LSD microdosing in major depressive disorder: results from an open-label trial

Major depressive disorder (MDD) affects approximately 5 % of the global population. Classic psychedelics have shown promise in treating various mental health disorders. This study evaluated the feasibility and tolerability of an 8-week regimen of microdosed lysergic acid diethylamide (LSD) as a treatment for major depressive disorder in an open-label phase 2A trial (LSDDEP1). Nineteen participants (15 male), most of whom were taking an antidepressant medication (n = 15), took 16 doses of LSD (8 μg initially, then 6-20 μg twice weekly at home), with the first dose administered in the clinic. We assessed tolerability through withdrawal rates due to adverse events and feasibility by clinic visit attendance. Safety measures included adverse events, blood laboratory tests, electrocardiography (ECG), and echocardiography. Depression was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS). No serious or severe adverse events and clinical alterations in safety measures were observed, being this the first study to evaluate valvulopathy after repeated psychedelic administration in humans. One participant withdrew due to experiencing anxiety when dosing; all scheduled clinic visits were attended. MADRS scores were reduced by 59.5 % at the end of the intervention and were sustained for up to six months. Improvements were also noted in anxiety, rumination, stress, and quality of life. While limited by an open-label design and small sample size, this study provides preliminary evidence supporting the safety and feasibility of treating moderate depression with microdosed LSD and underscores a need for further randomised controlled trials. Trial registration: ANZCTR, ACTRN12623000486628 (12 May 2023).