Fast antidepressant effects of the psychedelic ayahuasca in hard-to-treat depression: a controlled trial

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.

On average, patients met criteria for moderate-to-severe depression (mean ± s.d.): HAM-D = 21.83 ± 5.35; MADRS = 33.03 ± 6.49. They had been experiencing depressive symptoms for 11.03 ± 9.70 years and had tried 3.86 ± 1.66 different previous unsuccessful antidepressants. Two patients had a previous history of electroconvulsive therapy. Most patients (76%) had a comorbid personality disorder, and 31% had a comorbid anxiety disorder. All patients were under regular use of benzodiazepines during the trial (online Supplementary Table S2 for clinical and demographics).

Between-groups effect size was large at D1 (Cohen's d = 0.84; 95% CI 0.05–1.62) and D2 (Cohen's d = 0.84; 95% CI 0.05–1.63) and largest at D7 (Cohen's d = 1.49; 95% CI 0.67–2.32). Within-group effect sizes (online Supplementary Table S4) were large for the ayahuasca at all time points: Cohen's d = 2.78 at D1 (95% CI 1.74–3.82), d = 3.05 at D2 (95% CI 1.94–4.16), and d = 2.90 at D7 (95% CI 1.84–3.97).

HAM-D response rate was significantly different between-groups at D7, with 57% of responders in the ayahuasca group against 20% in the placebo group [OR 5.33 (95% CI 1.11–22.58); p = 0.04; NNT = 2.69]. HAM-D remission rate showed a trend toward significance at D7: 43% in ayahuasca v. 13% in placebo [OR 4.87 (95% CI 0.77–26.73); p = 0.07; NNT = 3.39].

Online Supplementary Figs. S1 and S2 show individual MADRS scores %-changes from baseline, at all time points. Although individual variance was high, we found improvement in depression severity for all patients in the ayahuasca group 7 days after dosing, while four patients in the placebo group have worsened their symptoms.

Patients exhibited transient acute changes in CADSS and BPRS+ scales, with slightly increased scores at +1:40 h after ayahuasca intake: 34.8% (BPRS+) and 21.6% (CADSS) (online Supplementary Table S5). There was a trend increased toward significance observed in CADSS scores at 1:40 h after ayahuasca intake (p = 0.052). There were no significant changes in BPRS+ scores at any time point (online Supplementary Table S5). Changes in BPRS+ and CADSS scores did not correlate with improvements in depression symptoms (online Supplementary Fig. S3). We did not observe significant increased manic symptoms as measured by the YMRS at 1:40 h after ayahuasca intake (p = 0.26). We also observed transient nausea (Aya = 71%, Pla = 26%; p = 0.027), vomiting (Aya = 57%, Pla = 0%; p = 0.0007), transient anxiety (Aya = 50%, Pla = 73%; p = 0.263), restlessness (Aya = 50%, Pla = 20%; p = 0.128), and transient headache (Aya = 42%, Pla = 53%; p = 0.715) (online Supplementary Table S6).

The average and standard error of mean (s.e.m.) for each factor of both scales (HRS and MEQ30) are presented in online Supplementary Table S7, and in online Supplementary Figs. S4 and S5. Two patients did not respond to the HRS, leaving 27 respondents: 13 in the ayahuasca group, 14 in the placebo. The MEQ30 was added to the study with the trial already ongoing, and only 15 patients responded to it: eight in the ayahuasca group, seven in the placebo.

Correlations between HRS and MADRS changes from baseline to D7 were not statistically significant when assessing each group separately, ayahuasca, or placebo (online Supplementary Fig. S6). However, we observed a positive significant correlation between MADRS changes at D7 with the HRS subscale ‘perception’ (r = 0.90, p = 0.002), when considering the subgroup of ayahuasca responders only (online Supplementary Fig. S7).

Despite the small number of patients, we found a negative correlation between changes in MADRS scores and the MEQ30 factor transcendence of time and space in patients in the ayahuasca group (r = −0.84, p = 0.009). The remaining three factors (ineffability, mystical, and positive mood) and MEQ30 total score were not significantly correlated with MADRS score changes (online Supplementary Fig. S8).

