Ayahuasca is a psychedelic plant decoction that has been consumed for centuries by Indigenous peoples in Peru, Columbia, Ecuador, and Brazil for medicinal and spiritual purposes (Luna, 2011). It contains the powerful classic psychedelic, N,N-dimethyltryptamine (DMT), usually from the leaves of Psychotria viridis, as well as several beta-carboline alkaloids, from the vine of Banisteriopsis caapi (McKenna et al., 1984). Recent decades have witnessed growing worldwide popularity of ayahuasca via expanding ayahuasca tourism in South American countries, the international expansion of Brazilian Christian-syncretic ayahuasca churches, and the growth of neo-shamanic ayahuasca ceremonies (typically for therapeutic purposes) in Western countries (Trichter, 2010; Kavenská and Simonová, 2015; Fotiou, 2020).

Mounting evidence suggests that ayahuasca and its DMT and harmala alkaloids may provide therapeutic benefit for mental health conditions, including depression, anxiety, and substance abuse disorders (Sarris et al., 2021; Uthaug et al., 2021; van Oorsouw et al., 2021; James et al., 2022). Placebo-controlled preclinical studies, as well as double-blind randomized placebo-controlled and observational naturalistic studies have reported antidepressant and anxiolytic effects (Dos Santos et al., 2016; Cameron et al., 2018; Palhano-Fontes et al., 2018; Santos da Silva et al., 2018; Almeida et al., 2019; Sarris et al., 2021; Zeifman et al., 2021). Naturalistic ayahuasca studies have also reported increases in self-compassion, and self-assurance alongside mental health improvements (Dominguez-Clave et al., 2021; Ruffell et al., 2021). A large cross-sectional study linked aspects of the subjective ayahuasca experience including self-insights with perceived improvements in depression and anxiety, suggesting that such subjective experiences play an important role in therapeutic response (Perkins et al., 2021; Sarris et al., 2021; Perkins et al., 2022).

Observational and preclinical studies also suggest that ayahuasca may reduce alcohol and other drug use (Rodrigues et al., 2021). Several studies have reported ayahuasca consumption to lower recidivism in drug-dependent adults and be a possible protective factor for alcohol and substance abuse in adolescents (Doering-Silveira et al., 2005; Fábregas et al., 2010; Barbosa et al., 2018; Rodrigues et al., 2021). Similarly, a recent large study of ayahuasca drinkers in different contexts of use reported ayahuasca consumption to be associated with increased odds of rarely or never consuming alcohol, not engaging in ‘risky drinking’, and having no recent use of a range of drugs, with these effects evident for those with and without a substance use disorder and after adjusting for religious and social group effects (Perkins et al., 2021).

Ayahuasca has also been linked to changes in personality traits (Bouso et al., 2015; Mendes Rocha et al., 2021; Weiss et al., 2021). Increases in agreeableness and openness and decreases in neuroticism have been observed, with reductions in neuroticism correlating with the subjective intensity of the mystical experience (Netzband et al., 2020). Mediators of ayahuasca’s therapeutic effects may involve changes in personality structure, as ayahuasca-induced reductions in grief, for example, have been linked to increases in acceptance and the ability to psychologically decenter (Gonzalez et al., 2021). Research to date suggests that ayahuasca may produce trait-level changes more rapidly than behavioural interventions targeting these traits (Soler et al., 2018).

Accumulating evidence suggest that ayahuasca is relatively safe and nontoxic (Gable, 2007; Barbosa et al., 2012). Cross-sectional studies have reported long-term ayahuasca drinkers to score higher on measures of well-being and life purpose, perform better on executive functioning tasks, and have lower levels of psychopathology compared to non-psychedelic users (Bouso et al., 2012; Lawn et al., 2017).

Together, these studies suggest ayahuasca may produce a range of clinically meaningful improvements. However, it is unclear if baseline individual differences predict improvements in mental health and substance use, an important step towards personalized medicine. Moreover, while research suggests ayahuasca may alter personality traits, how these changes relate to therapeutic efficacy remains to be investigated. This longitudinal, naturalistic observational study sought to examine mental health, substance use, personality traits, acute subjective effects, and relationship satisfaction outcomes after a facilitated ceremony in ayahuasca naïve adult participants. Relationships between personality traits and acute subjective effects and long-term outcomes were explored to identify predictors of therapeutic response.

Such observational research may yield more ecologically valid ayahuasca health-related data than clinical trials conducted in highly controlled settings (cf. Carhart-Harris et al., 2022). Less strict inclusion criteria, for example, can enable an assessment of risk factors for negative outcomes, which would otherwise be missed by the stricter criteria of double-blind clinical trials. Naturalistic longitudinal studies with new ayahuasca users can also gather “real-world” evidence of psychological and contextual variables that influence potential therapeutic benefits and risks (Pallavicini et al., 2021). The ecological validity of observational studies can provide valuable data to inform public health and drug regulation relating to the use of this Schedule I substance-containing brew in diverse therapeutic and religious/spiritual settings in the North America and elsewhere (cf. Bullis, 2008). Finally, the data relating to positive or negative outcomes for different conditions can inform clinical trials in the emerging field of psychedelic science.

