This open-label trial (n=19) found that repeated microdosed LSD (8 to 20 μg) was associated with short-term improvements in daily mood, but not same-day changes in self-reported depression, in people with major depressive disorder. It also provided pharmacokinetic data for sublingual LSD and found no evidence of tolerance or sensitisation across the 8-week dosing regimen.
Introduction: Despite growing interest in microdosed psychedelics, clinical trial evidence remains limited. We present daily mood, subjective perception of effects, and pharmacokinetics from an 8-week regimen of microdosed lysergic acid diethylamide (LSD) as a treatment for major depressive disorder in an open-label trial in which participants reported a mean symptom reduction of 60%.
Methods: Participants took 16 sublingual LSD doses: 8 μg onsite, with bloods collected at eight time-points, then twice weekly at home with titration (6-20 μg). Pharmacokinetic parameters were estimated using non-compartmental and compartmental modelling. Daily questionnaires were used to assess depression severity with the self-reported Hamilton Depression Rating Scale (HAMD6), and mood with visual analogue scales (VAS). Drug effects were recorded with VAS scales on each dosing day. Linear mixed models were used to compare dosing days to one- and two-day post-dosing, and to identify linear trends (tolerance/sensitisation) of drug effects.
Results: Nineteen participants (males n = 15, 79%) received the intervention. Daily VAS indicated increased scores of mood-related states (e.g., more creative, happier) on dosing days (p = 0.009 to 0.039), but not in depression (p = 0.291). There was no indication of tolerance or sensitisation (p > 0.081). Non-compartmental AUC0-tlast was 836 ± 319 pg.h/mL, Cmax 212 ± 77.7 pg/mL and Tmax 1.17 ± 0.56 h.
Discussion: Results suggest short-term improvements in mood following microdosed LSD in people with depression, warranting confirmation in controlled trials. It provides the pharmacokinetic parameters of 8 μg of LSD in a sample of people with depression and indicates no tolerance or sensitisation to repeated microdoses of LSD, despite incremental dose titration.
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.
This work is a secondary analysis of an open-label Phase 2a trial (acronym: LSDDEP1) of microdosing LSD to treat depression (N = 19). Participants enrolled in this study met the DSM-5 diagnosis criteria of major depressive disorder and had a Montgomery-Asberg Depression Rating Scale (MADRS) score between 18 and 35 at the time of screening. Participants in the trial attended three onsite visits: a baseline visit, followed by a first dosing visit (day one; seven days after baseline), and a final visit scheduled two to seven days after taking the final microdose. Between the dosing visit and the final measure visit, each participant took a further 15 LSD doses twice a week for 8 weeks (16 doses in total). For each at-home dose, participants were encouraged to engage in a selfselected psychologically beneficial activity. At the end of the intervention, participants reported a mean reduction of 60% of depressive symptoms as measured with the MADRS. A full methods protocol for this study was published prospectively, and safety and depression severity data are published elsewhere. Data for this trial were collected between 11 July 2023 and 18 April 2024; all onsite visits were conducted at the University of Auckland Clinical Research Centre in New Zealand. This trial was prospectively registered at the Australian New Zealand Clinical Trials Register (ANZCTR), reference: ACTRN12623000486628 (12 May 2023).
