A new insight into ayahuasca’s adverse effects: Reanalysis and perspectives on its mediating role in mental health from the Global Ayahuasca Survey (GAS)

Óscar Andión; José Carlos Bouso; Jerome J. Sarris; Luís Fernando Tófoli; Emérita Satiro Opaleye; Daniel Perkins

doi:10.1371/journal.pmen.0000097

Abstract

Ayahuasca is a decoction native to the Amazon, where it plays a central role in the traditional medicine of many local cultures and has expanded internationally over the last decades. Ayahuasca has also attracted the interest of scientists for its potential benefits on mental health, but its adverse effects are under-researched. We analyzed data from the Global Ayahuasca Survey, including 10,836 participants who rated predetermined adverse effects. Data were collected from March 1st, 2017, to December 31st, 2019, and accessed for analysis on November 30th, 2021. Only DP and JJS had access to identifiable participant data. Machine learning and statistical methods were used to examine the relationship between sample characteristics, post-ayahuasca adverse mental states, and mental health outcomes measured by the 12-Item Short Form Survey (SF-12). Among participants, 14.2% (767) had a prior anxiety disorder and 19.7% (1,064) a depressive disorder. Despite this, the median SF-12 score was 50.16, comparable to the general population. A history of anxiety or depression was associated with more adverse mental states after ayahuasca use. However, increased experiences of “visual distortions” and higher ayahuasca use correlated with better mental health. Women reported more adverse states but did not show worsened mental health. The classification of adverse mental states in psychedelic research should be reconsidered, as certain experiences traditionally labeled as negative may contribute to long-term psychological benefits. The context in which these experiences occur, along with individual factors, plays a crucial role in determining whether these states lead to positive or negative outcomes. Understanding these dynamics is essential for improving harm reduction strategies and maximizing therapeutic potential. Individuals with a history of depression require special attention, as they are more prone to experiencing post-ayahuasca adverse mental states and may benefit from additional psychological support.

Citation: Andión Ó, Bouso JC, Sarris JJ, Tófoli LF, Opaleye ES, Perkins D (2025) A new insight into ayahuasca’s adverse effects: Reanalysis and perspectives on its mediating role in mental health from the Global Ayahuasca Survey (GAS). PLOS Ment Health 2(4): e0000097. https://doi.org/10.1371/journal.pmen.0000097

Editor: Renato de Filippis, Magna Graecia University of Catanzaro: Universita degli Studi Magna Graecia di Catanzaro, ITALY

Received: July 9, 2024; Accepted: March 13, 2025; Published: April 30, 2025

Copyright: © 2025 Andión et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The datasets presented in this article are not readily available because Ethics approval and consent signed by participants was for data access by research team members only. Requests to access the datasets would require a new Ethics submission and should be directed to HumanEthics-Enquiries@unimelb.edu.au.

Funding: The authors received no specific funding for this work.

Competing interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: DP and JJS hold equity in a commercial entity, Psychae Therapeutics, which is undertaking research with psychedelic compounds and are co-CEOs of the same organisation.

Introduction

Ayahuasca is a decoction native to the Amazon, where it plays a central role in the traditional medicine of many local cultures, likely for millennia [1]. Ayahuasca is also the sacrament of some syncretic Brazilian religions, some of which have expanded internationally across all continents over the last four decades [2]. Ayahuasca itself has undergone a more recent process of globalization [3] to the point where both psychiatrists and priests have made respective calls to their colleagues to be more informed [4,5]. At the same time, scientific production of ayahuasca research is also exponentially increasing, although this mostly focuses on its potential benefits for mental health and less on its potential risks and adverse effects [6].

Ayahuasca is both the Quichua name for the vine Banisteriopsis caapi and for any decoction made with it. B. caapi contains harmala alkaloids (mainly harmine, harmaline, and tetrahydroharmine), which are MAOI inhibitors in the gastrointestinal tract [7]. The most common plants mixed with B. caapi are the leaves of the bush Psychotria viridis or the leaves of the vine Diplopterys cabrerana, both containing the amine N,N-Dimethyltryptamine (DMT). DMT is a partial agonist of serotonin receptors, mainly 5-HT2A and 5-HT1A, and is responsible for the hallucinatory effects of ayahuasca [8]. When administered in a laboratory, ayahuasca slightly increases heart rate and blood pressure [9,10], transiently increases prolactin and cortisol, and modifies immunological markers [11,12]. It induces decreases in EEG power in the delta, theta, and alpha frequency bands [12–14], reduces top-down control, and increases bottom-up information transfer in the brain [15]. It increases blood perfusion in the frontal and paralimbic brain regions in both normal [16] and depressed subjects [17], and decreases the activity of the default mode network [18].

In terms of subjective effects, ayahuasca increases dose-dependent responses compared to placebo on visual analog scales of “any effect”, “good effects”, “liking”, “visions”, “stimulated”, and “high”, without altering “drunkenness”. It increases the subscales of Affect, Cognition, Somaesthesia, Perception, Intensity but not Volition of the Hallucinogen Rating Scale (HRS), and the measures of stimulatory effects (A scale), euphoria (MBG scale), and somatic symptoms (LSD scale) from the Addiction Research Center Inventory (ARCI) questionnaire [9–12]. This profile of subjective effects has also been observed in naturalistic settings, alongside the induction of mystical experiences assessed with the Mystical Experience Questionnaire (MEQ) [19].

Contemporary clinical research has studied the effects of ayahuasca on depression [19–22], anxiety disorders [23,24], grief [25–27], emotional regulation [28], drug dependence [29], general wellbeing [30,31], quality of life, and general mental health [32], and even creativity [33]. Studies using health indicators employed by governments to assess the general health of their populations have found improved results in such indicators as healthy daily habits, use of psychiatric drugs, cholesterol, and other imbalances caused by lifestyle in large samples of regular ayahuasca users in both Spain and the Netherlands [34,35]. Regular long-term use of ayahuasca has been associated with slight improvements in neuropsychological functions [36–39] and neuroplasticity [38,40].

Despite the scientific interest and increasing number of publications regarding the effects of ayahuasca in both clinical and naturalistic settings, little research has been conducted on its potential acute and subacute adverse effects, as well as its possible consequences for health and/or mental health. Recently, we published a report in which we reviewed all the scientific knowledge reporting ayahuasca’s adverse effects, and where we also reported the adverse effects collected in the Global Ayahuasca Survey (GAS), a survey conducted on more than 10,000 subjects who attended an ayahuasca ceremony, comprising participants from more than 50 countries [6]. In that paper, we reported a high prevalence (55.4%) of adverse mental sates after ayahuasca use, with 12% seeking professional support for these effects, but also a low frequency of severe post-use adverse states (4.4%). Moreover, more post-use adverse states were reported for participants with higher ayahuasca uses, with previous mental health disorders, and in non-traditional contexts of ayahuasca use. However, our previous study did not analyze the relationship of the adverse mental states with the participants’ current mental health. Moreover, previous studies analyzing the relationship of ayahuasca’s adverse effects with participants’ health status seem to show contradictory results. While acute adverse effects have been related to psychiatric condition improvement [41], the number of adverse effects after ayahuasca use was negatively associated with current mental health and perceived improvement in psychological wellbeing in another study [42]. Moreover, subjective experiences typically experienced by ayahuasca users, such as visual distortions or hallucinations, could be perceived as beneficial rather than adverse effects. In this context, It seems necessary to explore the mediating variables involved in the development of potential harms or benefits following an adverse event.

In this new analysis, we aim to extend our previous study results by trying to answer the question raised above. As noted, post-use adverse mental effects are related to independent variables (e.g., sociodemographic, clinical, or history of ayahuasca use variables) that are also expected to be related to participants’ current mental health status. Thus, we hypothesize a mediational relationship where we will test the relationships of the independent variables on reported adverse states increment after ayahuasca use and the relationships of these variables (the independent variables and adverse effects) on ayahuasca users’ current mental health. Moreover, in this study, we include as independent variables acute ayahuasca experiences, the spiritual significance, and the extreme fear experienced during the ceremonies. The first has been associated with psychedelic experiences [43,44] and an increased likelihood of experiencing adverse effects [6]. The second has been related to extended difficulties following psychedelic drugs use [45] and has been linked with “bad trips” [46]. As explanatory models can be difficult to interpret when a high number of exogenous and mediation variables are included in the analysis, in this study, a machine learning and classical statistical combined approach is used [47,48] to better analyze our aims.

Methods

Ethics statement

The study was approved by the University of Melbourne Human Research Ethics Committee (HREC number 1545143.3), and all participants provided their informed consent via an initial question in the online survey. Participants were unable to proceed if consent was not provided.

Sample

The study sample was drawn from 10,836 participants of an online survey conducted between 2017 and 2019. The survey was available in six languages (English, Portuguese, Spanish, German, Italian, and Czech) and collected data from participants in more than 50 countries. All participants were over 18 years old and had used ayahuasca on one or more occasions.

Survey participation was promoted through websites and email invitations from relevant organizations, ayahuasca retreat centers, ayahuasca churches, online groups and forums, via Facebook, and flyers at conferences and events. No financial incentives were offered. Data was cross-checked to remove suspected duplicate responses, and information from partially completed surveys was preserved. Given the opaque nature of the ayahuasca-using population in many countries (where this practice is either prohibited or where its legal status remains unclear) a non-random sampling method was chosen.

After missingness was explored, only participants without missing responses in any of the study variables were included in the analyses (5,400; 49.8%; see Statistical Analysis section). No significant differences were observed between included and excluded participants in terms of sex distribution, context of ayahuasca use, age at first ayahuasca use, frequency of ayahuasca uses in the last year, lifetime ayahuasca uses, current physical or mental health scores, and prevalence of lifetime anxiety or alcohol use disorders (all ps ≥.082). However, participants included in the analyses were older [40.94 (12.01) vs. 39.63 (12.39); t_(10,687) = 5.54; p <.001], had higher educational levels [university education: 65.2% (3,522) vs. 58.6% (3,133); χ²₍₁₎ = 49.23; p <.001] (To reduce the comparison of education levels between included and excluded participants, previous to the analyses the between groups difference in the variable, it was recoded to a dichotomic variable measuring university studies.), and reported fewer ayahuasca mental adverse effects [2.70 (4.26) vs. 2.95 (4.55); t_(7,833) = 2.28; p =.023} than the excluded participants. Finally, a lower frequency of lifetime depression [19.7% (1,064) vs. 21.6% (516); χ²₍₁₎ = 3.74; p =.053] and substance use disorders [9.2% (496) vs. 12.4% (296); χ²₍₁₎ = 18.73; p <.001] was observed among the included participants compared to those excluded.

Measures

Demographic information such as age, sex, education, and country of residence was obtained from participants, in addition to their lifetime history of mental health diagnoses and detailed ayahuasca drinking history, including frequency, patterns, and contexts of use [42]. A single item question was used to measure the extent to which extreme fear or panic was experienced during the ayahuasca session, scored from 0 “Not at all” to 10 “Very much.” The degree of spiritual significance of ceremonies was reported using the spirituality component of the Persisting Effects Questionnaire [49] that involved a six-point scale (ranging from not at all significant to the single most spiritually significant experience of my life). The mental component score of the SF-12 instrument was used to evaluate current mental health status in accordance with the guidelines for the SF-12 instrument, with scores ranging from 0 to 100 and higher scores signifying better mental health [50].

Acute adverse mental health effects were assessed using a question about short- to medium-term mental health, emotional, or perceptual changes occurring in the weeks or months after consumption. This was based on the PHQ-4 [51], supplemented with six additional items derived from the ayahuasca literature. The question asked respondents, “In the weeks or months after your ayahuasca ceremonies/sessions, have you ever experienced an increase in any of the following?” Responses were collected using a modified version of the PHQ-4 four-point scale (Not at all, Slightly, Moderately, Very Much). Note that this question did not specifically describe these items as adverse effects.

Statistical analysis

Data analysis strategy.

The main objective of the study is to analyze the relationships between participants’ reported adverse mental states after ayahuasca use and their current mental health status using Structural Equation Modeling (SEM). As mentioned above, due to the expected relationships between the study variables, we test a hypothesized mediational model. The mediational model is briefly presented in Fig 1.

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Fig 1. Hypothesized mediational post-ayahuasca use adverse mental states model.

https://doi.org/10.1371/journal.pmen.0000097.g001

Before applying Structural Equation Modeling (SEM) analysis, we employ the Random Forest algorithm to select from the 24 initial predictors those that would improve the R-squared and reduce the root mean square error (RMSE) when predicting participants’ current mental health. This step aims to refine our predictor set, enhancing the clarity of the SEM model by potentially reducing the number of variables involved. Random Forest is a widely used machine learning procedure for feature selection that can enhance the efficiency of models [52,53]. It has been applied in mental health research to similar ends (e.g., [54,55]. Prior to these analyses, participants were selected, data were explored, pre-processed, and a multivariate outlier detection algorithm was employed to finalize the sample to be used. This preparatory phase ensures that the data feeding into both the Random Forest and SEM analyses are optimized for quality and relevance.

Sample selection and data pre-processing.

As it is an online survey research and missing response are frequently observed, missingness responses were explored prior to the analyses. As this is an exploratory study and none previous research has specifically analyzed the relationships between clinical, ayahuasca history of use variables and the adverse post-ayahuasca use states with participants’ current mental health, after the data exploration, in this study participants with missing response were deleted. Given that the distribution of variables is a critical factor when using multivariate statistical procedures based on Euclidean distances, such as k-nearest neighbors algorithms and SEM, before proceeding with the analyses, an exploration of the distributions of the included variables was conducted to ensure the appropriateness of the statistical techniques and to facilitate accurate interpretations of the findings.

