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.
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
Dosing
Integration
Study Arms & Interventions
Ayahuasca
experimentalSingle-dose ayahuasca treatment arm.
Interventions
- Ayahuasca1 othervia 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
inactivePassive inert placebo comparator.
Interventions
- Placebo1 othervia 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
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.
Primary Results(8 publications)
Participants
Response Rates
reduction of 50% or more in baseline scores
≥50% reduction in baseline scores
HAM-D ≤7 (remission)
MADRS ≤10 (remission)
Adverse Events (from all publications)
| Arm / Group | n | Any TEAE | Severe | Serious | Discont. |
|---|---|---|---|---|---|
| Ayahuascaexperimental | 6 | 3(50.0%) | — | 0(0.0%) | — |
| Placeboinactive | — | — | — | — | — |
| Ayahuascaexperimental | 35 | — | — | — | — |
| Placeboinactive | 36 | — | — | — | — |
| Ayahuascaexperimental | 8 | — | — | — | — |
| Placeboinactive | — | — | — | — | — |
| Ayahuascaexperimental | 14 | — | — | 0(0.0%) | — |
| Placeboinactive | 15 | — | — | 0(0.0%) | — |
| Ayahuascaexperimental | 35 | — | — | — | — |
| Placeboinactive | 34 | — | — | — | — |
| Ayahuascaexperimental | 14 | — | — | — | — |
| Placeboinactive | 15 | — | — | — | — |
| Ayahuascaexperimental | 17 | — | — | — | 1(5.9%) |
| Ayahuascaexperimental | 14 | — | — | — | 0(0.0%) |
| Placeboinactive | 18 | — | — | — | 4(22.2%) |
| Placeboinactive | 14 | — | — | — | 0(0.0%) |
| Ayahuascaexperimental | 23 | — | — | — | — |
| Placeboinactive | 23 | — | — | — | — |
* Vomiting was reported by 50% of volunteers (3 out of 6). The study was open-label and did not include a placebo arm. Adverse effects were not systematically assessed, but vomiting was the only spontaneously reported adverse effect. Participants considered the effects mild and short-lived.
* No placebo arm was used in this open-label study.
* The paper reports on physiological responses (cortisol) rather than clinical adverse events. The study population for patients was 28, and for controls was 43. The text mentions that the placebo induced 'light gastrointestinal discomfort' (page 4, line 197), but does not provide summary counts for TEAEs.
* The paper is a qualitative follow-up of 8 patients who previously participated in an open-label trial. While it mentions 'negative effects included mostly nausea and vomiting', it does not provide summary counts for TEAEs in this follow-up cohort.
* No placebo arm data reported in this specific qualitative follow-up paper.
* The paper reports transient acute effects: nausea (71%), vomiting (57%), transient anxiety (50%), restlessness (50%), and transient headache (42%). No serious adverse events were observed.
* The paper reports transient acute effects: nausea (26%), transient anxiety (73%), restlessness (20%), and transient headache (53%). No serious adverse events were observed.
* No summary counts for treatment-emergent adverse events (TEAEs), severe AEs, serious AEs, or discontinuations due to AEs are reported for this arm.
* No summary counts for treatment-emergent adverse events (TEAEs), severe AEs, serious AEs, or discontinuations due to AEs are reported for this arm. The paper mentions that the placebo was designed to simulate organoleptic properties of ayahuasca, 'besides giving rise to some nausea, vomiting and diarrhea', but no counts for these events are provided.
* The paper focuses on suicidality (MADRS-SI) scores rather than reporting a summary table of all TEAEs. No specific total TEAE count is provided in the text or tables.
* 1 participant dropped out during dosing session. Total patients in PG arm = 17. Nausea (90%) and vomiting (57%) reported during dosing.
* Safety data for D2 focuses on biomarker changes; no specific TEAE counts provided for this window.
* 4 participants did not receive allocated intervention: 3 did not meet criteria for depression after wash-out, 1 insufficient sample. Total patients in placebo arm = 18.
* No specific TEAE summary counts provided in the text or tables. The paper focuses on subjective experiences and EEG oscillations.
Study Details
- StatusCompleted
- PhasePhase IPhase II
- Typeinterventional
- DesignRandomizedtriple Blind
- Target Enrollment35 participants
- TimelineStart: 2014-02-01End: 2016-12-01
- Compounds
- Topic
Study Team
Sponsors & Collaborators
- Federal University of Rio Grande do Norte (UFRN)Primary Sponsor
- Federal University of São Paulo (UNIFESP)Collaborator
Investigators
- DADraulio Araújo