What small studies report about ayahuasca and depression, the serious antidepressant (MAOI) interaction risk, and how federal law treats ayahuasca.
Small studies report lower depression scores after a single dose of ayahuasca: one randomized trial of 29 people with treatment-resistant depression, and two open-label studies of 6 and 17 patients. No large trial exists, no regulator approval appears in the sources reviewed, and a published warning describes a serious interaction risk when ayahuasca is combined with SSRI antidepressants.
At The Psychedelic Journal, we reviewed the published abstracts of three clinical studies, two 2026 reviews, a 1998 interaction paper and the 2006 Supreme Court opinion on October 20, 2026. This is a desk review of published documents, and nobody on this site has tested, handled or sourced ayahuasca. For background on ayahuasca itself, see our ayahuasca guide. If you are considering ayahuasca for depression, take the studies below to your clinician first.
Three small clinical studies report lower depression scores after one dose of ayahuasca, and one of them is a 2019 randomized trial. Palhano-Fontes and colleagues, writing in Psychological Medicine, ran a parallel-arm, double-blind, placebo-controlled trial in 29 patients with treatment-resistant depression. Each patient received a single dose of either ayahuasca or placebo, and the trial is registered as NCT02914769.
The team measured depression severity with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale at baseline and at 1, 2 and 7 days after dosing. The authors report MADRS scores were statistically significantly lower in the ayahuasca group than the placebo group at day 1 and day 2 (p = 0.04) and at day 7 (p < 0.0001). Between-group effect sizes, measured as Cohen's d, were 0.84 at day 1, 0.84 at day 2 and 1.49 at day 7.
Response rates were high in both groups at day 1 and day 2. By day 7, the ayahuasca group's response rate was 64% against 27% for placebo (p = 0.04). Remission showed a trend toward significance at day 7, at 36% versus 7% (p = 0.054).
The authors describe the study as, to their knowledge, the first controlled trial of a psychedelic substance in treatment-resistant depression. It remains a single trial of 29 people.
Two earlier studies used an open-label design, which means there was no placebo group to compare against. Osório and colleagues (Brazilian Journal of Psychiatry, 2015) gave a single dose to six volunteers with a current depressive episode in an inpatient psychiatric unit. They report statistically significant reductions of up to 82% in depressive scores at 1, 7 and 21 days, with no change on a mania rating scale.
Sanches and colleagues (Journal of Clinical Psychopharmacology, 2016) gave one oral dose of ayahuasca to 17 inpatients with recurrent depression. The authors report depression scale scores fell significantly from 80 minutes to day 21, and brain scans eight hours after the dose showed increased blood flow in three regions they link to mood regulation. They describe ayahuasca as well tolerated in that setting, with vomiting, reported by 47% of the volunteers, as the only adverse effect recorded.
Two 2026 reviews of ayahuasca and treatment-resistant depression add cautions. A narrative review by Civardi and colleagues in Frontiers in Psychiatry reports rapid reductions in depressive symptoms with both psilocybin and ayahuasca, and finds stronger evidence for sustained effects with psilocybin. Our ayahuasca vs psilocybin comparison sets the two side by side.
A systematic review by Mano-Sousa and colleagues in the Journal of Psychoactive Drugs screened 6,633 records and kept five studies. The authors report that, despite methodological heterogeneity, those studies consistently show reductions in suicidal ideation and depressive symptoms. They also call for large-scale, methodologically rigorous longitudinal studies before clinical guidelines can be set.
The evidence reviewed here cannot show long-term results, because the 2019 placebo-controlled trial followed one dose for seven days. Nothing in the sources reviewed reports longer follow-up for that 2019 trial. The two open-label studies ran to day 21, and they had no placebo comparison at all.
The 2026 Civardi review names the wider problems with the trials it covered, which it found by searching two research databases through August 2025. It notes the trials were done in highly controlled settings and systematically exclude people with other conditions, high suicide risk or multiple medications. It adds that blinding is hard to maintain, expectations are high and samples are small.
The Civardi authors conclude that current evidence reflects clinically stable, selected patients rather than real-world patients with treatment-resistant depression. Every study described above took place in a controlled clinical setting, and two of them in an inpatient psychiatric unit. A retreat or ceremony is a different setting, and none of the sources reviewed studied one.
No regulator approval of ayahuasca for depression appears in the sources reviewed. Check current FDA status at the FDA website.
Mano-Sousa and colleagues call for large-scale, methodologically rigorous longitudinal trials before guidelines are set. Readers can compare other options in our treatment-resistant depression options guide.
Ayahuasca contains harmala alkaloids that inhibit monoamine oxidase (MAO). In a 1998 paper in the Journal of Psychoactive Drugs, Callaway and Grob address this interaction. They write that combining these MAO-inhibiting alkaloids with the selective serotonin reuptake inhibitor (SSRI) class of antidepressants may induce a serotonin syndrome with potentially grave outcome. They advise caution when combining ayahuasca with certain pharmaceutical drugs.
