Clinical trial NCT02914769: Antidepressant Effects of Ayahuasca: a Randomized Placebo Controlled Trial in Treatment Resistant Depression
Official title: Antidepressant Effects of Ayahuasca: a Randomized Placebo Controlled Trial in Treatment Resistant Depression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Major Depression
Keywords: Depression
Ayahuasca
Psychedelics
Lead sponsor: Universidade Federal do Rio Grande do Norte
Sponsor class: OTHER
Collaborators: name: University of Sao Paulo
First posted: 2016-09-26
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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. 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.

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.

2. 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).

Eligibility 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:

* 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 outcomes:
measure: Hamilton Depression Rating Scale (HAM-D) Effect Seven Days After Dosing (D7)
timeFrame: seven days after dosing
Secondary outcomes:
measure: Montgomery-Asberg Depression Rating Scale (MADRS) Effect at D1, D2 and D7
timeFrame: one, two and seven days after dosing
measure: Number of Participants With Reduction of 50% or More in Hamilton Depression Rating Scale(HAM-D) Scores at D7
timeFrame: seven days after dosing
measure: Number of Participants With Reduction of 50% or More in Montgomery-Asberg Depression Rating Scale (MADRS) at D1, D2 and D7
timeFrame: one, two, and seven days after dosing
measure: Number of Participants With a Score Lower Then or Equal to 7 in the Hamilton Depression Rating Scale (HAM-D) at D7
timeFrame: seven days after dosing
measure: 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
timeFrame: one, two and seven days after dosing
Other outcomes:
Locations:
city: Natal
country: Brazil
facility: Draulio B de Araujo
state: Rio Grande Do Norte
Study officials:
affiliation: Brain Institute - UFRN
name: Draulio B de Araujo, Ph.D
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.