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

Attention-deficit hyperactivity disorder (ADHD) is highly heterogeneous in adulthood, with differences in symptom profiles and cognitive difficulties. The authors frame this variability using the Triple Pathway Model, which proposes that impairments in inhibitory control, motivational processing, and temporal processing may contribute to ADHD in different combinations across individuals. Previous research has suggested that low-dose psychedelic use, including LSD, might relieve ADHD symptoms, but controlled evidence in adults with ADHD has been limited. Earlier controlled work in the same broader trial programme found that repeated low-dose LSD was safe and well tolerated, but it did not improve core ADHD symptoms compared with placebo. Haijen-Bongers and colleagues therefore examined whether six weeks of twice-weekly low-dose LSD produced cumulative changes in objective neuropsychological performance in adults with ADHD, focusing on attention, inhibition, delay aversion, and time perception. They also explored whether baseline ADHD symptoms and baseline task performance predicted treatment outcomes, reflecting the possibility that different neurocognitive profiles might respond differently to low-dose LSD. The study addressed outcomes that were not covered in the parent trial report, with particular interest in whether any effects would extend beyond acute drug exposure into a drug-free assessment at the end of treatment.

This was a double-blind, placebo-controlled, parallel-group randomised study. Adults aged 18 to 65 years with ADHD, confirmed by the Mini International Neuropsychiatric Interview, were eligible if they had at least moderate symptom severity on the Adult ADHD Investigator Symptom Rating Scale and met additional screening criteria. Participants had to stop ADHD medication before randomisation if they were taking it; those unable or unwilling to do so were excluded. Major exclusions included psychotic disorders, bipolar disorder, recent LSD use, pregnancy or breastfeeding, positive drug screening, and large changes in ADHD severity between screening and baseline. Fifty-three participants were randomised 1:1 to LSD or placebo; 46 completed the study. The treatment consisted of 29 µg LSD tartrate (equivalent to 20 µg LSD base) or matching placebo, taken twice weekly for six weeks under supervision. The present paper analysed neuropsychological task data from the trial rather than the parent trial’s symptom outcomes. The study was conducted at sites in Maastricht and Basel, although most participants were assessed in Basel. The trial was registered, approved by relevant ethics committees, and reported in line with CONSORT. Objective performance tasks were completed at baseline and again at week 6, before the final dose was taken, so the analyses targeted cumulative rather than acute effects. The tasks assessed sustained attention with the Psychomotor Vigilance Task, temporal processing with the Time Production Task and Time Reproduction Task, inhibition with the Stop-Signal Task, and motivational processing with the Delay Discounting Task. Age was included as a covariate. The authors used marginal regression models with a Time by Treatment interaction as the main effect of interest, and random intercepts for participants to account for repeated measures. Where residuals were non-normal, variables were transformed; if assumptions still were not met, change-score ANCOVA was used. To address multiple testing within the temporal-processing domain, a stricter threshold of 0.025 was applied to the two timing tasks.

The final sample included 53 participants, with 27 allocated to LSD and 26 to placebo; 46 completed the study. The mean age was 36.7 years, 42% were female, and most participants had received their ADHD diagnosis in adulthood. The LSD group was older than the placebo group at baseline, but the groups did not differ on other measured baseline characteristics or on baseline task performance. Four implausibly fast responses in the Time Reproduction Task at week 6, all in the LSD group, were excluded as likely technical failures. For sustained attention, the Psychomotor Vigilance Task showed no Time by Treatment interaction for mean reaction time or attentional lapses. There was a general improvement over time in mean reaction time and in the proportion of correctly inhibited stop trials, but these changes occurred in both groups rather than being specific to LSD. There was also no treatment effect on stop-signal reaction time, go-trial performance, or delay discounting switch points. In other words, the study did not find evidence that six weeks of low-dose LSD improved attention, inhibition, or motivational processing relative to placebo. The clearest signal was in temporal processing. The overall Time Production Task did not show a significant treatment effect once the authors applied their corrected threshold for the timing domain, although the pattern suggested some improvement over time. For the Time Reproduction Task, however, the authors observed a significant Time by Treatment interaction for the long intervals of 30 and 45 seconds. Participants in the LSD group showed greater reduction in underreproduction than those in the placebo group, and this remained significant in a sensitivity analysis adjusting for baseline differences. The interaction for the overall Time Reproduction Task was reported as significant before correction but was not considered significant after the stricter threshold for temporal-processing outcomes was applied. No significant interactions were found for short or medium intervals. In exploratory analyses, baseline task performance predicted week 6 performance for most outcomes, indicating substantial stability over time. Some of these baseline-to-follow-up relationships differed between the LSD and placebo groups, particularly for time reproduction and some inhibition measures. Baseline ADHD symptom severity did not predict week 6 task outcomes and did not interact with treatment.

The authors interpret the findings as showing no convincing evidence that six weeks of repeated low-dose LSD produced broad cumulative benefits across neuropsychological domains in adults with ADHD. The one notable exception was time reproduction: participants receiving LSD improved more than placebo on reproducing longer intervals, which the authors describe as a possible effect on temporal processing. They emphasise, however, that this was a laboratory-based task outcome and did not correspond to clinical improvement in the parent trial, where ADHD symptoms did not improve. They therefore suggest that any neuropsychological effect under this dosing regimen may be limited in size or may not translate into meaningful symptom change. Haijen-Bongers and colleagues place these results alongside earlier research showing acute cognitive effects of low-dose LSD in healthy volunteers, noting that those findings may not generalise to cumulative effects in a clinical ADHD sample. They also point out that the lack of effects on attention, inhibition, and motivational processing contrasts with some acute findings in healthy participants, and may reflect differences between acute versus repeated dosing, between healthy volunteers and adults with ADHD, or both. The authors interpret the timing result as potentially relevant because adults with ADHD often show underestimation on timing tasks, especially for longer intervals, and because reproduction tasks rely more heavily on maintaining internal temporal representations than production tasks. They suggest the effect may therefore reflect a partial normalisation of a reproduction-specific timing process rather than a broad change in timing ability. The discussion also links the timing findings to possible serotonergic and dopaminergic mechanisms, while making clear that direct evidence for low-dose dopaminergic effects in humans remains limited. The authors note that previous low-dose LSD work in healthy volunteers has reported different timing effects, which may relate to methodological differences such as dose, timing, and number of trials. They also mention that evidence from other psychedelics is mixed. Exploratory analyses suggest that baseline neuropsychological performance, rather than baseline symptom severity, may help predict later task performance, hinting that individual neurocognitive profiles could moderate response. The authors cautiously propose that ADHD heterogeneity may be important if low-dose psychedelics preferentially affect certain domains or subgroups. Key limitations include the relatively small sample size, which was powered for the parent trial’s symptom outcome rather than these neuropsychological analyses; the long and potentially fatiguing task battery; the fact that one site enrolled nearly all participants; and the absence of direct assessment of expectancy effects. They also note that most participants had been diagnosed with ADHD in adulthood, which may limit generalisability to people with childhood-onset persistent ADHD. Additional limitations were the fixed dosing schedule and the lack of assessments during the acute drug phase, meaning short-lived effects could have been missed. The authors suggest that future studies should consider dose titration, include both acute and cumulative assessments, and examine moderators such as developmental history, baseline functioning, genetics, pharmacokinetics, and, in women, reproductive status and menstrual cycle phase. They also argue that broader outcomes such as mood and emotion regulation may be important in future work.