The GMP-quality LSD hemitartrate Active Pharmaceutical Ingredient (API) from Psygen Ltd. (Calgary, Canada) was formulated according to GMP standards by Biocell Corp.to create MB-22001, a titratable liquid formulation of LSD used in this study. MB-22001 was taken sublingually by holding the liquid under the tongue for approximately 30 s and then swallowing it. On each dosing day, participants completed a five-point Likert scale indicating whether they thought the dose was too much, too little or adequate. They were instructed to decrease their next dose if they experience any disturbance of daily functioning. The starting dose of LSD (onsite session) was 8 μg. The following 15 doses were taken at home and could be titrated within the limits of 4 to 20 μg based on the self-perception of the effects. During the trial, the titration scheme was amended and updated based on the observation that the first system was inefficient; participants took many doses before reaching their titrated dose. For the first titration scheme (7 participants), the dose could be increased by 1 μg at each dosing or decreased by 3 μg if the previous dose had tolerability issues. For the second titration scheme (12 participants), the dose could be increased by 2 or 1 μg increments at each dosing and decreased by 2 μg or 1 μg if the previous dose had tolerability issues. The first and second titration schemes were based on three and five-point Likert scales, respectively, filled out at the end of every dosing day. For the first titration scheme, the following questions were used: "I felt too little of the effects" (+ 1 μg), "It was adequate" (+ 0 μg), and "I felt too much of the effects" (-3 μg). For the second titration scheme, the following questions were used: "I felt no effect" (+ 2 μg), "I felt too little of the effects" (+ 1 μg), "It was adequate" (+ 0 μg), "I felt too much of the effects" (-1 μg), and "I felt way too much of the effects" (-2 μg).
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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.
During the dosing-at-home period, participants filled out a short survey daily using a customised phone application designed for this trial. The survey contained the HAM-D6 psychometric instrument, six visualanalogue rating scales (VAS) of mood, and an additional Likert-type scale rating their sleep. Surveys were unlocked at 7 pm (with a notification in the mobile phone app) and locked at midnight. If the participant did not fill out the survey within this time frame, the survey for the day was recorded as missing.
A short, self-reported, unidimensional scale based on the Hamilton Depression Rating Scale, which provides a score (0-24) measuring depression severity. Questions are prompted on how the person has been feeling over the past three days.
The Sleep Quality Scale (SQS) is a single-item VAS scale rated from "Terrible" (0) to "Excellent" (10) assessing the overall quality of sleep over the past week. The SQS question was adapted to refer to the sleep of the previous night.
Daily VAS ratings consisted of six scales on which participants rated effects from "Less than usual" (-50) to "More than usual" (+50), with "Usual" (0) as the middle anchor point. Scale questions were: "How connected did you feel today?", "How creative did you feel today?", "How much energy did you feel today?", "How happy did you feel today?", "How irritable did you feel today?" and "How jittery did you feel today?". Data were analysed using the categorical variable "day" with three levels, dose day and the two subsequent non-dose days (dose/post1/post2), repeated through 16 cycles (Dose 1 to Dose 16).
At the end of every dosing day at home, participants filled out a survey inquiring about their experience during the time they felt the most potent drug effect on that day. Like the daily questionnaire, this survey was unlocked at 7 pm and locked at midnight. Drug VAS ratings consisted of 16 scales on which participants rated effects from "Not at all" (0) to "Extremely" (100). As the first dose was taken onsite, only Drug Effects data from dosing-at-home were included in the analysis (Dose 2 to Dose 16). Items covered general drug effects (feeling a drug effect, feeling high, wanting more), valence of the effects (liking or disliking effects, feeling unusually happy, sad, or fearful), somatic (feeling sick, sleepy, dizzy), and perceptual changes (altered body sensations or surroundings, seeing movement in still objects). Additional items assessed arousal and cognition, including stimulation and unusual thoughts.
Blood samples were obtained during the first dosing session done at the laboratory before, atreceiving their first 8 μg dose. Blood samples were collected using 4 mL lithium heparin tubes (with the actual time recorded for each sample), and were centrifuged immediately at 1500g at 4 • C for 15 min, pipetted into 500 μL plasma aliquots and stored at -80 • C. Liquid chromatography-tandem mass spectrometry (LC-MS/S) analysis was performed as described in. An ultra-high-pressure liquid chromatography coupled with tandem mass spectrometry was performed using a Vanquish UHPLC system, coupled with a TSQ Quantiva triple quadrupole mass spectrometer, controlled by Xcalibur 4.3 software (Thermo Scientific), using a heated electrospray ionisation source (H-ESI) in positive ionisation mode. The assay's performance characteristics included a lower limit of quantification (LLOQ) of 25 pg/ mL, an upper limit of quantification (ULOQ) of 1000 pg/mL and a limit of detection (LOD) of 10 pg/mL for LSD, isoLSD and 2-Oxo-3-hydroxy-LSD.