We found evidence of rapid antidepressant effect after a single dosing session with ayahuasca when compared with placebo. Depression severity changed significantly but differently for the ayahuasca and placebo groups. Improvements in the psychiatric scales in the ayahuasca group were significantly higher than those of the placebo group at all time points after dosing, with increasing between-group effect sizes from D1 to D7. Response rates were high for both groups at D1 and D2 and were significantly higher in the ayahuasca group at D7. Between-groups remission rate showed a trend toward significance at D7.

The within-group effect size found for ayahuasca at D7 (Cohen's d = 2.22) is compatible with our earlier open-label study (Cohen's d at D7 = 1.83) (Sanches et al., 2016), and compatible with the one found in a recent open-label trial with psilocybin for depression (Hedges’ g = 3.1) (Carhart-Harris et al., 2016). Our results are comparable with randomized controlled trials that used ketamine in treatment-resistant depression. Although both ketamine and ayahuasca are associated with rapid antidepressant effects, their response time-courses and mechanisms of action seem to differ. Previous studies with ketamine have found the largest between-group effect size at D1 (Cohen's d = 0.89), reducing toward D7 (Cohen's d = 0.41) (Berman et al., 2000; Zarate et al., 2006; Murrough et al., 2013; Lapidus et al., 2014). In contrast, the effect sizes observed herein were large, but smallest, at D1 (Cohen's d = 0.84), and largest at D7 (Cohen's d = 1.49). These differences are also reflected in the response rates. At D1, the response rate to ketamine lies between 37 and 70%, whereas in our study 50% of the patients responded to ayahuasca. At D7, the ketamine response rate ranges between 7 and 35% (Berman et al., 2000; Zarate et al., 2006; Murrough et al., 2013; Lapidus et al., 2014), while in our study 64% responded to ayahuasca.

The placebo effect was high in our study, and higher than most studies with. While we find a response rate to placebo of 46% at D1, and 26% at D7, ketamine trials have found a placebo effect of the order of 0–6% at D1, and 0–11% at D7 (Berman et al., 2000; Zarate et al., 2006; Murrough et al., 2013; Lapidus et al., 2014). Several factors may account for the high placebo effect observed herein. First, the higher placebo effect has been found in patients with low socioeconomic status (Sonawalla and Rosenbaum, 2002), which was the case of our study. Most patients were living under significant psychosocial stressors, and during our trial, they stayed at a ‘very comfortable and very supportive environment’, as reported by the patients themselves. Therefore, part of the increased placebo effects found in our study might be due to this ‘care effect’. Second, patients with comorbid personality disorders present higher placebo responses (Ripoll, 2013), and in our study, most patients (76%) also suffered from personality disorders, most of them in cluster B.

A growing body of evidence gives support to the observed rapid antidepressant effects of ayahuasca (Palhano-Fontes et al., 2014). For instance, sigma-1 receptors (σ1R) have been implicated in depression, and it was reported to be activated by N, N-DMT (Cai et al., 2015; Carbonaro and Gatch, 2016). Moreover, it has been shown that the administration of σ1R agonists results in antidepressant-like effects, which are blocked by σ1R antagonism (Cai et al., 2015). Furthermore, σ1R upregulates neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), proteins whose regulation and expression seem to be involved in the pathophysiology of depression (Cai et al., 2015). Nevertheless, it is worth mentioning that antidepressants with σ1R agonist profile do not present clinically significant antidepressant effect. For instance, the antidepressant fluvoxamine, which has a high affinity for σ1R do not present response rates compatible to that was found herein (Delgado et al., 1988; Hashimoto, 2009).

The effects observed might be in part due to the presence of MAOi in the brew. In fact, studies in animal models reported that chronic administration of harmine reduces immobility time, increases climbing and swimming time, reverses anhedonia, increases adrenal gland weight, and increases BDNF levels in the hippocampus (Fortunato et al., 2010a, 2010b). All of these are compatible with antidepressant effects. Likewise, harmine seems to stimulate neurogenesis of human neural progenitor cells, derived from pluripotent stem cells (Dakic et al., 2016), and progenitor cells from adult mice brains (Morales-García et al., 2017), a mechanism also observed in rodents following antidepressant treatment. In addition, a recent study in rodents found that a single ayahuasca dose increases swimming time in a forced-swim test (Pic-Taylor et al., 2015).

