In a 6‑week, multicentre, double‑blind randomised phase 2A trial of 53 adults with moderate–severe ADHD, twice‑weekly low‑dose LSD (20 μg) was physically safe and psychologically well tolerated. However, LSD did not reduce ADHD symptoms more than placebo on the AISRS.
Papers cited by this study that are also in Blossom
Fadiman, J., Korb, S. · Journal of Psychoactive Drugs (2019)
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 μg) 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.
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition in adults, characterised by inattention and/or hyperactivity–impulsivity and associated with substantial functional impairment and frequent psychiatric comorbidity. Standard pharmacotherapies—stimulants (eg, methylphenidate, amphetamines) and nonstimulants (eg, atomoxetine)—are effective for many patients but leave approximately 20% to 40% with an inadequate response and face problems with adverse effects and long‑term adherence. In parallel, microdosing of psychedelics such as LSD has gained popular and scientific interest, with surveys and naturalistic studies reporting perceived benefits for mood, cognition, and self‑treatment of disorders including ADHD, but randomised clinical evidence in patient populations is lacking. Mueller and colleagues therefore undertook a multicentre, double‑blind, placebo‑controlled Phase 2A randomised clinical trial to test whether repeated low doses of LSD reduce ADHD symptoms in adults with moderate to severe ADHD. The intervention was a 20 μg LSD dose administered twice weekly for 6 weeks (12 doses total); the primary aim was to compare change in ADHD symptoms (observer‑rated AISRS) from baseline to week 6 versus placebo, while also assessing safety, pharmacokinetics, acute subjective effects, and blinding.
This was a 6‑week, multicentre, double‑blind, parallel‑group Phase 2A randomised clinical trial conducted at two centres (University Hospital Basel, Switzerland, and Maastricht University, the Netherlands). Eligible participants were adults aged 18–65 years with a preexisting DSM‑IV/V diagnosis of ADHD and current moderate to severe symptoms, operationalised as an Adult Investigator Symptom Rating Scale (AISRS) score ≥26 and a Clinical Global Impression‑Severity (CGI‑S) score ≥4. Key exclusions included past or present psychotic disorders in participants or first‑degree relatives, current substance use disorder, and other psychiatric or somatic conditions likely to require hospitalisation or interacting treatments. The extracted text does not provide the full list of prohibited medications in this section but refers to supplements for details. Participants were randomised 1:1 to receive either LSD or placebo, with stratification by site and computer‑generated block randomisation. The sponsor conducted randomisation and provided allocation to the medication manufacturer; study staff and participants remained blinded until study completion. Study drug was manufactured under GMP as a 1 mL drinking solution containing 29 μg LSD tartrate (equivalent to 20 μg LSD base) in 20% v/v alcohol; placebo was the same alcohol solution without active drug. All doses were administered on‑site under supervision twice weekly for 6 weeks (12 doses). After the first dose participants remained on site for 6 hours for monitoring and pharmacokinetic sampling; subsequent dosing visits permitted immediate departure after administration. Participants were asked to guess treatment allocation after the first and last doses to assess blinding. The primary efficacy outcome was the least squares mean (LSM) change in AISRS score from baseline to week 6, analysed using a Mixed Model for Repeated Measures (MMRM) with fixed effects for treatment, visit, treatment-by‑visit interaction and covariates baseline AISRS, sex, and age; an unstructured variance–covariance matrix and the Satterthwaite method for degrees of freedom were used. The trial planned to enrol 52 participants (n = 26 per group) to provide 80% power to detect an effect size of 0.6 with a one‑sided α of .10; analyses followed an intention‑to‑treat principle including all randomised participants who received at least one dose. Secondary outcomes used the same MMRM and imputation procedures but applied two‑sided testing with α = .05; multiple testing correction was reserved for any significant post hoc findings. Missing data were handled by multiple imputation (details referenced to supplements). Safety assessments included pre‑dose pregnancy tests, vital signs, C‑SSRS for suicidal ideation, adverse event monitoring, routine blood tests every 2 weeks, and ECGs at screening and 2 hours after the first and last doses. Pharmacokinetic sampling after the first dose occurred at 0, 0.5, 1, 2, 3, 4, and 6 hours, and acute subjective effects were measured with Visual Analog Scales (VAS), the 5D‑ASC and the MEQ30.