For the Daily VAS measures, linear mixed-effects models were used to assess the effects of dosing days on each outcome. Dosing days were treated as a categorical variable (Dosing Day, Post 1, Post 2) and modelled as fixed effects; participants were modelled as random effects. Post hoc multiple comparisons were accounted for with a Bonferroniadjusted alpha threshold for each domain (Dosing Day vs Post 1 and Post 2; α = 0.05/2 = 0.025). For the Drug VAS measures, linear mixed-effects models were used to assess whether there were linear trends over time for each outcome. Dosing days were treated as continuous variables (Doses 2 to 16) and were modelled as random effects to account for dose variation, given the titration scheme; participants were also modelled as random effects. Due to the absence of post-hoc analysis in these models, the p-value was not corrected, and a threshold below 0.05 was considered statistically significant. For both the Daily VAS and Drug VAS models, C max was then added as a fixed-effects covariate. Non-compartmental analysis was performed using plasma drug concentration-time data for each participant with PKanalix (version 2024R1, Lixoft). The parameters derived were peak plasma concentration (C max ), time to maximum concentration (T max ), the area under the concentration curve from 0 to 6 h (AUC 0-tlast ; calculated using the trapezoidal linear/log method), the area under the curve to infinity (AUC 0-∞ ), apparent total clearance (CL/F), and volume of distribution during the terminal phase (V D /F). Non-compartmental pharmacokinetic parameters (AUC 0-∞ , AUC 0-tlast , C max , and T max ) were correlated with dosing metrics (mean dose, total dose exposure, and most frequently dose taken) using the Spearman correlation. Visual plot inspection was performed with mean titrated dose, comparing low versus high AUC 0- tlast , C max and T max . Population modelling was then carried out in Monolix (version 2024Rq, Lixoft) using a one-compartment model with no delay, first-order absorption, and linear elimination based on previous research with micro LSD doses; additional settings included oral/extravascular administration and clearance parameterisation. Simulations were performed in Simulx. All statistics were done in R (V. 2.5.1). Linear mixed-effects models were computed using the lmer function of the lme4 package.
In total, 19 people received the intervention. Participants consisted mainly of males (n = 15, 78.94%), people of European descent (n = 13, 68.42%), with an undergraduate (n = 10, 52.63%) level of education, and with a mean age of 41.52 (SD = 11.67) years. Most participants were taking antidepressant medication when they started the trial (n = 15, 78.94%) and had at least one psychedelic experience in their lives (n = 11, 57.84%). A detailed report on safety, outcomes and dosing is presented elsewhere. Briefly, participants presented a 59.52% reduction of depression severity (assessed by MADRS), with a mean (SD) score of 23.7 ± 6.72 and 9.59 ± 7.67 at the start and end of intervention, respectively.
There was a total of 620 daily questionnaires: 244/275 (88.72%, missing n = 31 [11.27%]) on dosing days, 188/188 (100%) on the day after dosing, and 157/157 (100%) on the day after dosing. The ratings of Daily VAS are plotted in Figs.and. There was no effect of dosing day for HAM-D6 (F (2, 569.08) = 1.23, p = 0.291), and sleep quality (F (2, 569.77) = 1.15, p = 0.317) ratings. However, participants reported feeling more connected (F (2, 570.11) = 3.77, p = 0.023; post1: β = 3.49, SE = 1.33, t = 2.62, p = 0.008), more creative (F (2, 570.04) = 3.25, p = 0.039; post1: β = 3.13, SE = 1.4, t = 2.23, p = 0.025), and with more energy (F (2, 569.99) = 4.68, p = 0.009; post1: β = 4.30, SE = 1.46, t = 2.94, p = 0.003) on dosing days compared to one day after dosing. They also reported being less irritable (F (2, 570.02) = 3.96, p = 0.019) two days after dosing (β = -3.83, SE = 1.38, t = -2.78, p = 0.006), and happier (F (2, 569.71) = 6.93, p = 0.001) one (β = 3.95, SE = 1.28, t = 3.10, p = 0.002) and two (β = 4.26, SE = 1.34, t = 3.17, p = 0.001) days after dosing. Feeling more creative (β = 3.02, SE = 1.47, t = 2.05, p = 0.04) and with more energy (β = 3.04, SE = 1.54, t = 1.97, p = 0.04) on dosing day compared to two days after dosing were also significant but did not survive Bonferroni correction (p threshold = 0.025). There was no effect for feeling jittery (F (2, 569.59) = 0.13, p = 0.876). When added as a fixed-effect covariate to the models, there was no significant effect of C max , indicating no effect of maximal LSD plasma concentration, on any of the outcomes.