Lifetime and last year ayahuasca use displayed high non-normality values (Skewness > 8.475 and Kurtosis > 98.80), to reduce excessive kurtosis these variables were transformed to ordered one based on the 10th to 100th percentiles (see Table 1). Additionally, the two categorical variables included in the study were recoded to dichotomous variables: traditional vs. non-traditional countries (Brazil, Ecuador, Peru, Bolivia, Colombia and Venezuela countries of birth vs. other countries), and traditional vs. non-traditional context of use (Ayahuasca Church and Traditional Shaman vs. non-traditional supervision and others contexts of use). A high correlation was observed between lifetime and last year ayahuasca use. However, since no linear dependence was detected between the variables, and one of the random forest algorithms we plan to use in our analysis, Recursive Feature Elimination, has been recommended for variable selection in the context of multiple correlated variables [56], the last year ayahuasca use variable was not deleted.

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Table 1. Sample description (n = 5,400).

https://doi.org/10.1371/journal.pmen.0000097.t001

The studied variables were pre-processed specifically for each statistical test. For k-nearest neighbors multivariate outlier detection algorithms and numerical data (continuous and ordered variables) for SEM were standardized and scaled, respectively. No multivariate outliers were detected. For Random Forest tests, variables were used in their original scale and data were spilt into training dataset (n = 4,320) and test dataset (n = 1,080) for feature selection and model training and for model evaluation respectively. SEM was performed using the total sample, leveraging the full dataset to ensure robust analysis and comprehensive results.

Data analyses.

The statistical analyses were performed using R version 4.2.3 [57]. Multivariate outlier detection was conducted using the Natural Neighbor searching algorithm [58] as implemented in the DDoutlier package [59]. Data preprocessing and Random Forest analyses were carried out using the caret package version 6.0-94 [60]. The mediational model was tested using the lavaan package version 0.6-12 [61].

For the Random Forest Recursive Feature Elimination (RFE) variables selection, the number of resamples was set to 50 and bootstrap was set to 1000. Random Forest was performed using repeated k-fold cross-validation, with 10 partitions and 5 repetitions. The mediational model (Fig 1) was tested following the recommendations by Bauer and Curran (2019) for SEM analyses with the lavaan package. The Robust Diagonally Weighted Least Squares (DWLS; [62,63]) estimation method was used to test the models. Fit indices (Chi-square test, RMSEA, TLI, CFI, and SRMR) were used to assess the model’s fit to the data [64,65]. Covariance between exogenous variables was fixed to their sample values.

For a clearer interpretation of the effects studied, both fully standardized and partially standardized estimates were reported for the numerical and dummy variables, respectively [66]. Finally, statistical power analyses for mediational, indirect, direct, and total effects (π) based on Monte Carlo Simulation were conducted using the Webpower package [67]. The number of Monte Carlo simulations and bootstraps were set to 100 and 5000, respectively.

While sociodemographic variables are included in the analyses and tables, the results section primarily focuses on the history of use, clinical, acute experiences, context, and country as exogenous variables.

Results

The sample characteristics are summarized in Table 1. Approximately half of the participants were female (47.1%; 2,546), with an average age of 40.9 years (SD = 12.01). The majority of the participants (80.9%; 4,363) held an education level higher than a diploma or advanced diploma and were from Brazil (46.0%; 2,485). The mean age at which participants first used ayahuasca was 31.5 years (SD = 12.34). Only 16.0% (865) of the participants had not used ayahuasca during the previous year, while 59.9% (3,236) had used ayahuasca more than 31 times and 20.0% (1,079) had used it more than 397 times in their lifetime. In terms of context, 67.4% (3,637) of the sample used ayahuasca in a traditional setting. Additionally, 14.2% (767) of participants reported a previous anxiety disorder, 19.7% (1,064) a depressive disorder, and the mean mental health score of the sample, assessed with the SF-12, was 50.16 (SD = 9.11).

Predictors selections: Random forest analyses

From the initial set of 24 variables included in the study, the RFE algorithm selected 23 variables that showed the highest R-squared and the lowest RMSE (.259 and 7.91, respectively). However, it was determined that a set of 20 features could represent an optimal balance, exhibiting an R² of.256 and an RMSE of 7.92. Moreover, the Random Forest regression model with 20 variables, used to predict participants’ current mental health, exhibited R-squared and RMSE values of.282 and 7.794, respectively and revealed that gender had no significant impact on predicting mental health outcomes in this sample (see Table A and B in S1 Text). Consequently, the variables Alcohol use disorder, Drug use disorder, “Not being able to stop or control worrying”, “Nightmares, or disturbing thoughts, feelings, or sensations” and gender were not included in the subsequent analyses.

Ayahuasca adverse mental effects mediational model

The model fit indices indicated a high fit to data for the hypothesized Ayahuasca adverse mental effect mediational model (χ² = 1.295, p =.523; CFI = 1.00; TLI = 1.00; RMSEA <.001; RMSEA90% CI =.000 -.024, and SRMR =.001). Although the hypothesized mediational model explained nearly 30.0% (R² =.298) of the variance in participants’ current mental health, the explained variance for the ayahuasca adverse effects included in the model ranged from R² =.060 to R² =.206 (“Visual distortions” and “Difficulty knowing what is real and not real”). The relationships between the variables studied are detailed below by sections.

Exogenous variables relationships with participants’ reported adverse mental states

As observed in Table 2, ayahuasca history of use variables did not show significant relationships with the participants’ reported increases for half of the adverse mental states studied. However, higher participants’ age of onset and lifetime use were related to greater reported increases of “Feeling down, depressed, or hopeless” (β =.091 -.097; ps <.037); “Hearing or seeing things that other people do not hear or see” (β =.178 -.103; p <.006), “Visual distortions” (β =.113 -.146; p <.001), and “Feeling energetically attacked or a harmful connection with a spirit world” (β =.116 -.226; p ≤.001).

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Table 2. Exogenous variables relationships with reported increases in post-ayahuasca use adverse mental states.

https://doi.org/10.1371/journal.pmen.0000097.t002

Related to participants’ previous mental health disorders, anxiety was associated with greater reported increases of “Feeling nervous, anxious, or on edge” (β =.245; p <.001) and “Difficulty knowing what is real and not real” (β =.113; p =.054). Moreover, anxiety approached significant levels in increasing “Feeling disconnected or alone” (β =.096; p =.057) and “Feeling energetically attacked or a harmful connection with a spirit world” (β =.109; p =.060). However, a previous diagnosis of depression was associated with greater reported increases of all the studied adverse post-ayahuasca states (β ≥.103; p ≤.036), with the sole exception of “Feeling nervous, anxious, or on edge” (β =.080; p =.100) (Table 2).

Participants who used ayahuasca in non-traditional contexts reported greater increases of all the adverse states (β ≥.108; p ≤.007), with the only exception of “Little interest or pleasure in doing things” (p =.558). However, a different pattern of associations was observed for traditional vs. non-traditional countries. Participants from non-traditional countries showed greater increases of “Feeling disconnected or alone” (β =.135; p =.002) and “Difficulty knowing what is real and not real” (β =.102; p =.038), but they also reported lower increases in “Hearing or seeing things that other people do not hear or see” (β = -.172; p <.001), “Visual distortions” (β = -.191; p <.001), and “Feeling energetically attacked or a harmful connection with a spirit world” (β = -.200; p <.001) (Table 2).

As it was observed for context and country variables, the participants’ reported increases of acute ayahuasca experiences showed a specific pattern of relationships with the post-use adverse mental states. While participants reported the intensity of extreme fear was related to higher increases of all the adverse states (β ≥ -.155; ps <.001), participants’ reported intensity of spiritual significance was related to lower increases of “Feeling nervous, anxious, or on edge,” “Little interest or pleasure in doing things,” “Feeling down, depressed, or hopeless,” and “Feeling disconnected or alone” (β = -.051; p ≤.002), but with higher intensity of “Difficulty knowing what is real and not real,” “Hearing or seeing things that other people do not hear or see,” “Visual distortions” (β ≥.063; ps ≤.002) (Table 2).

Ayahuasca mental adverse effects relationships with participants’ current mental health

The relationships of post ayahuasca use adverse mental states on participants’ current mental health are presented in Table 3. Five of the eight adverse states included in the model were significantly related to participants’ current mental health. Participants’ reported increases of “Visual distortions” (β =.074; p =.004) was related to better current mental health. However, “Little interest or pleasure in doing things,” “Feeling down, depressed, or hopeless,” “Feeling disconnected or alone,” and “Feeling energetically attacked or a harmful connection with a spirit world” (β ≤ -.074; ps ≤.026) were related to participants’ worse current mental health. Among the post ayahuasca use adverse states that were negatively related to participants’ current mental health, “Feeling down, depressed, or hopeless” presented the highest effect (β = -.200; p <.001).

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Table 3. Post-ayahuasca use adverse mental states relationships with participants’ current mental health.

https://doi.org/10.1371/journal.pmen.0000097.t003

Exogenous variables indirect relationships with participants’ current mental health

For clarity in the results section, only the main indirect effects results are presented here. The complete results of the exogenous variables indirect effects through those adverse states that showed significant relationships with participants’ current mental health are presented in Table C in S1 Text. While the majorities of the exogenous variables were not significant related with participants’ current mental health through the adverse states, previous depression, spiritual significance and extreme fear were significant related with mental health through the majorities of the adverse stated. Concretely, higher intensity of extreme fear was significant related with lower current mental health through “Little interest or pleasure in doing things” (β = -.018; p =.007), “Feeling down, depressed, or hopeless” (β = -.019; p =.029), “Feeling desconeted or alone” (β = -.019; p =.029), and “Feeling energetically attacked or a harmful connection with a spirit world” (β = -.016; p =.033), but it also was positively related with mental health through “Visual distortions” (β =.012; p =.006). Contrary to the observed with extreme fear, higher intensity of the participants spiritual significant experiences was positively related with current mental health through the adverse states (Little interest or pleasure in doing things”: β =.006; p =.022; “Feeling down, depressed, or hopeless”: β =.016; p =.001; “Visual distortions” (β =.006; p =.019). Finally previous depression significantly reduces current participants’ mental health through “Feeling down, depressed, or hopeless” (β = -.058; p <.001), “Feeling desconeted or alone” (β = -.018; p =.035), but it was related with higher mental health through “Visual distortions” (β =.011; p =.033) (see Table C in S1 Text).

Exogenous variables direct relationships with participants’ current mental health

The direct effects of exogenous variables on participants’ current mental health are presented in Table 4. Higher participant-reported ayahuasca use variables were related to better participants’ current mental health (β ≥.097; ps <.001), with last year’s use having the strongest relationship with participants’ current mental health (β =.170; p <.001). In contrast to the history of ayahuasca use variables, previous mental disorders were related to worse current mental health (β = -.184 and -.240; p <.001 for anxiety and depression, respectively). Finally, while participants’ reported intensity of spiritual significance was related to better mental health (β =.101; p <.001), the intensity of extreme fear (β = -.054; p <.001) was related to worse participants’ current mental health.

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Table 4. Exogenous variables direct effects on participants’ current Mental Health.

https://doi.org/10.1371/journal.pmen.0000097.t004

Total effects on participants’ current mental health

Finally, to test our main hypothesis, we performed the total effect (the direct effect plus the indirect effect through the post ayahuasca use adverse states) of each of the ayahuasca history of use, clinical, and ayahuasca acute experiences variables. All the ayahuasca history of use variables studied were related to participants’ better current mental health (β ≥.088; ps ≤.001). Participants’ reported history of anxiety and depression were related to worse current mental health (β ≤ -.220; ps <.001). The participants’ reported intensity of spiritual significance was related to better mental health (β =.130; p <.001), while the intensity of extreme fear was related to worse participants’ current mental health (β = -.151; p <.001) (Table 4).

Discussion

In our previous analysis of the database from the Global Ayahuasca Survey (GAS), we found a prevalence of adverse mental states after ayahuasca use in almost 60% of the sample. However, approximately 88% of respondents considered such states as part of a positive process of growth and integration [6]. Further analysis of other variables collected in the GAS revealed improvements in mood disorders such as anxiety and depression [68], as well as reductions in alcohol and drug use [69], enhancements in mental health and wellbeing [70], and changes in life and lifestyle [71]. We have also reported, through qualitative analysis, that ayahuasca experiences can be challenging and that facilitating positive growth may depend on working through those integration challenges [72]. Taking all these data together, it seems necessary to explore deeper into the knowledge of the so-called adverse mental states following ayahuasca use because of their unusual psychopharmacological nature. Such effects, depending on a series of factors, may lead to benefits rather than harms [32,41,45,46].

In this extended analysis of the adverse mental states after ayahuasca use based on data from the Global Ayahuasca Survey (GAS) [6], we have used machine learning and statistical analysis to identify specific relationships between these adverse mental states, participants’ current mental health, and key influencing factors.

From the 5,400 subjects included in the analysis, almost 60% of the sample had used ayahuasca more than 31 times, suggesting a sufficiently reliable sample for carefully studying the potential adverse effects of ayahuasca. Furthermore, half of the sample were women, allowing for an analysis of potential adverse events segregated by gender. The mean age of our sample was 40.9 years, with the initiation of ayahuasca use at 31.1 years and a high educational level. This suggests, from a sociological perspective, that individuals who start and continue using ayahuasca are mature, with their personalities already formed, and that ayahuasca use is not merely about seeking to get high. This aligns with previous personality studies which found that users do not score higher than controls on novelty seeking but do score higher on self-transcendence both in religious [37,38,73,74] and non-religious settings [32]. Additionally, both ethnographic and studies using public health-based indicators conclude that participating in ayahuasca ceremonies is a form of self-care and self-attention in both religious and non-religious users [34,35,75].

