LSD microdosing for major depressive disorder: Mood and pharmacokinetic outcomes from a Phase 2a trial

Classic psychedelics such as LSD, psilocybin and DMT have been investigated for possible psychiatric uses, particularly in depression, but evidence for microdosing remains limited. The paper notes that microdosing typically involves repeated doses below the threshold for substantial perceptual changes, yet people increasingly use it in attempts to self-treat depression. Although earlier work suggested that low doses of LSD can acutely affect mood, cognition and brain connectivity, it was still unclear whether repeated microdosed LSD might produce mood benefits in people with major depressive disorder, how subjective effects change across an 8-week regimen, and what the pharmacokinetics look like in this population. Daldegan-Bueno and colleagues therefore set out to report additional outcomes from an open-label Phase 2a trial of LSD microdosing for major depressive disorder. Specifically, they aimed to examine daily mood ratings, subjective drug-effect ratings across repeated dosing days, and pharmacokinetic parameters after an 8 μg sublingual dose administered in the laboratory. The study is presented as preliminary work intended to inform controlled trials.

This was a secondary analysis of an open-label Phase 2a trial, described as LSDDEP1, involving 19 participants with major depressive disorder. Eligibility required a DSM-5 diagnosis of major depressive disorder and a Montgomery–Åsberg Depression Rating Scale (MADRS) score between 18 and 35 at screening. The trial took place in New Zealand, with onsite visits at the University of Auckland Clinical Research Centre and data collected between 11 July 2023 and 18 April 2024. The study was prospectively registered, and the authors note that a full protocol and separate reports on safety and depression severity had already been published elsewhere. Participants attended three onsite visits: baseline, a first dosing visit one week later, and a final visit 2 to 7 days after the last microdose. They received 16 sublingual doses in total: an initial 8 μg dose onsite, followed by 15 home doses over 8 weeks, taken twice weekly. The LSD was supplied as a GMP-quality hemitartrate active ingredient and formulated as a titratable liquid preparation. Participants held the dose under the tongue for about 30 seconds before swallowing. At home, they were encouraged to pair dosing with a self-selected psychologically beneficial activity. The dosing regimen was adaptive. Participants used self-report Likert scales to indicate whether the dose felt too weak, adequate or too strong, and subsequent doses were adjusted within a 4 to 20 μg range. The paper describes two titration schemes, one used in the first seven participants and a revised version used in the remaining 12, because the initial scheme appeared too slow to reach an appropriate dose. The authors also note that participants were advised to reduce their next dose if daily functioning was disturbed. During the at-home period, participants completed daily surveys via a custom smartphone application, unlocked in the evening and locked at midnight. These included a self-reported HAM-D6 measure of depressive symptoms, six visual analogue scale (VAS) items assessing mood, and a sleep rating. On each dosing day, participants also completed drug-effect VAS items covering general subjective effects, valence, somatic effects, perceptual changes, arousal and cognition. For pharmacokinetics, blood was drawn during the first laboratory dosing session before and after the 8 μg dose, processed promptly, and analysed using liquid chromatography-tandem mass spectrometry. The assay’s quantification limits are reported in the extracted text. Daily mood data were analysed using linear mixed-effects models, with day type treated categorically as dosing day, one day post-dose, or two days post-dose. Participants were modelled as random effects, and post hoc comparisons used a Bonferroni-adjusted threshold. Drug-effect ratings across repeated home dosing days were analysed with linear mixed-effects models using dose number as a continuous predictor to assess linear trends over time, with participants and dose variation modelled as random effects. In both sets of models, maximal plasma concentration was also entered as a covariate. Pharmacokinetic analyses used non-compartmental methods to estimate parameters such as peak concentration, time to peak, exposure and clearance, and a one-compartment population model was also fitted. Correlations between pharmacokinetic measures and titration metrics were assessed with Spearman correlations.

