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

Depression affects over 300 million people worldwide, and about one-third fail to respond to at least three adequate antidepressant trials. Most licensed antidepressants act on monoamine systems and require weeks to show benefit. By contrast, ketamine, an NMDA antagonist, produces rapid antidepressant effects that peak within a day and can last about a week. Interest has grown in serotonergic psychedelics as potential fast-acting treatments: open-label trials of ayahuasca and psilocybin have reported rapid reductions in depressive symptoms, but these studies lacked placebo controls and are vulnerable to large placebo responses. Palhano-Fontes and colleagues report a parallel-arm, double-blind, randomised placebo-controlled trial designed to test whether a single dose of ayahuasca produces rapid antidepressant effects in patients with treatment-resistant major depressive disorder. The investigators also explored correlations between antidepressant outcomes and acute psychedelic effects measured during the dosing session.

This was a double-blind, parallel-arm randomised placebo-controlled trial conducted at a Brazilian university hospital. Adults aged 18–60 with unipolar major depressive disorder and treatment resistance (inadequate response to at least two antidepressants from different classes) were recruited; eligible patients had moderate-to-severe depression at screening (HAM-D ⩾ 17). Key exclusions included prior ayahuasca experience, current medical disease, pregnancy, neurological disorders, personal or family history of schizophrenia or bipolar disorder, substance abuse, and suicidal risk. The research ethics committee approved the trial and participants provided written informed consent. Randomisation used permuted blocks of size 10 to allocate patients 1:1 to ayahuasca or placebo. Blinding was supported by enrolling only ayahuasca-naïve patients and by assigning different psychiatrists for dosing-session and follow-up assessments; assignment codes were held only in the database and pharmacy. The investigators note psychiatrist blindness was not formally assessed. Participants underwent a washout of prior antidepressants (about 2 weeks on average) and were off antidepressant medication during the dosing session; benzodiazepines were permitted as needed. A single batch of ayahuasca was used and its alkaloid content was quantified by mass spectrometry (mean ± SD per ml: N,N-DMT 0.36 ± 0.01 mg; harmine 1.86 ± 0.11 mg; harmaline 0.24 ± 0.03 mg; tetrahydroharmine 1.20 ± 0.05 mg). Dosing involved a single oral administration of 1 ml/kg of the brew or placebo adjusted to contain 0.36 mg/kg of N,N-DMT; placebo was a bitter brown liquid (water, yeast, citric acid, zinc sulfate, caramel) designed to mimic taste and produce modest gastrointestinal distress. Primary and secondary outcomes were prespecified. The primary outcome was change in HAM-D from baseline to day 7 (D7). Secondary outcomes included change in MADRS from baseline to day 1 (D1), day 2 (D2), and D7, plus response (⩾50% reduction) and remission (HAM-D ⩽ 7 or MADRS ⩽ 10) rates at those time points. Acute effects and safety during the session were assessed with CADSS (dissociation), BPRS (psychopathology), YMRS (mania), and later HRS and MEQ30 for phenomenology. Assessments occurred at baseline, during the session (-10 min, +1:40 h, +2:40 h, +4:00 h), and at D1, D2, and D7. Analyses followed a modified intent-to-treat principle, including patients with baseline, dosing and D7 assessments. An initial sample size calculation had estimated 42 participants to detect a five-point HAM-D difference with 80% power. Primary statistical tests used fixed-effects linear mixed models with baseline scores as covariates and a Toeplitz covariance structure; missing data were handled by restricted maximum-likelihood estimation. Post-hoc between-group comparisons used t tests with Sidak correction. Effect sizes (Cohen's d) were reported for between- and within-group comparisons. Fisher's exact tests assessed categorical differences (responders, remitters, adverse events); odds ratios and number needed to treat (NNT) were calculated. Correlations between acute effects and MADRS change used Pearson correlations with multiple-comparisons correction by number of factors per scale. Significance was set at p < 0.05, two-tailed.