Although our primary aim was to analyze the mediational relationship of the adverse mental states reported after ayahuasca use on mental health, this study enabled us to draw a general conclusion about the effect of ayahuasca use on users’ current mental health. As indicated in previously cited studies [32,41,42,76], the results from various analyses performed showed that more ayahuasca use is related to better current mental health in users. Concretely, all the ayahuasca history of use variable were among the more important predictors of current mental health in Random Forest analysis and, despite ayahuasca use was related with higher increases of some adverse mental states, the total effects of these variables in the mediational analysis showed that higher use is related to better participant’s current mental health. Furthermore, the sample SF-12 Mental Health score, (mean 50.16 and standard deviation 9.11), closely matches the expected score for the general population (mean 50, standard deviation 10) [77]. In that sense, although there are subsamples with histories of mood, substance, and drug disorders, our sample is completely normal in terms of mental health. Thus, we find initial evidence of the psychological safety of ayahuasca in general terms, independent of specific cases of adverse consequences of its use. From this finding, we could extrapolate that generally, ayahuasca practices do not pose a risk to public health.

Of the 24 initial predictors of mental health, 19 were identified as the most significant in assessing participants’ current mental health. Alcohol and substance use disorders, along with the adverse post-ayahuasca states of “not being able to stop or control worrying” and “nightmares or disturbing thoughts, feelings, or sensations,” showed little relevance, despite the latter typically being associated with depression, anxiety, and PTSD [78]. This may reflect symptomatic improvements within the sample, though the relatively low prevalence of these disorders (19.7% depressive, 14.2% anxiety, 9.2% substance use, and 10.0% alcohol use disorders) could also explain their diminished importance. Further research is needed to explore potential reductions in sleep disturbances, as effective treatments for nightmares remain critical for mental health populations [79].

Interesting results were also observed when analyzing the relationships between the predictors and the increases of the ayahuasca adverse states. Higher after use increases of “Hearing or seeing things that other people do not hear or see,” “Visual distortions,” and “Feeling ‘energetically attacked’ or a harmful connection with a spirit world” were observed in those participants with a higher frequency of ayahuasca use. More interesting is the result of no significant relationships of the history of ayahuasca use variables with the increases of the majority of the adverse emotional-cognitive states.

On the other side, higher increases of all the adverse effects, except for “Feeling nervous, anxious, or on edge,” was related to having a previous depressive disorder. In that same sense, participants’ previous anxiety disorder was the most significant predictor of experiencing any adverse effect from both the emotional-cognitive and psychotomimetic categories [6], a finding that was also observed in a study with regular religious ayahuasca ceremony attendees [80]. Anxiety disorders have led to psychological adverse states even in laboratory settings [81]. Conversely, this study showed that previous anxiety disorder only significantly increased the two adverse “anxiety-like symptoms” mental states included in the study: “Feeling nervous, anxious, or on edge” and “Difficulty knowing what is real and not real.” Thus, the increment of adverse emotional-cognitive experiences seems to be more strongly related to users’ vulnerabilities rather than to the history of ayahuasca use variables studied. These findings align with current studies that highlight the importance of studying users’ vulnerabilities to better understand the psychedelic experience [45,46,82]. This emphasis on individual vulnerability underscores the complex interplay between pre-existing mental health conditions and the psychoactive effects of ayahuasca, pointing to a nuanced understanding of how such experiences impact different users.

We have found that experiencing ayahuasca ceremonies as spiritually significant increases the psychotomimetic states (“Hearing or seeing things that other people do not hear or see” and “Visual distortions”), but it also reduced the adverse emotional-cognitive states (“Feeling nervous, anxious, or on edge”, “Little interest or pleasure in doing things”, “Feeling down, depressed, or hopeless”, “Feeling disconnected or alone”). So, ayahuasca spiritual significant experiences are related to better current mental health by directly increasing mental health and the psychotomimetic effects, but also by reducing the adverse emotional-cognitive states. In accordance with our results, the relationships of spirituality with better mental health have been reported previously [83]; moreover, psilocybin has been also linked in a dose-dependent way with mystical-type experiences and wellbeing [84]; and finally, mystical significance has been recently related with the beneficial effects of different psychedelic substances [44], or considered a necessary experience for the beneficial effects of these substances [43].

Experiencing extreme fear during the ceremonies was the strongest predictor of all the adverse mental states reported after ayahuasca use, showing the greatest effect among all the studied variables in increasing post-use adverse states. Despite the necessary caution due to our study design, it is interesting to recall that fear has traditionally been linked to anxiety (e.g., [44]), and anxiety has been related to fearfulness (e.g., [85]). Moreover, the complexity of defensive networks is central in emotional processing and response (e.g., [86]). This complexity has been related not only to fear and anxiety but also to depression, as all these states are connected with the functional interplay of top-down and bottom-up processing [87], and these neurological processes have been related to the ayahuasca experience as well [88]. Experiencing extreme fear during ceremonies and prior anxiety disorders, linked to emotional processing, warrant further study to better manage adverse post-ayahuasca mental states and enhance positive outcomes.

Cultural background influences the quality and intensity of adverse mental states after ayahuasca use, with participants from non-traditional contexts reporting higher feelings of disconnection but fewer visual distortions, emphasizing the need for culturally diverse studies given the established cultural differences in how psychedelics affect various domains of mental health [89–91].

Despite 10 post-ayahuasca use adverse mental states being initially included in the analyses, only 5 were significantly related to participants’ current mental health. Four of these adverse states were negatively related to mental health, while the increase in “visual distortion” was related to better participants’ current mental health. The adverse states strongly related to poorer current mental health were all mentioned above as the “depression-like symptoms” adverse states (“Little interest or pleasure in doing things”, “Feeling down, depressed, or hopeless”, and “Feeling disconnected or alone”), while “Feeling nervous, anxious, or on edge”, which was strongly predicted by previous anxiety disorder, was not significantly related to current mental health. Moreover, a previous depressive disorder emerged as one of the strongest predictors of negative impacts on participants’ current mental health among all the adverse states analyzed. This finding appears counterintuitive considering existing evidence on the positive effects of psychedelic therapy for depressive symptoms [92]. From a descriptive point of view, this result emphasizes the importance of caution when ayahuasca users with a history of previous depressive disorders experience after ayahuasca use an increased states of “Feeling down, depressed, or hopeless” and highlights an interesting focus of research in the complexity of the psychedelic experience as has been proposed recently [93]. Finally, another interesting result and future topic of research is the positive relationship of experiencing visual distortion and spiritual significance with better current ayahuasca users’ mental health.

Finally, despite not being a main topic of analysis in this study, since we did not find any notable results related to gender, there is still something to consider regarding gender differences in adverse mental states after ayahuasca use. In our previous classical regression analysis, we found that being female significantly increased the risk of experiencing adverse states [6]. However, in this study, which looks more closely at the potential mediational variables of suffering adverse states, being female was not related to participants’ current mental health. So, even if women suffer more adverse states after ayahuasca use than men, that does not imply a negative consequence for their mental health. To our knowledge, there are no other gender studies on ayahuasca’s adverse effects, and even in a recent systematic review on the topic, results were not segregated by gender [94]. Other studies focused on studying adverse effects of psychedelics neither analyze their results by gender nor from a gender perspective [45,46,82,95]. In a study with a sample of 380 regular Spanish ayahuasca users (47% women), there were no differences between genders in the GHQ-12 questionnaire, which measures mental health, while in the general population men have 10 points better mental health than women [34]. There are two hypotheses: that women with better mental health are the ones who attend ayahuasca ceremonies, or that participating in ayahuasca ceremonies improves mental health of participants, especially women.

In previous results from the GAS, gender disappeared as a predictor of improvements in mental health and wellbeing [42], and life and lifestyle changes [71]. Moreover, some field researches have shown how women create protective strategies when they get involved in the use of psychoactive plants, by means of enhancing social cohesion through women circles and other self-care strategies [75,96]. An alternative explanation for the good outcomes on women’s mental health despite their greater presence of potential adverse effects may be the social protective factors that they deploy. This may also explain how mental health adverse states were negatively associated with consumption in religious settings, as we found in our previous study [6]. Perhaps the explanation is not based on the religious context but on the fact that the ayahuasca use was conducted in the context of a cohesive group where there is social support among members. When designing different contexts of use, we did not create a category referred to taking ayahuasca in a cohesive group, something that future studies should consider. This aspect is of special interest in this context of ‘psychedelic renaissance’, where psychedelics are becoming medicalized while communal use is prosecuted [97] in a world suffering a global mental health pandemic where the loss of social bonds and self-perception of loneliness are among its main causes [98].

As this study is a second analysis of the GAS sample relating to adverse mental states, it is affected by the same limitations our previous one. The study design prevents us from establishing causality, and the retrospective evaluations of predictors and adverse states, as well as the self-selection bias, are all limitations that must be considered [6]. Specifically, first, recall bias may affect participants’ memories of past experiences, especially in cases where ayahuasca use occurred months or years prior. Additionally, selective reporting bias could influence participants to emphasize positive or negative experiences based on personal beliefs or expectations about ayahuasca. The survey’s voluntary and self-selected nature may also attract individuals with particularly strong opinions or unusual experiences, potentially skewing the results. Finally, cultural and contextual variations among participants from different regions may introduce variability that affects the interpretation of findings across diverse populations. Moreover, lower frequencies of lifetime depression and substance use disorders were found in the participants excluded compared with those included. Despite this, the sample size and its global representativeness make the study results interesting to explore possible relationships between the studied variables. Spiritual significance and extreme fear were treated as predictors. Despite the covariance between exogenous variables in the mediational test being fixed to the dataset values, which allows for accounting for the relationships between exogenous variables, both experiences should be treated in future studies as mediational ones using intensity measures [99]. Finally, an interesting result, which should not necessarily be considered a limitation, was that despite the high explained variance for participants’ current mental health (30.0%), the explained variance for the increment of the adverse mental states was lower (ranging from 6.0% to 20.6% for ‘Visual distortions’ and ‘Difficulty knowing what is real and what is not’). Thus, other predictors not included in our study must be considered in future studies to better understand the so-called post-ayahuasca use adverse mental states.

Despite the limitations, some conclusions can be drawn from this study’s results. In a sample of frequent ayahuasca users, although its use is associated with some negative reactions, higher usage is related to better mental health. The majority of the so-called ayahuasca adverse states did not have a negative impact on users’ current mental health. However, adverse depressive-like symptoms experienced after ayahuasca use seem to be related to poorer mental health, while experiencing visual distortions has a positive effect on users’ current mental health. Therefore, it may be necessary to reconceptualize what are considered adverse mental states after ayahuasca use, since some effects that have traditionally been defined as “adverse” actually lead to positive outcomes, as is the case with the ones just referred to, and other, as those adverse anxiety-like symptoms could be related with user symptoms improvement. Moreover, our results underline the importance of studying individual vulnerabilities when analyzing the beneficial or harmful consequences of ayahuasca adverse reactions, as spiritual significance, extreme fear, and previous mental disorders were observed to be both beneficial and harmful factors. Finally, it is warranted to explore the roles of social bonding in the positive mental health outcomes of participants in ayahuasca ceremonies as a possible determinant factor in improving the mental health of participants [100].

Practical, professional, and policy implications of our observed mediational effects. Our analysis identified distinct mediational effects of post-ayahuasca mental states that impact participants’ current mental health, revealing both detrimental and beneficial influences shaped by contextual and individual factors. Experiences of extreme fear during ceremonies were associated with a higher likelihood of all adverse post-ceremony mental states, which in turn correlated with poorer mental health outcomes. Ayahuasca experience are modulated by non-pharmacological factors [42,76] like set (personal disposition) and setting (context). One way to mitigate potential experiences of fear is to work beforehand with the person who will take ayahuasca, offering them appropriate information about both the positive and negative effects of the plant, reassuring them they will be cared for, and instilling trust. It is essential that those conducting ceremonies spend time before the ceremony speaking with attendees, both individually and as a group. Maintaining a space that is considered safe can also help prevent experiences of fear.

Specific adverse states, such as emotional disconnection, sensations of feeling “energetically attacked” or connected to a harmful “spirit world,” and feelings of hopelessness or depression, were linked to significant declines in mental health, particularly among participants in non-traditional settings and those with pre-existing depressive disorders. Again, it is crucial that guides spend time talking to attendees. In our experience, what are referred to as “spiritual attacks” can be highly threatening, and people may end up traumatized. For shamanism, as well as for some ayahuasca churches, healing occurs in the spiritual realm, where friendly forces battle hostile ones. This explains the occasional experience of feeling spiritually attacked. Guides must ensure attendees feel protected during ceremonies. Regardless of whether one believes in this ayahuasca-based conception of healing, it is essential that guides communicate confidence that they, not the attendees, are the ones dealing with hostile forces in the spiritual realm. If someone feels spiritually attacked after the ceremony, it is necessary to initiate an integration process to help them reframe their experience [73,101]. Guides also need to pay attention to individuals who show signs of depression and provide them with special care, as these individuals may be at a higher risk of worsening mental health outcomes. Paradoxically, clinical trials have found an antidepressant effect of ayahuasca [92]. This discrepancy with our results may be due to the fact that, in clinical trials, patients receive extensive attention. Thus, providing additional attention to individuals with a history of depression could potentially prevent negative outcomes.

On the other hand, certain adverse effects were associated with improved mental health. Visual distortions, for example, positively correlated with better current mental health, especially in participants who reported frequent ayahuasca use. Additionally, the spiritual significance of the experience acted as a protective factor, reducing adverse emotional effects such as anxiety and disconnection while fostering overall mental health benefits. Knowing these positive effects of visual distortions and spiritual significance, guides can emphasize these aspects in pre-experience interviews with participants, helping them understand and appreciate the spiritual importance of the experience.

