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Home/Research/LSD/Major Depressive Disorder (MDD)

LSD for Major Depressive Disorder (MDD)

21 papers and 6 clinical trials exploring lsd as a treatment for major depressive disorder (mdd).

Compoundclassic psychedelic

LSD

LSD is a classic psychedelic ergoline with high potency at microgram doses and an 8-12 hour duration of action, mediated primarily via 5-HT2A receptor agonism. Modern Phase IIb data in generalised anxiety disorder and FDA Breakthrough Therapy Designation for MM120 have reignited clinical development.

Full LSD profile
IndicationOver 264 million worldwide.

Major Depressive Disorder (MDD)

Major Depressive Disorder (MDD) represents a significant mental health challenge, with emerging research into the efficacy of psychedelics like psilocybin and ketamine offering new avenues for treatment. Recent studies have demonstrated the potential of these compounds to alleviate symptoms, particularly in treatment-resistant cases of MDD.

Full Major Depressive Disorder (MDD) profile

Academic Research

21 papers
Open Accessindividual

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

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.

Published
March 1, 2026
Journal
Progress in Neuro-Psychopharmacology and Biological Psychiatry
Authors
Daldegan-Bueno, D., Donegan, C. J., Sumner, R., Forsyth, A., Jeong, S. H., Evans, W., Alshakhouri, M., Murphy, R. J., Reynolds, L., Hoeh, N., Allen, N., Sundram, F., Menkes, D. B., Muthukumaraswamy, S.
Open Accessindividual

LSD microdosing in major depressive disorder: results from an open-label trial

This open-label Phase IIa trial (n=19, 15 male) found that an 8-week regimen of microdosed LSD (8μg initially, then 6-20μg twice weekly) for major depressive disorder was well-tolerated with no serious adverse events or cardiac valvulopathy, achieved 59.5% reduction in MADRS scores sustained for six months, and had only one withdrawal due to anxiety.

Published
February 1, 2026
Journal
Neuropharmacology
Authors
Daldegan-Bueno, D., Donegan, C. J., Sumner, R. L., Forsyth, A., Evans, W. J., Alshakhouri, M., Reynolds, L. M, Roop, P., Ponton, R., Smith, T., Hoeh, N. R., Allen, N., Sundram, F., Menkes, D. B., Muthukumaraswamy, S.
Open Accessindividual

What is it like to microdose LSD for depression? a thematic analysis of participant interviews from an open-label trial

In an open‑label 8‑week pilot trial, thematic analysis of interviews with 17 people with major depressive disorder found that many participants reported enhanced self‑determination, increased connectedness, clearer cognitive processing and improved emotional well‑being that they linked to reduced depressive symptoms. However, responses were heterogeneous—some reported negative effects or no benefit—and the open‑label design without a placebo control limits causal conclusions and emphasises the need for careful dosing and realistic expectations.

Published
December 4, 2025
Journal
Therapeutic Advances in Psychopharmacology
Authors
Joy Donegan, C., Daldegan-Bueno, D., Sumner, R. L., Forsyth, A., Evans, W., Hoeh, N. R., Sundram, F., Menkes, D., Muthukumaraswamy, S., Reynolds, L.
Open Accessindividual

Efficacy and safety of low- versus high-dose-LSD-assisted therapy in patients with major depression: A randomized trial

This double-blind controlled trial (n=61) found that high-dose LSD-assisted therapy (100μg + 200μg) reduced depression symptoms more than low-dose LSD (25μg + 25μg) in patients with moderate-to-severe major depressive disorder (MDD), with benefits lasting up to 12 weeks and similar side effects between groups.

Published
September 1, 2025
Journal
Med
Authors
Mu, F., Zaczek, H., Becker, A. M., Auernig, M., Boehlke, C., Liechti, M. E., Ley, L., Borgwardt, S., Santos De Jesus, J., Loh, N., Kohut, J.
Open Accessindividual

Pilot Data on Salivary Oxytocin as a Biomarker of LSD Response in Patients with Major Depressive Disorder

In a pilot observational study of patients with treatment‑resistant MDD given a single 100–150 µg dose of LSD, salivary oxytocin levels and self‑reported psychedelic intensity changed significantly over the 180‑minute session, supporting acute oxytocin dynamics as a potential biomarker of LSD response. Larger, controlled trials are needed to replicate these findings and determine links between oxytocin changes and clinical outcomes such as depressive symptoms and mental flexibility.