A ttention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by symptoms of inattention and/or hyperactivityimpulsivity, with an estimated global prevalence of 2.6% among adults.Adults with ADHD often experience substantial impairment in various aspects of their livesand have a high frequency of psychiatric comorbidities.ADHD is typically treated with stimulants (eg, methylphenidate and amphetamines) and nonstimulants (eg, atomoxetine). These medications are generally effective, particularly in the short term, but approximately 20% to 40% of patients do not achieve an adequate response.Furthermore, adverse effects may lead to treatment discontinuation,and long-term adherence is low. For example, only approximately 50% of patients continue methylphenidate treatment after 6 years.In recent years, the microdosing of psychedelics has gained considerable attention.It involves the repeated use of low doses of psychedelics, such as lysergic acid diethylamide (LSD) or psilocybin, with the aim of enhancing well-being, cognitive functions, and emotional processes.Surveys and naturalistic studies have reported that individuals also use microdosing to self-treat various disorders, including ADHD,with findings indicating a positive impact on symptoms.A microdose is generally considered to be one-tenth to onetwentieth of a recreational dose, an amount that does not induce significant acute perceptual changes or interfere with daily activities.Microdoses or low doses of LSD typically range from of 5 to 20 μg, with a common practice of taking the psychedelic once every 3 days over several weeks.However, clinical evidence from controlled studies in patients is lacking.Here, we present the first double-blind, placebo-controlled phase 2A randomized clinical trial that investigated effects of repeated low doses of LSD in adults with ADHD.
This was a 6-week, double-blind, placebo-controlled, parallelgroup phase 2A randomized clinical trial that was conducted at 2 centers: University Hospital in Basel, Switzerland, and at Maastricht University in the Netherlands. The trial was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice. The trial was approved by local ethics committees and the respective competent authorities (eMethods in Supplement 2). Mind Medicine acted as the legal sponsor, monitored the study, and provided the data for the analysis. The study protocol is detailed in Supplement 1.
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Papers in Blossom that reference this study
Joy Donegan, C., Daldegan-Bueno, D., Sumner, R. L. et al. · Therapeutic Advances in Psychopharmacology (2025)
Mueller, F., Hawrot, T., Schmid, Y. · Neuroscience Applied (2025)
Fifty‑three participants were randomised (LSD n = 27, placebo n = 26). Mean (SD) age was 37 (12) years and 22 participants (42%) were female. Baseline mean (SD) AISRS scores were 37 (6) in the LSD group and 36 (5) in the placebo group. As the primary endpoint, the LSD group showed an LSM AISRS improvement of −7.1 points (95% CI, −10.1 to −4.0) and the placebo group an LSM improvement of −8.9 points (95% CI, −12.0 to −5.8). The between‑group LSM difference in change was reported as 1.8 points with a 95% CI that is not clearly legible in the extracted text (the upper bound could not be reliably determined from the extraction), and the difference did not reach statistical significance. Sensitivity analyses, including a missing‑at‑random imputation approach and stratification by disease severity, likewise did not produce significant between‑group differences. Secondary efficacy analyses also showed no significant differences between groups; both arms exhibited statistically significant within‑group improvements over time across self‑rated and observer‑rated measures, which persisted up to 3 weeks after dosing. Blinding checks indicated that after the last dose a high proportion of respondents believed they had received LSD: the extracted text reports 37 of 46 participants (80%) guessed LSD after the last dose, with 21 of 22 in the LSD group and 16 of 24 in the placebo group; overall, 29 participants (63%) were reported to have correctly guessed their allocation (21 of 22 in LSD and 8 of 24 in placebo). The extraction does not clearly explain why the denominator for the blinding question differs from the full randomised sample. Participants who believed they had received LSD showed nominally larger LSM reductions than those who believed they received placebo. Acute subjective effects were substantially greater with LSD than placebo. The extracted text reports a higher proportion reporting any drug effect in the LSD group versus placebo (statistical comparison P < .001), higher mean 5D‑ASC total scores (13% [SD 11] vs 4.9% [SD 7.8], P = .005) and higher MEQ30 total scores (mean [SD] 22 [20] vs 10 [16], P = .02). Several VAS items and subscales of the 5D‑ASC and MEQ30 also differed significantly in favour of LSD. Pharmacokinetic data indicated rapid absorption with maximal plasma concentrations reached after approximately 1.3 hours; detailed PK parameters were reported in supplements. Safety outcomes showed more adverse events in the LSD group (124 events) than in placebo (64 events). No serious adverse events or deaths occurred. The five most common treatment‑related adverse events were headache, nausea, fatigue, insomnia, and visual alterations; these were more frequent in the LSD arm (23 treatment‑related events) than in placebo (8 events). Two participants in the LSD arm discontinued treatment because of strong or impairing acute effects (one after the first dose, one after five doses). One participant in the placebo group was excluded after a positive pregnancy test. There were no new cases of suicidal ideation during dosing. ECGs, blood pressure, heart rate and routine laboratory values showed no clinically relevant differences between groups that were attributed to the study drug according to the extracted text.