Contextual and personal background variables further influenced these outcomes: participants in non-traditional ayahuasca settings and those from non-traditional countries experienced higher rates of adverse effects (e.g., emotional disconnection and difficulties discerning reality) that were detrimental to their mental health. This phenomenon may be related to the preparation of the guides, who, given their cultural background in traditional ayahuasca-using contexts and countries, are often highly experienced (they may be curanderos, taitas, onayas, mestres, maestros, pajés, etc.). Therefore, it is important for those seeking ayahuasca ceremonies to do so in contexts and with people where there is a long-standing tradition of use, where negative experiences are less likely to occur.

Last, in terms of policy implications, ayahuasca ceremonial practices have spread across the planet [3], and the participation in the GAS of people from more than 50 countries is further evidence of this. A recent report by the NGO ICEERS estimated that around 4 million people have taken ayahuasca all over the world [102], and it does not appear that this phenomenon is decreasing; on the contrary, it seems to be growing. The aim of this paper is not to discuss the causes of this phenomenon. What is evident is that the phenomenon exists even in the face of punitive measures, as in the cases of France, Italy, Russia, and China, where ayahuasca use is specifically targeted and penalized. Although DMT is controlled according to the United Nations 1971 Convention on Psychotropic Substances, neither ayahuasca nor any preparation made from plants containing DMT is controlled [103]. In contrast to punitive countries, there are others like Peru, Colombia, and Brazil where certain levels of protection are in place. We have seen that guides and the context in which the experience takes place are very important for the mental health outcomes of participants in ceremonies. The more persecuted the ceremonies are, the more likely it is that safety criteria will not be met. Recently, the Government of Catalonia published a safety guide for ayahuasca facilitators created by the ICEERS Foundation [104]. This is a measure that other regions and countries could adopt. But perhaps the most important step would be to create a regulatory framework that establishes a set of criteria and safety measures that must be met by centers and the people who work in them. In Spain, the Netherlands, and other countries, initiatives are underway in which guides are forming associations that establish safety criteria and ethical codes that require compliance among their members. For administrations to guarantee the legal safety of these associations is another way to ensure the safety of participants. Obviously, these measures should only be implemented outside indigenous contexts, as indigenous communities already have their own forms of self-regulation. Allowing the political and legal context for good practices to occur is the best way to prevent negative consequences of participation in ayahuasca ceremonies and enhance the positive ones.

Supporting information

S1 Text. Supporting Tables.

https://doi.org/10.1371/journal.pmen.0000097.s001

(DOCX)

