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Home/Research/Placebo/Depressive Disorders

Placebo for Depressive Disorders

49 papers and 297 clinical trials exploring placebo as a treatment for depressive disorders.

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
IndicationApproximately 260 million people worldwide are affected by depression.

Depressive Disorders

Depressive disorders, particularly major depressive disorder (MDD), are significant contributors to global mental health issues. Research into the therapeutic potential of psychedelics, such as psilocybin and ketamine, offers promising avenues for treatment, especially for cases that are resistant to conventional therapies.

Full Depressive Disorders profile

Academic Research

49 papers
Paywallindividual

Changes in anxiety, quality of life, and functioning following psilocybin-assisted therapy in veterans with treatment-resistant depression

This secondary analysis of an open-label trial (n=15) examined a single 25 mg dose of psilocybin with psychological support in veterans with treatment-resistant depression, focusing on anxiety, quality of life, functioning, and PTSD symptoms. Improvements were observed across these measures, but most were no longer significant after accounting for concurrent improvements in depression.

Published
June 4, 2026
Journal
Journal of Affective Disorders
Authors
Kelly, C. M., Fradet, M., Bostian, C. M., Donnelly, A., Ellis, S., Ostacher, M., Aaronson, S., Suppes, T.
Open Accessindividual

Long-Term Efficacy of Psilocybin with Adjunct Psychotherapy in Treatment-Resistant Major Depression (EPIsoDE): 6- and 12-Month Naturalistic Follow-Up of a Phase 2b Trial

This naturalistic follow-up of a Phase IIb randomised active placebo-controlled trial (n=144) found that one or two 25 mg doses of psilocybin with psychotherapy were linked to sustained reductions in depression symptoms in treatment-resistant major depression (TRD) at six and twelve months. Benefits were similar across groups, while restarting antidepressant medication during follow-up was associated with worse scores.

Published
May 27, 2026
Journal
Psychotherapy and Psychosomatics
Authors
Mertens, L. J., Betzler, F., Brand, M., Evens, R., Jungaberle, A., Jungaberle, H., Kärtner, L., Majić, T., Schmitz, C. N., Ströhle, A., Scharf, D., Spangemacher, M., Wolff, M., Assadi, Z., Bahri, S., Becher, L., Färber, L. V., Harder, H., Kirchen, N., Kulakova, E., Kunz, L. C., Meijer, A., Rohrmoser, B., Wellek, S., Berger, M. M., Koslowski, M., Gründer, G.
Open Accessindividual

Low-Dose Buprenorphine Following Ketamine Treatment for Suicidal Ideation in Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial

This randomised, double-blind, placebo-controlled trial (n=50) tested low-dose sublingual buprenorphine after ketamine in adults with major depressive disorder and suicidal thoughts. Buprenorphine led to a greater and longer-lasting reduction in suicidal ideation than placebo, while depression scores were similar and no serious treatment-related side effects occurred.

Published
May 18, 2026
Journal
American Journal of Psychiatry
Authors
Tucciarone, J. M., Bandeira, I. D., Blasey, C., Kratter, I. H., Ehrie, J., Keller, J., Pankow, H., Chang, M., Hawkins, J., Evers, A. G., Bernert, R., DeBattista, C., Truong, H., Rodriguez, C. I., Heifets, B. D., Schatzberg, A. F.
Open Accessindividual

Short-Term and Late-Term Effects of Psilocybin on Symptoms in Major Depression: A Randomized Clinical Trial.

This double-blind placebo-controlled randomised clinical trial (n=35) found that a single 25 mg dose of psilocybin, given with psychotherapy, reduced depression symptoms in people with moderate to severe recurrent major depressive disorder within days and for more than three months on some measures. Most side effects were mild or moderate, but two participants had severe anxiety that needed medical attention.

Published
May 15, 2026
Journal
JAMA Network Open
Authors
Yngwe, H., Plavén-Sigray, P., Ekman, C. J., Henje, E., Berglund, A., Tiger, M., Beckman, M., Lundberg, J.
Open Accessindividual

A phase 1 study of a second experience with Group Retreat Psilocybin Therapy for partial responders after a first experience

This Phase 1 study (n=13) tested a second group retreat psilocybin therapy session in people with metastatic cancer who had only partly responded before. It found no serious side effects, and anxiety and depression scores improved, with more participants reporting a full mystical experience after the second session.