Published
June 11, 2025
Journal
Preprints
Authors
Cazorla, L., Alaux, S., Amberger, C., Mabilais, C., Furtado, L., Buchard, A., Thorens, G., Penzenstadler, L., Zullino, D., Aboulafia-Brakha, T.
Open Accessmeta

‘Equal-unblinding’ meta-analysis of psychedelic therapy vs. antidepressants for the treatment of depression

In a pre-registered meta-analysis of 8 PAT trials (548 patients) and 16 open‑label traditional antidepressant studies (9,751 patients), psychedelic-assisted therapy was not more effective than open‑label antidepressants on the 17‑item Hamilton Depression Rating Scale (difference 0.3 favouring tAD; 95% CI −1.39 to 1.98; p=0.73). This equal‑unblinding comparison emphasises that blinding integrity materially influences apparent treatment effects and that both PAT and tAD produced robust, clinically meaningful improvements.

Published
June 9, 2025
Journal
OSF Preprints
Authors
Williams, Z. J., Barnett, H., Szigeti, B.

Clinical Trials

6 trials
Not yet recruitingPhase I

Shortened LSD Intervention for Major Depressive Disorder

This Phase I, open-label, single-group trial (n=10) will evaluate the safety and potential clinical effectiveness of a shortened LSD experience in adults with major depressive disorder (MDD). Participants will receive oral LSD hemi-L-tartrate 250 µg followed 45 minutes later by oral risperidone 1 mg, with the aim of assessing whether risperidone can abbreviate the subjective effects of LSD while still offering possible antidepressant benefit. The study will enrol adults aged 21 to 70 years with DSM-5 MDD and a Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 28 at screening. Participants will be monitored for 10.5 hours after dosing and assessed at several time points for subjective effects and discharge readiness. The primary outcome is change in MADRS at 1 month.

Started
July 1, 2026
Type
interventional
Blinding
none
Randomized
No
Registry ID
NCT07503002
RecruitingPhase III

A Phase 3 Trial of DT120 for Major Depressive Disorder (Ascend)

This Phase III, randomised, double-blind, placebo-controlled trial (n=165) will evaluate the efficacy and safety of oral DT120 (LSD) in adults aged 18 to 74 years with major depressive disorder (MDD). Participants will be assigned to placebo, 50µg DT120 or 100µg DT120, with the main efficacy measure being change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6. The study includes a 12-week single-dose treatment period in Part A, followed by a 40-week open-label extension in Part B. Adults must have a DSM-5-confirmed diagnosis of MDD, a current major depressive episode lasting 8 weeks to 24 months, a MADRS score of at least 26 and a Clinical Global Impression-Severity (CGI-S) score of at least 4 at screening and baseline. During the extension phase, participants may receive open-label retreatment with DT120 based on pre-specified safety and symptom severity criteria, and will be monitored for efficacy and safety.

Started
May 10, 2026
Type
interventional
Blinding
triple
Randomized
Yes
Registry ID
NCT07592689
Active not recruitingPhase III

A Phase 3 Trial of MM120 for Major Depressive Disorder (Emerge)

This randomised, double-blind, placebo-controlled Phase III trial (n=140) will evaluate the efficacy and safety of a single oral dose of MM120 (100 µg LSD D-tartrate) for the treatment of major depressive disorder (MDD).

Started
April 14, 2025
Type
interventional
Blinding
triple
Randomized
Yes
Registry ID
NCT06941844
Not yet recruitingPhase II

Assessing the effects of Lysergic acid diethylamide (LSD) microdosing in people experiencing depression (LSDDEP2)

Randomised, double-dummy, triple-blind, placebo-controlled, parallel groups trial (n=90) investigating sublingual LSD microdosing (2–20 µg, start 8 µg) twice weekly for 8 weeks versus active placebo (caffeine or methylphenidate) in people with MDD.

Started
March 11, 2024
Type
interventional
Blinding
triple
Randomized
Yes
Registry ID
ACTRN12624000128594
RecruitingPhase II

Assessing the effects of Lysergic acid diethylamide (LSD) microdosing in people experiencing depression (LSDDEP1)

This open-label pilot trial (n=20) aims to evaluate the tolerability and feasibility of LSD microdosing in patients with major depressive disorder (MDD).

Started
August 14, 2023
Type
interventional
Blinding
none
Randomized
No
Registry ID
ACTRN12623000486628
CompletedPhase II

LSD Therapy for Persons Suffering From Major Depression

Randomised, double-blind, active-placebo-controlled Phase II trial (n=60) of two-session LSD-assisted psychotherapy (100 µg → 100/200 µg) versus low-dose LSD (25 µg ×2) for Major Depressive Disorder.

Started
January 11, 2019
Type
interventional
Blinding
quadruple
Randomized
Yes
Registry ID
NCT03866252

Explore further

Search all LSD papers Search all Major Depressive Disorder (MDD) trials Full LSD profile Full Major Depressive Disorder (MDD) profile