Following encouraging initial data from human and animal studies with ayahuasca, there is growing interest in the potential medical use of this substance for the treatment of mental health conditions. Our findings relating to mental health effects for individuals with and without a lifetime mental health diagnosis are in-line with reports of depression, anxiety, and stress reductions in placebo-controlled studies (Palhano-Fontes et al., 2018), observational studies with follow-up periods up to 6 months (Barbosa et al., 2005; Barbosa et al., 2009; Jiménez-Garrido et al., 2020; Ruffell et al., 2021), and cross-sectional studies comparing ayahuasca users to non-users (Kaasik and Kreegipuu, 2020; Sarris et al., 2021). Participants also reported less problematic alcohol and cannabis use 1-month post-ceremony, corroborated by decreased frequency of alcohol use and a trend toward decreased alcohol binges. These findings represent the first longitudinal assessment of ayahuasca’s effects on alcohol consumption in a moderately-sized sample (n∼34). A small observational study (n = 12) found reductions in alcohol, tobacco, and cocaine use after ayahuasca with no changes in cannabis use (Thomas et al., 2013). This study marks the first to detect significant changes in cannabis consumption where other studies have been underpowered to detect changes in cannabis (Thomas and colleagues (2013). These findings are in-line with cross-sectional reports suggesting that ayahuasca consumption is negatively associated with alcohol and drug use, however it is still uncear if ayahuasca may reduce intake of other drugs of abuse, such as amphetamines and opiates (Halpern et al., 2008; Fábregas et al., 2010; Rodrigues et al., 2021; Perkins et al., 2022).

Consistent with previous studies we detected changes in the personality traits agreeableness and open-mindedness (Netzband et al., 2020; Kiraga et al., 2021; Weiss et al., 2021). However, a novel finding was of increases in extraversion, which although reported with psilocybin has not previously been reported with ayahuasca (Erritzoe et al., 2018). Further, decreases in negative emotionality and trending increases in conscientiousness, implicating all 5 BFI traits, suggests ayahuasca broadly influences personality structure, some of which (e.g., agreeableness) are thought to remain relatively stable throughout adult life (Specht, 2017). Previous work has found associations between the Big Five personality trait ‘neuroticism’ and psychopathology, and traits ‘extraversion’ and ‘agreeableness’ with positive mental health (Lamers et al., 2012). We propose the ayahuasca-induced changes observed in personality structure may reflect resilience toward psychopathology and improved mental health. While this study did not specifically examine predictors of personality change (Weiss et al., 2021), reported that baseline personality traits, acute experiences, ceremonial elements, and purgative experiences moderate changes in personality traits; this is consistent with our results, showing baseline personality traits predict ayahuasca attributed personality trait changes. Given this, future work may utilise mediation/moderation analyses to better understand how the ayahuasca experience and acute effects have enduring effects on personality traits and how these changes may contribute to mental health improvements. Previous cross-sectional work found that members of the UDV ayahuasca church have a greater propensity toward self-reflection versus impulsivity (McKenna, 2004). Although we found no significant change in behavioural and cognitive impulsivity, the trend in both measures warrants future investigation.

Previous cross-cultural studies have noted improvements in relationships (Kaasik and Kreegipuu, 2020); and again we found a trend towards significance for improvements in relationships with friends, parents, and children.

This study also included a range of novel measures intended to evaluate change in self-connection, most of which identified significant positive change. We provide the first evidence of improvements in general self-efficacy, a construct negatively associated with the likelihood of suffering from mental illness (Andersson et al., 2014). We found increases in personal authenticity, which is related to self-esteem and psychological well-being (Wood et al., 2008). Moreover, reductions in body dissociation (but not increases in body awareness) were identified, suggesting a longer-term effect of the enhanced somatic awareness and interoception known to occur with the acute ayahuasca experience (Shanon, 2002; Espinoza, 2014; Kaufman, 2015). Neurologically, ayahuasca activates brain areas involved in somatic awareness, emotional states, and arousal, namely the insular and anterior cingulate cortices and amygdala, offering potential neural correlates of the observed behavioural changes (Riba et al., 2006). Importantly, ayahuasca-induced alterations to body dissociation, but not body awareness, may expand our understanding of the complex role of the mind-body connection. Together, our findings suggest personal relationships, self-efficacy, personal authenticity, and body awareness may be important variables to consider in the context of transformative and healing psychedelic experiences.

Previous longitudinal and cross-sectional studies have showed concomitant augmentation of spirituality and religiousness, while the present study identified increases in spirituality in the absence of changes in religious practices (Bouso et al., 2012; Gonzalez et al., 2021). Lack of change in religious practices may be attributed to differences in instrument selection or in sampling differences between studies. The DUREL used in this study consists of questions pertaining to frequency of religious practices while the WHO Quality of Life Spirituality, Religiousness, and Personal Beliefs scale employed by Gonzalez and colleagues (2021) consists of questions pertaining to quality of life, personality traits, and attitudes/beliefs. Additionally, our sample was collected from a neo-shamanic ceremony setting, whereas other study samples may have consisted of members with a more religious background.

