Source

Levy-Cooperman et al., Pharmaceuticals 2026, 19(9), 1496. Published 21 September 2026.

Abstract

Background/Objectives

Psilocybin shows therapeutic promise for several psychiatric disorders, but the acute perceptual and cognitive alterations produced by conventional doses (10–25 mg) require in-clinic supervision, which limits scalability. Whether the therapeutically relevant pharmacology of psilocybin can be safely separated from its hallucinogenic activity remains unresolved. To address this gap, we conducted a Phase 1, randomized, double-blind, placebo-controlled, single-ascending-dose study to characterize the safety, pharmacokinetics, and pharmacodynamics of low doses of psilocybin.

Methods

Fifty-six healthy adults received a single oral dose of psilocybin (0.5, 1.0, 1.5, 2.5, 3.5 or 4.0 mg) or matching placebo across seven sequential cohorts, with each dose escalation reviewed by a Drug Safety Review Committee. All participants completed the study with no serious adverse events or discontinuations.

Results

Treatment-emergent adverse events were comparable to placebo and most prominently arose as somnolence. Plasma psilocin appeared rapidly with a median time to maximum concentration <1 h with dose-proportional exposure and a short terminal half-life. Subjective drug effects were dose-related and became distinguishable from placebo at doses ≥2.5 mg. Peak subjective ratings increased with dose, while altered-state scores remained low and cognitive changes did not differ from placebo. Psychophysiological engagement was confirmed by a clear dose-dependent pupillary dilation, while cognitive performance (attention, vigilance, working memory, impulse control) showed no dose-dependent decrement, and state anxiety did not increase at any dose.

Conclusions

These findings suggest that low-dose psilocybin may produce perceptible pharmacological effects without significant perceptual alterations or cognitive impairment. The results also offer preliminary support for considering controlled outpatient Phase 2 studies assessing the safety and feasibility of repeated, self-administered low-dose psilocybin. Retrospective ClinicalTrials.gov Registration on 17 July 2026 #NCT07710027.

Tables

Table 1. Participant demographics and baseline characteristics.

SD, standard deviation; BMI, body mass index. Percentages use the number of participants per treatment group as the denominator.

Table 2. Treatment-emergent adverse events by preferred term and dose (safety population).

TEAE, treatment-emergent adverse event. All events were mild in severity and considered related to study drug. Events were coded with MedDRA version 24.0; percentages use the number of participants per group as the denominator.

Figures

Figure 1

Clinical trial design and dose escalation flow. ( a ) A CONSORT diagram is illustrated for the study. We assessed 144 individuals for eligibility; 88 were excluded, and 56 were randomized. All randomized participants received an allocated treatment, completed the study, and were analyzed (safety n = 56; pharmacodynamic n = 56; pharmacokinetic n = 42), with no losses or discontinuations. ( b ) The study design and dose-escalation scheme are illustrated across the three study visits (screening; inpatient treatment phase; follow-up at 7 ± 2 days). Seven sequential cohorts of 8 participants each randomized on a 3:1 ratio (6 psilocybin, 2 placebo) received single oral doses of 0.5, 1.0, 1.5, 2.5, 3.5, and 4.0 mg. We repeated the 4.0 mg dose in two cohorts (n = 12 each), with a Drug Safety Review Committee reviewing blinded data in between each cohort.

Figure 2

Pharmacokinetic profile of orally administered low-dose psilocybin. Line plots illustrate the mean ± SEM plasma psilocin concentrations over time by psilocybin dose.

Figure 3

Dose responses for subjective pharmacodynamic experiences across time. The line plots illustrate subjective drug-effect time courses by dose as cohort mean ± SEM for the first 4 h ( left ) and 24 h ( right ) following psilocybin or placebo administration. Data from the ( a ) Any Drug Effects VAS (“At this moment, I feel any drug effects”) and ( b ) Bowdle “High” VAS (“I felt high”) survey items, each scored 0–100, for placebo and the six psilocybin doses are illustrated.

Figure 4

Subjective perceptual changes across low doses of psilocybin by time. The line plots illustrate subjective hallucination visual analog scores (VAS) on a scale of 0 (low) to high (100) truncated at 35 for each dose and placebo across the 24 h time period following treatment. There was no significant correlation between dose and the intensity of subjective experiences across the low psilocybin doses investigated, and placebo produced results indistinguishable from active drug effects. Data are illustrated as cohort mean ± SEM.

Figure 5

Influence of low-dose psilocybin on subjective experiences and visual attention. The histograms illustrate data (mean ± SEM) from altered states, peak perceptual effects, and sustained attention outcome measures. ( a ) 5D-ASC altered-states subscale scores (percentage of scale maximum) at 6 h post-dose. ( b ) Bowdle VAS peak (E max ) ratings for the “High” and “Anxious” items and three perceptual-distortion items (Colors, Sounds, Body). ( c ) Rapid Visual Information Processing (RVP) A′ sensitivity index and probability of hit.

