This qualitative follow-up study (n=8) interviewed patients 4-7 years after the intake of ayahuasca (123.2 mg DMT, 32.34mg Harmine) within the context of a previous open-label study; most patients reported that the experience was among the most important of their lives, but no long-term improvements in depression scores (MADRS) were found.
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Introduction
Ayahuasca is a botanical hallucinogenic preparation traditionally used by indigenous populations of Northwestern Amazonian countries for ritual and therapeutic purposes. It is rich in β-carboline alkaloids and N,N-dimethyltryptamine (DMT). Preclinical, observational, and experimental studies suggest that ayahuasca and its alkaloids have anxiolytic and antidepressive effects. We recently reported in an open-label trial that ayahuasca administration was associated with significant decreases in depression symptoms for 2-3 weeks after the experimental session in 17 patients with treatment-resistant major depressive disorder.
Objectives
To investigate if the experiment had any long-lasting effects on patients.
Methods
Eight patients were interviewed 4 to 7 years after ayahuasca intake.
Results
Our results suggest that ayahuasca was well tolerated and that symptom reductions were limited to a few weeks. Importantly, most patients believed that the experience was among the most important of their lives, even 4-7 years later.
Discussion
To the best of our knowledge, this is the first long-term follow-up of a clinical sample that participated in an ayahuasca trial. Further studies with different and repeated dosing should be designed to further explore the antidepressive and anxiolytic effects of ayahuasca.
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 that was closely involved with the volunteers during the study (RFS) tried to contact the volunteers by telephone. At least three attempts, in three different times of the day, were made to try to contact the volunteers. The contacted volunteers were then asked the following questions by a telephone interview: #1. experience that you think is important to mention? Questions #1 to #13 could be answered as positive (+), negative (-), or neutral/stable (=). Question #14 could be answered more freely.
The results of the interview are described in Table. Of the 17 patients that participated in the study, we could contact only eight (seven women; mean age 39.87 years; range 28-54). The other nine patients could not be contacted after several attempts. All the non-participant subjects were not able to be located, thus, there were no subjects that refused to participate in the study. The contacted patients had a mean baseline HAM-D score of 20.37 (range 17-24) and a mean baseline MADRS score of 27.12 (range 21-32). Means HAM-D and MADRS scores on D21 were 6.75 (range 2-15) and 8.75 (range 1-19), respectively. Patients have participated in the experiment from October 2010 (patient #1) to January 2013 (patient #8), and the follow-up interviews were conducted from January to May 2017. Therefore, patients were interviewed after a mean of 56.37 months (range 49-76), or 4.7 years. As can be observed in Table, although volunteers had difficult experiences, most of them reported that participation on the study was positive and had a positive impact on their general and daily lives, and that they would like to experiment ayahuasca again (although none did). Furthermore, six patients reported that the experience was among the 10 most important experiences of their lives, with four patients reporting that the experience was among the five most important experiences of their lives. However, four patients reported neutral effects or that their symptoms remained stable, nine reported that their medications were unchanged (one reported that the medication was changed, and none have stopped the medication), and almost all patients that reported positive effects also noted that they were short-lived. Furthermore, only three patients reported improvements in their relationships with friends, family, or at work, and only one described a positive effect of the experiment on music and art perception and on spirituality/ religiosity or in the way one sees the world and nature. Negative effects included mostly nausea and vomiting.
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De Araujo, D. B., Ribeiro, S., Cecchi, G. A. et al. · Human Brain Mapping (2011)
Palhano-Fontes, F., Andrade, K. C., Tófoli, L.F. et al. · PLOS ONE (2015)
Dos Santos, R. G., Osório, F. L., Crippa, J. A. et al. · Neuroscience and Biobehavioral Reviews (2016)
Osório, F. L., Sanches, R. F., Macedo, L. et al. · brazilian Journal of Psychiatry (2015)
Sanches, R. F., Osório, F. L., Dos Santos, R. G. et al. · Journal of Clinical Psychopharmacology (2016)
Dos Santos, R. G., Osório, F. L., Crippa, J. A. et al. · brazilian Journal of Psychiatry (2016)
Nunes, A. A., Dos Santos, R. G., Osório, F. L. et al. · Journal of Psychoactive Drugs (2016)
Dos Santos, R. G., Balthazar, F. M., Bouso, J. C. et al. · Journal of Psychopharmacology (2016)
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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.
Previous observational studies in members of the Brazilian ayahuasca churches reported the potential effects of ayahuasca on anxiety and mood regulation. Moreover, a controlled study in members of these groups also reported anxiolytic and antidepressive effects, which were corroborated in recent open-label and controlled studies with depressed patients. In the present work, the first long-term follow-up of those depressed volunteers, we found that ayahuasca was well tolerated and associated with antidepressive effects. The main limitations of this follow-up are the long time that passed since the experimental session was conducted and that not all volunteers were contacted. The first limitation could have increased the chances of recollection bias in the sample, and the second makes it impossible to know if the other volunteers had the same kind of responses, thus limiting the extrapolation of the results for the whole sample. Nevertheless, to the best of our knowledge, this is the first study long-term follow-up of depressed patients that have ingested ayahuasca. Even considering the above-cited limitations, our results suggest that ayahuasca was well tolerated by these patients and that the reductions in depressive symptoms attributed to ayahuasca intake were limited to a few weeks. Moreover, most patients that participated in the interview believed that the experience was among the most important of their lives, even 4-7 years later. This last observation could be related to the fact the patients had been suffering with their depressive symptoms for a long time, and a significant (although limited in time) improvement in their symptoms could have a great significance for them. The results and limitations of this qualitative study suggest that future studies involving administration of ayahuasca should try to perform follow-ups after shorter periods of time to try to observe any effects that could appear a few months of the experiments and to try to avoid losing contact with the volunteers, so that a clearer image of the results can be achieved. Furthermore, the present results and the data from our open-label and controlled studies suggest that Table. Depressive symptoms assessed with the Hamilton Depression Rating Scale (HAM-D) and the Montgomery-Åsberg Depression Rating Scale (MADRS) and results from the follow-up questions ayahuasca holds some promise as a viable treatment for refractory depression. Nevertheless, future studies designed to further explore the antidepressive and anxiolytic effects of ayahuasca should be performed with more volunteers, different doses and also with repeated dosing for longer periods of time.