Nineteen people received the intervention. The sample was mainly male (15/19, 78.94%), mostly of European descent, with just over half having undergraduate education. The mean age was 41.52 years. Most participants were taking antidepressant medication at baseline (15/19, 78.94%), and over half had previous psychedelic experience. The paper states that depressive symptoms fell by 59.52% on the MADRS, from a mean of 23.7 at baseline to 9.59 at the end of the intervention. There were 620 daily questionnaires in total. Completion was high on post-dose days, while 11.27% of dosing-day questionnaires were missing. Daily HAM-D6 scores did not differ by day type, and sleep quality also did not change significantly. By contrast, several positive mood ratings improved on dosing days compared with the day after dosing: participants felt more connected, more creative and more energetic. Happiness was higher one and two days after dosing, and irritability was lower two days after dosing. Some contrasts for creativity and energy versus two days after dosing were also significant, but the authors note these did not survive Bonferroni correction. There was no effect on jitteriness. Adding maximum plasma concentration as a covariate did not materially change these findings. For repeated drug-effect ratings across the 15 at-home dosing days, the authors found no significant linear trends, indicating no evidence of tolerance or sensitisation in the reported subjective effects over time. When plasma concentration was added as a covariate, it significantly predicted ratings of liking and drug effect, but the overall pattern of no dosing-day trend remained unchanged. The mean titrated dose was 14.61 μg, with doses ranging from 6 to 20 μg. The most common titrated dose was 15 μg, and the mean total LSD exposure across the intervention was 196.61 μg. Non-compartmental pharmacokinetics after the 8 μg laboratory dose showed a mean peak plasma concentration of 211.66 pg/mL at 1.17 hours post-dose. Mean exposure was 836.25 pg·h/mL to the last observed time point and 1464 pg·h/mL extrapolated to infinity. Apparent clearance and volume of distribution were also reported. The one-compartment model produced similar estimates. There were no significant correlations between pharmacokinetic measures and later titrated dose metrics. However, visual inspection suggested that participants with lower exposure or lower peak concentration tended to titrate upwards more, whereas those with higher exposure or peak concentration tended to stay at lower doses. The extracted text does not report any serious divergence between the non-compartmental and model-based findings.

The authors interpret the study as providing preliminary evidence that microdosed LSD may acutely improve mood in people with major depressive disorder. They emphasise that the positive VAS findings on dosing days, especially greater connectedness, creativity, energy and happiness, are consistent with earlier research in healthy volunteers and in people with mildly depressed mood. They suggest these mood-enhancing effects could be relevant to depression treatment, particularly because many participants also showed a substantial end-of-trial reduction in MADRS scores, although they are careful not to claim causation from an open-label trial. Daldegan-Bueno and colleagues argue that the acute mood changes may help explain, at least in part, the observed improvement in depressive symptoms. They propose that increased connection, creativity and energy may help counter anhedonia and support behavioural engagement. They also note that the daily HAM-D6 did not show change, which they say does not necessarily conflict with the mood findings, but does indicate that the daily depression measure did not capture the same signal as the structured MADRS assessment. The authors further interpret the pharmacokinetic findings as, to their knowledge, the first data on sublingual microdosed LSD in people with major depressive disorder, and as broadly comparable to previous low-dose LSD pharmacokinetic reports. In relation to repeated dosing, the authors interpret the stable drug-effect ratings as evidence against tolerance or sensitisation over the 15 home doses, even though the dose was gradually increased. They suggest that the relationship between plasma concentration and subjective liking or drug effect supports the idea that inter-individual pharmacokinetic variability may influence subjective responses, and they propose that self-regulated titration could help compensate for this variability. They also mention that future work might examine genetic or other predictors of concentration differences. The main limitations they acknowledge are the uncontrolled, open-label design, the small sample size, and the exploratory nature of the analysis. They caution that the absence of a control group makes the mood findings hard to interpret, especially because some effects were more pronounced on post-dosing days rather than immediately after dosing. They also note that the daily mood items were single VAS ratings rather than validated mood instruments, and that the daily HAM-D6 was not well suited to repeated daily use because it asks about the previous three days, creating overlap between assessments. They further point to possible expectancy effects in psychedelic trials, and note that the sample may not generalise to people not taking antidepressants. Overall, they conclude that the results should be treated as exploratory and require confirmation in controlled trials.

The authors conclude that the trial adds early evidence that microdosed LSD can acutely elevate mood in people with depression during an 8-week regimen of 16 doses. They also state that the study provides the first pharmacokinetic parameters for 8 μg of LSD in this patient group and found no evidence of tolerance or sensitisation with repeated microdosing.