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Major DepressionPhase 1/2NCT02914769

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

A Phase 1/2 study testing Ayahuasca in people with Major Depression, run by Universidade Federal do Rio Grande do Norte at 1 site in Brazil.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The purpose of the present trial is to test the efficacy of Ayahuasca in treatment-resistant depression. Ayahuasca is a decoction of two plants, long used by Amazonian Amerindians. Traditionally, it is prepared by decoction of a bush (Psychotria viridis) with a liana (Banisteriopsis caapi). P. Read more about this study

Who is it for?
Ages 18 to 60 yearsHealthy volunteers can take part
Conditions the study is for
Major Depression
What is being tested?
Ayahuasca
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
35 participants
Where
1 siteBrazil
Study dates
Feb 2014to Dec 2016
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 60 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • 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).

Who cannot join

  • 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.

Trial locations and contacts

1 site in 1 country.

Brazil1 site
  • Draulio B de Araujo

    Natal, Rio Grande do Norte, 59012-300

Other trials in Brazil

About this study

The purpose of the present trial is to test the efficacy of Ayahuasca in treatment-resistant depression. Ayahuasca is a decoction of two plants, long used by Amazonian Amerindians. Traditionally, it is prepared by decoction of a bush (Psychotria viridis) with a liana (Banisteriopsis caapi). P. viridis is a rich source of N,N-dimethyltryptamine (DMT), a serotonergic agonist, and B. caapi contains potent monoamine oxidase-A inhibitors (MAOi-A), such as harmine, harmaline. The study is designed as a randomized placebo controlled trial with two parallel arms, and it will also evaluate changes of different biomarkers of depression including anatomical and functional Magnetic Resonance Imaging (MRI), serum levels of BDNF, TNF-a, cortisol, IL-6, and IL-10, polysomnography, neuropsychological, psychiatric scales and questionnaires.

Read the detailed description
  1. Background

The therapeutic effectiveness of currently available antidepressant is low. Less than 50% of the patients achieve remission after single treatment, and about 30% after four different treatments. Besides low response rates, pharmacological treatment are associated with several side effects and response onset is usually long (~2-3 weeks). Thus, great effort has been made to the development of alternative antidepressants. For instance, ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, has rapid and potent antidepressant effects in treatment of major depressive and bipolar disorders.

This proposal aims at testing the antidepressant effects of Ayahuasca, traditionally prepared by decoction of two plants: Psychotria viridis and Banisteriopsis caapi, long used by Amazonian Amerindians. P. viridis is a rich source of the serotonergic agonist N,N-dimethyltryptamine (DMT), whereas B. caapi contains potent monoamine oxidase-A inhibitors (MAOi-A) such as harmine, harmaline, and tetrahydroharmine, a serotonin reuptake inhibitor.

Common effects of Ayahuasca include sedation, gastrointestinal distress, changes of spatiotemporal scaling, dissociation, sense of well-being, insights, feelings of apprehension, increased interoceptive attention and sensory pseudo-hallucinations. Effects begin at 30-40 min after oral intake, and last up to 4 hours. Previous studies suggest the absence of psychological, neuropsychological or psychiatric harm caused by prolonged Ayahuasca consumption, and it is not addictive, on the contrary, it also shows promise in treating addiction.

Recently, two preliminary open label studies have tested tolerability, safety and the antidepressant effect of Ayahuasca in treatment-resistant depression. In the first study, six patients were recruited, in the second, 17 patients. The results show significant decrease in depression severity (HAM-D \& MADRS scales) already at 2 hours after intake, which lasted for 21 days. Although the results are promising, they must be considered with caution, specially due to the lack of control of the placebo effect, which is generally high in clinical trials.

Thus, the present study is a randomized placebo-controlled trial in 50 patients with treatment resistant depression. Besides the Antidepressant effects of Ayahuasca, this study will also evaluate different biomarkers of depression, including anatomical and functional Magnetic Resonance Imaging (MRI), serum levels of BDNF, TNF-a, cortisol, IL-6, and IL-10, polysomnography, neuropsychological and psychiatric scales and questionnaires.

  1. Methods

All 50 patients will undergo routine evaluation, including complete blood testing for individual glycemic profile, serum cholesterol and triglyceride, plasma sodium and potassium, urea and creatinine.

Patients will undergo a wash-out period, between 7 and 14 days prior to the experimental session, depending on the lifetime of the antidepressant in use. Experiments will take place at the Hospital Universitário Onofre Lopes, a tertiary university hospital affiliated to the Universidade Federal do Rio Grande do Norte (UFRN), Brazil.

In the treatment session, 25 patients will drink Ayahuasca, 25 will drink an inert placebo. Psychiatric scales (HAM-D, MADRS, BPRS, CADSS and YMRS) will be completed during treatment session, day one before (-D1), one day after (+D1), two days (+D2), seven days (+D7), fourteen days (+D14), one month (+M1), and up to six months (+M6) following the treatment session. The following exams will also be conducted at D-1 and D+1: neuropsychological tests (watch test, trail test, and N-back), structural and functional MRI, polysomnography and blood testing (BDNF, TNF-a, cortisol, oxytocin, IL-6, and IL-10).

Being tested
Ayahuasca, placebo
Keywords
Depression, Ayahuasca, Psychedelics
Medical subject headings
Depressive Disorder, Major, Depression

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AyahuascaDrug

    Also called treatment

    patients will receive a single dose of ayahuasca.

  • placeboDrug

    patients will receive a single dose of a passive placebo.

Study groups in NCT02914769
Study groupRoleWhat they receive
placeboPlacebo comparatorpatients receiving a passive placebo
Receives: Drug: placebo
AyahuascaExperimentalpatients receiving Ayahuasca
Receives: Drug: Ayahuasca

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Hamilton Depression Rating Scale (HAM-D) Effect Seven Days After Dosing (D7)

    changes in depression severity, assessed by the Hamilton Depression Rating Scale (HAM-D) scale, from baseline to 7 days after dosing.