Between January 2014 and June 2016, 218 patients were screened, 35 met inclusion criteria, and six were excluded before dosing (five no longer met depression criteria on dosing day; one withdrew). Data from 29 patients were analysed: 14 received ayahuasca and 15 received placebo. The sample was predominantly female (72%), mean age 42.0 ± 11.7 years, and of low socioeconomic status (41% with <8 years education; 41% earning <2 minimum wages). The extracted text reports mean baseline HAM-D = 21.83 ± 5.35; the baseline MADRS mean is not clearly reported in the extracted text. Primary outcome (HAM-D change to D7): a significant between-group difference was reported at D7 (F1 = 6.31; p = 0.019), with the ayahuasca group showing greater reduction than placebo. Between-group effect size at D7 was large (Cohen's d = 0.98; 95% CI 0.21–1.75). Within-group effect sizes were large for ayahuasca (Cohen's d = 2.22; 95% CI 1.28–3.17) and medium for placebo (Cohen's d = 0.46; 95% CI −0.27–1.18). HAM-D response rate at D7 was 57% for ayahuasca versus 20% for placebo (p = 0.04; NNT = 2.69). HAM-D remission showed a trend favouring ayahuasca at D7 (43% v. 13%; OR 4.87; 95% CI 0.77–26.73; p = 0.07; NNT = 3.39). MADRS outcomes (D1, D2, D7): the linear mixed model showed significant main effects of time (F2,34.4 = 3.96; p = 0.028) and treatment (F1,27.7 = 10.52; p = 0.003), with no treatment-by-time interaction. MADRS scores were significantly lower in the ayahuasca group at D1 (F1,49.7 = 4.58; p = 0.04), D2 (F1,50.3 = 4.67; p = 0.04), and D7 (F1,47 = 14.81; p < 0.0001). Between-group Cohen's d values were 0.84 (D1; 95% CI 0.05–1.62), 0.84 (D2; 95% CI 0.05–1.63), and 1.49 (D7; 95% CI 0.67–2.32). Within-group effect sizes for ayahuasca were large at all time points (D1 d = 2.78; D2 d = 3.05; D7 d = 2.90). MADRS response rates: at D1 response was 50% (ayahuasca) v. 46% (placebo) (p = 0.87); at D2 77% v. 64% (p = 0.43); at D7 64% v. 27% (p = 0.04; NNT = 2.66). MADRS remission rates did not differ at D1 or D2; at D7 remission trended higher in the ayahuasca group (36% v. 7%; OR 7.78; 95% CI 0.81–77.48; p = 0.054; NNT = 3.44). The authors report that all patients in the ayahuasca group improved by D7, while four placebo patients worsened. Acute session effects and safety: transient increases on CADSS and BPRS+ occurred at +1:40 h after ayahuasca (34.8% BPRS+; 21.6% CADSS), with CADSS showing a trend (p = 0.052); BPRS+ changes did not reach significance and neither CADSS nor BPRS+ correlated with antidepressant improvement. YMRS scores did not increase significantly (p = 0.26). Adverse events more frequent with ayahuasca included nausea (71% v. 26%; p = 0.027) and vomiting (57% v. 0%; p = 0.0007); transient anxiety, restlessness and headache were reported but differences were not statistically significant. No serious adverse events were reported. Phenomenology scales: HRS scores were higher with ayahuasca than placebo on five subscales (perception, somaesthesia, cognition, intensity, volition; all p < 0.001 to p = 0.0003); affect did not differ. MEQ30 scores were higher in the ayahuasca group for mystical experience, transcendence of time and space, ineffability, and total score; positive mood did not differ. The MEQ30 was added mid-trial and only 15 patients completed it (8 ayahuasca, 7 placebo). Correlations between acute phenomenology and antidepressant outcome were selective: among ayahuasca responders, the HRS perception subscale correlated positively with MADRS change at D7 (r = 0.90; p = 0.002), and in the ayahuasca group the MEQ30 transcendence factor correlated negatively with MADRS change (r = −0.84; p = 0.009). The extracted text notes small subgroup sizes for these correlations.

Palhano-Fontes and colleagues interpret their findings as evidence that a single dosing session with ayahuasca produces a rapid antidepressant effect in treatment-resistant depression, with improvements greater than placebo at D1, D2 and D7 and increasing between-group effect sizes through day 7. They compare the time-course with ketamine trials, noting that ketamine tends to show the largest between-group effect at D1 that attenuates by D7, whereas in this study the ayahuasca effect was largest at D7. Response rates were high early in both groups but diverged by D7 with significantly more responders in the ayahuasca arm. The authors acknowledge a notably high placebo response in their sample and propose several contributing factors: participants' low socioeconomic status and the provision of a comfortable, supportive study environment may have produced a strong 'care effect'; high rates of comorbid personality disorder (76%, mainly cluster B) could also elevate placebo responsiveness. Mechanistic hypotheses discussed include N,N-DMT activation of sigma-1 receptors (σ1R) and the presence of monoamine oxidase inhibitors (harmine and related alkaloids) in the brew; preclinical evidence cited links harmine and σ1R agonists to antidepressant-like effects, BDNF modulation and neurogenesis. The investigators also point to prior imaging work showing ayahuasca-related increases in blood flow to mood-related brain regions and reductions in Default Mode Network activity, and to observational studies associating regular ayahuasca use with preserved cognition and reduced anxiety and depressive symptoms. The authors note relationships between aspects of the subjective psychedelic experience and clinical outcome: higher MEQ30 subscales and HRS dimensions were observed with ayahuasca, and selected subscales (perception; transcendence of time and space) correlated with symptom change in small subsamples. Safety considerations are summarised: no serious adverse events occurred, though many patients experienced psychological distress, nausea and vomiting during the session. Key limitations acknowledged include the modest sample size, the restriction to treatment-resistant patients with long illness duration and high comorbidity (limiting generalisability), and the intrinsic difficulty of maintaining double blind in psychedelic research despite measures taken (naïve patients, separated raters, an active-tasting placebo). The authors report that some patients misclassified placebo as ayahuasca, which they argue supports preserved blinding. They conclude that, while larger trials are needed, this study is the first randomised placebo-controlled trial to test a psychedelic in treatment-resistant depression and provides preliminary evidence for the safety and therapeutic potential of ayahuasca when administered in an appropriate setting.