The sources reviewed give no washout length, and none is given here.
Do not stop, taper or change any prescribed medicine on your own. Ask the clinician who prescribed it before any change. Our psychedelic medication safety guide covers drug interactions in more detail, and our serotonin syndrome warning signs guide describes the condition the 1998 paper warns about.
Ayahuasca contains DMT, which is listed in Schedule I at 21 CFR 1308.11 of the Code of Federal Regulations (CFR). Religious exemptions held under the Drug Enforcement Administration (DEA) are explained in our ayahuasca guide, and our guide to what psychedelics are legal in the US gives the wider picture. Nothing in the sources reviewed covers any state's law, so no state-level claim is made here.
In Gonzales v. O Centro Espírita Beneficente União do Vegetal, 546 U.S. 418, decided February 21, 2006, the Supreme Court addressed one church's sacramental use of hoasca. Chief Justice Roberts wrote the opinion, and every other Justice joined except Justice Alito, who did not take part. The Court held the lower courts did not err in finding the government "failed to demonstrate, at the preliminary injunction stage, a compelling interest" in barring that use.
The opinion describes DMT as "a hallucinogen regulated under Schedule I of the Controlled Substances Act." It rejected the government's position that no exceptions could be made, writing that the Religious Freedom Restoration Act (RFRA) operates by mandating consideration, under the compelling interest test, of exceptions to generally applicable laws.
The O Centro ruling protected one church's religious use. It did not legalize ayahuasca generally, and it is not a medical access route. Our O Centro case page covers the ruling in full.
As of October 20, 2026, as our Iowaska church agreement page reports, citing Iowa Capital Dispatch and Marijuana Moment, the Iowaska Church of Healing signed a confidential agreement with the DEA under RFRA, disclosed in June 2026. The Iowa Board of Pharmacy agreed on October 5, 2026 to issue a probationary certificate of registration, and the terms remain under seal.
DMT remains Schedule I, and these religious-exemption processes are not a path to treatment for depression. The Brazilian rules are on our Brazil ayahuasca authorization page.
Anyone taking an antidepressant or another prescribed medicine should talk to the prescribing clinician before any decision about ayahuasca. The 1998 Callaway and Grob warning names the SSRI class directly, and its authors advise caution with certain other pharmaceutical drugs as well.
People with depression symptoms should also talk to a clinician first. The trials described above enrolled selected patients in controlled settings, and the Civardi review notes that such trials systematically exclude people at high suicide risk. The published results therefore do not describe that group.
A clinician can advise on a specific situation. If depression symptoms become an emergency, contact local emergency services.
We give no dose, brewing or preparation information, no sourcing and no retreat recommendation, because none of the sources reviewed supports one for use outside a trial. Each study gave a single dose inside a clinical research setting, and that is the only setting the sources describe.
The concrete next step for anyone weighing ayahuasca for depression is a conversation with a treating clinician.
Small studies report lower depression scores after a single dose, but the evidence is limited. In a 2019 randomized trial of 29 people with treatment-resistant depression, the authors report a 64% response rate with ayahuasca versus 27% with placebo at day 7. Two open-label studies of 6 and 17 patients also reported falling scores. No large trial exists, and no regulator approval appears in the sources reviewed.
Yes, in one small randomized placebo-controlled trial published in Psychological Medicine in 2019 and registered as NCT02914769. It enrolled 29 patients with treatment-resistant depression, gave each a single dose of ayahuasca or placebo, and measured outcomes through day 7. The authors call it, to their knowledge, the first controlled trial of a psychedelic substance in treatment-resistant depression.
A 1998 paper by Callaway and Grob warns that the MAO-inhibiting harmala alkaloids in ayahuasca, combined with SSRI antidepressants, may induce a serotonin syndrome with potentially grave outcome. The sources reviewed give no washout length. Do not stop or change any prescribed medicine on your own, and ask the prescribing clinician before any change.
We found no approval of ayahuasca for depression in the sources reviewed. Check current FDA status at the FDA website.
Ayahuasca contains DMT, which is listed in Schedule I under federal law. The 2006 Supreme Court ruling in Gonzales v. O Centro protected one church's sacramental use without legalizing ayahuasca generally, and religious-exemption agreements such as the Iowaska church's are not a path to treatment. The sources reviewed cover no state law.
The sources reviewed do not establish that ayahuasca is safe for people with depression. Trials systematically excluded people with other conditions, high suicide risk or multiple medications, and the SSRI interaction warning still applies. In a 2016 inpatient study of 17 patients, the authors report it was well tolerated, with vomiting in 47% of volunteers as the only recorded adverse effect. A clinician can advise on a specific situation.
They are different substances. A 2026 narrative review by Civardi and colleagues reports rapid symptom reductions with both psilocybin and ayahuasca but stronger evidence for sustained effects with psilocybin. Ayahuasca contains DMT and MAO-inhibiting harmala alkaloids.
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