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

Study Overview
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Brief Summary
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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
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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).

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

Conditions
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Major Depression

Intervention / Treatment
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* Drug: Ayahuasca
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo<br>patients receiving a passive placebo | Drug: placebo<br>* patients will receive a single dose of a passive placebo.<br>|
| Experimental: Ayahuasca<br>patients receiving Ayahuasca | Drug: Ayahuasca<br>* patients will receive a single dose of ayahuasca.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HAM-D effect at D7 | changes in depression severity, assessed by HAM-D scale, from baseline to 7 days after dosing | seven days after dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MADRS effect at D1, D2 and D7 | changes in depression severity, assessed by MADRS scale, from baseline to 1 day, 2 days, and 7 days after dosing | one, two and seven days after dosing | 
| Response rate at D7 (HAM-D) | response rate: reduction of 50% or more in baseline scores, assessed seven days after dosing by the HAM-D scale. | seven days after dosing | 
| Response rate at D1, D2 and D7 (MADRS) | 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. | one, two, and seven days after dosing | 
| Remission rate at D7 (HAM-D) | remission rate: HAM-D≤7 at D7. | seven days after dosing | 
| Remission rate at D1, D2 and D7 (MADRS) | remission rate: MADRS≤10 at D1, D2 and D7 | one, two and seven days after dosing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Depression, Ayahuasca, Psychedelics