Mueller and colleagues report that this is the first double‑blind, placebo‑controlled randomised clinical trial testing repeated low‑dose LSD (20 μg twice weekly for 6 weeks) in adults with ADHD. The main finding is that the trial did not meet its predefined primary endpoint: LSD did not reduce ADHD symptoms more than placebo on the AISRS or on secondary measures. Both treatment arms showed clinically meaningful within‑group improvements, but no between‑group advantage for LSD was observed. The investigators consider LSD to have been generally well tolerated in the outpatient setting, with treatment‑related adverse reactions mostly mild. The authors note that the chosen 20 μg dose sits at the upper end of commonly described microdosing ranges and may be better characterised as a low dose; it produced measurable acute subjective effects that were substantially greater than placebo. They acknowledge considerable interindividual variability in acute responses and report two discontinuations in the LSD arm due to strong acute effects. While the investigators argue that the selected dose was unlikely to be too low to detect an effect, they do not exclude the possibility that other doses, dosing intervals, or titration strategies could yield different results. A prominent theme in the discussion is the role of expectancy and placebo response. The trial design—with frequent supervised dosing visits, extensive assessments and media attention around psychedelics—may have heightened participant expectations and contributed to the observed improvements in both groups. The majority of participants reported believing they had received LSD at study end, and those who believed so tended to show larger symptom reductions. The authors compare these findings with prior placebo‑susceptible effects reported in ADHD trials and with naturalistic microdosing surveys, concluding that observed benefits in uncontrolled settings may reflect expectancy rather than specific pharmacological effects. Strengths cited include the randomised placebo‑controlled design, supervised on‑site dosing, comprehensive safety and pharmacokinetic monitoring, and use of both observer‑rated and self‑rated efficacy measures. Limitations acknowledged by the investigators are that the trial was powered to detect a relatively large effect (so smaller effects could have been missed), one site contributed the vast majority of participants (95%), expectancy was not systematically quantified, and only a fixed twice‑weekly dosing regimen at a single dose was tested. They also note that other ADHD‑relevant domains (eg, emotion regulation) were not comprehensively assessed. The authors conclude that randomised placebo‑controlled trials are essential to validly assess low‑dose psychedelic interventions, which appear prone to expectancy and placebo effects.
In this Phase 2A randomised clinical trial, repeated low‑dose LSD (20 μg twice weekly for 6 weeks) was safe and generally well tolerated in an outpatient adult ADHD population but did not demonstrate efficacy versus placebo in reducing ADHD symptoms. The findings underscore the importance of placebo‑controlled designs in evaluating microdosing claims and suggest that observed benefits in uncontrolled settings may be driven by expectancy effects rather than pharmacological action.
Recruitment occurred via advertisement, referral, and word of mouth. All participants provided written informed consent. Individuals aged 18 to 65 years with a previously established (according to DSM-IV/V criteria) diagnosis of ADHD and moderate to severe current symptoms, defined by an Adult Investigator Symptom Rating Scale (AISRS)score of 26 or higher and a Clinical Global Impression Severity (CGI-S)score of 4 or higher, were eligible. Key exclusion criteria included a past or present diagnosis of psychotic disorders in the participants or their first-degree relatives, current substance use disorder, and other psychiatric or somatic disorders likely to require hospitalization or treatments that could interfere with the study. The complete list of inclusion and exclusion criteria is provided in the eMethods in Supplement 2.
Eligible participants were randomly assigned in a 1:1 ratio to receive either LSD or placebo. Randomization was stratified by site, using computer-generated randomization with balanced blocks of varying sizes. The sponsor conducted the randomization and provided the allocation details to the medication producer. All study staff and participants were blinded to treatment allocation until the entire study's conclusion.
The study medication was produced by Apotheke Dr Hysek, Biel, Switzerland, in accordance with Good Manufacturing Practice (GMP). LSD was prepared as a drinking solution that contained 29 μg of GMP-grade LSD tartrate (MM-120 [Onyx Scientific]), corresponding to 20 μg of LSD base, dissolved in 1 mL of alcohol solution, 20% (volume per volume [v/v]). The placebo consisted of 1 mL of the same alcohol solution, 20% (v/v), without the active substance.