References

1. Miller MJ, Albarracin-Jordan J, Moore C, Capriles JM. Chemical evidence for the use of multiple psychotropic plants in a 1,000-year-old ritual bundle from South America. Proc Natl Acad Sci U S A. 2019;116(23):11207–12. pmid:31061128
- View Article
- PubMed/NCBI
- Google Scholar
2. Labate BC, de Rose IS, dos Santos RG, editors. Ayahuasca Religions: A Comprehensive Bibliography & Critical Essays. San Jose (CA): MAPS, Multidisciplinary Association for Psychedelic Studies; 2008.
3. Labate BC, Jungaberle H, editors. The Internationalization of Ayahuasca. Berlin/Zurich: Lit Verlag; 2011.
4. Prue R, Voss R. Indigenous healing practice: Ayahuasca. Opening a discussion. J Pastoral Care Counsel. 2014;68(1–2):6.
- View Article
- Google Scholar
5. Stiffler J. Ayahuasca: From the Amazon to a city near you. Am J Addict. 2018;27(8):648–9.
- View Article
- Google Scholar
6. Bouso JC, Andión Ó, Sarris JJ, Scheidegger M, Tófoli LF, Opaleye ES, et al. Adverse effects of ayahuasca: Results from the Global Ayahuasca Survey. PLOS Glob Public Health. 2022;2(11):e0000438. pmid:36962494
- View Article
- PubMed/NCBI
- Google Scholar
7. Riba J, McIlhenny EH, Valle M, Bouso JC, Barker SA. Metabolism and disposition of N,N-dimethyltryptamine and harmala alkaloids after oral administration of ayahuasca. Drug Test Anal. 2012;4(7–8):610–6. pmid:22514127
- View Article
- PubMed/NCBI
- Google Scholar
8. Strassman RJ. Human psychopharmacology of N,N-dimethyltryptamine. Behav Brain Res. 1996;73(1–2):121–4. pmid:8788488
- View Article
- PubMed/NCBI
- Google Scholar
9. Riba J, Rodríguez-Fornells A, Urbano G, Morte A, Antonijoan R, Montero M, et al. Subjective effects and tolerability of the South American psychoactive beverage Ayahuasca in healthy volunteers. Psychopharmacology (Berl). 2001;154(1):85–95. pmid:11292011
- View Article
- PubMed/NCBI
- Google Scholar
10. Riba J, Valle M, Urbano G, Yritia M, Morte A, Barbanoj M. Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics. J Pharmacol Exp Ther. 2003;306(1):73–83.
- View Article
- Google Scholar
11. Dos Santos RG, Valle M, Bouso JC, Nomdedéu JF, Rodríguez-Espinosa J, McIlhenny EH, et al. Autonomic, neuroendocrine, and immunological effects of ayahuasca: a comparative study with d-amphetamine. J Clin Psychopharmacol. 2011;31(6):717–26. pmid:22005052
- View Article
- PubMed/NCBI
- Google Scholar
12. Dos Santos RG, Grasa E, Valle M, Ballester MR, Bouso JC, Nomdedéu JF, et al. Pharmacology of ayahuasca administered in two repeated doses. Psychopharmacology (Berl). 2012;219(4):1039–53. pmid:21842159
- View Article
- PubMed/NCBI
- Google Scholar
13. Schenberg E, Alexandre J, Filev R, Cravo A, Sato J, Muthukumaraswamy S. Acute biphasic effects of ayahuasca. PLoS One. 2015;10(9).
- View Article
- Google Scholar
14. Valle M, Maqueda AE, Rabella M, Rodríguez-Pujadas A, Antonijoan RM, Romero S, et al. Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans. Eur Neuropsychopharmacol. 2016;26(7):1161–75. pmid:27039035
- View Article
- PubMed/NCBI
- Google Scholar
15. Alonso JF, Romero S, Mañanas MÀ, Riba J. Serotonergic psychedelics temporarily modify information transfer in humans. Int J Neuropsychopharmacol. 2015;18(8):pyv039. pmid:25820842
- View Article
- PubMed/NCBI
- Google Scholar
16. Riba J, Romero S, Grasa E, Mena E, Carrió I, Barbanoj MJ. Increased frontal and paralimbic activation following ayahuasca, the pan-Amazonian inebriant. Psychopharmacology (Berl). 2006;186(1):93–8. pmid:16575552
- View Article
- PubMed/NCBI
- Google Scholar
17. Sanches RF, de Lima Osório F, Dos Santos RG, Macedo LRH, Maia-de-Oliveira JP, Wichert-Ana L, et al. Antidepressant Effects of a Single Dose of Ayahuasca in Patients With Recurrent Depression: A SPECT Study. J Clin Psychopharmacol. 2016;36(1):77–81. pmid:26650973
- View Article
- PubMed/NCBI
- Google Scholar
18. Palhano-Fontes F, Andrade KC, Tofoli LF, Santos AC, Crippa JAS, Hallak JEC, et al. The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network. PLoS One. 2015;10(2):e0118143. pmid:25693169
- View Article
- PubMed/NCBI
- Google Scholar
19. Bouso JC, Pedrero-Pérez EJ, Gandy S, Alcázar-Córcoles MÁ. Measuring the subjective: revisiting the psychometric properties of three rating scales that assess the acute effects of hallucinogens. Hum Psychopharmacol. 2016;31(5):356–72. pmid:27470427
- View Article
- PubMed/NCBI
- Google Scholar
20. Osório F de L, Sanches RF, Macedo LR, Santos RG dos, Maia-de-Oliveira JP, Wichert-Ana L, et al. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Braz J Psychiatry. 2015;37(1):13–20. pmid:25806551
- View Article
- PubMed/NCBI
- Google Scholar
21. Palhano-Fontes F, Barreto D, Onias H, Andrade KC, Novaes MM, Pessoa JA, et al. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med. 2019;49(4):655–63. pmid:29903051
- View Article
- PubMed/NCBI
- Google Scholar
22. van Oorsouw K, Toennes SW, Ramaekers JG. Therapeutic effect of an ayahuasca analogue in clinically depressed patients: a longitudinal observational study. Psychopharmacology (Berl). 2022;239(6):1839–52. pmid:35072760
- View Article
- PubMed/NCBI
- Google Scholar
23. Dos Santos RG, Osório F de L, Rocha JM, Rossi GN, Bouso JC, Rodrigues LS, et al. Ayahuasca Improves Self-perception of Speech Performance in Subjects With Social Anxiety Disorder: A Pilot, Proof-of-Concept, Randomized, Placebo-Controlled Trial. J Clin Psychopharmacol. 2021;41(5):540–50. pmid:34166299
- View Article
- PubMed/NCBI
- Google Scholar
24. Dos Santos RG, Rocha JM, Rossi GN, Osório FL, Ona G, Bouso JC, et al. Effects of ayahuasca on the endocannabinoid system of healthy volunteers and in volunteers with social anxiety disorder: Results from two pilot, proof-of-concept, randomized, placebo-controlled trials. Hum Psychopharmacol. 2022;37(4):e2834. pmid:35107855
- View Article
- PubMed/NCBI
- Google Scholar
25. González D, Carvalho M, Cantillo J, Aixalá M, Farré M. Potential use of ayahuasca in grief therapy. Omega (Westport). 2019;79(3):260–85.
- View Article
- Google Scholar
26. González D, Cantillo J, Pérez I, Farré M, Feilding A, Obiols JE, et al. Therapeutic potential of ayahuasca in grief: a prospective, observational study. Psychopharmacology (Berl). 2020;237(4):1171–82. pmid:31938878
- View Article
- PubMed/NCBI
- Google Scholar
27. González D, Aixalà M, Neimeyer R, Cantillo J, Nicolson D, Farré M. Restorative retelling for processing psychedelic experiences: rationale and case study of complicated grief. Front Psychol. 2022;13:832879.
- View Article
- Google Scholar
28. Domínguez-Clavé E, Soler J, Pascual JC, Elices M, Franquesa A, Valle M, et al. Ayahuasca improves emotion dysregulation in a community sample and in individuals with borderline-like traits. Psychopharmacology (Berl). 2019;236(2):573–80. pmid:30406413
- View Article
- PubMed/NCBI
- Google Scholar
29. Rodrigues LS, Rossi GN, Rocha JM, L Osório F, Bouso JC, Hallak JEC, et al. Effects of ayahuasca and its alkaloids on substance use disorders: an updated (2016-2020) systematic review of preclinical and human studies. Eur Arch Psychiatry Clin Neurosci. 2022;272(4):541–56. pmid:33914164
- View Article
- PubMed/NCBI
- Google Scholar
30. Gonzalez D, Cantillo J, Perez I, Carvalho M, Aronovich A, Farre M. The Shipibo ceremonial use of ayahuasca to promote well-being: An observational study. Front Pharmacol. 2021;12:623923.
- View Article
- Google Scholar
31. Kiraga M, Mason N, Uthaug M, van Oorsouw K, Toennes S, Ramaekers J. Persisting effects of ayahuasca on empathy, creative thinking, decentering, personality, and well-being. Front Pharmacol. 2021;12:721537.
- View Article
- Google Scholar
32. Jiménez-Garrido DF, Gómez-Sousa M, Ona G, Dos Santos RG, Hallak JEC, Alcázar-Córcoles MÁ, et al. Effects of ayahuasca on mental health and quality of life in naïve users: A longitudinal and cross-sectional study combination. Sci Rep. 2020;10(1):4075. pmid:32139811
- View Article
- PubMed/NCBI
- Google Scholar
33. Kuypers KPC, Riba J, de la Fuente Revenga M, Barker S, Theunissen EL, Ramaekers JG. Ayahuasca enhances creative divergent thinking while decreasing conventional convergent thinking. Psychopharmacology (Berl). 2016;233(18):3395–403. pmid:27435062
- View Article
- PubMed/NCBI
- Google Scholar
34. Ona G, Kohek M, Massaguer T, Gomariz A, Jiménez DF, Dos Santos RG, et al. Ayahuasca and Public Health: Health Status, Psychosocial Well-Being, Lifestyle, and Coping Strategies in a Large Sample of Ritual Ayahuasca Users. J Psychoactive Drugs. 2019;51(2):135–45. pmid:30732540
- View Article
- PubMed/NCBI
- Google Scholar
35. Kohek M, Ona G, van Elk M, Dos Santos RG, Hallak JEC, Alcázar-Córcoles MÁ, et al. Ayahuasca and Public Health II: Health Status in a Large Sample of Ayahuasca-Ceremony Participants in the Netherlands. J Psychoactive Drugs. 2023;55(3):247–58. pmid:35635152
- View Article
- PubMed/NCBI
- Google Scholar
36. Barbosa PCR, Strassman RJ, da Silveira DX, Areco K, Hoy R, Pommy J, et al. Psychological and neuropsychological assessment of regular hoasca users. Compr Psychiatry. 2016;71:95–105. pmid:27653781
- View Article
- PubMed/NCBI
- Google Scholar
37. Bouso JC, González D, Fondevila S, Cutchet M, Fernández X, Ribeiro Barbosa PC, et al. Personality, psychopathology, life attitudes and neuropsychological performance among ritual users of Ayahuasca: a longitudinal study. PLoS One. 2012;7(8):e42421. pmid:22905130
- View Article
- PubMed/NCBI
- Google Scholar
38. Bouso J, Palhano-Fontes F, Rodríguez-Fornells A, Ribeiro S, Sanches R, Crippa J. Long-term use of psychedelic drugs is associated with differences in brain structure and personality in humans. Eur Neuropsychopharmacol. 2015;25(4):483–92.
- View Article
- Google Scholar
39. Fonseca AM, Dos Santos RG, de Medeiros LS, Veiga TAM, Cassas F, Bruniera CP, et al. Long-term ayahuasca use is associated with preserved global cognitive function and improved memory: a cross-sectional study with ritual users. Eur Arch Psychiatry Clin Neurosci. 2025;275(2):519–31. pmid:38780800
- View Article
- PubMed/NCBI
- Google Scholar
40. Mallaroni P, Mason NL, Kloft L, Reckweg JT, van Oorsouw K, Ramaekers JG. Cortical structural differences following repeated ayahuasca use hold molecular signatures. Front Neurosci. 2023;17:1217079. pmid:37869513
- View Article
- PubMed/NCBI
- Google Scholar
41. Gómez-Sousa M, Jiménez-Garrido D, Ona G, Dos Santos R, Hallak J, Alcázar-Córcoles M. Acute psychological adverse reactions in first-time ritual ayahuasca users: A prospective case series. J Clin Psychopharmacol. 2021;41(2):163–71.
- View Article
- Google Scholar
42. Perkins D, Schubert V, Simonová H, Tófoli LF, Bouso JC, Horák M, et al. Influence of Context and Setting on the Mental Health and Wellbeing Outcomes of Ayahuasca Drinkers: Results of a Large International Survey. Front Pharmacol. 2021;12:623979. pmid:33967757
- View Article
- PubMed/NCBI
- Google Scholar
43. Yaden DB, Griffiths RR. The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects. ACS Pharmacol Transl Sci. 2020;4(2):568–72. pmid:33861219
- View Article
- PubMed/NCBI
- Google Scholar
44. Ko K, Knight G, Rucker JJ, Cleare AJ. Psychedelics, mystical experience, and therapeutic efficacy: A systematic review. Front Psychiatry. 2022;13:917199.
- View Article
- Google Scholar
45. Evans J, Robinson OC, Argyri EK, Suseelan S, Murphy-Beiner A, McAlpine R, et al. Extended difficulties following the use of psychedelic drugs: A mixed methods study. PLoS One. 2023;18(10):e0293349. pmid:37874826
- View Article
- PubMed/NCBI
- Google Scholar
46. Gashi L, Sandberg S, Pedersen W. Making “bad trips” good: How users of psychedelics narratively transform challenging trips into valuable experiences. Int J Drug Policy. 2021;87:102997. pmid:33080454
- View Article
- PubMed/NCBI
- Google Scholar
47. Bzdok D, Ioannidis JPA. Exploration, Inference, and Prediction in Neuroscience and Biomedicine. Trends Neurosci. 2019;42(4):251–62. pmid:30808574
- View Article
- PubMed/NCBI
- Google Scholar
48. Rajula HSR, Verlato G, Manchia M, Antonucci N, Fanos V. Comparison of Conventional Statistical Methods with Machine Learning in Medicine: Diagnosis, Drug Development, and Treatment. Medicina (Kaunas). 2020;56(9):455. pmid:32911665
- View Article
- PubMed/NCBI
- Google Scholar
49. Griffiths RR, Johnson MW, Richards WA, Richards BD, McCann U, Jesse R. Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology (Berl). 2011;218(4):649–65. pmid:21674151
- View Article
- PubMed/NCBI
- Google Scholar
50. Maruish ME. User’s manual for the SF-12v2 health survey. 3rd ed. Lincoln, RI: Quality Metric Incorporated; 2012.
51. Kroenke K, Spitzer RL, Williams JBW, Löwe B. An ultra-brief screening scale for anxiety and depression: the PHQ-4. Psychosomatics. 2009;50(6):613–21. pmid:19996233
- View Article
- PubMed/NCBI
- Google Scholar
52. Wang Y, Li Y, Pu W, Wen K, Shugart Y, Xiong M, et al. Random Bits Forest: a Strong Classifier/Regressor for Big Data. Sci Rep. 2016;6:30086.
- View Article
- Google Scholar
53. Speiser JL, Miller ME, Tooze J, Ip E. A Comparison of Random Forest Variable Selection Methods for Classification Prediction Modeling. Expert Syst Appl. 2019;134:93–101. pmid:32968335
- View Article
- PubMed/NCBI
- Google Scholar
54. Shahab S, Mulsant BH, Levesque ML, Calarco N, Nazeri A, Wheeler AL, et al. Brain structure, cognition, and brain age in schizophrenia, bipolar disorder, and healthy controls. Neuropsychopharmacology. 2019;44(5):898–906. pmid:30635616
- View Article
- PubMed/NCBI
- Google Scholar
55. Ward MM, Pajevic S, Dreyfuss J, Malley JD. Short-term prediction of mortality in patients with systemic lupus erythematosus: classification of outcomes using random forests. Arthritis Rheum. 2006;55(1):74–80. pmid:16463416
- View Article
- PubMed/NCBI
- Google Scholar
56. Gregorutti B, Michel B, Saint-Pierre P. Correlation and variable importance in random forests. Stat Comput. 2017;27:659–78.
- View Article
- Google Scholar
57. R Core Team. R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2018.
58. Huang J, Zhu Q, Yang L, Feng J. A non-parameter outlier detection algorithm based on Natural Neighbor. Knowl-Based Syst. 2016;92:71–7.
- View Article
- Google Scholar
59. Madsen JH. DDoutlier: Distance & Density-Based Outlier Detection. R package version 0.1.0; 2018. Available from: https://CRAN.R-project.org/package=DDoutlier
- View Article
- Google Scholar
60. Kuhn M. Building predictive models in R using the caret package. J Stat Softw. 2008;28(5):1–26.
- View Article
- Google Scholar
61. Rosseel I. lavaan: An R Package for Structural Equation Modeling. J Stat Softw. 2012;48(2):1–36.
- View Article
- Google Scholar
62. Lei P. Evaluating estimation methods for ordinal data in structural equation modeling. Qual Quant. 2009;43:495–507.
- View Article
- Google Scholar
63. Li C-H. Statistical estimation of structural equation models with a mixture of continuous and categorical observed variables. Behav Res Methods. 2021;53(5):2191–213. pmid:33791955
- View Article
- PubMed/NCBI
- Google Scholar
64. Xia Y, Yang Y. RMSEA, CFI, and TLI in structural equation modeling with ordered categorical data: The story they tell depends on the estimation methods. Behav Res Methods. 2019;51(1):409–28. pmid:29869222
- View Article
- PubMed/NCBI
- Google Scholar
65. Shi D, Maydeu-Olivares A. The Effect of Estimation Methods on SEM Fit Indices. Educ Psychol Meas. 2020;80(3):421–45. pmid:32425213
- View Article
- PubMed/NCBI
- Google Scholar
66. Bauer DJ, Curran PJ. Structural equation modeling: R demonstration notes (Version 2019.3). Curran-Bauer Analytics, Durham: NC; 2019.
67. Zhang Z, Yuan K-H, editors. Practical Statistical Power Analysis Using Webpower and R. Granger, IN: ISDSA Press; 2018. Available from: https://webpower.psychstat.org
68. Sarris J, Perkins D, Cribb L, Schubert V, Opaleye E, Bouso JC, et al. Ayahuasca use and reported effects on depression and anxiety symptoms: An international cross-sectional study of 11,912 consumers. J Affect Disord Rep. 2021;4:100098.
- View Article
- Google Scholar
69. Perkins D, Opaleye ES, Simonova H, Bouso JC, Tófoli LF, GalvÃo-Coelho NL, et al. Associations between ayahuasca consumption in naturalistic settings and current alcohol and drug use: Results of a large international cross-sectional survey. Drug Alcohol Rev. 2022;41(1):265–74. pmid:34308566
- View Article
- PubMed/NCBI
- Google Scholar
70. Perkins D, Pagni BA, Sarris J, Barbosa PCR, Chenhall R. Changes in mental health, wellbeing and personality following ayahuasca consumption: Results of a naturalistic longitudinal study. Front Pharmacol. 2022;13:884703. pmid:36386199
- View Article
- PubMed/NCBI
- Google Scholar
71. Perkins D, Opaleye E, Bouso JC, Tófoli LF, Sarris J, Schubert V, et al. Insights, Life Changes and Lifestyle Changes Reported by Individuals Consuming Ayahuasca in Naturalistic Settings: Nature, Frequency and Associations with Mental Health and Wellbeing. Psychoactives. 2023;2(4):256–86.
- View Article
- Google Scholar
72. Cowley-Court T, Chenhall R, Sarris J, Bouso JC, Tófoli LF, Opaleye ES, et al. Life after Ayahuasca: A Qualitative Analysis of the Psychedelic Integration Experiences of 1630 Ayahuasca Drinkers from a Global Survey. Psychoactives. 2023;2(2):201–21.
- View Article
- Google Scholar
73. Barbosa PCR, Cazorla IM, Giglio JS, Strassman R. A six-month prospective evaluation of personality traits, psychiatric symptoms and quality of life in ayahuasca-naïve subjects. J Psychoactive Drugs. 2009;41(3):205–12. pmid:19999673
- View Article
- PubMed/NCBI
- Google Scholar
74. Grob CS, McKenna DJ, Callaway JC, Brito GS, Neves ES, Oberlaender G, et al. Human psychopharmacology of hoasca, a plant hallucinogen used in ritual context in Brazil. J Nerv Ment Dis. 1996;184(2):86–94. pmid:8596116
- View Article
- PubMed/NCBI
- Google Scholar
75. Kohek M. Through the looking-glass: The use of psychoactive plants in Catalonia [doctoral thesis]. Tarragona: Universitat Rovira I Virgili; 2021. Available from: http://hdl.handle.net/10803/671199.
76. Uthaug MV, Mason NL, Toennes SW, Reckweg JT, de Sousa Fernandes Perna EB, Kuypers KPC, et al. A placebo-controlled study of the effects of ayahuasca, set and setting on mental health of participants in ayahuasca group retreats. Psychopharmacology (Berl). 2021;238(7):1899–910. pmid:33694031
- View Article
- PubMed/NCBI
- Google Scholar
77. Ware J Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care. 1996;34(3):220–33. pmid:8628042
- View Article
- PubMed/NCBI
- Google Scholar
78. So CJ, Miller KE, Gehrman PR. Sleep Disturbances Associated With Posttraumatic Stress Disorder. Psychiatr Ann. 2023;53(11):491–5. pmid:38293647
- View Article
- PubMed/NCBI
- Google Scholar
79. Skeie-Larsen M, Stave R, Grønli J, Bjorvatn B, Wilhelmsen-Langeland A, Zandi A, et al. The Effects of Pharmacological Treatment of Nightmares: A Systematic Literature Review and Meta-Analysis of Placebo-Controlled, Randomized Clinical Trials. Int J Environ Res Public Health. 2022;20(1):777. pmid:36613097
- View Article
- PubMed/NCBI
- Google Scholar
80. Durante Í, Dos Santos RG, Bouso JC, Hallak JE. Risk assessment of ayahuasca use in a religious context: self-reported risk factors and adverse effects. Braz J Psychiatry. 2021;43(4):362–9. pmid:33146343
- View Article
- PubMed/NCBI
- Google Scholar
81. Rocha JM, Rossi GN, Osório FL, Hallak JEC, Dos Santos RG. Adverse Effects After Ayahuasca Administration in the Clinical Setting. J Clin Psychopharmacol. 2022;42(3):321–4. pmid:35289542
- View Article
- PubMed/NCBI
- Google Scholar
82. Bremler R, Katati N, Shergill P, Erritzoe D, Carhart-Harris RL. Case analysis of long-term negative psychological responses to psychedelics. Sci Rep. 2023;13(1):15998. pmid:37749109
- View Article
- PubMed/NCBI
- Google Scholar
83. Weber SR, Pargament KI. The role of religion and spirituality in mental health. Curr Opin Psychiatry. 2014;27(5):358–63. pmid:25046080
- View Article
- PubMed/NCBI
- Google Scholar
84. Griffiths R, Johnson M, Richards W, Richards B, Jesse R, MacLean K. Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors. J Psychopharmacol. 2018;32(1):49–69.
- View Article
- Google Scholar
85. Goldsmith HH, Lemery KS. Linking temperamental fearfulness and anxiety symptoms: a behavior-genetic perspective. Biol Psychiatry. 2000;48(12):1199–209. pmid:11137060
- View Article
- PubMed/NCBI
- Google Scholar
86. Headley DB, Kanta V, Kyriazi P, Paré D. Embracing Complexity in Defensive Networks. Neuron. 2019;103(2):189–201. pmid:31319049
- View Article
- PubMed/NCBI
- Google Scholar
87. LeDuke DO, Borio M, Miranda R, Tye KM. Anxiety and depression: A top-down, bottom-up model of circuit function. Ann N Y Acad Sci. 2023;1525(1):70–87. pmid:37129246
- View Article
- PubMed/NCBI
- Google Scholar
88. McKenna D, Riba J. New world tryptamine hallucinogens and the neuroscience of ayahuasca. Current Topics in Behavioral Neuroscience. 2018;36:283–311.
- View Article
- Google Scholar
89. Bouso JC, Révész D, Ona G, Rossi GN, Rocha JM, Dos Santos RG, et al. Longitudinal and transcultural assessment of the relationship between hallucinogens, well-being, and post-traumatic growth during the COVID-19 pandemic. Sci Rep. 2023;13(1):14052. pmid:37696900
- View Article
- PubMed/NCBI
- Google Scholar
90. Ona G, Révész D, Kohek M, Rossi G, Rocha J, Dos Santos R. Tripping to cope: Coping strategies and use of hallucinogens during the COVID-19 pandemic in three cultural contexts. Psychoactives. 2022;1(1):16–30.
- View Article
- Google Scholar
91. Révész D, Ona G, Rossi GN, Rocha JM, Dos Santos RG, Hallak JEC, et al. Cross-Sectional Associations Between Lifetime Use of Psychedelic Drugs and Psychometric Measures During the COVID-19 Confinement: A Transcultural Study. Front Psychiatry. 2021;12:687546. pmid:34220590
- View Article
- PubMed/NCBI
- Google Scholar
92. Palhano-Fontes F, Soares BL, Galvão-Coelho NL, Arcoverde E, Araujo DB. Ayahuasca for the Treatment of Depression. Curr Top Behav Neurosci. 2022;56:113–24. pmid:34761362
- View Article
- PubMed/NCBI
- Google Scholar
93. Ko K, Kopra EI, Cleare AJ, Rucker JJ. Psychedelic therapy for depressive symptoms: A systematic review and meta-analysis. J Affect Disord. 2023;322:194–204. pmid:36209780
- View Article
- PubMed/NCBI
- Google Scholar
94. White E, Kennedy T, Ruffell S, Perkins D, Sarris J. Ayahuasca and Dimethyltryptamine Adverse Events and Toxicity Analysis: A Systematic Thematic Review. Int J Toxicol. 2024;43(3):327–39. pmid:38363085
- View Article
- PubMed/NCBI
- Google Scholar
95. Schlag AK, Aday J, Salam I, Neill JC, Nutt DJ. Adverse effects of psychedelics: From anecdotes and misinformation to systematic science. J Psychopharmacol. 2022;36(3):258–72. pmid:35107059
- View Article
- PubMed/NCBI
- Google Scholar
96. Kohek M, Sánchez Avilés C, Romaní O, Bouso JC. Ancient psychoactive plants in a global village: The ritual use of cannabis in a self-managed community in Catalonia. Int J Drug Policy. 2021;98:103390. pmid:34340169
- View Article
- PubMed/NCBI
- Google Scholar
97. Kohek M, Bouso J, Oña G. De crecer en la selva a practicar la ayahuasca en la ciudad: una exploración de la globalización de la ayahuasca en términos de autenticidad, autoatención y de los retos de dicha globalización para la antropología médica. Rev Antropol Soc. 2023;32(2):141–54.
- View Article
- Google Scholar
98. Wickramaratne PJ, Yangchen T, Lepow L, Patra BG, Glicksburg B, Talati A, et al. Social connectedness as a determinant of mental health: A scoping review. PLoS One. 2022;17(10):e0275004. pmid:36228007
- View Article
- PubMed/NCBI
- Google Scholar
99. Ko K, Carter B, Cleare AJ, Rucker JJ. Predicting the Intensity of Psychedelic-Induced Mystical and Challenging Experience in a Healthy Population: An Exploratory Post-Hoc Analysis. Neuropsychiatr Dis Treat. 2023;19:2105–13. pmid:37818448
- View Article
- PubMed/NCBI
- Google Scholar
100. Ona G, Berrada A, Bouso JC. Communalistic use of psychoactive plants as a bridge between traditional healing practices and Western medicine: A new path for the Global Mental Health movement. Transcult Psychiatry. 2022;59(5):638–51. pmid:34665080
- View Article
- PubMed/NCBI
- Google Scholar
101. Aixalà MB. Psychedelic Integration: Psychotherapy for Non-Ordinary States of Consciousness. Santa Fe: Synergetic Press; 2022.
102. International Center for Ethnobotanical Education, Research, and Service (ICEERS). Ayahuasca: Global Consumption & Reported Deaths. ICEERS; 2023. Available from: https://www.iceers.org/ayahuasca-global-consumption-deaths/
103. International Narcotics Control Board (INCB). Report of the International Narcotics Control Board for 2010. Vienna: United Nations; 2011. Available from: https://www.incb.org/documents/Publications/AnnualReports/AR2010/AR_2010_English.pdf
104. International Center for Ethnobotanical Education, Research, and Service (ICEERS). Ayahuasca Technical Report: A 2019 Guide. Barcelona: ICEERS; 2019 [Internet]. Disponible en: https://www.iceers.org/wp-content/uploads/2020/05/Guia-ayahuasca_eng_30.09.19.pdf