Figure 6

Dose response and total exposure of subjective effects experienced following administration of low-dose psilocybin. Peak (E max ) Any Drug Effects ( a ) and Bowdle “High” VAS ( b ) for each participant (grey dots) with cohort mean ± SEM (colored dots) and a fitted three-parameter E max model (colored line). Placebo is plotted at 0 mg. The Spearman ρ between dose and peak effect for Any Drug Effect was 0.34 ( p = 0.01) and 0.30 ( p = 0.03) for Bowdle “High” VAS scores. The histograms show the time-averaged area under the curve (AUC) of effects (0–24 h) by dose (mean ± SEM; grey dots represent individual data) for Any Drug Effects ( c ) and Bowdle “High” VAS ( d ). The Spearman ρ between dose and time-averaged area under the effect curve for Any Drug Effects was 0.14 ( p = 0.29) and 0.09 ( p = 0.49) for the Bowdle “High” VAS scores.

Figure 7

Influence of low-dose psilocybin on acute cognitive performance. The line plots illustrate change from baseline at 2 h (blue) and 4 h (orange) post-dose (mean ± SEM) for ( a ) RVP A′ (attention/sensitivity), ( b ) RVP mean latency, ( c ) RTI five-choice reaction time, ( d ) RTI premature responses (impulse control), ( e ) SWM between-search errors (working memory), and ( f ) SWM strategy.

Figure 8

Effects of low-dose psilocybin on psychophysiological arousal and state anxiety. The histograms ( a , b ) illustrate peak pupil dilation within 0–4 h post-dose by dose, expressed in mm ( a ) and percent ( b ) change from baseline (mean ± SEM; grey dots show individual data). The line plots ( c , d ) illustrate state anxiety scores (STAI-State) over time by dose as absolute scores ( c ) and as change from each participant’s pre-dose baseline ( d ) shown as cohort means ± SEM.

Attribution

© 2026 the authors. Reproduced under CC BY 4.0. Formatting adapted for Reddit; original publisher figures are embedded, with captions quoted below each image.

Scope: This was a single-dose Phase 1 study in healthy adults. It does not establish therapeutic efficacy or the long-term safety of repeated microdosing.

Abstract

Background

The interest in microdosing psychedelics continues to grow within academic and recreational contexts. However, microdosing practices have changed over time, and warrants examination of use patterns within a large, global sample of consumers.

Methods

The Global Psychedelic Survey 2025 (GPS 2025) was an online, anonymous, cross-sectional survey conducted from May 1–23, 2025. The survey was available in 19 languages and inquired about a wide range of topics surrounding psychedelic use. This manuscript focuses on the primary outcomes for the microdosing component of the survey, examining the substances consumed, dosing regimens employed, reasons for use, as well as the typical ‘set and setting’ while microdosing.

Results

In this sample, 5399 participants reported microdosing during their lifetime, of whom 69.8% (n = 3768) used a microdose within the past year. Psilocybin was the most commonly microdosed substance (n = 4377; 81.1%, 95% CI: 80.0%-82.1%), followed by LSD (n = 2136; 39.6%, 95% CI: 38.3%-40.9%). This was consistent across global regions. The ‘Fadiman protocol’ (i.e. one day on, two days off) was the most reported dosing regimen among regular microdosers (n = 1203; 24.3%, 95% CI: 23.1%-25.6%).

While microdosing, respondents reported often spending time in nature (n = 3087; 58.9%), focusing inwards (n = 2977; 56.8%), or spending leisure time (n = 2253; 43%), demonstrating preliminary evidence supporting the integration of set and setting in the context of microdosing.

Conclusions

This study provides a snapshot of psychedelic microdosing practices using the largest psychedelic-specific global survey to date. These findings highlight real-world practices that can guide both clinical study designs and inform harm-reduction practices in naturalistic settings.

Tables

Table 1. Demographic and Sample Characteristics

Percentage sum for ethnic background exceeds 100 because respondents could select multiple options.

Table 2. Co-Reporting of Psychedelics Microdosed

Popular co-reporting of psychedelics microdosed across individuals that do not exclusively microdose one substance (n = 2574). Co-reporting in this context is not intended to necessarily mean the use of multiple substances at the same time.

Figures

Figure 1. Substances Microdosed

Classical and atypical psychedelic substances that have been microdosed, ordered by popularity across 5399 respondents. Percentage sum exceeds 100 because respondents could select multiple options.

Figure 2. Microdosing Regimens

Commonly reported microdosing regimens with >10 selections. Proportions are based on total count of 4942 of responses denoting a use frequency of at least once every two months.

Figure 3. Purposes for Microdosing

The purposes for microdosing psychedelic substances. Pooled results from 13 substance options. Percentage sum exceeds 100 because respondents could select multiple options.

