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

Placebo for Major Depressive Disorder (MDD)

25 papers and 177 clinical trials exploring placebo as a treatment for major depressive disorder (mdd).

CompoundComparator / Control

Placebo

Placebo is the most widely referenced comparator in psychedelic clinical research, appearing in over 500 trials. Understanding how placebos are designed, administered, and interpreted is essential to evaluating the evidence base for psychedelic-assisted therapies — and one of the field’s most contested methodological challenges.

Full Placebo 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

25 papers
Paywallindividual

Safety, tolerability and subjective effects of vaporized N,N-Dimethyltryptamine: A randomized double-blind clinical trial

This first RCT (n=25) of vaporised DMT (60mg) demonstrated that DMT significantly increased subjective experience measures while causing only transient, safe physiological changes and predominantly mild adverse events. This suggests that inhaled DMT is safe, well-tolerated, and effective at inducing profound altered states of consciousness. Significant correlations were observed between physiological responses and subjective experiences.

Published
June 17, 2025
Journal
European Neuropsychopharmacology
Authors
Wießner, I., Falchi-Carvalho, M., Laborde, S., Barros, H., Bolcont, R., Ruschi Silva, S., Pantrigo, E. J., Medina, M., Arichelle, F., Almeida, R., Aires, R., Nunes Ferreira, L. F., Dantas Correa, L., da Costa Bezerra, R. B., Thie, K., Silva-Costa, N., Araújo, D. B., de Araujo Costa Neto, L. A., Lima de Queiroz, M. V. J., Galvão-Coelho, N. L., Palhano-Fontes, F.
Open Accessindividual

Reduced Brain Responsiveness to Emotional Stimuli With Escitalopram But Not Psilocybin Therapy for Depression

This secondary analysis of an RCT (n=59) investigates the impact of psilocybin-assisted therapy (PAT) and escitalopram (SSRI) on responsiveness to emotional stimuli in patients with moderate-to-severe major depressive disorder over a 6-week trial period. Responses to emotional faces were reduced in the SSRI group, not the psilocybin group at the follow-up.

Published
May 7, 2025
Journal
American Journal of Psychiatry
Authors
Wall, M. B., Demetriou, L., Giribaldi, B., Roseman, L., Ertl, N., Erritzoe, D., Nutt, D. J., Carhart-Harris, R. L.
Paywallmeta

Rapidity of Symptom Improvement With Intranasal Esketamine for Major Depressive Disorder: A Systematic Review and Meta-Analysis

This meta-analysis (s=8, n=1437) compared the effect of intranasal esketamine to placebo (both in combination with standard antidepressants) as a treatment for major depressive disorder (MDD). It was found that intranasal esketamine, in combination with the standard treatment, did effectively reduce depression severity when compared to the placebo, with higher doses having a longer-lasting effect.

Published
December 1, 2022
Journal
Journal of Clinical Psychiatry
Authors
Hock, R. S., Feeney, A., Iovieno, N., Murrough, J. W., Sanjay, ;., Mathew, J., Iosifescu, D. V., Fava, M., Jha, M. K., Papakostas, G. I.
Open Accessindividual

Intranasal esketamine effectively treats treatment-resistant depression in adults regardless of baseline irritability

This post hoc analysis of two Phase III double-blind studies assessed the effects of baseline irritability on clinical outcomes in participants with treatment-resistant depression (TRD) (n=560) treated with intranasal ketamine (esketamine) plus an oral antidepressant (ESK + AD). ESK + AD improved symptoms of depression regardless of baseline irritability level and increased odds of achieving a response in all participants.

Published
October 20, 2022
Journal
Journal of Affective Disorders
Authors
Jha, M. K., Williamson, D. J., Magharehabed, G., Turkoz, I., Daly, E. J., Trivedi, M. H.
Paywallindividual

The potential pro-cognitive effects with intravenous subanesthetic ketamine in adults with treatment-resistant major depressive or bipolar disorders and suicidality

This single-blind, placebo-controlled study (n=111) assessed the cognitive effects of six ketamine infusions (35 mg/70 kg) in patients with unipolar or bipolar depression. Results indicate that ketamine improved processing speed independently of its antidepressant effects, while improvements in verbal learning were mediated by reductions in depressive symptoms.

Published
October 23, 2021
Journal
Journal of Psychiatric Research
Authors
Zhou, Y-L., Wang, C., Lan, X-F., Zheng, W., Chao, Z., McIntyre, R. S., Ning, Y-P., Li, H., Wu, K.
Open Accessindividual

Nitrous oxide as an adjunctive therapy in major depressive disorder: a randomized controlled double-blind pilot trial

This double-blind placebo-controlled between-subjects study (n=23) tested the antidepressant efficacy of inhaled nitrous oxide (50% N2O|50% O2 versus 100% O2) in patients diagnosed with major depression (MDD). Across multiple treatment sessions administered across a period of 4 weeks, there were significant reductions in depressive symptoms in the acute response to treatment and accumulatively across sessions.

