Safety and Efficacy of Repeated Low-Dose LSD for ADHD Treatment in Adults: A Randomized Clinical Trial

Importance Microdosing psychedelics, including lysergic acid diethylamide (LSD), has gained attention for its potential benefits in several psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). However, LSD's efficacy in reducing ADHD symptoms remains unknown. Objective To determine the safety and efficacy of repeated low doses of LSD in reducing ADHD symptoms compared with placebo. Design, Setting, and Participants This was a 6-week, multicenter, double-blind, placebo-controlled, parallel-group phase 2A randomized clinical trial conducted between December 17, 2021, and December 4, 2023. Data were analyzed from March 22, 2024, to August 19, 2024. Outpatient treatment was provided at 2 centers: University Hospital in Basel, Switzerland, and Maastricht University in the Netherlands. Adults aged 18 to 65 years with a prior ADHD diagnosis who presented with moderate to severe symptoms (Adult Investigator Symptom Rating Scale [AISRS] score >= 26 and Clinical Global Impression Severity score >= 4) were eligible for inclusion. Key exclusion criteria included selected current major psychiatric or somatic disorders and the use of potentially interacting medications. Intervention Participants received either LSD (20 mu g) or placebo twice weekly for 6 weeks (total of 12 doses). Main Outcome and Measures The primary outcome was the change in ADHD symptoms from baseline to week 6, assessed by the AISRS and analyzed with a mixed-effects model for repeated measures. Results A total of 53 participants were randomized to LSD (n = 27) or placebo (n = 26). Mean (SD) participant age was 37 (12) years, and 22 participants (42%) were female. The LSD group presented a mean AISRS improvement of -7.1 points (95% CI, -10.1 to -4.0). The placebo group presented a mean AISRS improvement of -8.9 points (95% CI, -12.0 to -5.8), with no difference between groups. LSD was physically safe and psychologically well tolerated overall. Conclusions and Relevance In this randomized clinical trial, repeated low-dose LSD administration was safe in an outpatient setting, but it was not more efficacious than placebo in reducing ADHD symptoms. Trial Registration ClinicalTrials.gov Identifier: NCT05200936