Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression : a randomized placebo-controlled trial

Fernanda Palhano-Fontes, Dayanna Barreto, Heloisa Onias, Katia C. Andrade, Morgana M. Novaes, Jessica A. Pessoa, Sergio A. Mota-Rolim, Flávia L. Osório, Rafael Sanches, Rafael G. dos Santos, Luís Fernando Tófoli, Gabriela de Oliveira Silveira, Mauricio Yonamine7, Jordi Riba, Francisco R. Santos, Antonio A. Silva-Junior, João C. Alchieri10, Nicole L. Galvão-Coelho5,11, Bruno Lobão-Soares5,12,
Jaime E. C. Hallak, Emerson Arcoverde, João P. Maia-de-Oliveira and Dráulio B. Araújo

Psychological Medicine, June 2018, 1-9

https://www.cambridge.org/core        doi.org/10.1017/S0033291718001356

Abstract

Background. Recent open-label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression.

Methods. To test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double- blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. We assessed changes in depression severity with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale at baseline, and at 1 (D1), 2 (D2), and 7 (D7) days after dosing.

Results.We observed significant antidepressant effects of ayahuasca when compared with placebo at all-time points. MADRS scores were significantly lower in the ayahuasca group compared with placebo at D1 and D2 ( p = 0.04), and at D7 ( p < 0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen’s d = 0.84; D2: Cohen’s d = 0.84; D7: Cohen’s d = 1.49). Response rates were high for both groups at D1 and D2, and significantly higher in the ayahuasca group at D7 (64% v. 27%; p = 0.04). Remission rate showed a trend toward significance at D7 (36% v. 7%, p = 0.054).

Conclusions. To our knowledge, this is the first controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression. This study is registered at http://clinicaltrials.gov (NCT02914769).

Introduction

The World Health Organization estimates that more than 300 million people suffer from depression (World Health Organization, 2017), and about one-third do not respond to appropriate courses of at least three different antidepressants (Conway et al., 2017). Most currently available antidepressants have a similar efficacy profile and mechanisms of action, based on the modulation of brain monoamines, and usually, take about 2 weeks to start being effective (Cai et al., 2015; Conway et al., 2017; Otte et al., 2016).

Recent evidence, however, shows a rapid and significant antidepressant effect of ketamine, an N-methyl-D-aspartate (NMDA) antagonist frequently used in anesthesia. In recent randomized placebo-controlled trials with ketamine in treatment-resistant depression, the antidepressant effects peaked 1 day after dosing and remained significant for about 7 days (Berman et al., 2000; Zarate et al., 2006; Murrough et al., 2013; Lapidus et al., 2014).

Additionally, research with serotonergic psychedelics has gained momentum (Vollenweider and Kometer, 2010). A few centers around the world are currently exploring how these substances affect the brain, and also probing their potential in treating different psychiatric conditions, including mood disorders (Grob et al., 2011; Osório et al., 2015; Carhart-Harris et al., 2016; Griffiths et al., 2016; Ross et al., 2016; Sanches et al., 2016). For instance, recent open-label trials show that psychedelics, such as ayahuasca and psilocybin, hold promise as fast-onset antidepressants in treatment-resistant patients (Osório et al., 2015; Carhart-Harris et al., 2016; Sanches et al., 2016).

Ayahuasca is a brew traditionally used for healing and spiritual purposes by indigenous populations of the Amazon Basin (Luna, 2011; Spruce and Wallace, 1908). In the 1930s, it began to be used in religious settings of Brazilian small urban centers, reaching large cities in the 1980s and expanding since then to several other parts of the world (Labate and Jungaberle, 2011). In Brazil, ayahuasca has a legal status for ritual use since 1987. Ayahuasca is most often prepared by decoction of two plants (McKenna et al., 1984): Psychotria viridis that contains the psychedelic N, N-dimethyltryptamine (N,N-DMT), a serotonin and sigma-1 receptors agonist (Carbonaro and Gatch, 2016), and Banisteriopsis caapi, rich in reversible monoamine oxidase inhibitors (MAOi) such as harmine, harmaline, and tetrahydroharmine (Riba et al., 2003).

The acute psychological effects of ayahuasca last around 4 h and include intense perceptual, cognitive, emotional, and affective changes (Shanon, 2002; Riba et al., 2003; Frecska et al., 2016). Although nausea, vomiting, and diarrhea are often reported, mounting evidence points to a positive safety profile of ayahuasca. For instance, ayahuasca is not addictive and has not been associated with psychopathological, personality, or cognitive deterioration, and it promotes only moderate sympathomimetic effects (Grob et al., 1996; Callaway et al., 1999; Dos Santos et al., 2011; Bouso et al., 2012; Barbosa et al., 2016).

In a recent open-label trial, 17 patients with major depressive disorder attended a single dosing session with ayahuasca. Depression severity was assessed before, during and after dosing, using the Hamilton Depression Rating scale (HAM-D) and the Montgomery–Åsberg Depression Rating Scale (MADRS) (Sanches et al., 2016). Significant reduction in depression severity was found already in the first hours after dosing, an effect that remained significant for 21 days (Osório et al., 2015; Sanches et al., 2016).

Although promising, these studies have not controlled for the placebo effect, which can be remarkably high in clinical trials for depression, reaching 30–40% of the patients (Sonawalla and Rosenbaum, 2002). To address this issue, and to further test the antidepressant effects of ayahuasca, we conducted a randomized placebo-controlled trial in patients with treatment-resistant depression. Additionally, we explored for correlations between the antidepressant and the acute effects of ayahuasca.

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