Antidepressant Effects of Ayahuasca: a Randomized Placebo Controlled Trial in Treatment Resistant Depression
Condition: Major Depression
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant
Study type: Interventional
Phase: Phase 1/Phase 2

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).
    

Intervention name(s): Ayahuasca; placebo
Intervention type(s): Drug; Drug
Intervention description(s): patients will receive a single dose of ayahuasca.; patients will receive a single dose of a passive placebo.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Depression; Ayahuasca; Psychedelics