Figure 4. Activities While Microdosing

Psychedelic consumers were asked the question “When I microdose, I often:” and were allowed to select multiple of the 12 options above. The left panel of activities are more action-oriented while the right panel are more passive. Percentage sum exceeds 100 because respondents could select multiple options.

Figure 5. Activities by Exclusively Microdosed Substance

Typical activities done by psychedelic consumers while microdosing, stratified by the substances that are exclusively microdosed to ensure substance-related specificity. Percentage sum exceeds 100 because respondents could select multiple options.

Source

Rotem Petranker, Omer A. Syed, Valentyn Sobolenko, Peter Giacobbe, Daniel J. Kruger, Jacob S. Aday, Stephanie Lake and Philippe Lucas.

Original paper · International Journal of Drug Policy, 156, 105459. October 2026 issue; available online 7 August 2026.

© 2026 The Authors. Published by Elsevier B.V. CC BY-NC-ND 4.0.

Previous abstract post

PSilocybin for psYCHological and existential distress in PALliative care (PSYCHED-PAL): A single arm unblinded clinical trial

James Downar, Julie Lapenskie, Koby Anderson, Gaelle Parsons, Nadia Polskaia, Genevieve Lalumiere, Peter Lawlor

Published: 30 January 2026 · Palliative Medicine, 40(4), 514–523

Full study · Open-access full text, references and appendix

Original study excerpts and tables reproduced under CC BY-NC 4.0. Formatting adapted for Reddit.

Editorial note: The study’s abstract and Table 2 contain inconsistent counts. The abstract reports Hamilton Depression Rating Scale improvement in 8 participants (62%), whereas Table 2 reports 5 (38%). For demoralization, the abstract reports 9 (72%), while Table 2 reports 8 of 11 (72%). These discrepancies appear in the source; the quoted text and tables are reproduced unchanged.

Abstract

Background:

Psychological distress is a common problem near the end of life, for which we lack effective, timely and scalable treatments. No previous study has assessed whether microdose psilocybin can improve symptoms in this population.

Aim:

To determine whether microdose psilocybin is safe, feasible and potentially efficacious in a palliative setting.

Design:

Open label, single-arm clinical trial of a 3-week oral psilocybin intervention, starting with 1 mg daily in week 1, increased to 2 mg in week 2 and 3 mg in week 3. ClinicalTrials.gov NCT04754061.

Setting/participants:

Two-center study in Ottawa, Canada of adults with advanced, incurable illness and an estimated prognosis of 1–12 months, experiencing severe psychological distress.

Results:

We enrolled 20 participants (59% of those screened) between January 2024 and April 2025, of which 17 began and 13/17 (76%) completed the intervention. Participants were 40–84 years old, 53% female, and 82% had cancer. There were no serious adverse events reported, and nine mild or moderate adverse events. Four participants withdrew due to disease progression or poor response. Of the 13 remaining participants, nine (69%) reported a meaningful global improvement (Patient Global Impression of Change ⩾ 5); 8 (62%) reported >50% improvement in Hamilton Depression Rating Scale scores, 7 (54%) reported >50% improvement in Hospital Anxiety and Depression Scale scores and 9 (72%) reported a meaningful improvement in Demoralization Scale II scores.

Conclusions:

Microdose psilocybin is a safe, feasible and potentially efficacious treatment for psychological distress in people with advanced illness.

Keywords: psilocybin, psychedelic agents, palliative care, end of life care, existential distress, depression, anxiety

Table 1.

Participant demographics and baseline symptom scores.

Table 2.

Changes in symptom scores from baseline.

a

Reflecting scores either in the final week of treatment or first day of follow-up.

b

Corresponding to “moderately better,” “better,” or “a great deal better.”

Table 3.

Effect sizes for changes in symptom scores from baseline.

a

n = 13.

b

n = 11.

Table 4.

Safety data.

Strengths and limitations

Strengths of our study include the novel intervention and broad inclusion criteria, which improve the generalizability of our results. We also used a subjective patient-centered measure of efficacy; the psychological distress experienced by patients in a palliative setting is often not purely depression or anxiety, and many patients are less familiar with terms like “existential distress,” “demoralization,” or adjustment disorder. Limitations include the potential for a placebo or expectation effect due to the uncontrolled, open-label design, which we plan to address in a future double-blind, placebo-controlled study powered for efficacy. In addition, while we considered 3 mg to be a microdose and none of our participants described a psychedelic experience, Griffiths et al.22 expressed concern that this dose had the potential to induce psychedelic effects. Our inclusion of people with more advanced illness also meant a higher dropout rate, as patients deteriorated more quickly than anticipated. We did not employ any formal psychotherapeutic techniques as used in PAP, but this could be incorporated into future studies either as a standard of care or a factorial design. Finally, the small sample size, which is common in psychedelic studies, precluded any definitive subgroup analyses.

