Effects of repeated low-dose LSD on neuropsychological functioning in adults with ADHD: a randomized placebo-controlled study

In adults with attention-deficit hyperactivity disorder, six weeks of biweekly low-dose lysergic acid diethylamide (20 µg) produced a limited effect on temporal processing, specifically on a time reproduction task, but did not improve performance on other neuropsychological measures of attention, inhibition, or motivational processing. The finding was observed in a secondary analysis of a double-blind, placebo-controlled trial with 46 completers. Baseline performance predicted some treatment outcomes differently between the LSD and placebo groups. The authors caution that the single positive result should be interpreted cautiously, especially because the parent trial showed no corresponding improvements in clinical symptoms.

Study at a glance

Abstract

RATIONALE: Attention-deficit hyperactivity disorder (ADHD) shows substantial heterogeneity in symptoms and cognitive deficits. According to the Triple Pathway Model, this variability may stem from impairments in three neuropsychological domains: inhibition, motivation, and temporal processing. Repeated low-dose administration of psychedelics is being explored as a treatment for ADHD, but evidence from controlled studies in this population remains limited. OBJECTIVES: This study investigated performance across neuropsychological domains relevant to ADHD: attention, inhibition, motivational processing, and temporal processing, before and after a six-week biweekly low-dose lysergic acid diethylamide (LSD) treatment (20 µg) in adults with ADHD. Based on previous findings, we expected improvements in attention and temporal processing and explored whether baseline ADHD symptoms and domain-specific task performance predicted treatment outcomes. METHODS: This study presents a secondary analysis of a double-blind, placebo-controlled, parallel group trial. Performance on objective behavioral tasks was assessed at baseline and after six weeks of treatment, before intake of the final dose. RESULTS: Fifty-three patients were randomized to LSD (n = 27) or placebo (n = 26), and 46 completed the study (LSD: n = 23; placebo: n = 23). An effect of LSD was observed on temporal processing (Time Reproduction Task), leaving performance on other tasks unaffected. Exploratory analyses indicated that baseline performance differentially predicted outcomes related to inhibition and time reproduction in the LSD and placebo groups. CONCLUSIONS: These findings do not provide convincing evidence for broad cumulative benefits of low-dose LSD treatment across neuropsychological domains in adults with ADHD. The observed effect was limited to a single time reproduction measure and should be interpreted cautiously, particularly given the absence of corresponding improvements in clinical symptoms in the parent trial. Future studies should investigate the robustness of this finding and whether effects are acute, cumulative, or subgroup-specific. REGISTRY: ClinicalTrials.gov, TRN: NCT05200936, Registration date: 21 December 2021.