Figureshows the study design. A detailed schedule of all assessments is provided in eTable 1 in Supplement 2. The screening process included assessments of demographics, medical history, psychiatric history using the Mini-International Neuropsychiatric Interview (MINI),lifetime suicidal tendencies using the Columbia-Suicide Severity Rating Scale (C-SSRS),concomitant medication use, clinical laboratory analysis, urine drug screening, pregnancy test, vital signs, clinical physical examination, and an electrocardiogram. Any ADHD or psychiatric medications and other drugs that could potentially interact with the study medication were discontinued at least 5 plasma elimination half-lives
Question Does twice-weekly low-dose (20 μg) lysergic acid diethylamide (LSD) over 6 weeks reduce symptoms of attention-deficit/hyperactivity disorder (ADHD) in adults with moderate to severe ADHD compared with placebo? Findings In this multicenter, double-blind, placebo-controlled randomized clinical trial in 53 individuals, both the LSD and placebo groups exhibited a significant reduction of ADHD symptoms. However, there was no difference in symptom reduction between the 2 groups. Meaning LSD was not efficacious in reducing ADHD symptoms compared with placebo; these results question the anecdotal practice and highlight the importance of placebo-controlled trials in low-dose psychedelic research. beforethe baseline visit, which was scheduled up to 4 weeks after screening. eTable 2 in Supplement 2 lists all prohibited medications. Dosing occurred twice weekly over a 6-week period for a total of 12 doses. All doses were administered on-site under supervision. After the first dose, participants stayed on-site for 6 hours for clinical surveillance and to assess acute effects and pharmacokinetics. On subsequent dosing days, the participants were allowed to leave the study center immediately after drug administration. During week 10, the participants completed an end-of-study visit to assess safety and efficacy. The participants were asked to guess their treatment allocation after receiving the first and last doses to assess blinding.
Efficacy ADHD symptoms were assessed using the observer-rated AISRSand CGI-S 18 at baseline, during treatment weeks 2 and 6, and at the end-of-study visit. The self-rated Conners' Adult ADHD Rating Scale (CAARS)and Adult ADHD Self-Report Scale (ASRS)were administered at baseline, during weeks 2, 4, and 6, and at the end-of-study visit. Assessment occurred on-site before dosing by trained investigators. A detailed description of these measures is provided in the eMethods in Supplement 2.
Before each dosing, urine pregnancy tests were performed, vital signs were measured, and participants were assessed for suicidal ideations using the C-SSRSand for adverse events (AEs). Every 2 weeks during the dosing period, routine blood laboratory tests were conducted. An electrocardiogram was obtained at screening and 2 hours after the first and last dose administrations. Further details regarding safety parameters are provided in the eResults in Supplement 2.
Blood plasma samples were collected 0, 0.5, 1, 2, 3, 4, and 6 hours after the first drug administration to determine the pharmacokinetics of LSD (eMethods in Supplement 2). At the same time points, a series of Visual Analog Scales (VASs) were used to measure acute effects. Additionally, the 5 Dimensional Altered States of Consciousness (5D-ASC) scaleand 30-item Mystical Experiences Questionnaire (MEQ30)were administered 6 hours after drug administration on day 1 (on-site) and after the last dose (at home).
A sample size of 52 participants (n = 26 participants per group) was calculated to provide 80% power to detect an effect size of 0.6 for the reduction of ADHD symptoms, measured by the AISRS, in the active treatment group compared with placebo, with a 1-sided significance level (α) of .10.
The a priori-determined primary outcome was the least squares mean (LSM) change in ADHD symptoms from baseline to week 6, assessed using the AISRS. This was evaluated using a Mixed Model for Repeated Measures (MMRM). Changes in AISRS scores at weeks 2 and 6 were incorporated as dependent variables. Fixed effects included treatment group, visit, visit-bytreatment group interaction, and covariates of baseline AISRS score, sex, and age. An unstructured variance-covariance matrix was used to model within-participant errors with the Satterthwaite method to approximate degrees of freedom. The analysis included all randomized participants who received at least 1 dose per the intention-to-treat principle. Changes in LSM from baseline with 95% confidence intervals were calculated for each group, and between-group LSM differences were analyzed with a 1-sided α level of . outs were handled using multiple imputation, details of which are provided in the eAppendix and in eTable 3 in Supplement 2. Sensitivity analyses included repeating the primary analysis with a missing-at-random imputation approach and stratifying results by disease severity (see the eAppendix in Supplement 2 for more details).
