Recent advancements in psychedelic research have examined the therapeutic potential of repeated low-dose LSD administration, commonly termed microdosing. A pivotal investigation, representing the most extensive placebo-controlled study in major depressive disorder to date, was conducted as a Phase 2a trial by MindBio Therapeutics. This triple-blind, active-placebo-controlled design involved 89 participants randomized to receive either individually titrated LSD microdoses ranging from 4 to 20 µg, administered twice weekly over an 8-week period, or an active placebo comprising caffeine and niacin. The primary outcome measure, assessed via changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) at week 8, revealed no statistically significant superiority of LSD microdosing over the active placebo. Specifically, the active placebo arm exhibited a 36.4% reduction in depression severity, whereas the LSD group demonstrated a 29.9% reduction, with a p-value exceeding 0.05. Regarding safety, no severe adverse events were reported; mild side effects predominantly included abdominal discomfort, transient elevations in blood pressure, and headaches. These findings stem from the MindBio Therapeutics Phase 2a trial, with topline results disseminated via a press release in November 2025 and a full manuscript undergoing peer review, maintaining consistency across public disclosures.
Prior double-blind, placebo-controlled trials, primarily involving healthy volunteers and focusing on single or limited repeated doses, have consistently documented acute enhancements in psychological domains. At LSD dosages of 5–20 µg, participants exhibited statistically significant improvements in mood, emotional well-being, vitality, openness, creativity, and interpersonal connectedness on administration days, as evidenced in studies such as those by Bershad et al. (2019) in Psychopharmacology, de Wit et al. (2022) in Neuropsychopharmacology, Hutten et al. (2022) in European Neuropsychopharmacology, and Kavenska et al. (2024) in Molecular Psychiatry. Although these immediate benefits surpass placebo effects, controlled environments have not substantiated enduring long-term advantages.
A more recent open-label trial, lacking a placebo control and published on November 5, 2025, explored the same microdosing protocol in 19 adults diagnosed with major depressive disorder. Administering 4–20 µg of LSD twice weekly, the study observed a mean MADRS score reduction of 59.5% by treatment conclusion, which persisted through a 6-month follow-up assessment. Safety profiles aligned with prior reports, with no serious adverse events noted. This uncontrolled investigation, detailed by Murphy et al. (2025) in the Journal of Psychopharmacology, underscores potential efficacy in non-blinded settings.
In synthesizing the rigorously evaluated evidence, repeated LSD microdosing within the 4–20 µg range demonstrates favorable safety and tolerability profiles. It consistently elicits transient positive mood and cognitive alterations in healthy subjects during dosing intervals.
However, in the context of major depression, the sole large-scale, triple-blind, active-placebo-controlled trial conducted in 2025 failed to establish antidepressant efficacy surpassing placebo effects after 8 weeks. Conversely, open-label designs yield more pronounced outcomes, emphasizing the substantial influence of placebo responses and participant expectations in psychedelic interventions.