The ratings of Drug VAS across 15 days are plotted in Fig.. There were no linear trends in any of the Drug VAS measures throughout the dosing days, indicating no tolerance or sensitisation on the reported effects (β = -0.85 to 0.52, t = -1.87 to 0.78, p = 0.081 to 0.924). When adding C max as a fixed-effect covariate, it had a significant effect on "Like" (β = -0.17, t = -3.01, p = 0.009) and "Drug Effect" (β = -0.13, t = -2.25, p = 0.040) measures, but it did not change the dosing day's effects, i.e., dosing days remained not significant.
The mean titrated dose was 14.61 μg (SD = 3.63), with a minimum and maximum titrated dose of 6 and 20 μg, respectively. The most frequently titrated dose was 15 μg (n = 6), with a total LSD mean dose across the 16 doses of 196.61 μg (SD = 52.07). Non-compartmental modelling indicated that the mean maximum concentration of LSD was 211.66 (± 77.7) pg/mL at 1.17 (± 0.56) hours post-dosing. Total mean exposure up to last time observed (AUC 0-tlast ) was 836.25 (± 318.70) and to infinity 1464 (± 767.24) pg.h/mL, with a mean apparent total clearance of 6.56 (± 2.53) L/h and a volume of distribution during the terminal phase of 46.63 (± 11.09) L. One compartmental modelling showed similar characteristics: AUC 0-tlast : 829 (± 288.93) pg.h/mL; AUC 0-∞ : 1332.51 (± 465.51) pg.h/mL; C max : 211.66 (± 77.7) pg/mL; T max : 1.48 (± 0.71) hours; CL/F: 6.65 (± 2.05) L/h, and V D /F: 36.3 (± 11.09) L. Raw and modelled peripheral blood concentrations are plotted in Fig., and pharmacokinetic parameters are described in Table. There were no significant correlations between non-compartmental pharmacokinetics characteristics (AUC 0-∞ , AUC 0-tlast , C max , and T max ) and subsequent titrated dose (mean dose, dose mode, total dose administered) (R = -0.32 to 0.14, p = 0.21 to 0.92). Visual plot inspection indicates that participants with low versus high AUC 0-tlast and C max , but not T max values titrated to higher doses (Fig.).
This work reported results of an open-label pilot trial of LSD microdosing at home in patients with major depressive disorder on daily ratings of mood, subjective perception of microdosed LSD effects taken repeatedly, and pharmacokinetics of 8 μg of LSD administered in the laboratory. We identified transient improvements in mood evaluated by VAS items (increased connectedness, creativity, energy, happiness, and decreased irritability) on dosing days at home compared to one or two post-dosing days. These findings are aligned with those from our doubleblind, placebo-controlled randomised trial of microdosing LSD at home with healthy, non-depressed male individuals. Other trials report similar mood-enhancing effects in healthy populationsand an increased blissful state and spiritual experience in people with depressionwith doses up to 20 μg. Taken together, this raises the possibility that LSD might have mood-enhancing effects of value for individuals with depression. Accordingly, participants in this trial also experienced a 60% reduction in depression severity at the end of the intervention. While it is not possible to attribute the reduction in depression to LSD (due to the open-label nature of the study), the acute mood improvement reported here may help account for the observed improvement in depression in this sample. Specifically, enhanced feelings of connection, creativity, and energy on dosing days could aid in mitigating anhedonia, a core symptom of depression, by acutely promoting engagement and enjoyment of social activities. Accordingly, qualitative data at the end of our intervention reports enhanced behavioural activation, feelings of connectedness and mental clarity, which, by presenting a bidirectional positive feedback loop, improved emotional well-being in some of the participants. Overall, these results add preliminary evidence that the moodenhancing effects of LSD may have therapeutic value for individuals with depression. However, the daily depression score (HAM -D6) had no significant alteration, indicating that acute mood improvements are not necessarily reflected in a daily measure of depression. It should be noted that the way this tool was implemented in this study had some methodological issues, which are discussed in more detail in the limitations section below. The pharmacokinetic parameters of