Therapeutic effect of an ayahuasca analogue in clinically depressed patients: a longitudinal observational study

Ayahuasca is an Amazonian plant brew that combines N,N-dimethyltryptamine (DMT) with monoamine oxidase inhibitors (MAO-I) and has been associated in earlier research with rapid antidepressant, anxiolytic, and stress-reducing effects. In Western settings, non‑traditional mixtures that combine DMT‑containing plants with MAO‑I sources (commonly called ayahuasca analogues or anahuasca) are used because they are easier to obtain; these analogues may differ in alkaloid composition and experiential effects. Prior clinical and observational studies have reported short‑term reductions in depressive symptoms after ayahuasca administration and suggested that acute subjective phenomena such as ego dissolution and oceanic boundlessness, as well as increases in mindfulness and post‑ceremony integration practices, may mediate improvements. Van Oorsouw and colleagues set out to evaluate depressive symptom changes and broader mental health outcomes in a naturalistic sample of clinically depressed participants who attended a single ayahuasca analogue ceremony. The study assessed depression with a validated clinical instrument and examined outcomes at baseline, about 1 day, 1 month, and approximately 1 year after the ceremony. A secondary aim was to test whether intensity of altered states of consciousness—particularly ego dissolution and oceanic boundlessness—was associated with changes in depression and other mental health measures.

This was a longitudinal observational study of ceremony attendants in the Netherlands who reported depression as their primary reason for participation. Ceremony facilitators referred potential participants, who were then contacted by the principal investigator and enrolled before the ceremony. From 33 initial consenters, 20 adults (9 males; mean age 35.3, SD = 10.1) met the inclusion criterion of Beck Depression Inventory (BDI) score > 13 and comprised the analytic sample. All participants had chronic depression (> 2 years) and most had prior psychological therapy; 18/20 had previously used antidepressant medication but had stopped at least 6 weeks before the ceremony. Nineteen participants were naive to the ayahuasca analogue; one had prior experience. Ceremonies took place in non‑religious evening settings led by facilitators with backgrounds as ayahuasqueros, coaches, or therapists. Groups averaged about 10 participants, two drinking rounds were administered per night (separated by about 2.5 h), and supportive care (caretakers, group sharing, post‑ceremony follow‑up) was provided. Participating centres prepared their own ayahuasca analogue brews using Peganum harmala (MAO‑I) combined with Mimosa hostilis, Jurema, or Banisteriopsis caapi (DMT sources). Doses varied by centre; samples were analysed by LC‑MS to estimate alkaloid concentrations and total ingested amounts (detailed sample concentrations were reported in the paper’s table). Participants completed identical online surveys at baseline (in the week before the ceremony), at a 1‑day post‑ceremony assessment (completed within 1–13 days, mean 4.35 days), at 1 month (31–70 days, mean 39 days), and at approximately 1 year (12–16 months, mean 13.47 months). The primary outcome was BDI‑II score; secondary measures included DASS‑21, BSI‑18, Five Facet Mindfulness Questionnaire‑15 (FFMQ‑15), Satisfaction With Life Scale (SWLS), and, at the 1‑day assessment only, the Ego Dissolution Inventory (EDI) and the 5D‑Altered States of Consciousness (5D‑ASC) scale. After study completion, follow‑up interviews asked about additional psychedelic use, medication, life events, and other therapies. Statistical analysis used linear mixed models with session (baseline, immediate post, 1 month, 1 year) as a within‑subject factor; the covariance structure was chosen by best fit (examples included heterogeneous compound symmetry and AR(1)). Significant session effects were followed by Bonferroni‑adjusted pairwise comparisons versus baseline. Pearson correlations tested associations between EDI, oceanic boundlessness (OB), anxious ego dissolution (AED) and outcome measures at post‑sessions. The extracted text does not clearly report some specific LC‑MS concentration values in the prose; these were said to appear in a table.

