Clinical TrialTreatment-Resistant Depression (TRD)AyahuascaPlaceboCompleted

Antidepressant Effects of Ayahuasca: a Randomized Placebo Controlled Trial in Treatment Resistant Depression

This randomised, placebo-controlled parallel trial (n=35) tested a single oral dose of ayahuasca versus placebo in patients with treatment-resistant depression.

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Target Enrollment
35 participants
Study Type
Phase I/II interventional
Design
Randomized, triple Blind

Detailed Description

This randomized, parallel-group trial evaluated the antidepressant effects of a single oral dose of ayahuasca compared with a passive placebo in patients with treatment-resistant major depression (n=35), with acute and longer-term follow-up.

Outcomes included depressive symptom scales (HAM-D, MADRS), psychiatric and neuropsychological assessments, MRI (structural and functional), polysomnography, and serum biomarkers (BDNF, TNF-α, cortisol, IL-6, IL-10).

Study Protocol

Preparation

sessions

Dosing

1 sessions
480 min each

Integration

sessions

Study Arms & Interventions

Ayahuasca

experimental

Single-dose ayahuasca treatment arm.

Interventions

  • Ayahuasca1 other
    via Oral• single dose• 1 doses total

    1 ml/kg of ayahuasca brew; single dosing session. Brew composition: mean ± SD: 0.36 ± 0.01 mg/ml of N,N-DMT, 1.86 ± 0.11 mg/ml of harmine, 0.24 ± 0.03 mg/ml of harmaline, and 1.20 ± 0.05 mg/ml of tetrahydroharmine.

Placebo

inactive

Passive inert placebo comparator.

Interventions

  • Placebo1 other
    via Oral• single dose• 1 doses total

    1 ml/kg of active placebo. Per 1 ml of water: 0.1 g of yeast, 0.02 g of zinc sulfate, and 0.02 g of citric acid. Designed to imitate bitter/sour taste, brownish color, and gastrointestinal distress of ayahuasca.

Participants

Ages
18 – 60
Sexes
Male & Female

Inclusion Criteria

  • Inclusion Criteria:
  • Age: 18-60 years old;
  • Diagnostic of major depressive disorder (DSM-IV);
  • At least two previous unsuccessful antidepressant medications;
  • Current depressive episode (HAM-D >= 17).

Exclusion Criteria

  • Exclusion Criteria:
  • History of psychosis;
  • Present or past history of bipolar disorder or schizophrenia;
  • Diagnosis of current clinical disease, based on history, physical examination and routine hematologic and biochemical tests;
  • Serious and imminent suicidal risk;
  • Pregnancy, current drug or alcohol dependence;
  • Previous experience with ayahuasca.

Study Details

Study Team

Investigators

  • DA
    Draulio Araújo

Locations

Draulio B de Araujo — Natal, Rio Grande do Norte, Brazil

Related Publications

Open AccessindividualLong-term follow-up

Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report

This open-label study (n=6) found that a single dose of ayahuasca has fast-acting anxiolytic and antidepressant effects (up to 21 days later, MADRS) in patients with a current depressive episode.

Published
Journal
brazilian Journal of Psychiatry
Authors
Osório, F. L., Sanches, R. F., Macedo, L., Dos Santos, R. G., Maia-de-Oliveira, J. P., Wichert-Ana, L., de Araujo, D. B., Riba, J., Crippa, J. A., Hallak, J. E.
Open AccessindividualSecondary analysis

A Single Dose Of Ayahuasca Modulates Salivary Cortisol In Treatment-Resistant Depression

A single dose of ayahuasca acutely raised salivary cortisol and, 48 hours later, normalised the blunted awakening salivary cortisol response in treatment‑resistant depression patients to levels seen in healthy controls, without changing plasma cortisol.

Published
Journal
Biorxiv
Authors
Adams, T.
Open AccessindividualLong-term follow-up

Longterm effects of ayahuasca in patients with recurrent depression: a 5-year qualitative follow-up

This qualitative follow-up study (n=8) interviewed patients 4-7 years after the intake of ayahuasca (123.2 mg DMT, 32.34mg Harmine) within the context of a previous open-label study; most patients reported that the experience was among the most important of their lives, but no long-term improvements in depression scores (MADRS) were found.

Published
Journal
Archives of Clinical Psychiatry (São Paulo)
Authors
Dos Santos, R. G., Osório, F. L., Hallak, J. E.
Open AccessindividualSecondary analysis

Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial

In a double-blind randomised placebo-controlled trial of 29 patients with treatment-resistant depression, a single dose of ayahuasca produced rapid antidepressant effects versus placebo at days 1, 2 and 7, with effect sizes increasing from Cohen’s d = 0.84 to 1.49 and higher response rates at day 7 (64% v. 27%). This first controlled trial of a psychedelic in this population supports the safety and therapeutic potential of ayahuasca when dosed in an appropriate setting.