Brain circuits modulated by psychedelics show great overlap with those involved in mood disorders (Vollenweider and Kometer, 2010). We recently found that a single ayahuasca session in patients with depression increases blood flow in brain regions consistently implicated in the regulation of mood and emotions, such as the left nucleus accumbens, right insula and left subgenual area (Otte et al., 2016; Sanches et al., 2016). Moreover, we have shown that ayahuasca reduces the activity of the Default Mode Network (Palhano-Fontes et al., 2015), a brain network found to be hyperactive in depression (Sheline et al., 2009).

Over the last two decades, mental health evaluations of regular ayahuasca consumers have shown preserved cognitive function, increased well-being, reduction of anxiety, and depressive symptoms when compared to non-ayahuasca consumers (Grob et al., 1996; Bouso et al., 2012; Barbosa et al., 2016). Moreover, a recent study observed that a single dose of ayahuasca enhanced mindfulness-related capacities (Soler et al., 2016), and meditation practices have been associated with antidepressant effects (Segal et al., 2010).

Prior studies suggest that elements of the psychedelic experience, such as experiences of mystical-type, account for the therapeutic benefit (Bogenschutz et al., 2015; Garcia-Romeu et al., 2015; Majić et al., 2015; Griffiths et al., 2016; Ross et al., 2016). We found significant increased MEQ30 scores during the effects of ayahuasca. We also observed an inverse correlation between MADRS score changes at D7 with ‘transcendence of time and space’ MEQ30 factor.

Furthermore, HRS dimensions seem important to the clinical outcome, particularly ‘perception’, a subscale that comprehends changes in visual, auditory, and body sensations. Visions are common during the effects of ayahuasca, and are most frequent with the eyes closed (Shanon, 2002; De Araujo et al., 2012). It has been suggested that visions may play an important role in the therapeutic effect of ayahuasca, as they may help bringing clarity to introspective events (Frecska et al., 2016). It is interesting to observe that changes in perception taken alone are not sufficient to predict the positive clinical outcome, as for instance, we find that some patients presented increased scores in ‘perception’ without significant clinical response.

No serious adverse events were observed during or after dosing. Although 100% of the patients reported feeling safe, the ayahuasca session was not necessarily a pleasant experience. In fact, some patients reported the opposite, as the experience was accompanied by much psychological distress. Most patients reported nausea, and about 57% have vomited, although vomiting is traditionally not considered a side effect of ayahuasca, but rather part of a purging process (Tafur, 2017).

Although promising, this study has some caveats and limitations worth mentioning. The number of participants is modest, and therefore randomized trials in larger populations are necessary. The study was limited to patients with treatment-resistant depression, with a long course of illness, and high comorbid personality disorder, which altogether precludes a simple extension of these results to other classes of depression. Another challenge of the research with psychedelics is maintaining double blindness, as the effects of psychedelics are unique. We were particularly keen to ensure blindness throughout the entire experiment, and to that end, we adopted a series of additional measures to preserve blindness. All patients were naïve to ayahuasca, with no previous experience with any other psychedelic substance. Clinical evaluations involved a team of five psychiatrists. For every patient, one psychiatrist was responsible for clinical evaluation during the dosing session and a different one for the follow-up assessments. The substance used as placebo increased anxiety and induced nausea. In fact, five patients misclassified placebo as ayahuasca, and two of them showed a response at D7 (online Supplementary Table S2). Therefore, we believe blindness was adequately preserved in our study.

Since the prohibition of psychedelics in the late 1960s, research with these substances has almost come to a halt. Before research restrictions, psychedelics were at early stage testing for many psychiatric conditions, including obsessive-compulsive disorder and alcohol dependence. By mid-1960s, over 40.000 subjects had participated in clinical research with psychedelics, most of them in uncontrolled settings (Vollenweider and Kometer, 2010). To our knowledge, this is the first randomized placebo-controlled trial to investigate the antidepressant potential of a psychedelic in a population of patients with treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of psychedelics, dosed within an appropriate setting, to help treat depression.