[ref1] 1. Miller MJ, Albarracin-Jordan J, Moore C, Capriles JM. Chemical evidence for the use of multiple psychotropic plants in a 1,000-year-old ritual bundle from South America. Proc Natl Acad Sci U S A. 2019;116(23):11207–12. pmid:31061128
View Article
PubMed/NCBI
Google Scholar

[2] View Article

[3] PubMed/NCBI

[4] Google Scholar

[ref2] 2. Labate BC, de Rose IS, dos Santos RG, editors. Ayahuasca Religions: A Comprehensive Bibliography & Critical Essays. San Jose (CA): MAPS, Multidisciplinary Association for Psychedelic Studies; 2008.

[ref3] 3. Labate BC, Jungaberle H, editors. The Internationalization of Ayahuasca. Berlin/Zurich: Lit Verlag; 2011.

[ref4] 4. Prue R, Voss R. Indigenous healing practice: Ayahuasca. Opening a discussion. J Pastoral Care Counsel. 2014;68(1–2):6.
View Article
Google Scholar

[8] View Article

[9] Google Scholar

[ref5] 5. Stiffler J. Ayahuasca: From the Amazon to a city near you. Am J Addict. 2018;27(8):648–9.
View Article
Google Scholar

[11] View Article

[12] Google Scholar

[ref6] 6. Bouso JC, Andión Ó, Sarris JJ, Scheidegger M, Tófoli LF, Opaleye ES, et al. Adverse effects of ayahuasca: Results from the Global Ayahuasca Survey. PLOS Glob Public Health. 2022;2(11):e0000438. pmid:36962494
View Article
PubMed/NCBI
Google Scholar

[14] View Article

[15] PubMed/NCBI

[16] Google Scholar

[ref7] 7. Riba J, McIlhenny EH, Valle M, Bouso JC, Barker SA. Metabolism and disposition of N,N-dimethyltryptamine and harmala alkaloids after oral administration of ayahuasca. Drug Test Anal. 2012;4(7–8):610–6. pmid:22514127
View Article
PubMed/NCBI
Google Scholar

[18] View Article

[19] PubMed/NCBI

[20] Google Scholar

[ref8] 8. Strassman RJ. Human psychopharmacology of N,N-dimethyltryptamine. Behav Brain Res. 1996;73(1–2):121–4. pmid:8788488
View Article
PubMed/NCBI
Google Scholar

[22] View Article

[23] PubMed/NCBI

[24] Google Scholar

[ref9] 9. Riba J, Rodríguez-Fornells A, Urbano G, Morte A, Antonijoan R, Montero M, et al. Subjective effects and tolerability of the South American psychoactive beverage Ayahuasca in healthy volunteers. Psychopharmacology (Berl). 2001;154(1):85–95. pmid:11292011
View Article
PubMed/NCBI
Google Scholar

[26] View Article

[27] PubMed/NCBI

[28] Google Scholar

[ref10] 10. Riba J, Valle M, Urbano G, Yritia M, Morte A, Barbanoj M. Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics. J Pharmacol Exp Ther. 2003;306(1):73–83.
View Article
Google Scholar

[30] View Article

[31] Google Scholar

[ref11] 11. Dos Santos RG, Valle M, Bouso JC, Nomdedéu JF, Rodríguez-Espinosa J, McIlhenny EH, et al. Autonomic, neuroendocrine, and immunological effects of ayahuasca: a comparative study with d-amphetamine. J Clin Psychopharmacol. 2011;31(6):717–26. pmid:22005052
View Article
PubMed/NCBI
Google Scholar

[33] View Article

[34] PubMed/NCBI

[35] Google Scholar

[ref12] 12. Dos Santos RG, Grasa E, Valle M, Ballester MR, Bouso JC, Nomdedéu JF, et al. Pharmacology of ayahuasca administered in two repeated doses. Psychopharmacology (Berl). 2012;219(4):1039–53. pmid:21842159
View Article
PubMed/NCBI
Google Scholar

[37] View Article

[38] PubMed/NCBI

[39] Google Scholar

[ref13] 13. Schenberg E, Alexandre J, Filev R, Cravo A, Sato J, Muthukumaraswamy S. Acute biphasic effects of ayahuasca. PLoS One. 2015;10(9).
View Article
Google Scholar

[41] View Article

[42] Google Scholar

[ref14] 14. Valle M, Maqueda AE, Rabella M, Rodríguez-Pujadas A, Antonijoan RM, Romero S, et al. Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans. Eur Neuropsychopharmacol. 2016;26(7):1161–75. pmid:27039035
View Article
PubMed/NCBI
Google Scholar

[44] View Article

[45] PubMed/NCBI

[46] Google Scholar

[ref15] 15. Alonso JF, Romero S, Mañanas MÀ, Riba J. Serotonergic psychedelics temporarily modify information transfer in humans. Int J Neuropsychopharmacol. 2015;18(8):pyv039. pmid:25820842
View Article
PubMed/NCBI
Google Scholar

[48] View Article

[49] PubMed/NCBI

[50] Google Scholar

[ref16] 16. Riba J, Romero S, Grasa E, Mena E, Carrió I, Barbanoj MJ. Increased frontal and paralimbic activation following ayahuasca, the pan-Amazonian inebriant. Psychopharmacology (Berl). 2006;186(1):93–8. pmid:16575552
View Article
PubMed/NCBI
Google Scholar

[52] View Article

[53] PubMed/NCBI

[54] Google Scholar

[ref17] 17. Sanches RF, de Lima Osório F, Dos Santos RG, Macedo LRH, Maia-de-Oliveira JP, Wichert-Ana L, et al. Antidepressant Effects of a Single Dose of Ayahuasca in Patients With Recurrent Depression: A SPECT Study. J Clin Psychopharmacol. 2016;36(1):77–81. pmid:26650973
View Article
PubMed/NCBI
Google Scholar

[56] View Article

[57] PubMed/NCBI

[58] Google Scholar

[ref18] 18. Palhano-Fontes F, Andrade KC, Tofoli LF, Santos AC, Crippa JAS, Hallak JEC, et al. The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network. PLoS One. 2015;10(2):e0118143. pmid:25693169
View Article
PubMed/NCBI
Google Scholar

[60] View Article

[61] PubMed/NCBI

[62] Google Scholar

[ref19] 19. Bouso JC, Pedrero-Pérez EJ, Gandy S, Alcázar-Córcoles MÁ. Measuring the subjective: revisiting the psychometric properties of three rating scales that assess the acute effects of hallucinogens. Hum Psychopharmacol. 2016;31(5):356–72. pmid:27470427
View Article
PubMed/NCBI
Google Scholar

[64] View Article

[65] PubMed/NCBI

[66] Google Scholar

[ref20] 20. Osório F de L, Sanches RF, Macedo LR, Santos RG dos, Maia-de-Oliveira JP, Wichert-Ana L, et al. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Braz J Psychiatry. 2015;37(1):13–20. pmid:25806551
View Article
PubMed/NCBI
Google Scholar

[68] View Article

[69] PubMed/NCBI

[70] Google Scholar

[ref21] 21. Palhano-Fontes F, Barreto D, Onias H, Andrade KC, Novaes MM, Pessoa JA, et al. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med. 2019;49(4):655–63. pmid:29903051
View Article
PubMed/NCBI
Google Scholar

[72] View Article

[73] PubMed/NCBI

[74] Google Scholar

[ref22] 22. van Oorsouw K, Toennes SW, Ramaekers JG. Therapeutic effect of an ayahuasca analogue in clinically depressed patients: a longitudinal observational study. Psychopharmacology (Berl). 2022;239(6):1839–52. pmid:35072760
View Article
PubMed/NCBI
Google Scholar

[76] View Article

[77] PubMed/NCBI

[78] Google Scholar

[ref23] 23. Dos Santos RG, Osório F de L, Rocha JM, Rossi GN, Bouso JC, Rodrigues LS, et al. Ayahuasca Improves Self-perception of Speech Performance in Subjects With Social Anxiety Disorder: A Pilot, Proof-of-Concept, Randomized, Placebo-Controlled Trial. J Clin Psychopharmacol. 2021;41(5):540–50. pmid:34166299
View Article
PubMed/NCBI
Google Scholar

[80] View Article

[81] PubMed/NCBI

[82] Google Scholar

[ref24] 24. Dos Santos RG, Rocha JM, Rossi GN, Osório FL, Ona G, Bouso JC, et al. Effects of ayahuasca on the endocannabinoid system of healthy volunteers and in volunteers with social anxiety disorder: Results from two pilot, proof-of-concept, randomized, placebo-controlled trials. Hum Psychopharmacol. 2022;37(4):e2834. pmid:35107855
View Article
PubMed/NCBI
Google Scholar

[84] View Article

[85] PubMed/NCBI

[86] Google Scholar

[ref25] 25. González D, Carvalho M, Cantillo J, Aixalá M, Farré M. Potential use of ayahuasca in grief therapy. Omega (Westport). 2019;79(3):260–85.
View Article
Google Scholar

[88] View Article

[89] Google Scholar

[ref26] 26. González D, Cantillo J, Pérez I, Farré M, Feilding A, Obiols JE, et al. Therapeutic potential of ayahuasca in grief: a prospective, observational study. Psychopharmacology (Berl). 2020;237(4):1171–82. pmid:31938878
View Article
PubMed/NCBI
Google Scholar