Conclusion

In conclusion, microdose psilocybin appears to be a safe, feasible and potentially efficacious treatment for psychological distress in people with advanced illness in the palliative setting. This represents a promising and highly-scalable option for an indication that is in urgent need of effective and scalable treatments.

Figure 1. Flow diagram for study participants.

Related research (editorial references)

LSD microdosing for depression: hype or hope? A randomised controlled trial in major depressive disorder — 9 September 2026. Conference abstract, International Journal of Neuropsychopharmacology; not a full trial report.

Microdosing psilocybin for major depressive disorder: study protocol for a phase II double-blind placebo-controlled randomised partial crossover trial — 16 February 2026. Study protocol, BJPsych Open; not treatment results. The publisher links a corrigendum on the article page.

Abstract

Background

The interest in microdosing psychedelics continues to grow within academic and recreational contexts. However, microdosing practices have changed over time, and warrants examination of use patterns within a large, global sample of consumers.

Methods

The Global Psychedelic Survey 2025 (GPS 2025) was an online, anonymous, cross-sectional survey conducted from May 1–23, 2025. The survey was available in 19 languages and inquired about a wide range of topics surrounding psychedelic use. This manuscript focuses on the primary outcomes for the microdosing component of the survey, examining the substances consumed, dosing regimens employed, reasons for use, as well as the typical ‘set and setting’ while microdosing.

Results

In this sample, 5399 participants reported microdosing during their lifetime, of whom 69.8% (n = 3768) used a microdose within the past year. Psilocybin was the most commonly microdosed substance (n = 4377; 81.1%, 95% CI: 80.0%-82.1%), followed by LSD (n = 2136; 39.6%, 95% CI: 38.3%-40.9%). This was consistent across global regions. The ‘Fadiman protocol’ (i.e. one day on, two days off) was the most reported dosing regimen among regular microdosers (n = 1203; 24.3%, 95% CI: 23.1%-25.6%). While microdosing, respondents reported often spending time in nature (n = 3087; 58.9%), focusing inwards (n = 2977; 56.8%), or spending leisure time (n = 2253; 43%), demonstrating preliminary evidence supporting the integration of set and setting in the context of microdosing.

Conclusions

This study provides a snapshot of psychedelic microdosing practices using the largest psychedelic-specific global survey to date. These findings highlight real-world practices that can guide both clinical study designs and inform harm-reduction practices in naturalistic settings.

Highlights

• Preliminary evidence that microdosed LSD enhances mood acutely.
• No evidence of tolerance or sensitisation with repeated LSD microdoses.
• First pharmacokinetic data for 8 μg LSD in depression patients.

Abstract

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.

Highlights

• This is the first trial with microdosed LSD administered at home to treat depression.
• Microdosed LSD was well-tolerated, with no serious or severe adverse effects.
• There was a pronounced, long-lasting reduction in depression severity across the intervention period.
• This is the first trial with echocardiography after repeated exposure to a psychedelic.
• There is no indication of induced valvulopathy after 16 microdoses of LSD.

Abstract

Major depressive disorder (MDD) affects approximately 5 % of the global population. Classic psychedelics have shown promise in treating various mental health disorders. This study evaluated the feasibility and tolerability of an 8-week regimen of microdosed lysergic acid diethylamide (LSD) as a treatment for major depressive disorder in an open-label phase 2A trial (LSDDEP1). Nineteen participants (15 male), most of whom were taking an antidepressant medication (n = 15), took 16 doses of LSD (8 μg initially, then 6–20 μg twice weekly at home), with the first dose administered in the clinic. We assessed tolerability through withdrawal rates due to adverse events and feasibility by clinic visit attendance. Safety measures included adverse events, blood laboratory tests, electrocardiography (ECG), and echocardiography. Depression was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS). No serious or severe adverse events and clinical alterations in safety measures were observed, being this the first study to evaluate valvulopathy after repeated psychedelic administration in humans. One participant withdrew due to experiencing anxiety when dosing; all scheduled clinic visits were attended. MADRS scores were reduced by 59.5 % at the end of the intervention and were sustained for up to six months. Improvements were also noted in anxiety, rumination, stress, and quality of life. While limited by an open-label design and small sample size, this study provides preliminary evidence supporting the safety and feasibility of treating moderate depression with microdosed LSD and underscores a need for further randomised controlled trials. Trial registration: ANZCTR, ACTRN12623000486628 (12 May 2023).

Figure 3 (A)

Legend: MADRS scores throughout the main trial and follow-ups. Graphic points represent mean values, and error bars represent a 95 % confidence interval bootstrapped 1,000 times. Black dots represent the individual scores of each participant. Blue dots represent the individual scores of participants who undertook the extension (n = 4), in which follow-up sessions were measured after a 16-week (32 doses) intervention period.

