Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression a SPECT study

Ayahuasca is an Amazonian botanical brew combining Banisteriopsis caapi, which provides reversible monoamine oxidase A (MAO-A) inhibitors (β-carbolines such as harmine), and Psychotria viridis, a source of N,N-dimethyltryptamine (DMT), a 5-HT1A/2A/2C receptor agonist. Because DMT is normally metabolised by MAO-A in the gut and liver, co‑administration with β-carbolines allows DMT to reach the systemic circulation and the brain. Earlier preclinical, observational and experimental studies in healthy volunteers suggested potential antidepressant effects of ayahuasca, and the authors previously reported rapid and lasting antidepressant effects in six patients with recurrent major depressive disorder (MDD).

This was an open‑label inpatient study of 17 patients with recurrent MDD (14 women; mean age 42.7 years, SD 12.11) who had an inadequate response to their current antidepressant and were undergoing a medication change. Three patients had a mild current episode, 13 had a moderate episode and one had a severe episode. After a 2‑week washout, volunteers underwent medical screening including clinical examination, laboratory tests, electrocardiogram and a diagnostic interview using the Structured Clinical Interview for DSM‑IV (SCID‑IV). Exclusion criteria included bipolar or psychotic disorder, active psychotic symptoms, pregnancy and a history of antidepressant- or substance‑induced mania/hypomania. All participants gave written informed consent and the protocol was approved by a local ethics committee.

Seventeen patients received a single oral dose of ayahuasca at 2.2 mL/kg (individual doses 120–200 mL), from a sample containing 0.8 mg/mL DMT and 0.21 mg/mL harmine; individual alkaloid doses therefore ranged approximately 96–160 mg DMT and 25–42 mg harmine. Psychiatric measures were taken at baseline (10 minutes before dosing), at 40, 80, 140 and 180 minutes after dosing, and at days 1, 7, 14 and 21 for the HAM‑D, MADRS and BPRS. Baseline mean HAM‑D was 19.24 (SD 5.52) and MADRS 25.6 (SD 7.6), consistent with moderate depression. After ayahuasca administration, significant reductions in HAM‑D and MADRS scores were observed from 80 to 180 minutes (P < 0.01) and sustained from day 1 through day 21 (P = 0.000). By day 21 mean HAM‑D had fallen to 7.56 (SD 4.7), a mild level of depression. Dissociative-type psychoactivity measured with the CADSS increased at 40–80 minutes (P < 0.01), consistent with the time of peak subjective effects; no significant changes were noted on the Young Mania Rating Scale (YMRS). On the BPRS, the Anxious‑Depression subscale decreased from 40 to 180 minutes (P < 0.01) and from day 1 to day 21 (P = 0.000). Improvements were also reported on Thinking Disorder and Withdrawal‑Retardation BPRS subscales (Thinking Disorder: 180 minutes, P < 0.05, and at day 1, day 14 and day 21; the extracted text is incomplete for the exact statistics of some later time points).

Sanches and colleagues interpret their findings as indicating rapid and sustained antidepressant effects after a single ayahuasca dose in patients with recurrent MDD, with similar patterns across patients regardless of baseline episode severity. The authors link clinical improvement to increased regional cerebral blood flow measured by SPECT eight hours after dosing: significant perfusion increases were observed in the left nucleus accumbens (peak intensity 7.179; voxels 45; MNI -8, 6, -10), right insula (peak 4.695; voxels 43; MNI 32, 24, -10) and left subgenual area (peak 4.523; voxels 30; MNI -10, 32, -8), regions implicated in mood and emotion regulation. Mechanistically, the investigators propose that DMT’s agonism at 5‑HT1A/2A/2C receptors may contribute to anxiolytic and antidepressant effects, and they note potential modulation of the default mode network and rumination as a complementary pathway. The discussion contrasts these SPECT/PET findings with some fMRI reports that show decreases in blood flow, suggesting that differences in timescale and tracer half‑life between modalities may explain discrepancies. In terms of safety, ayahuasca was generally well tolerated in this controlled setting: blood pressure and heart rate showed non‑significant increases and vomiting was the only recorded adverse effect (reported by 47%); no dysphoric or manic symptoms were observed. The authors acknowledge several important limitations: the study was open‑label, non‑randomised and lacked a placebo or active comparator, preventing causal attribution; the controlled inpatient environment differs from ritual contexts in which ayahuasca is typically consumed and this may limit generalisability; and patients with bipolar disorder were excluded, with the authors noting case reports of manic episodes after ayahuasca and advising caution in that population. They conclude that randomized, double‑blind, placebo‑controlled trials are necessary, and recommend investigating the role of ceremonial or ritual context in therapeutic outcomes.