[91] View Article

[92] PubMed/NCBI

[93] Google Scholar

[ref27] 27. González D, Aixalà M, Neimeyer R, Cantillo J, Nicolson D, Farré M. Restorative retelling for processing psychedelic experiences: rationale and case study of complicated grief. Front Psychol. 2022;13:832879.
View Article
Google Scholar

[95] View Article

[96] Google Scholar

[ref28] 28. Domínguez-Clavé E, Soler J, Pascual JC, Elices M, Franquesa A, Valle M, et al. Ayahuasca improves emotion dysregulation in a community sample and in individuals with borderline-like traits. Psychopharmacology (Berl). 2019;236(2):573–80. pmid:30406413
View Article
PubMed/NCBI
Google Scholar

[98] View Article

[99] PubMed/NCBI

[100] Google Scholar

[ref29] 29. Rodrigues LS, Rossi GN, Rocha JM, L Osório F, Bouso JC, Hallak JEC, et al. Effects of ayahuasca and its alkaloids on substance use disorders: an updated (2016-2020) systematic review of preclinical and human studies. Eur Arch Psychiatry Clin Neurosci. 2022;272(4):541–56. pmid:33914164
View Article
PubMed/NCBI
Google Scholar

[102] View Article

[103] PubMed/NCBI

[104] Google Scholar

[ref30] 30. Gonzalez D, Cantillo J, Perez I, Carvalho M, Aronovich A, Farre M. The Shipibo ceremonial use of ayahuasca to promote well-being: An observational study. Front Pharmacol. 2021;12:623923.
View Article
Google Scholar

[106] View Article

[107] Google Scholar

[ref31] 31. Kiraga M, Mason N, Uthaug M, van Oorsouw K, Toennes S, Ramaekers J. Persisting effects of ayahuasca on empathy, creative thinking, decentering, personality, and well-being. Front Pharmacol. 2021;12:721537.
View Article
Google Scholar

[109] View Article

[110] Google Scholar

[ref32] 32. Jiménez-Garrido DF, Gómez-Sousa M, Ona G, Dos Santos RG, Hallak JEC, Alcázar-Córcoles MÁ, et al. Effects of ayahuasca on mental health and quality of life in naïve users: A longitudinal and cross-sectional study combination. Sci Rep. 2020;10(1):4075. pmid:32139811
View Article
PubMed/NCBI
Google Scholar

[112] View Article

[113] PubMed/NCBI

[114] Google Scholar

[ref33] 33. Kuypers KPC, Riba J, de la Fuente Revenga M, Barker S, Theunissen EL, Ramaekers JG. Ayahuasca enhances creative divergent thinking while decreasing conventional convergent thinking. Psychopharmacology (Berl). 2016;233(18):3395–403. pmid:27435062
View Article
PubMed/NCBI
Google Scholar

[116] View Article

[117] PubMed/NCBI

[118] Google Scholar

[ref34] 34. Ona G, Kohek M, Massaguer T, Gomariz A, Jiménez DF, Dos Santos RG, et al. Ayahuasca and Public Health: Health Status, Psychosocial Well-Being, Lifestyle, and Coping Strategies in a Large Sample of Ritual Ayahuasca Users. J Psychoactive Drugs. 2019;51(2):135–45. pmid:30732540
View Article
PubMed/NCBI
Google Scholar

[120] View Article

[121] PubMed/NCBI

[122] Google Scholar

[ref35] 35. Kohek M, Ona G, van Elk M, Dos Santos RG, Hallak JEC, Alcázar-Córcoles MÁ, et al. Ayahuasca and Public Health II: Health Status in a Large Sample of Ayahuasca-Ceremony Participants in the Netherlands. J Psychoactive Drugs. 2023;55(3):247–58. pmid:35635152
View Article
PubMed/NCBI
Google Scholar

[124] View Article

[125] PubMed/NCBI

[126] Google Scholar

[ref36] 36. Barbosa PCR, Strassman RJ, da Silveira DX, Areco K, Hoy R, Pommy J, et al. Psychological and neuropsychological assessment of regular hoasca users. Compr Psychiatry. 2016;71:95–105. pmid:27653781
View Article
PubMed/NCBI
Google Scholar

[128] View Article

[129] PubMed/NCBI

[130] Google Scholar

[ref37] 37. Bouso JC, González D, Fondevila S, Cutchet M, Fernández X, Ribeiro Barbosa PC, et al. Personality, psychopathology, life attitudes and neuropsychological performance among ritual users of Ayahuasca: a longitudinal study. PLoS One. 2012;7(8):e42421. pmid:22905130
View Article
PubMed/NCBI
Google Scholar

[132] View Article

[133] PubMed/NCBI

[134] Google Scholar

[ref38] 38. Bouso J, Palhano-Fontes F, Rodríguez-Fornells A, Ribeiro S, Sanches R, Crippa J. Long-term use of psychedelic drugs is associated with differences in brain structure and personality in humans. Eur Neuropsychopharmacol. 2015;25(4):483–92.
View Article
Google Scholar

[136] View Article

[137] Google Scholar

[ref39] 39. Fonseca AM, Dos Santos RG, de Medeiros LS, Veiga TAM, Cassas F, Bruniera CP, et al. Long-term ayahuasca use is associated with preserved global cognitive function and improved memory: a cross-sectional study with ritual users. Eur Arch Psychiatry Clin Neurosci. 2025;275(2):519–31. pmid:38780800
View Article
PubMed/NCBI
Google Scholar

[139] View Article

[140] PubMed/NCBI

[141] Google Scholar

[ref40] 40. Mallaroni P, Mason NL, Kloft L, Reckweg JT, van Oorsouw K, Ramaekers JG. Cortical structural differences following repeated ayahuasca use hold molecular signatures. Front Neurosci. 2023;17:1217079. pmid:37869513
View Article
PubMed/NCBI
Google Scholar

[143] View Article

[144] PubMed/NCBI

[145] Google Scholar

[ref41] 41. Gómez-Sousa M, Jiménez-Garrido D, Ona G, Dos Santos R, Hallak J, Alcázar-Córcoles M. Acute psychological adverse reactions in first-time ritual ayahuasca users: A prospective case series. J Clin Psychopharmacol. 2021;41(2):163–71.
View Article
Google Scholar

[147] View Article

[148] Google Scholar

[ref42] 42. Perkins D, Schubert V, Simonová H, Tófoli LF, Bouso JC, Horák M, et al. Influence of Context and Setting on the Mental Health and Wellbeing Outcomes of Ayahuasca Drinkers: Results of a Large International Survey. Front Pharmacol. 2021;12:623979. pmid:33967757
View Article
PubMed/NCBI
Google Scholar

[150] View Article

[151] PubMed/NCBI

[152] Google Scholar

[ref43] 43. Yaden DB, Griffiths RR. The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects. ACS Pharmacol Transl Sci. 2020;4(2):568–72. pmid:33861219
View Article
PubMed/NCBI
Google Scholar

[154] View Article

[155] PubMed/NCBI

[156] Google Scholar

[ref44] 44. Ko K, Knight G, Rucker JJ, Cleare AJ. Psychedelics, mystical experience, and therapeutic efficacy: A systematic review. Front Psychiatry. 2022;13:917199.
View Article
Google Scholar

[158] View Article

[159] Google Scholar

[ref45] 45. Evans J, Robinson OC, Argyri EK, Suseelan S, Murphy-Beiner A, McAlpine R, et al. Extended difficulties following the use of psychedelic drugs: A mixed methods study. PLoS One. 2023;18(10):e0293349. pmid:37874826
View Article
PubMed/NCBI
Google Scholar

[161] View Article

[162] PubMed/NCBI

[163] Google Scholar

[ref46] 46. Gashi L, Sandberg S, Pedersen W. Making “bad trips” good: How users of psychedelics narratively transform challenging trips into valuable experiences. Int J Drug Policy. 2021;87:102997. pmid:33080454
View Article
PubMed/NCBI
Google Scholar

[165] View Article

[166] PubMed/NCBI

[167] Google Scholar

[ref47] 47. Bzdok D, Ioannidis JPA. Exploration, Inference, and Prediction in Neuroscience and Biomedicine. Trends Neurosci. 2019;42(4):251–62. pmid:30808574
View Article
PubMed/NCBI
Google Scholar

[169] View Article

[170] PubMed/NCBI

[171] Google Scholar

[ref48] 48. Rajula HSR, Verlato G, Manchia M, Antonucci N, Fanos V. Comparison of Conventional Statistical Methods with Machine Learning in Medicine: Diagnosis, Drug Development, and Treatment. Medicina (Kaunas). 2020;56(9):455. pmid:32911665
View Article
PubMed/NCBI
Google Scholar

[173] View Article

[174] PubMed/NCBI

[175] Google Scholar

[ref49] 49. Griffiths RR, Johnson MW, Richards WA, Richards BD, McCann U, Jesse R. Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology (Berl). 2011;218(4):649–65. pmid:21674151
View Article
PubMed/NCBI
Google Scholar

[177] View Article

[178] PubMed/NCBI

[179] Google Scholar

[ref50] 50. Maruish ME. User’s manual for the SF-12v2 health survey. 3rd ed. Lincoln, RI: Quality Metric Incorporated; 2012.

[ref51] 51. Kroenke K, Spitzer RL, Williams JBW, Löwe B. An ultra-brief screening scale for anxiety and depression: the PHQ-4. Psychosomatics. 2009;50(6):613–21. pmid:19996233
View Article
PubMed/NCBI
Google Scholar

[182] View Article

[183] PubMed/NCBI

[184] Google Scholar

[ref52] 52. Wang Y, Li Y, Pu W, Wen K, Shugart Y, Xiong M, et al. Random Bits Forest: a Strong Classifier/Regressor for Big Data. Sci Rep. 2016;6:30086.
View Article
Google Scholar

[186] View Article

[187] Google Scholar

[ref53] 53. Speiser JL, Miller ME, Tooze J, Ip E. A Comparison of Random Forest Variable Selection Methods for Classification Prediction Modeling. Expert Syst Appl. 2019;134:93–101. pmid:32968335
View Article
PubMed/NCBI
Google Scholar

[189] View Article

[190] PubMed/NCBI

[191] Google Scholar

[ref54] 54. Shahab S, Mulsant BH, Levesque ML, Calarco N, Nazeri A, Wheeler AL, et al. Brain structure, cognition, and brain age in schizophrenia, bipolar disorder, and healthy controls. Neuropsychopharmacology. 2019;44(5):898–906. pmid:30635616
View Article
PubMed/NCBI
Google Scholar

[193] View Article

[194] PubMed/NCBI

[195] Google Scholar

[ref55] 55. Ward MM, Pajevic S, Dreyfuss J, Malley JD. Short-term prediction of mortality in patients with systemic lupus erythematosus: classification of outcomes using random forests. Arthritis Rheum. 2006;55(1):74–80. pmid:16463416
View Article
PubMed/NCBI
Google Scholar

[197] View Article

[198] PubMed/NCBI

[199] Google Scholar

[ref56] 56. Gregorutti B, Michel B, Saint-Pierre P. Correlation and variable importance in random forests. Stat Comput. 2017;27:659–78.
View Article
Google Scholar

[201] View Article

[202] Google Scholar

[ref57] 57. R Core Team. R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2018.

[ref58] 58. Huang J, Zhu Q, Yang L, Feng J. A non-parameter outlier detection algorithm based on Natural Neighbor. Knowl-Based Syst. 2016;92:71–7.
View Article
Google Scholar

[205] View Article

[206] Google Scholar

[ref59] 59. Madsen JH. DDoutlier: Distance & Density-Based Outlier Detection. R package version 0.1.0; 2018. Available from: https://CRAN.R-project.org/package=DDoutlier
View Article
Google Scholar

[208] View Article

[209] Google Scholar

[ref60] 60. Kuhn M. Building predictive models in R using the caret package. J Stat Softw. 2008;28(5):1–26.
View Article
Google Scholar

[211] View Article

[212] Google Scholar

[ref61] 61. Rosseel I. lavaan: An R Package for Structural Equation Modeling. J Stat Softw. 2012;48(2):1–36.
View Article
Google Scholar

[214] View Article

[215] Google Scholar

[ref62] 62. Lei P. Evaluating estimation methods for ordinal data in structural equation modeling. Qual Quant. 2009;43:495–507.
View Article
Google Scholar

[217] View Article

[218] Google Scholar

[ref63] 63. Li C-H. Statistical estimation of structural equation models with a mixture of continuous and categorical observed variables. Behav Res Methods. 2021;53(5):2191–213. pmid:33791955
View Article
PubMed/NCBI
Google Scholar

[220] View Article

[221] PubMed/NCBI

[222] Google Scholar

[ref64] 64. Xia Y, Yang Y. RMSEA, CFI, and TLI in structural equation modeling with ordered categorical data: The story they tell depends on the estimation methods. Behav Res Methods. 2019;51(1):409–28. pmid:29869222
View Article
PubMed/NCBI
Google Scholar

[224] View Article

[225] PubMed/NCBI

[226] Google Scholar

[ref65] 65. Shi D, Maydeu-Olivares A. The Effect of Estimation Methods on SEM Fit Indices. Educ Psychol Meas. 2020;80(3):421–45. pmid:32425213
View Article
PubMed/NCBI
Google Scholar

[228] View Article

[229] PubMed/NCBI

[230] Google Scholar

[ref66] 66. Bauer DJ, Curran PJ. Structural equation modeling: R demonstration notes (Version 2019.3). Curran-Bauer Analytics, Durham: NC; 2019.