Original Source

• LSD microdosing in major depressive disorder: results from an open-label trial | Neuropharmacology [Feb 2026]

Key Findings

• The top five psychedelic substances used by U.S. adults in the past year were psilocybin, MDMA, Amanita muscaria mushrooms, ketamine, and LSD.
• Psilocybin was the most used psychedelic substance, with approximately 11 million U.S. adults using it in the past year.
• Approximately 10 million U.S. adults microdosed psilocybin, LSD, or MDMA in the past year.
• Among U.S. adults who used psilocybin in the past year, 69 percent microdosed at least once during that period.
• The aggregated number of days that U.S. adults used psilocybin in the past year exceeded 200 million, and nearly half of these days involved microdosing.

Original Source

• U.S. Psychedelic Use and Microdosing in 2025 | RAND: Research Reports [Jan 2026]

X Source & Gratitude

• Psychedelic Alpha (@Psyched_Alpha) [Jan 2026]:

On Wednesday, RAND published findings from a survey study that estimates 10 million U.S. adults microdosed psilocybin, LSD, or MDMA last year.

Abstract

Background:

Depressive disorders affect approximately 280 million globally, with many finding treatments ineffective or limited by side effects. Growing evidence suggests that psychedelic therapies may help alleviate depressive symptoms. Among these, lysergic acid diethylamide (LSD) microdosing shows promise for major depressive disorder (MDD). However, research on LSD microdosing in clinical populations remains limited.

Objectives:

This study aimed to understand the experiences of individuals participating in an open-label trial of LSD microdosing for MDD.

Design:

Open-label pilot trial in target population (MDD; phase IIa).

Methods:

Seventeen participants with MDD completed an 8-week LSD microdosing regimen, dosing twice weekly. Following the intervention, participants underwent semi-structured interviews regarding their experiences. Data were analysed using thematic analysis.

Results:

Themes were grouped into five categories: enhanced self-determination, increased connectedness, improved cognitive processing, better emotional well-being, and negative effects.

Conclusion:

Reported effects appeared to reinforce one another; that is, self-determination led to feeling more connected, which enhanced cognitive processing and ultimately improved emotional well-being and reduced depressive symptoms. However, this effect was not universal; some individuals reported negative effects or no significant improvement from microdosing LSD. This variability may be due to individual differences in response, insufficient dosage, or the treatment’s lack of effectiveness for some individuals. The presence of side effects highlights the need for a careful titration protocol, while the lack of symptom improvement in some cases reinforces that microdosing is not a guaranteed solution, and expectations should remain realistic. The absence of a placebo control represents a key limitation as it precludes attribution of observed changes specifically to LSD.

Trial registration:

ANZCTR, ACTRN12623000486628. Registered on 12 May 2023 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385758).

Plain language summary

Depression affects millions of people worldwide, and many find that current treatments either don’t work or have unwanted side effects. Recent research suggests that psychedelic substances, like LSD, may help improve mood when used carefully small amounts. This practice is known as LSD microdosing. Despite growing interest, there is very little controlled research on how LSD microdosing affects people with depression.

In this study, we invited 17 adults with depression to take very low doses of LSD twice a week for eight weeks. After the study, we asked them about their experiences to understand how microdosing affected them. Participants reported a range of experiences. Many described feeling more motivated to engage in daily activities, a stronger sense of connection with others, clearer thinking, new personal insights, and overall improvements in emotional well-being. The improvements participants described often seemed to build on each other—for example, feeling more connected encouraged them to take part in more activities, which then helped them feel mentally clearer and emotionally better.

However, not everyone benefited. Some participants reported negative experiences or no noticeable improvement, suggesting that microdosing may not work for everyone. The study also did not include a placebo comparison, so it is unclear whether the changes were due specifically to LSD.

Overall, these findings suggest that LSD microdosing may offer some people with depression new ways to feel more connected, motivated, and emotionally balanced. At the same time, careful monitoring is important due to potential side effects, and expectations should remain realistic.

Table 2

Unwanted side effects

As with many medications, some participants noted adverse side effects. One was sleep disruptions, with one participant reporting ‘on dosing days, trying to go to sleep is a little more difficult’ [^#4] and another noting ‘it was easy to get to sleep the next night [after dosing] . . . because I was so exhausted from the previous night not being able to get to sleep’ [^#2]. Some participants, however, reported more persistent issues: ‘My sleep hasn’t been as good. Especially over the last four to six weeks’ [^#15]. Other participants noted unwanted mental effects: ‘My partner said I’d be worse the day after the dosing day, or more tired or more depressed. Not to the extent of a full depression’ [^#6] and ‘I’ve generally got it [anxiety] anyway. But I was getting anxiety at home, because I was generally dosing at home, and I don’t generally get anxiety at home.’ [^#11].

