Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report

Depression is highly prevalent, causes substantial suffering, and current antidepressant treatments have limitations including delayed onset, incomplete response, and adverse effects. The introduction frames interest in rapidly acting treatments, citing ketamine as an example of a novel rapid antidepressant, and positions ayahuasca (AYA) — a traditional Amazonian brew containing DMT and b-carboline MAO-A inhibitors (harmine, THH, harmaline) — as a candidate for investigation. The authors describe AYA’s pharmacology as a combination of peripheral MAO-A inhibition by b-carbolines and central serotonergic agonism by DMT, and they note animal and limited human data suggesting antidepressant potential for AYA or its alkaloids, while also acknowledging the paucity of controlled clinical data and limited evidence on long-term safety. This preliminary, open-label study set out to evaluate whether a single dose of AYA produces acute antidepressant effects in patients with recurrent major depressive disorder (MDD). The stated objective was to measure changes in clinician-rated depressive and related symptoms over hours to weeks after administration, testing the hypothesis that AYA could produce rapid reductions in depressive symptoms in a clinical population.

This was an open-label trial conducted on an inpatient psychiatric unit. Six volunteers (two men, four women; mean age 44.17 ± 13.55 years) with recurrent MDD and a current depressive episode (two mild, three moderate, one severe) participated. Participants were recruited by advertisement and clinical referral. At enrolment they were not taking psychotropic medications, were reported never to have used illicit drugs or ayahuasca, and were screened to exclude bipolar disorder, prior mania/hypomania, pregnancy, and significant medical conditions by interview, physical examination and laboratory tests. Written informed consent was obtained and the trial had local ethics committee approval. The intervention was a single oral dose of a standard ayahuasca batch prepared by members of the Santo Daime community. Each subject drank 120–200 mL (reported as 2.2 mL/kg). The extraction text reports alkaloid concentrations for the batch as 0.8 mg/mL DMT and 0.21 mg/mL harmine with harmaline below the 0.02 mg/mL detection threshold; however, the Discussion later refers to a DMT concentration of 0.08 mg/mL, a discrepancy in the extracted text that is not resolvable here. Quantification was performed by GC/MS as described in the methods text. Patients were admitted two weeks before dosing and remained medication-free during that period. The experimental session lasted on average about 4 hours; participants were seated in a quiet, dimly lit room and monitored, then observed for 24 hours post-session and discharged if no complications occurred. Clinical assessments included the SCID-IV at screening and clinician-administered scales at baseline (–10 min), at +40, +80, +140 and +180 minutes post-dose, and on days 1, 7, 14 and 21 after administration. Scales used were the Hamilton Rating Scale for Depression (HAM-D), Montgomery–Åsberg Depression Rating Scale (MADRS), Brief Psychiatric Rating Scale (BPRS) with subscales (Withdrawal–Retardation, Thinking Disorder, Anxious–Depression, Activation), and the Young Mania Rating Scale (YMRS). Vital signs (systolic and diastolic blood pressure) were recorded at the same short-term time points. Adverse effects were not systematically assessed; dysphoric effects were recorded via spontaneous reports. For analysis the investigators used descriptive statistics and repeated-measures analysis of variance (ANOVA) after verifying data distribution. Statistical significance was set at p < 0.05.

Baseline characteristics indicated moderate depression on average: mean HAM-D 17.56 ± 7.73 and mean MADRS 23.56 ± 11.14. On the HAM-D there was a 62% mean decrease at day 1 (D1) compared with baseline (p = 0.01) and a 72% decrease at day 7 (D7, p = 0.01). Scores increased by D14 but remained 45% below baseline (this D14 change did not reach statistical significance, p = 0.11), and a further significant decrease was reported at D21 (p = 0.01). The largest item-level reductions were in depressed mood, guilt, suicidal ideation, and work/activity difficulties. MADRS results paralleled HAM-D findings. A significant 38% decrease was observed at +180 minutes (p = 0.01). By D1 the reduction was more robust (p = 0.003) and by D7 mean MADRS scores were 82% below baseline (p = 0.009). A significant increase occurred at D14 (p = 0.001), followed by a significant decrease at D21 (p = 0.002). The most marked MADRS item changes concerned apparent sadness, pessimistic thinking, suicidal ideation, and concentration difficulties. On the BPRS, participants were generally asymptomatic at baseline on the Withdrawal–Retardation, Thinking Disorder and Activation subscales. Nonsignificant increases in these subscales were observed, peaking around +80 minutes then returning to baseline by +180 minutes; reported acute features included transient disorientation/confusion, conceptual disorganisation, psychomotor retardation and emotional withdrawal. The Anxious–Depression subscale, which was elevated at baseline, showed significant reductions at +140 minutes (p = 0.02) and remained approximately 72% below baseline until D7, when scores began to rise but stayed significantly lower than baseline. The YMRS showed no significant changes across the study, although transient irritability, reduced insight and sleep disturbance were more prevalent during the first 80 minutes. AYA was described as well tolerated. Vomiting occurred in 50% of participants; this was reported as expected and not regarded by participants as severe. Blood pressure rose moderately but nonsignificantly. The authors note that adverse effects were not systematically queried, so reporting of subtler or less spontaneously reported effects may be incomplete.

Crippa and colleagues interpret the findings as evidence that a single dose of ayahuasca produced rapid and clinically meaningful reductions in depressive and anxiety-related symptoms that persisted for days in this small, treatment-seeking sample. They highlight the similarity of effects across participants regardless of baseline severity and note that the time course — early improvement evident at hours and maintained at D1 and D7 — contrasts with the typical multi-week onset of conventional antidepressants, making AYA of interest as a putative fast-acting treatment. The authors discuss possible mechanisms linking AYA pharmacology to antidepressant action, including MAO-A inhibition by b-carbolines, THH-mediated serotonin reuptake inhibition, and animal evidence that harmine can increase brain-derived neurotrophic factor (BDNF) and exert antidepressant-like effects. They draw a parallel to ketamine in which synaptogenesis and BDNF have been implicated in sustained antidepressant effects, while acknowledging that intracellular cascades underlying AYA’s time course remain speculative. In terms of subjective and psychotomimetic effects, the study found only transient, mild increases in thinking-disorder and related BPRS subscales around the peak subjective effect window; these effects were not statistically significant and resolved by +180 minutes. The Discussion notes that the relatively low DMT concentration reported for the batch used in this study (the extracted text contains an inconsistent report of batch DMT levels, see Methods) may explain the limited psychotropic effects and suggests that marked changes in sensory perception or thought content may not be necessary for antidepressant benefit. Important limitations are acknowledged: a very small sample size, open-label uncontrolled design, lack of placebo or active comparator, and absence of systematic adverse-effect assessment. The investigators recommend larger, controlled trials, systematic side-effect monitoring, exploration of optimal dosing and formulations (for example freeze-dried AYA which may induce less vomiting), cautious consideration of antiemetic premedication given potential interactions, and incorporation of neuroimaging and other biological measures in future work. They position the present results as preliminary but supportive of further investigation into AYA and related alkaloids as sources of faster-acting antidepressant treatments.