviews were analysed using a human-in-the-loop machine learning paradigm to identify thematic differences between the LSD and active placebo groups.

Results: Microdosed LSD was not superior to placebo (β = 1.4252, T = 0.9340, p = 0.3510), with moderate evidence in favour of the null hypothesis (BF = 0.31, 95% Cl[-4.609, 7.962]); MADRS reduction: 36.4% (placebo), 29.9% (LSD). The LSD arm was effectively masked (Bang Blinding Index β = -0.047, SE = 0.134, 95% CI [-0.311, 0.214]). Qualitative analyses are ongoing but are expected to provide rich insight into participants’ subjective experiences beyond standard clinical measures. Discussion & Conclusions When effectively masked, microdosed LSD is not effective for treating depression above and beyond caffeine as measured by the MADRS. While qualitative results are still preliminary, these analyses may help explain the mechanisms behind any improvements or lack thereof in depressive symptoms. These findings will also highlight any differences in side effects, mood changes, or other experiential factors between the groups.