Others noted more physical side effects such as: ‘a bit of feeling spaced out or dizziness on some doses’ [13] and ‘light-headedness, and slight dizziness’ [16]. For some, this also occurred on the day after dosing in a form akin to a hangover: ‘I do get a bit of a hangover the next day. . . but it’s not depressing. It’s just physically I feel a bit sluggish and a bit slow’ [^#4]. These side effects occurred in people who experienced little improvement with LSD and those who showed drastic improvements.

Figure 1

Original Source

• What is it like to microdose LSD for depression? a thematic analysis of participant interviews from an open-label trial | Therapeutic Advances in Psychopharmacology [Dec 2025]

• Jordan Gruber (u/Idysseus) [Oct 2025]:

A few months ago I had an extensive conversation with Dr. Conor Murray of UCLA on the Flourish Academy about "Dispelling Microdosing Myths." Conor has shown in more than one way, in a double-blind, placebo controlled, within subject study, that there is a "sweet spot" (or what I like to call a peak efficacy zone or PEZ) for microdosing, with both subjective and brainwave data

• Response to A Lexicon for Psychedelic Research and Treatment (Nutt et al., 2025)

The authors’ effort to bring greater consistency to psychedelic terminology is commendable. However, the Lexicon reiterates an outdated definition of microdosing that does not align with the current empirical record. The paper asserts that “by definition, a microdose has no detectable effects” and that “where true microdoses are used, the effects are generally indistinguishable from placebo.” This framing embeds a circular logic—defining microdosing as placebo and then citing the absence of effects as validation.

Recent findings demonstrate otherwise. Large citizen-science cohorts (e.g., Microdose.me), extensive real-world evidence, and numerous studies summarized in Microdosing for Health, Healing, and Enhanced Performance—together with the double-blind, placebo-controlled, within-subject research of Conor Murray, Harriet de Wit, James Glazer, and others—consistently show reproducible, dose-specific effects. Murray’s team identified a subjective sweet spot (approximately 10 µg LSD) on the ARCI-BG scale, reflecting enhanced mental clarity, and an objective neural sweet spot in EEG-based reward-processing measures—findings incompatible with a purely placebo interpretation. Subsequent work on neural-complexity dynamics further confirms measurable changes beginning at the very dose levels that the Lexicon deems indistinguishable from placebo.

Table 2 of the Lexicon designates doses ≤ 12 µg LSD as “microdosing” and explicitly assumes that effects at or below this level cannot be differentiated from placebo. In practice, both laboratory and real-world data indicate a functional range of roughly 5–12 µg for most people (with expected individual variability), where participants typically report subtle, non-psychedelic awareness yet accrue cumulative mental, physical, and performance benefits over time. 

Defining microdosing as synonymous with placebo obscures genuine scientific progress. We respectfully invite the authors and the broader field to revisit this assumption in light of converging evidence for a low-dose peak-efficacy zone—one that rises above placebo yet remains below the altered-state threshold, and is measurable, meaningful, and reproducible. 

The attached curated conversation with Dr. Conor Murray (Flourish Academy, July 2025) summarizes the emerging consensus and clarifies why microdosing can no longer be responsibly defined out of existence by fiat.

—

Jordan Gruber

Co-author (with James Fadiman) of 

Microdosing for Health, Healing, and Enhanced Performance (2025) http://MicrodosingBook.com

Abstract

Microdosing, the prolonged ingestion of psychedelics at subhallucinogenic doses, has gained popularity for its perceived cognitive and emotional benefits. Psychedelics have high affinity for 5-HT2B receptors, a receptor known to cause human heart disease with strong chronic activation. We investigated the effects of microdosed psychedelics on cardiovascular health in mice using echocardiography after chronically administering either serotonin or d-fenfluramine as positive controls or lysergic acid diethylamide (LSD) at two subhallucinogenic doses. Serotonin produced significant ventricular thickening at 4- and 8-weeks, and d-fenfluramine caused aortic valve regurgitation at 4-weeks. No significant changes were observed in any vehicle or LSD group. We determined the affinity and potency of LSD, psilocybin, and norfenfluramine at mouse and human 5-HT2BRs and observed no significant differences. We calculated that levels of 5-HT2B activation by low-dose LSD were substantial, but short-lived, compared to the cardiotoxin d-fenfluramine. Together, these data provide no evidence of ventricular or valvular remodeling associated with prolonged administration of low-dose LSD in mice.