The same MMRM and imputation that were used for the primary outcome were applied to secondary efficacy outcomes with the following changes. All available time points were incorporated into the model, and a 2-tailed confidence interval with a 2-sided significance level of .05 was applied. These analyses were post hoc, and we decided to correct them for multiple testing only in the event of significant findings. Furthermore, associations between acute drug effects, guessed treatment allocation, baseline characteristics, and outcomes were explored (see also the eMethods in Supplement 2).
Two-sided t tests for independent groups were used to compare acute effects between treatments on the VAS, 5D-ASC, and MEQ30.
Statistical analyses were performed using R version 4.3.2 (R Foundation for Statistical Computing) and KNIME version 5.2.5 soft-ware (KNIME AG). MMRMs were created with the mmrm package in R,and the rbmi package in Rwas used for imputation.
Primary and secondary efficacy outcomes at week 6 are summarized in Table. The mean (SD) baseline AISRS scores were 37 (6) in the LSD group and 36 (5) in the placebo group (Table). As the primary end point, there was an improvement in LSM on the AISRS of -7.1 points (95% CI, -10.1 to -4.0) for the LSD group and -8.9 points (95% CI, -12.0 to -5.8) for the placebo group. The difference between groups was not significant, with an LSM difference in score change of 1.8 points (95% CI, -1.0 to ϱ). In line with this, none of the sensitivity analyses of the primary outcome reached significance. Secondary efficacy analyses tested 2-sided showed no significant differences between treatment groups. Both groups presented significant improvements in the change from baseline over time across all outcome measures. Results for secondary efficacy outcomes at all time points are detailed in eTables 5-16 and eFigures 1-3 in Supplement 2.
A total of 37 of 46 participants (80%) guessed they were allocated to the LSD group after the last dose (21 of 22 participants in the LSD group and 16 of 24 participants in the placebo group). Overall, 29 participants (63%) correctly guessed their allocation (21 of 22 for the LSD group and 8 of 24 for the placebo group; see also eTable 4 in Supplement 2). After 6 weeks, participants who believed they received LSD showed nominally larger LSM reductions compared with those who thought they received placebo (eFigure 4 in Supplement 2).
Acute effects are shown in eTables 17 for any drug effect were 52% (33) in the LSD group and 22% (29) in the placebo group (P < .001). The mean (SD) 5D-ASC total scores were 13% (11) in the LSD group and 4.9% (7.8) in the placebo group (P = .005). The mean (SD) MEQ30 total scores were 22 (20) in the LSD group and 10 (16) in the placebo group (P = .02). Several further VAS items and subscales of the 5D-ASC and MEQ30 also showed significantly higher acute effects of LSD compared with placebo (eTable 18 in Supplement 2).
Pharmacokinetic parameters for LSD are summarized in eTable 19 and eFigure 8 in Supplement 2.
A total of 124 AEs occurred in the LSD group, and 64 occurred in the placebo group. No serious AEs and no deaths were recorded during the study. The 5 most common treatment-related AEs were headache, nausea, fatigue, insomnia, and visual alterations. These AEs were more frequent in the LSD group than in the placebo group (23 vs 8). Complete lists of all AEs and related AEs are provided in eTables 20 and 21 in Supplement 2. One participant in the placebo group was excluded after a positive pregnancy test. Additionally, 2 participants in the LSD group dropped out after the first dose and after 5 doses, respectively, because of uncomfortably strong acute effects or effects that impaired daily activities. No newly occurring suicidal ideations were reported during the dosing period (eTable 22 in Supplement 2). Electrocardiographic parameters are summarized in eTable 23 in Supplement 2, showing no differences between LSD and placebo over time. Acute effects on blood pressure and heart rate are illustrated in eFigure 9 in Supplement 2, with no significant differences between treatment groups. Laboratory parameters are detailed in eTable 24 in Supplement 2. None of the laboratory values outside the reference range were attributed to the study drug.