Published
Journal
Psychological Medicine
Authors
Palhano-Fontes, F., Barreto, D., Onias, H., Andrade, K. C., Novaes, M. M., Pessoa, J. A., Mota-Rolim, S. A., Osório, F. L., Sanches, R., Dos Santos, R. G., Tófoli, L. F., De Oliveira Silveira, G., Yonamine, M., Riba, J., Santos, F. R., Silva-Junior, A. A., Alchieri, J. C., Galvão-Coelho, N. L., Lobão-Soares, B., Hallak, J. E. C., Arcoverde, E., Maia-De-Oliveira, J. P., Araújo, D. B.
Open AccessindividualPrimary

Modulation of Serum Brain-Derived Neurotrophic Factor by a Single Dose of Ayahuasca: Observation From a Randomized Controlled Trial

This placebo-controlled, double-blind randomised trial study (n=73) investigated the impact of BDNF (a protein related to the growth of neurons) on patients with depression who were administrated ayahuasca. The trial results observed a potential link between the changes in serum BDNF levels and the antidepressant effects of ayahuasca and also supported using psychedelics as an antidepressant.

Published
Journal
Frontiers in Psychology
Authors
Galvão-Coelho, N. L., de Almeida, R. N., de Menezes Galvão, A. C., da Silva, F. S., dos Santos Silva, E. A., Palhano-Fontes, F., Maia-de-Oliveira, J. P., de Araujo, D. B., Lobão-Soares, B.
Open AccessindividualSecondary analysis

The Impact of Ayahuasca on Suicidality: Results From a Randomized Controlled Trial.

This secondary analysis of a double-blind, parallel-arm, randomised placebo-controlled trial (n=29) investigates the impact of ayahuasca on suicidality (SI) in individuals with treatment-resistant depression (TRD). It found that ayahuasca may show potential as a fast-acting and innovative intervention for SI, but didn't find significant results (only a trend with a large effect size). This is the first study to investigate the use of ayahuasca for SI.

Published
Journal
Frontiers in Pharmacology
Authors
Araújo, D. B., Zeifman, R. J., Palhano-Fontes, F., Hallak, J. E., Arcoverde, E., Maia-de-Oliveira, J. P.
Open AccessindividualSecondary analysis

Changes in inflammatory biomarkers are related to the antidepressant effects of Ayahuasca

In a double‑blind placebo‑controlled trial of treatment‑resistant depression patients and healthy controls, ayahuasca produced a significant 48‑hour reduction in C‑reactive protein (CRP) and, in patients, larger CRP decreases correlated with greater reductions in depressive symptoms. No significant effects were seen for interleukin‑6 or BDNF, and these biomarkers did not predict antidepressant response or remission.

Published
Journal
Journal of Psychopharmacology
Authors
Galvão-Coelho, N. L., de Menezes Galvão, A. C., de Almeida, R. N., Palhano-Fontes, F., Campos Braga, I., Lobão-Soares, B., Maia-de-Oliveira, J. P., Perkins, D., Sarris, J., de Araujo, D. B.
Open Accessmeta

A review of psychedelics trials completed in depression, informed by European regulatory perspectives

This systematic review (s=8) analyses completed controlled trials of psychedelics for depression, including psilocybin, LSD, ayahuasca, and DMT, all in Phase II or I/II. It evaluates methodological patterns against the draft European Medicines Agency guideline revision, highlighting challenges such as unblinding, expectancy, and adverse event characterisation, while calling for larger studies to assess long-term efficacy and safety.

Published
Journal
Neuroscience Applied
Authors
Silva, F., Butlen-Ducuing, F., Guizzaro, L., Balabanov, P., Meyer-Lindenberg, A.
Paywallindividual

Predicting and exploring ayahuasca effects: Perception, mind-wandering, and EEG oscillations

In a double-blind, placebo-controlled trial of 50 volunteers, ayahuasca produced robust perceptual, emotional and mystical experiences alongside EEG changes (notably reduced global alpha and increased frontomedial delta and right-posterior theta/beta), with acute lower theta linked to stronger mystical effects and baseline theta and beta oscillations predicting interoceptive and emotional responses.

Published
Journal
Journal of Psychopharmacology
Authors
Silva-Costa, N., Pessoa, J. A., Andrade, K. C., Mota-Rolim, S., Palhano-Fontes, F., Araujo, D. B., Wießner, I.