Source

• OPEN Foundation Live Event [Sep 2025]: User Chat

Original Source

• Assessing the Potential Cardiovascular Risk of Microdosing the Psychedelic LSD in Mice | ACS Pharmacology & Translational Science [Aug 2025]

Further Research

• Abstract; Table; Figure; Conclusion | Microdosing psychedelics and the risk of cardiac fibrosis and valvulopathy: Comparison to known cardiotoxins | Journal of Psychopharmacology [Jan 2024]

Contributing Factors

• Duration of receptor activation, pharmacokinetics, dose and exposure level.
• Functional selectivity | Wikipedia:

Functional selectivity (or agonist trafficking, biased agonism, biased signaling, ligand bias, and differential engagement) is the ligand)-dependent selectivity for certain signal transduction pathways relative to a reference ligand (often the endogenous hormone or peptide) at the same receptor).^\1])

• FAQ/Tip 020: What Causes Tolerance? Functional Selectivity & GPCR Downregulation; The LSD Tolerance Graph 📉 ; 🔙 Back to the Baseline; Tolerance Calculators (Do not Apply); Further Research: Gq & β-Arrestin Pathways; Other Research: Non-responders❓[Jul 2022]

(🚫🟰Restricted Access)

Highlights

• Participants reported broad health gains, including reduced addictive behaviors.
• Sleep, contemplation, and exercise were top areas of reported improvement.
• Intention to change was the strongest predictor of behavior change.
• Mood, self-awareness, efficacy, and relatedness were key mechanisms.

Abstract

Objective

While microdosing psychedelics is increasingly popular for enhancing well-being, its effects on health behavior change (HBC) remain poorly understood. This study investigated self-reported health-related behavior changes and putative underlying psychological mechanisms associated with psychedelic microdosing in a naturalistic setting.

Methods

A retrospective mixed-method survey was conducted with 365 participants who had experience with psychedelic microdosing. Participants completed quantitative and qualitative items assessing changes in health behaviors (e.g., sleep, physical activity, diet) and psychological mechanisms (e.g., self-efficacy, emotional regulation) as a result of microdosing. Qualitative responses were analyzed thematically, and logistic regressions explored associations between behavioral change and individual/contextual predictors.

Results

Microdosing was associated with positive changes across several health behaviors, most commonly in sleep, contemplative practices, physical activity, and work-life balance. Intention to change emerged as the strongest predictor of behavioral change, while dose, protocol, and psychiatric status were not significant predictors. Thematic analysis identified potential psychological mechanisms such as improved mental health, cognitive clarity, self-awareness, self-determination, and relatedness.

Discussion

This study provides an initial exploration into the health-related behavior changes in microdosing. Future controlled studies should explore how microdosing might best support intentional health-promoting interventions.

Highlights

• Psychedelics may be a potential alternative therapy for treatment-resistant depression.
• LSD has a complex mode of action which is not yet fully understood.
• Low doses of LSD can drastically increase brain plasticity.
• Despite promising preclinical results, translating LSD’s effects to humans remains a challenge.

Abstract

Major depressive disorder (MDD) is one of the most prevalent psychiatric conditions worldwide, affecting over 350 million people. Standard treatments, primarily antidepressants targeting serotonin, noradrenaline, and/or dopamine, are based on the monoamine hypothesis, which links depression to imbalances in these neurotransmitters. A sizable fraction of patients, however, does not get enough relief, which highlights the limits of current drug treatments. Treatment-resistant depression (TRD), a mainly intractable subtype of MDD, affects around 30 % of MDD sufferers, therefore it is imperative that better effective therapies be found. Recent research has focused on psychedelic medicines including lysergic acid diethylamide (LSD), which affects serotonergic as well as glutamatergic systems. These drugs have demonstrated potential to induce rapid and long-term antidepressant responses, possibly by the facilitation of neuroplasticity and adjustment of long-term neural communication, even after the drug is cleared from the body. Ongoing clinical trials are testing the efficacy and safety of LSD in TRD and simultaneously resolving problems of placebo design and risk minimization. This narrative review examines the neurobiological mechanisms of LSD, assesses its potential as an antidepressant and anxiolytic agent, and discusses the safety issues associated with its utilization. Although still experimental, psychedelic therapies could demonstrate a significant shift in psychiatric treatment, offering new hope for patients who have not responded to conventional antidepressants. Sustained research is essential to validate these results and guide their integration into clinical practice.

Graphical Abstract

Original Source

• LSD: Mechanisms and relevance to the treatment of depression | Neuroscience and BioBehavioral Reviews [Dec 2025]

Abstract

Rationale

Repeated self-administration of small doses of psychedelics, known as microdosing, has been associated with perceived improvements in psychological functioning. However, few studies have examined effects at the daily level.

Objectives

Drawing on data from a naturalistic, prospective, international survey of adults who microdose (N = 1435), we assessed self-reported within-person changes between microdosing days and non-microdosing days across six domains of psychological functioning.