sublingual LSD identified in this study were comparable to previously reported parameters of oral and sublingual LSD doses of 5 to 10 μg, providing further data on dose-proportional changes in plasma LSD concentrations. It further adds, to the best of our knowledge, the first pharmacokinetic data of microdosed LSD administered sublingually in individuals with major depressive disorder. While no correlations between pharmacokinetics and titration parameters were found (possibly due to the small sample size), visual exploration suggests that participants with higher AUC 0-tlast or C max on a dosing day tended to be less likely to titrate their dose higher and vice versa. This suggests, not surprisingly, that the plasma concentration of LSD is related to the subjective perception of effects of the drug. Moreover, we have previously indicated that adding a titration protocol for LSD microdosing at home reduced the occurrence of adverse events leading to withdrawal. These results further add preliminary evidence that a self-regulated dosage may help compensate for individual drug pharmacokinetics. It also provides a rationale for continued investigations into predictors of individual concentration variations, such as genetic determinants of cytochrome P450 enzyme activity, and microdose-sensitive pharmacodynamic measures. Ratings of the drug effects on dosing days throughout the 15-dose regimen at home were stable throughout time, indicating no tolerance or sensitisation to repeated LSD microdoses, despite the dose being incremented throughout the intervention. It also indicates that positive effects were more substantial than negative ones. Overall, our results add to the evidence that LSD subjective effects are reported at doses between 5 and 10 μgby demonstrating this in individuals experiencing depression, most of whom were on concurrent antidepressant pharmacotherapy.
The results reported in this work are from an uncontrolled, openlabel, pilot trial with a small sample size and are exploratory. The lack of a control group is especially relevant to the daily mood results, which effects often were more pronounced on post-dosing days, hindering the interpretation of a direct dosing effect. Also, our daily measures of mood were based on single VAS items as opposed to psychometrically validated instruments. The HAM-D6 daily results do not corroborate the primary outcome measure (MADRS), which reported a substantial average reduction (60%) in depression severity. However, while the MADRS was conducted under optimal conditions in this study, with a structured interview guideline, the HAM-D6 was not. Several participants reported struggling with completing the HAM-D6 daily because the items in this questionnaire asked about the past three days (data not presented), whereas in this study, the survey was filled out daily, so each report was overlaid with the previous one. Therefore, we adapted the HAM-D6 for our upcoming trialto have the questions based on the day the participants are responding. Another potential limitation is tolerance this issue, the doses and subjective effects identified here may not generalise to individuals not using antidepressants. Finally, it is critical to consider the impacts of participant expectations when taking part in a trial using psychedelicsand the modulatory effect this may have on subjective ratings. Altogether, the mood-related results presented here should be interpreted as exploratory and warrant controlled trials.
This work adds preliminary evidence that microdosing LSD can acutely elevate mood in people with depression throughout an intervention of 16 LSD microdoses. It provides, for the first time, pharmacokinetic parameters of 8 μg of LSD in a sample of people with depression and indicates no tolerance or sensitisation effects of repeated microdoses of LSD.
The study sponsor is the University of Auckland, contactable via the Office of Research Strategy and Integrity at humanethics@auckland.ac. nz. The study sponsor was not involved in the study design, collection, management, analysis, interpretation of the data, writing of the report, or the decision to submit the report for publication.
Murphy, R., Muthukumaraswamy, S., De Wit, H. · Biological Psychiatry (2024)
Vizeli, P., Straumann, I., Holze, F. et al. · Scientific Reports (2021)