    Minimum and maximum scores are 0 and 50, respectively. Although the HAM-D form lists 21 items, the scoring is based on the first 17. Eight items are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine items are scored from 0-2.

    Lower HAM-D score indicates less severe depression (better outcome). Usual cutoff points are a total score ranging from: 0 to 7 indicates that the patient is in the normal range (no depression); 8 to 16 indicates "mild depression"; 17 to 23 indicates "moderate depression"; a score of 24 and greater indicates "severe depression".

    Measured: seven days after dosing

Secondary outcomes (5)
  1. Montgomery-Asberg Depression Rating Scale (MADRS) Effect at D1, D2 and D7

    changes in depression severity, assessed by Montgomery-Asberg Depression Rating Scale (MADRS scale), from baseline to 1 day, 2 days, and 7 days after dosing. Lower MADRS score indicates less severe depression (better outcome).

    Minimum and maximum scores are 0 and 60, respectively. Usual cutoff points are a total score ranging from: 0 to 6 indicates that the patient is in the normal range (no depression); 7 to 19 indicates "mild depression"; 20 to 34 indicates "moderate depression"; a score of 35 and greater indicates "severe depression".

    Measured: one, two and seven days after dosing

  2. Number of Participants With Reduction of 50% or More in Hamilton Depression Rating Scale(HAM-D) Scores at D7

    Response Rate:Number of Participants with reduction of 50% or more in Hamilton Depression Rating Scale (HAM-D) in baseline scores, assessed seven days after dosing.

    Measured: seven days after dosing

  3. Number of Participants With Reduction of 50% or More in Montgomery-Asberg Depression Rating Scale (MADRS) at D1, D2 and D7

    response rate: reduction of 50% or more in baseline scores, assessed at one day, two days and seven days after dosing by the MADRS scale.

    Measured: one, two, and seven days after dosing

  4. Number of Participants With a Score Lower Then or Equal to 7 in the Hamilton Depression Rating Scale (HAM-D) at D7

    Number of Participants With a score lower then or equal to 7 in the Hamilton Depression Rating Scale (HAM-D) at seven days after dosing.

    Measured: seven days after dosing

  5. Number of Participants With a Score Lower Then or Equal to 10 in the Montgomery-Asberg Depression Rating Scale (MADRS) at D1, D2 and D7

    Number of Participants With a Score Lower Then or Equal to 10 in the Montgomery-Asberg Depression Rating Scale (MADRS) at one, two and seven days after dosing.

    Measured: one, two and seven days after dosing

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Sep 2016 (estimated)
  2. Study startFeb 2014
  3. Primary completionDec 2016
  4. Study completionDec 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
35 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02914769
Sponsor's protocol ID
CNPq-466760/2014-0
Status last verified
Apr 2025
First submitted
21 Sep 2016
Last updated
6 Apr 2025
Data monitoring committee
Yes
Individual data sharing
No

Publications

  • Sanches RF, de Lima Osorio F, Dos Santos RG, Macedo LR, Maia-de-Oliveira JP, Wichert-Ana L, de Araujo DB, Riba J, Crippa JA, Hallak JE. Antidepressant Effects of a Single Dose of Ayahuasca in Patients With Recurrent Depression: A SPECT Study. J Clin Psychopharmacol. 2016 Feb;36(1):77-81. doi: 10.1097/JCP.0000000000000436.

    PubMed 26650973
  • Osorio Fde L, Sanches RF, Macedo LR, Santos RG, Maia-de-Oliveira JP, Wichert-Ana L, Araujo DB, Riba J, Crippa JA, Hallak JE. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Braz J Psychiatry. 2015 Jan-Mar;37(1):13-20. doi: 10.1590/1516-4446-2014-1496.

    PubMed 25806551
  • Zeifman RJ, Palhano-Fontes F, Hallak J, Arcoverde E, Maia-Oliveira JP, Araujo DB. The Impact of Ayahuasca on Suicidality: Results From a Randomized Controlled Trial. Front Pharmacol. 2019 Nov 19;10:1325. doi: 10.3389/fphar.2019.01325. eCollection 2019.

    PubMed 31798447
  • de Almeida RN, Galvao ACM, da Silva FS, Silva EADS, Palhano-Fontes F, Maia-de-Oliveira JP, de Araujo LB, Lobao-Soares B, Galvao-Coelho NL. Modulation of Serum Brain-Derived Neurotrophic Factor by a Single Dose of Ayahuasca: Observation From a Randomized Controlled Trial. Front Psychol. 2019 Jun 4;10:1234. doi: 10.3389/fpsyg.2019.01234. eCollection 2019.

    PubMed 31231276
  • Palhano-Fontes F, Barreto D, Onias H, Andrade KC, Novaes MM, Pessoa JA, Mota-Rolim SA, Osorio FL, Sanches R, Dos Santos RG, Tofoli LF, de Oliveira Silveira G, Yonamine M, Riba J, Santos FR, Silva-Junior AA, Alchieri JC, Galvao-Coelho NL, Lobao-Soares B, Hallak JEC, Arcoverde E, Maia-de-Oliveira JP, Araujo DB. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med. 2019 Mar;49(4):655-663. doi: 10.1017/S0033291718001356. Epub 2018 Jun 15.

    PubMed 29903051

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Ayahuasca in people with Major Depression, run by Universidade Federal do Rio Grande do Norte at 1 site in Brazil.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 6 Apr 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Hamilton Depression Rating Scale (HAM-D) Effect Seven Days After Dosing (D7) (time frame: seven days after dosing). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02914769, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Apr 2025.

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