Published
April 14, 2026
Authors
Back, A. L., McGregor, B. A., Thorn, L. L., Harvey, K., Blom, D., Callan, G., Guy, J., Kumar, S., Hershberg, R., Layer, M., Levin, J., Myers, S., Perez, J., Salmonson, K., Thompson, P., Whinney, J.
Open Accessindividual

Intranasal 5-MeO-DMT Concomitant with SSRI for Treatment-Resistant Depression: A Proof-of-Concept Trial

This open-label phase 2a trial (n=12) tested a single intranasal dose of 5-MeO-DMT given alongside stable SSRI treatment in adults with treatment-resistant depression and found it was generally well tolerated, with mostly short-lived nasal and stomach side effects. Depressive symptoms fell quickly and stayed lower over 12 weeks in both dose groups.

Published
March 24, 2026
Journal
CNS Drugs
Authors
Seynaeve, M., Dunbar, F., Hindocha, C., Ermakova, A. O., Pierce, M., Conley, R. R., Roberts, C.

Clinical Trials

297 trials
CompletedPhase II

A Study to Assess the Use of Methylone in the Treatment of PTSD (IMPACT-1)

This Phase II, two-part, multicentre trial (n=64) will assess methylone as a treatment for adults with post-traumatic stress disorder (PTSD). It is designed to evaluate the drug’s safety, tolerability, and efficacy in participants aged 18–65 years in the UK, including people who have previously tried at least one PTSD treatment without sufficient benefit.

Type
interventional
Blinding
double
Randomized
Yes
Not yet recruitingPhase II

Anesthesia-Masked Psilocybin Therapy for Major Depression

This Phase II, randomised, double‑blind, crossover trial (n=10) will assess the safety, feasibility and effectiveness of masking psilocybin therapy with general anaesthesia in adults with major depressive disorder (age 25–65). Participants will receive oral psilocybin (10 mg and 25 mg) and placebo (0 mg) across repeated sessions administered under intravenous propofol anaesthesia so that both participants and outcome assessors remain blinded; the study will also collect preliminary data on changes in depressive symptoms. All participants complete four weekly dosing sessions (placebo, 10 mg, and two separate 25 mg sessions) in one of two counterbalanced sequences so every participant receives every dosing condition. Psilocybin or placebo capsules are given approximately 30 minutes before induction of general anaesthesia with propofol, with anaesthesia provided by a board‑certified anaesthesiologist at Stanford Hospital. Primary outcomes are blinding success measures (correct identification of psilocybin and accuracy of guessed dose) assessed 1 day after the final dosing session (Visit 21, Week 4); secondary data collection includes mood, sleep, wellbeing and anxiety questionnaires, optional consumer‑grade EEG sleep monitoring, and overall study duration per participant of about 7 weeks across ~25 visits.

Started
July 1, 2026
Type
interventional
Blinding
double
Randomized
Yes
Registry ID
NCT07479550
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
Not yet recruitingPhase II

Ketamine With Dialectical Behavioural Therapy (DBT) for Suicidality in Individuals With Treatment-Resistant Depression and Borderline Personality Disorder (KET-DBT)

This Phase II randomised, quadruple-masked trial (n=120) will study adults aged 18 to 70 years with borderline personality disorder, treatment-resistant major depressive disorder or bipolar disorder, and suicidal ideation, evaluating whether intravenous ketamine plus dialectical behavioural therapy (DBT) reduces suicidal ideation more rapidly and robustly than midazolam plus DBT. The main purpose is to assess change in suicidal ideation severity from baseline to Day 35 using the Modified Scale for Suicidal Ideation (MSSI). All participants will receive DBT for 6 months, starting before the infusions, with weekly individual sessions and the addition of weekly group sessions from Week 5. The experimental arm will receive six intravenous ketamine infusions over 1 month: the first two at 0.5 mg/kg over 40 minutes, infusions 3 and 4 flexibly dosed at 0.5 mg/kg to 0.75 mg/kg, and infusions 5 and 6 flexibly dosed at 0.5 mg/kg to 0.85 mg/kg. The comparator arm will receive six intravenous midazolam infusions over the same period: the first two at 0.02 mg/kg over 40 minutes, infusions 3 and 4 at 0.02 mg/kg to 0.03 mg/kg, and infusions 5 and 6 at 0.2 mg/kg to 0.035 mg/kg. Participants will also complete hospital visits, remote follow-up by call or videocall, and a range of mood, cognitive and behavioural assessments.

Started
June 1, 2026
Type
interventional
Blinding
quadruple
Randomized
Yes
Registry ID
NCT07569198
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

Explore further

Search all Placebo papers Search all Depressive Disorders trials Full Placebo profile Full Depressive Disorders profile