Longterm effects of ayahuasca in patients with recurrent depression: a 5-year qualitative follow-up

Ayahuasca is a traditional Amazonian botanical preparation that combines a Banisteriopsis caapi vine rich in β-carboline alkaloids (harmine, harmaline, tetrahydroharmine) with Psychotria viridis leaves that contain N,N-dimethyltryptamine (DMT). The β-carbolines act as reversible monoamine oxidase A (MAO-A) inhibitors and thereby render orally administered DMT centrally active; DMT itself acts primarily at serotonin receptors (including 5-HT1A/2A/2C). Earlier preclinical, observational and experimental work has implicated ayahuasca and its constituents in anxiolytic, antidepressant and antiaddictive effects, and studies in members of Brazilian ayahuasca churches and in controlled settings have reported tolerability and short-term reductions in anxiety and depressive symptoms. Dos and colleagues previously ran an open-label trial in 17 patients with treatment-resistant major depressive disorder that found statistically and clinically meaningful reductions on clinician-rated depression scales (HAM-D and MADRS) from about 80 minutes after dosing through day 21; a subsequent randomised, placebo-controlled trial with 35 patients produced similar short-term antidepressant signals. Despite these short-term findings, the long-term consequences of a single ayahuasca session in a clinical sample remained uncertain. This study therefore set out to explore possible long-lasting effects by conducting qualitative telephone interviews with volunteers 4–7 years after their single ayahuasca administration.

An experienced psychiatrist who had been closely involved with the original trial (identified in the extraction as RFS) attempted to contact all 17 original trial participants by telephone. At least three call attempts were made at different times of the day for each volunteer. Those who were reached underwent a structured telephone interview consisting of 14 questions. Questions 1–13 were scored categorically as positive (+), negative (–), or neutral/stable (=), while question 14 was answered in a free-text format. The follow-up therefore took the form of a brief qualitative telephone survey of reachable former participants. The extracted text does not report additional procedures such as written consent for the follow-up, ethics approvals specific to this contact, nor an analytic protocol for the qualitative responses beyond the +/–/= coding and the open-ended final question. The interview items themselves and the full table of responses are referenced but not reproduced in the extracted text.

Of the 17 patients who had taken part in the original open-label trial, eight were contacted and interviewed (seven women; mean age 39.87 years, range 28–54). The remaining nine subjects could not be located after multiple attempts; the extracted text specifies that no contacted individual refused participation, but does not clarify reasons for inability to locate the others. The follow-up interviews were carried out from January to May 2017, yielding a mean interval of 56.37 months (range 49–76) between the experimental session and the telephone contact. For the eight contacted patients the extracted text reports mean baseline depression scores of HAM-D 20.37 (range 17–24) and MADRS 27.12 (range 21–32). Reported means at day 21 after the original session were HAM-D 6.75 (range 2–15) and MADRS 8.75 (range 1–19). None of the eight reported having taken ayahuasca again after the trial. Qualitatively, most interviewed participants described the study experience as positive and said it had a favourable impact on their general and daily lives, although many of those positive effects were characterised as short-lived. Six of the eight stated the experience ranked among the 10 most important events of their lives, and four placed it among the five most important; four participants reported neutral effects or that their symptoms had remained stable. Only three participants reported improvements in relationships with friends, family or at work, and a single participant described positive effects on music and art perception, spirituality/religiosity or worldview. Adverse physical effects reported were mainly nausea and vomiting. The extracted text also contains a numerical statement that "nine reported that their medications were unchanged (one reported that the medication was changed, and none have stopped the medication)," but this count exceeds the eight contacted participants and the extraction does not make it clear whether that item refers to the contacted subset or to the full original cohort; this inconsistency is not resolved in the available text.

Dos and colleagues place these findings in the context of prior observational and controlled work that has reported anxiolytic and antidepressant effects of ayahuasca. From this long-term follow-up of former trial participants they report that ayahuasca was generally well tolerated and that reductions in depressive symptoms observed in the original trial appear to have been limited to a period of weeks rather than years. The investigators highlight that most of the interviewed participants nonetheless rated the ayahuasca session as one of the most important experiences of their lives even after 4–7 years, a perception the authors suggest may reflect the personal significance of an episode of symptomatic relief for people with long-standing depression. Key limitations acknowledged by the authors include the long interval between the experimental session and the follow-up, which could introduce recall bias, and the fact that nine of the original 17 participants could not be contacted, limiting the representativeness of the follow-up sample and the ability to generalise results to the full trial cohort. The authors therefore recommend that future research include larger samples, shorter-interval follow-ups to capture effects occurring in the months after dosing, exploration of different doses and repeated-dosing regimens, and strategies to reduce loss to follow-up. They conclude that, while the present qualitative follow-up is preliminary and constrained by its limitations, the combined data from their open-label and controlled studies indicate that ayahuasca warrants further investigation as a potential treatment for refractory depression.