[ref67] 67. Zhang Z, Yuan K-H, editors. Practical Statistical Power Analysis Using Webpower and R. Granger, IN: ISDSA Press; 2018. Available from: https://webpower.psychstat.org

[ref68] 68. Sarris J, Perkins D, Cribb L, Schubert V, Opaleye E, Bouso JC, et al. Ayahuasca use and reported effects on depression and anxiety symptoms: An international cross-sectional study of 11,912 consumers. J Affect Disord Rep. 2021;4:100098.
View Article
Google Scholar

[234] View Article

[235] Google Scholar

[ref69] 69. Perkins D, Opaleye ES, Simonova H, Bouso JC, Tófoli LF, GalvÃo-Coelho NL, et al. Associations between ayahuasca consumption in naturalistic settings and current alcohol and drug use: Results of a large international cross-sectional survey. Drug Alcohol Rev. 2022;41(1):265–74. pmid:34308566
View Article
PubMed/NCBI
Google Scholar

[237] View Article

[238] PubMed/NCBI

[239] Google Scholar

[ref70] 70. Perkins D, Pagni BA, Sarris J, Barbosa PCR, Chenhall R. Changes in mental health, wellbeing and personality following ayahuasca consumption: Results of a naturalistic longitudinal study. Front Pharmacol. 2022;13:884703. pmid:36386199
View Article
PubMed/NCBI
Google Scholar

[241] View Article

[242] PubMed/NCBI

[243] Google Scholar

[ref71] 71. Perkins D, Opaleye E, Bouso JC, Tófoli LF, Sarris J, Schubert V, et al. Insights, Life Changes and Lifestyle Changes Reported by Individuals Consuming Ayahuasca in Naturalistic Settings: Nature, Frequency and Associations with Mental Health and Wellbeing. Psychoactives. 2023;2(4):256–86.
View Article
Google Scholar

[245] View Article

[246] Google Scholar

[ref72] 72. Cowley-Court T, Chenhall R, Sarris J, Bouso JC, Tófoli LF, Opaleye ES, et al. Life after Ayahuasca: A Qualitative Analysis of the Psychedelic Integration Experiences of 1630 Ayahuasca Drinkers from a Global Survey. Psychoactives. 2023;2(2):201–21.
View Article
Google Scholar

[248] View Article

[249] Google Scholar

[ref73] 73. Barbosa PCR, Cazorla IM, Giglio JS, Strassman R. A six-month prospective evaluation of personality traits, psychiatric symptoms and quality of life in ayahuasca-naïve subjects. J Psychoactive Drugs. 2009;41(3):205–12. pmid:19999673
View Article
PubMed/NCBI
Google Scholar

[251] View Article

[252] PubMed/NCBI

[253] Google Scholar

[ref74] 74. Grob CS, McKenna DJ, Callaway JC, Brito GS, Neves ES, Oberlaender G, et al. Human psychopharmacology of hoasca, a plant hallucinogen used in ritual context in Brazil. J Nerv Ment Dis. 1996;184(2):86–94. pmid:8596116
View Article
PubMed/NCBI
Google Scholar

[255] View Article

[256] PubMed/NCBI

[257] Google Scholar

[ref75] 75. Kohek M. Through the looking-glass: The use of psychoactive plants in Catalonia [doctoral thesis]. Tarragona: Universitat Rovira I Virgili; 2021. Available from: http://hdl.handle.net/10803/671199.

[ref76] 76. Uthaug MV, Mason NL, Toennes SW, Reckweg JT, de Sousa Fernandes Perna EB, Kuypers KPC, et al. A placebo-controlled study of the effects of ayahuasca, set and setting on mental health of participants in ayahuasca group retreats. Psychopharmacology (Berl). 2021;238(7):1899–910. pmid:33694031
View Article
PubMed/NCBI
Google Scholar

[260] View Article

[261] PubMed/NCBI

[262] Google Scholar

[ref77] 77. Ware J Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care. 1996;34(3):220–33. pmid:8628042
View Article
PubMed/NCBI
Google Scholar

[264] View Article

[265] PubMed/NCBI

[266] Google Scholar

[ref78] 78. So CJ, Miller KE, Gehrman PR. Sleep Disturbances Associated With Posttraumatic Stress Disorder. Psychiatr Ann. 2023;53(11):491–5. pmid:38293647
View Article
PubMed/NCBI
Google Scholar

[268] View Article

[269] PubMed/NCBI

[270] Google Scholar

[ref79] 79. Skeie-Larsen M, Stave R, Grønli J, Bjorvatn B, Wilhelmsen-Langeland A, Zandi A, et al. The Effects of Pharmacological Treatment of Nightmares: A Systematic Literature Review and Meta-Analysis of Placebo-Controlled, Randomized Clinical Trials. Int J Environ Res Public Health. 2022;20(1):777. pmid:36613097
View Article
PubMed/NCBI
Google Scholar

[272] View Article

[273] PubMed/NCBI

[274] Google Scholar

[ref80] 80. Durante Í, Dos Santos RG, Bouso JC, Hallak JE. Risk assessment of ayahuasca use in a religious context: self-reported risk factors and adverse effects. Braz J Psychiatry. 2021;43(4):362–9. pmid:33146343
View Article
PubMed/NCBI
Google Scholar

[276] View Article

[277] PubMed/NCBI

[278] Google Scholar

[ref81] 81. Rocha JM, Rossi GN, Osório FL, Hallak JEC, Dos Santos RG. Adverse Effects After Ayahuasca Administration in the Clinical Setting. J Clin Psychopharmacol. 2022;42(3):321–4. pmid:35289542
View Article
PubMed/NCBI
Google Scholar

[280] View Article

[281] PubMed/NCBI

[282] Google Scholar

[ref82] 82. Bremler R, Katati N, Shergill P, Erritzoe D, Carhart-Harris RL. Case analysis of long-term negative psychological responses to psychedelics. Sci Rep. 2023;13(1):15998. pmid:37749109
View Article
PubMed/NCBI
Google Scholar

[284] View Article

[285] PubMed/NCBI

[286] Google Scholar

[ref83] 83. Weber SR, Pargament KI. The role of religion and spirituality in mental health. Curr Opin Psychiatry. 2014;27(5):358–63. pmid:25046080
View Article
PubMed/NCBI
Google Scholar

[288] View Article

[289] PubMed/NCBI

[290] Google Scholar

[ref84] 84. Griffiths R, Johnson M, Richards W, Richards B, Jesse R, MacLean K. Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors. J Psychopharmacol. 2018;32(1):49–69.
View Article
Google Scholar

[292] View Article

[293] Google Scholar

[ref85] 85. Goldsmith HH, Lemery KS. Linking temperamental fearfulness and anxiety symptoms: a behavior-genetic perspective. Biol Psychiatry. 2000;48(12):1199–209. pmid:11137060
View Article
PubMed/NCBI
Google Scholar

[295] View Article

[296] PubMed/NCBI

[297] Google Scholar

[ref86] 86. Headley DB, Kanta V, Kyriazi P, Paré D. Embracing Complexity in Defensive Networks. Neuron. 2019;103(2):189–201. pmid:31319049
View Article
PubMed/NCBI
Google Scholar

[299] View Article

[300] PubMed/NCBI

[301] Google Scholar

[ref87] 87. LeDuke DO, Borio M, Miranda R, Tye KM. Anxiety and depression: A top-down, bottom-up model of circuit function. Ann N Y Acad Sci. 2023;1525(1):70–87. pmid:37129246
View Article
PubMed/NCBI
Google Scholar

[303] View Article

[304] PubMed/NCBI

[305] Google Scholar

[ref88] 88. McKenna D, Riba J. New world tryptamine hallucinogens and the neuroscience of ayahuasca. Current Topics in Behavioral Neuroscience. 2018;36:283–311.
View Article
Google Scholar

[307] View Article

[308] Google Scholar

[ref89] 89. Bouso JC, Révész D, Ona G, Rossi GN, Rocha JM, Dos Santos RG, et al. Longitudinal and transcultural assessment of the relationship between hallucinogens, well-being, and post-traumatic growth during the COVID-19 pandemic. Sci Rep. 2023;13(1):14052. pmid:37696900
View Article
PubMed/NCBI
Google Scholar

[310] View Article

[311] PubMed/NCBI

[312] Google Scholar

[ref90] 90. Ona G, Révész D, Kohek M, Rossi G, Rocha J, Dos Santos R. Tripping to cope: Coping strategies and use of hallucinogens during the COVID-19 pandemic in three cultural contexts. Psychoactives. 2022;1(1):16–30.
View Article
Google Scholar

[314] View Article

[315] Google Scholar

[ref91] 91. Révész D, Ona G, Rossi GN, Rocha JM, Dos Santos RG, Hallak JEC, et al. Cross-Sectional Associations Between Lifetime Use of Psychedelic Drugs and Psychometric Measures During the COVID-19 Confinement: A Transcultural Study. Front Psychiatry. 2021;12:687546. pmid:34220590
View Article
PubMed/NCBI
Google Scholar

[317] View Article

[318] PubMed/NCBI

[319] Google Scholar

[ref92] 92. Palhano-Fontes F, Soares BL, Galvão-Coelho NL, Arcoverde E, Araujo DB. Ayahuasca for the Treatment of Depression. Curr Top Behav Neurosci. 2022;56:113–24. pmid:34761362
View Article
PubMed/NCBI
Google Scholar

[321] View Article

[322] PubMed/NCBI

[323] Google Scholar

[ref93] 93. Ko K, Kopra EI, Cleare AJ, Rucker JJ. Psychedelic therapy for depressive symptoms: A systematic review and meta-analysis. J Affect Disord. 2023;322:194–204. pmid:36209780
View Article
PubMed/NCBI
Google Scholar

[325] View Article

[326] PubMed/NCBI

[327] Google Scholar

[ref94] 94. White E, Kennedy T, Ruffell S, Perkins D, Sarris J. Ayahuasca and Dimethyltryptamine Adverse Events and Toxicity Analysis: A Systematic Thematic Review. Int J Toxicol. 2024;43(3):327–39. pmid:38363085
View Article
PubMed/NCBI
Google Scholar

[329] View Article

[330] PubMed/NCBI

[331] Google Scholar

[ref95] 95. Schlag AK, Aday J, Salam I, Neill JC, Nutt DJ. Adverse effects of psychedelics: From anecdotes and misinformation to systematic science. J Psychopharmacol. 2022;36(3):258–72. pmid:35107059
View Article
PubMed/NCBI
Google Scholar

[333] View Article

[334] PubMed/NCBI

[335] Google Scholar

[ref96] 96. Kohek M, Sánchez Avilés C, Romaní O, Bouso JC. Ancient psychoactive plants in a global village: The ritual use of cannabis in a self-managed community in Catalonia. Int J Drug Policy. 2021;98:103390. pmid:34340169
View Article
PubMed/NCBI
Google Scholar

[337] View Article

[338] PubMed/NCBI

[339] Google Scholar

[ref97] 97. Kohek M, Bouso J, Oña G. De crecer en la selva a practicar la ayahuasca en la ciudad: una exploración de la globalización de la ayahuasca en términos de autenticidad, autoatención y de los retos de dicha globalización para la antropología médica. Rev Antropol Soc. 2023;32(2):141–54.
View Article
Google Scholar

[341] View Article

[342] Google Scholar

[ref98] 98. Wickramaratne PJ, Yangchen T, Lepow L, Patra BG, Glicksburg B, Talati A, et al. Social connectedness as a determinant of mental health: A scoping review. PLoS One. 2022;17(10):e0275004. pmid:36228007
View Article
PubMed/NCBI
Google Scholar

[344] View Article

[345] PubMed/NCBI

[346] Google Scholar

[ref99] 99. Ko K, Carter B, Cleare AJ, Rucker JJ. Predicting the Intensity of Psychedelic-Induced Mystical and Challenging Experience in a Healthy Population: An Exploratory Post-Hoc Analysis. Neuropsychiatr Dis Treat. 2023;19:2105–13. pmid:37818448
View Article
PubMed/NCBI
Google Scholar

[348] View Article

[349] PubMed/NCBI

[350] Google Scholar

[ref100] 100. Ona G, Berrada A, Bouso JC. Communalistic use of psychoactive plants as a bridge between traditional healing practices and Western medicine: A new path for the Global Mental Health movement. Transcult Psychiatry. 2022;59(5):638–51. pmid:34665080
View Article
PubMed/NCBI
Google Scholar

[352] View Article

[353] PubMed/NCBI

[354] Google Scholar

[ref101] 101. Aixalà MB. Psychedelic Integration: Psychotherapy for Non-Ordinary States of Consciousness. Santa Fe: Synergetic Press; 2022.

[ref102] 102. International Center for Ethnobotanical Education, Research, and Service (ICEERS). Ayahuasca: Global Consumption & Reported Deaths. ICEERS; 2023. Available from: https://www.iceers.org/ayahuasca-global-consumption-deaths/

[ref103] 103. International Narcotics Control Board (INCB). Report of the International Narcotics Control Board for 2010. Vienna: United Nations; 2011. Available from: https://www.incb.org/documents/Publications/AnnualReports/AR2010/AR_2010_English.pdf

[ref104] 104. International Center for Ethnobotanical Education, Research, and Service (ICEERS). Ayahuasca Technical Report: A 2019 Guide. Barcelona: ICEERS; 2019 [Internet]. Disponible en: https://www.iceers.org/wp-content/uploads/2020/05/Guia-ayahuasca_eng_30.09.19.pdf

Figures

Abstract

Introduction

Methods

Ethics statement

Sample

Measures

Statistical analysis

Data analysis strategy.

Sample selection and data pre-processing.

Data analyses.

Results

Predictors selections: Random forest analyses

Ayahuasca adverse mental effects mediational model

Exogenous variables relationships with participants’ reported adverse mental states

Ayahuasca mental adverse effects relationships with participants’ current mental health

Exogenous variables indirect relationships with participants’ current mental health

Exogenous variables direct relationships with participants’ current mental health

Total effects on participants’ current mental health

Discussion

Supporting information

S1 Text. Supporting Tables.

References