To our knowledge, this is the first double-blind, placebocontrolled randomized clinical trial to investigate effects of repeated low-dose (20 μg) LSD administration in adults with ADHD. The study did not meet its predefined primary end point (ie, change in ADHD symptoms from baseline to week 6 of treatment). Generally, LSD did not improve ADHD symptoms over placebo on any of the measures. LSD was well-tolerated in the outpatient setting. Treatment-related adverse reactions were mostly mild and included headache, nausea, fatigue, insomnia, and visual alterations. A study in healthy volunteers who received 10 μg LSD every 3 days for 6 weeks found that LSD microdosing was safe in adult men, but the study noted increases in treatmentrelated anxiety.Pharmacokinetic parameters demonstrated rapid absorption of LSD, with maximal plasma concentrations reached after 1.3 hours, and were generally in line with data from previous studies in healthy participants.Overall, LSD produced substantial and significantly stronger acute subjective effects compared with placebo that were qualitatively similar to high doses of LSD, but to a lesser extent.Controlled studies in healthy participants have reported that perceptual threshold doses of LSD are around 10 μg of LSD base, with 20 μg producing mild effects that were comparable to, but generally lower than, those in the present study.This study's 20-μg dose of LSD base is at the upper end of the microdosing range and might rather be consid-ered a low dose instead. The same dose has been shown to produce stronger acute subjective effects in healthy participants, with high self-rated depressive symptoms compared with participants with low ratings.Overall, the findings indicate potentially greater acute subjective effects of low doses of LSD in patient populations compared with healthy individuals. High interindividual variability in effects of low doses of LSD on mood and cognition has been observed in healthy people.In the present study, 2 participants in the LSD group stopped treatment because of strong acute effects. One participant described the effects as very intense and uncomfortable and withdrew after the first dose. The other participant found the effects generally pleasant but felt too impaired to perform daily activities and withdrew after 5 doses. In this proof-of-concept study, a rather high microdose was selected to increase the likelihood of detecting a positive response and efficacy. Accordingly, we consider it unlikely that the dose was too low to be efficacious. In contrast, we cannot exclude the possibility that a lower dose or a different dosing interval could have yielded beneficial effects on ADHD symptoms, although the present study does not suggest such benefits. Both the LSD and placebo groups showed improvements in self-rated and observer-rated ADHD measures over the course of treatment, which persisted for 3 weeks after the dosing period. Compared indirectly to methylphenidate and at- omoxetine in other trials, the verum group showed slightly lower and the placebo group comparable to slightly higher responses.Most participants, including the majority of those who received placebo, believed that they had been allocated to the LSD group at the end of the dosing period, and they presented nominally larger ADHD symptom reductions on most outcome measures than those who did not. Relevant placebo responses have been shown for other medications in previous clinical trials with patients with ADHD.The present study design, with multiple dosing visits and extensive symptom assessments, may have contributed to the placebo response. Additionally, media reports of potential benefits of psychedelics in psychiatric patients could have heightened expectations. A high motivation of participants can be assumed by their commitment to commute to the study center twice weekly over 6 weeks for dosing on-site. Our findings are consistent with a previous study that used a self-blinding approach in healthy participants,showing that subjective well-being was enhanced in both recreational microdosing and placebo groups.These findings indicate that observed benefits of psychedelic microdosing may be attributable more to expectancy than to pharmacological effects of the psychedelic itself. Exploratory analysis in our study did not identify predictors of favorable outcomes, such as acute effect strength, ratings on the 5D-ASC, age, or sex. Altogether, these results do not confirm possible positive effects of low doses of LSD on symptoms as suggested by user surveysor naturalistic studies.This discrepancy underscores the need for randomized placebo-controlled trials when validly assessing potential benefits of low-dose psychedelics that are likely prone to a placebo response and expectancy bias.
The present experimental trial of low-dose psychedelics in a patient population with clinically relevant symptoms has several strengths, including a placebo-controlled design, supervised dosing, and comprehensive assessments of safety, pharmacokinetics, and both self-rated and observer-rated efficacy. Nevertheless, our study has several limitations. The trial was powered to find a rather large effect size, while very small effects may have been missed. Although a multicenter trial, 1 site enrolled 95% of the participants, which was due to logistical problems. Expectancy was not systematically assessed. We only tested twiceweekly dosing with a relatively high (for microdosing) and fixed dose of LSD, which may not account for potential interindividual variability in the response to psychedelics. Daily dosing, alternateday dosing, or titrationto produce the desired effect without impairing activities of daily life may produce different results. Furthermore, other ADHD-related outcomes, such as emotion regulation, were not comprehensively addressed.
In conclusion, although repeated low-dose LSD administration was safe in an outpatient setting, it failed to demonstrate efficacy compared with placebo in improving ADHD symptoms among adults.