Twenty participants completed baseline and the 1‑day survey; 19 completed the 1‑month survey and 17 completed the 1‑year survey. At baseline, all participants had previously received (psycho)therapy and 16/20 (80%) reported prior antidepressant use. Between the 1‑month and 1‑year assessments, 9 participants (53% of those remaining) reported additional psychedelic use (four ayahuasca, three psilocybin, two LSD; one reported PCP once), and three participants (17%) had resumed antidepressant medication. At the time of the 1‑year follow‑up, eight participants reported ongoing therapy. Primary outcome (BDI): BDI scores fell significantly across sessions (mixed model: F(3,19.21) = 11.88, p < 0.001). Mean BDI scores reported in the paper were M = 22.7 at baseline and M = 11.45, 12.89, and 8.88 at 1‑day, 1‑month, and 1‑year follow‑ups respectively (these means were reported in the abstract). Remission (BDI < 13) and response (> 50% reduction) rates were: 1‑day remission 12/20 (60%) and response 55%; 1‑month remission 13/19 (68%) and response 47%; 1‑year remission 12/17 (71%) and response 65%. A secondary analysis including centralised baseline BDI as a covariate showed a significant session × baseline interaction (F(2,36.45) = 5.47; p = 0.008), indicating reductions over time were more evident among participants with relatively high baseline BDI scores, although those with high baseline scores were less likely to achieve remission or the 50% response threshold in all cases. Other mental health measures: DASS‑21 depression and stress scores decreased significantly between baseline and all follow‑ups (DASS‑21 depression: F(3,19.05) = 8.94, p = 0.001; stress: F(3,39.87) = 6.03, p = 0.002). DASS‑21 anxiety showed a significant session effect (F(3,35.28) = 4.25, p = 0.012) with a significant decrease by 1 month. BSI‑18 depression scores declined across all follow‑ups (F(3,42.48) = 11.47, p < 0.001); BSI‑18 anxiety showed reductions at 1 day and 1 year (F(3,19.70) = 5.86, p = 0.005). No change was detected for BSI‑18 somatisation. Satisfaction with life (SWLS) increased from baseline to 1 month and 1 year (session effect p = 0.033). On the FFMQ‑15, facets of non‑judging and non‑reacting increased from baseline to all follow‑ups; observing increased at 1 day and 1 year, and describing increased at 1 year. Mindful awareness did not show a significant session effect. Subjective psychedelic experience and correlations with outcomes: Mean EDI (ego dissolution) was 44.09 (SD = 32.48). On 5D‑ASC subscales, oceanic boundlessness (OB) mean was 45.55 (SD = 30.80) and anxious ego dissolution (AED) mean was 25.30 (SD = 22.54); other subscales indicated moderate altered states. Higher levels of EDI correlated with lower BDI scores at 1 day (r = -0.545, p = 0.010) and at 1 month (r = -0.455, p = 0.050), but not at 1 year. OB correlated negatively with BDI at 1 day (r = -0.650, p = 0.002) and at 1 month (reported r = -0.521, p = 0.022); these correlations were not present at 1 year. No significant correlations were found between BDI and AED at any follow‑up. There was no significant correlation between BDI scores and the use of psychedelics or medication between 1 month and 1 year (r = 0.038, p = 0.879), and participants who used additional psychedelics did not show a statistically greater reduction in BDI between 1 month and 1 year than those who did not (88% vs 62% reduction proportion, Pearson χ2 = 1.64, p = 0.20). Follow‑up interviews (n = 16 reached): among participants contacted, five of seven who had additional psychedelic experiences judged those experiences beneficial; all three participants who resumed antidepressants reported benefit; seven of eight who received therapy reported beneficial effects. Most participants (88%) reported lifestyle changes by 1 year (e.g., meditation, breathwork, nature walks, reduced substance use, occupational or relationship changes) that they considered relevant to their mental state.

Van Oorsouw and colleagues interpret their findings as suggesting that a single ayahuasca analogue ceremony was associated with reductions in depressive symptoms and improvements in anxiety, stress, mindfulness facets, and life satisfaction that persisted up to 1 year in this naturalistic sample. Remission rates were 60% at 1 day, 68% at 1 month, and 71% at 1 year; 65% of participants met a 50% reduction threshold by 1 year. The investigators note that antidepressant effects appeared most pronounced in participants with mild to moderate baseline depression, although absolute symptom decrements were larger among those with higher baseline BDI scores even if they less often attained remission. The study team highlights that short‑term improvements correlated with the intensity of the acute psychedelic experience—higher ego dissolution and oceanic boundlessness related to lower depression up to 1 month—consistent with previous work linking mystical‑type experiences to clinical benefit. However, by 1 year those correlations were no longer present, and the authors attribute sustained improvements to a combination of factors beyond the acute pharmacological/experiential event. Follow‑up interviews indicated that many participants engaged in additional treatments, resumed or began antidepressant medication, undertook personal lifestyle changes, or used other psychedelics; the authors present these as plausible contributors to maintained benefit. The investigators acknowledge several important limitations. There was no control or comparison group, so expectancy, placebo, and setting effects cannot be disentangled from pharmacological action. The majority of participants had positive expectations and ceremonies occurred in supportive, supervised settings, both of which may have affected outcomes. The study used ayahuasca analogues prepared at different centres, and alkaloid composition varied; absence of a standardised recipe limits comparability. In addition, uncontrolled intervening factors between 1 month and 1 year—additional psychedelics, recommencement of antidepressants, psychotherapy, and lifestyle changes—mean that sustained improvements at 1 year cannot be attributed solely to the initial ceremony. Finally, the naturalistic and small sample limits generalisability. In conclusion, the authors present these observational data as adding to evidence that ayahuasca or its analogues have therapeutic potential for depression and recommend that more rigorously controlled clinical trials investigate long‑term antidepressant effects while accounting for expectancy, setting, and integration interventions.