Published
September 1, 2021
Journal
brazilian Journal of Psychiatry
Authors
Guimarães, M. C., Guimarães, T. M., Hallak, J. E., Abrão, J., Machado-de-Sousa, J. P.

Clinical Trials

177 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
Not yet recruitingPhase I

Psilocybin as a Novel Therapy for Residual Anhedonia

This Phase I, randomised, triple-masked, parallel-group trial (n=90) will evaluate whether a single oral dose of psilocybin 25 mg can improve residual anhedonia and emotional blunting in adults with major depressive disorder who remain symptomatic despite ongoing SSRI or SNRI treatment. The study will compare psilocybin with placebo and will assess whether treatment can restore fronto-striatal reward circuit function and reduce anhedonia. Participants in both arms will complete six MRI sessions, with two scans before the administration day and four afterwards. The psilocybin group will receive a supervised one-time 25 mg capsule dose, while the control group will receive a matching placebo capsule containing 25 mg of inert filler. Key outcomes include change in Dimensional Anhedonia Rating Scale score and change in fronto-striatal connectivity (pgACC-NAcc functional connectivity) from baseline to end of study, with assessments planned from week -3 to week 8.

Started
July 1, 2026
Type
interventional
Blinding
triple
Randomized
Yes
Registry ID
NCT07607938
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
Not yet recruitingPhase NA

Neural Mechanisms of Ketamine Antidepressant Treatment 2.0: Exploring how ketamine affects the brain function in people with difficult-to-treat depression.

This is a randomised, quadruple‑blind, placebo‑controlled mechanistic clinical trial enrolling 90 participants (60 adults with major depressive disorder, including treatment‑resistant cases, and 30 healthy controls) at the Royal Melbourne Hospital, Australia, with recruitment from February 2026 and completion expected December 2027. Participants receive a single subcutaneous administration of ketamine 0.75 mg/kg versus placebo (0.9% saline). The primary outcome is change in habenula activity measured using ultra‑high‑field 7T MRI at baseline and 24–48 hours after dosing, designed to probe rapid neural mechanisms underlying ketamine’s antidepressant effects. Secondary outcomes assess clinical and behavioural effects using the Montgomery–Åsberg Depression Rating Scale (MADRS), QIDS‑C, Snaith–Hamilton Pleasure Scale (SHAPS), GAD‑7, and objective activity monitoring by actigraphy. The protocol includes healthy controls to facilitate mechanistic comparisons between clinical and non‑clinical neural responses. The study phase is not specified in the available data. The quadruple‑blind design and saline comparator aim to isolate drug‑specific neural changes and early clinical signal following a single subcutaneous ketamine exposure in treatment‑resistant and broader MDD populations.

Started
February 2, 2026
Type
interventional
Blinding
quadruple
Randomized
Yes
Registry ID
ACTRN12625001087448
RecruitingPhase III

A Study to Evaluate the Efficacy and Safety of Esketamine for Reduction of Symptoms of Major Depressive Disorder (AVENUE)

This Phase III, double-blind, randomised, placebo-controlled trial (n=258) will evaluate the efficacy and safety of intranasal esketamine 84 mg in addition to comprehensive standard of care for rapidly reducing symptoms of major depressive disorder (MDD) in adolescent participants aged 12 to 17 with acute suicidal ideation or behaviour. The primary outcome is the change in depressive symptoms measured by the Children's Depression Rating Scale - Revised (CDRS-R) total score at 24 hours post-first dose. Participants will be randomly assigned to receive either intranasal esketamine (84 mg, with potential dose adjustments to 56 mg) plus oral placebo or intranasal placebo plus oral midazolam (0.0625 mg/kg) twice weekly for four weeks. The treatment will occur on specific days, with assessments conducted to monitor the efficacy and safety of the interventions. The trial is sponsored by Janssen Research & Development, LLC, with an estimated start date of January 8, 2026, and a completion date of September 15, 2031.

Started
January 8, 2026
Type
interventional
Blinding
double
Randomized
Yes
Registry ID
NCT07227454
RecruitingPhase III

Ketamine Augmentation of ECT in Treatment-Resistant Depression (Ketamina)

Phase III double-blind, randomised, placebo-controlled trial (n=30) testing IV ketamine 0.5 mg/kg given during ECT sessions 2, 4 and 6 in hospitalised adults with treatment-resistant MDD.

Started
July 10, 2025
Type
interventional
Blinding
double
Randomized
Yes
Registry ID
NCT07088380

Explore further

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