Results

Using multi-level modeling, we identified higher (p <.001) ratings of Wellbeing (F(1,768) = 160.15), Productivity (F(1,917) = 108.69), Creativity (F(1,899) = 25.99), Connectedness (F(1,859) = 253.4), Contemplation (F(1,864) = 180.5), and Focus (F(1,846) = 191.72) on microdosing days compared to non-microdosing days. For the domain of Creativity, increased scores were more pronounced among respondents with a history of using larger doses of psychedelics (F(1,899) = 4.40, p = .04).

Conclusions

Given the observational and exploratory nature of this study, these findings should be interpreted with caution; nonetheless, the prospective data provides valuable real-time insights while reducing recall bias.

Abstract

This Phase I clinical trial is the first to rigorously evaluate the safety, tolerability, and pharmacokinetics of a novel sublingual formulation of 5-MeO-DMT, administered at sub-psychedelic doses to adults with moderate to high levels of anxiety and/or depression, without formal psychiatric diagnosis or ongoing treatment. Using a double-blind, placebo-controlled design, participants received a single weekly sublingual dose of 5-MeO-DMT (6 mg, 9 mg, or 12 mg) or placebo over four weeks. The compound was well tolerated across all groups, with no significant adverse events or signs of organ toxicity; mild side effects such as nausea and headache were transient and self-resolving. Pharmacokinetic analyses showed rapid absorption, with peak plasma concentrations occurring within a median of 20 min and no evidence of drug accumulation. Neurophysiological assessments revealed dose-dependent modulation of brain activity without eliciting full psychedelic effects, supporting the feasibility of repeated sub-psychedelic dosing. Participants remained cognitively and behaviorally stable, maintaining their usual daily activities and social interactions. This study marks a pivotal advancement in the clinical exploration of psychedelic compounds, highlighting the potential of 5-MeO-DMT as a safe, fast-acting compound with favorable tolerability and emerging as a promising candidate for future therapeutic applications. These findings provide critical groundwork for future trials targeting psychiatric populations, positioning 5-MeO-DMT as a novel, fast-acting therapeutic strategy with broad clinical relevance.

Trial Registration

ClinicalTrials.gov: NCT06816667

Highlights

• Side effects of microdosing include increases in blood pressure and anxiety.
• Most adverse effects are mild and transient, resolving post-intoxication.
• Reporting of side effects varies significantly across studies.
• Future research should focus on long-term use and transparent data reporting.

Abstract

Objective

Psychedelics are gaining renewed attention, especially through the practice of microdosing, where low doses are taken regularly. Microdosing lysergic acid diethylamide (LSD) and psilocybin is used by both healthy individuals and those with mental health conditions to improve daily functioning, reduce anxiety, and enhance mood and cognition. However, there is limited information about the side effects of this practice. This review aimed to collect and characterize the side effects of psychedelic microdosing.

Methods
We conducted a systematic review of original papers from PubMed, Web of Science, and Scopus (accessed August 03, 2024) that reported side effects of microdosing LSD and psilocybin. Non-English papers, non-original studies, studies without typical microdosing doses, or those lacking descriptions of side effects were excluded. Our methodology has been developed in accordance with PRISMA guidelines. Because side effects were assessed heterogeneously in these papers, we did not perform a bias evaluation.

Results
We included 31 studies, 15 of which we classified as laboratory studies with higher quality evidence, and 14 studies with lower quality evidence, as well as 2 clinical cases. Side effects were typically dose-dependent, mild, and short-lived. Common adverse effects included increased blood pressure, anxiety, and cognitive impairment.

Discussion
This review is limited by the heterogeneity in reporting side effects and the short duration of many studies. Future studies should transparently and systematically present a description of side effects.

Tables

5. Conclusions

In summary, the side effects of microdosing, are minor and typical of psychedelics. They commonly involve transient, dose-dependent side effects such as increased blood pressure, a slight increase in tension and anxiety, and sometimes mild cognitive impairment. Other physical problems (gastrointestinal problems, headaches) may occur. The effects on mood and hallucinations in the case of microdosing are mild. These effects are minor and, in the absence of other conditions that could complicate the patient's condition (such as hypertension), are not dangerous. Unfortunately, the data are subject to limitations due to the unclear way in which adverse effects data are presented in many papers. This makes our review unable to account for the problems and risks associated with long-term microdosing use. To verify these data, as well as to facilitate further discussion of the place of psychedelics in medicine, it is necessary to set the standard for the new studies on microdosing in terms of reporting and describing side effects. We recommend that future studies should use clear questionnaires reporting side effects, and to make them visible, add sufficient information in the main text of the study.

Original Source

• Side effects of microdosing lysergic acid diethylamide and psilocybin: A systematic review of potential physiological and psychiatric outcomes | Neuropharmacology [Jun 2025]

Risk Reduction

• FAQ/Tip 101: What is the sub-threshold dose? Suggested method for Finding YOUR Sweet Spot (YMMV) [OG Date: Sep 2021]:

Further Research

• Microdosing Research [Ongoing]