Facets of the mystical experience, as measured via the MEQ, have been reported to predict psilocybin-occasioned improvements in mental health, however such an association was not present in this study (Roseman et al., 2018), a finding consistent with other ayahuasca research utilising the MEQ (Palhano-Fontes et al., 2018; Ruffell et al., 2021). Since only ∼50% of our sample achieved a “complete mystical experience”, it is possible the analysis was underpowered to detect MEQ-outcome relationships. Alternatively, the MEQ may not be an optimal instrument for detecting ayahuasca induced spiritual experience, as other ayahuasca studies using alternative instruments have reported consistent associations between subjective spiritual experience and improvements in mental health, wellbeing and alcohol and drug use (Sarris et al., 2021; Perkins et al., 2022). Other aspects of the subjective experience not measured in this study, including the number of personal self-insights gained and level of extreme fear have also been reported to be associated with ayahuasca’s therapeutic outcomes (Perkins et al., 2021).

This study also identified new predictors of mental health and addiction-related improvements. Instead of subjective effects, based on the MEQ, predicting therapeutic outcomes, baseline personal characteristics pertaining to personality traits, general self-efficacy, and body dissociation at baseline strongly predicted improvements in mental health and alcohol and cannabis misuse/abuse. In our study, participants who had higher negative emotionality and body dissociation and lower self-efficacy at baseline demonstrated larger improvements on mental health outcomes. Upon close examination, the directions of correlations were identical for negative emotionality and body dissociation, and inverse that of self-efficacy for all significant behavioural change associations. The overall relationship between baseline predictors and outcomes measures suggests those who have greater psychopathological indications on these measures may be preferred candidates for therapeutic effects. The consistency of these predictors across a variety of measures fosters confidence, however the effects need to be replicated in randomised clinical trials. While others have established links between personality traits and acute effects (e.g., neuroticism associated with unpleasant/anxious experiences, trail-level ‘absorption’ associated with enjoyable psychedelic experiences, and openness and optimism associated with acute psychedelic effects; (Studerus et al., 2012; Smigielski et al., 2019; Studerus et al., 2021), this study is the first to characterize the influence personality factors have on ayahuasca-attributed improvements in mental health and alcohol/cannabis use. Moreover, these findings mark a valuable first step toward developing the personalized application of psychedelic medicine.

Therapeutic mechanisms of ayahuasca likely range from the molecular to the psychological: ayahuasca administration has been shown to up-regulate serotonin reuptake transporters in blood platelets which are downregulated in alcoholism (Callaway et al., 1994; Storvik et al., 2007). Both DMT and the beta-carbolines found in ayahuasca have been linked to physiological and psychological markers of improved mental health (Samoylenko et al., 2010). For example, DMT and the three main alkaloids of ayahuasca–namely, harmine, tetrahydroharmine, harmaline, and the metabolite harmol–stimulate neurogenesis, spinogenesis, and synaptogenesis, providing a potential biological basis for some of ayahuasca’s therapeutic effects ((Morales-García et al., 2017; Ly et al., 2018; Morales-Garcia et al., 2020). Moreover, antidepressant effects correlate with brain-derived neurotrophic factor (BDNF) concentrations 48-h after administration of a single dose of ayahuasca with enduring antidepressant effects 7 days after administration (Palhano-Fontes et al., 2018; Almeida et al., 2019). On a systems level, ayahuasca modulates the default mode network (DMN), theorized to underlie the neuropathology of depression and anxiety and support the sense of self. Reorganization of the structural and functional architecture of the DMN may mediate clinically relevant improvements across various psychiatric and substance use disorders (Palhano-Fontes et al., 2015). Finally, personality trait changes appear to drive some of ayahuasca’s therapeutic effects, including reductions in alcohol and substance use, which offers novel psychological mechanisms outside of the traditional addiction framework centred around impulsivity and novelty seeking (Ismael Eduardo Apud, 2020). Further, associations between ayahuasca use and personality traits have been correlated with cortical thickness in the posterior cingulate cortex, suggesting ayahuasca-induced structural DMN changes may support alterations to personality (Bouso et al., 2015). Future work should seek to elucidate the inter-relationships between genetics, epigenetic, biochemistry, and network dynamics in the context of psychedelic medicine.

There are important limitations in this study to acknowledge, most notably the absence of an active comparison group with which to compare findings. A placebo-controlled naturalistic study and large cross-sectional ayahuasca study both noted significant therapeutic effects associated with non-pharmacological factors (e.g., ceremony, community, etc), which are likely to also contribute to changes identified in our sample (Perkins et al., 2021; Uthaug et al., 2021). However, similar to reports from Griffiths and colleagues studying psilocybin, ayahuasca users have reported their experiences to be among the most important of their lives (Dos Santos et al., 2016) (Perkins et al., 2021).

Further limitations include the modest sample size, use of self-report measures, which are at greater risk of participant biases, lack of data on participant expectations, and slight variations in the day of response. Future work could include neuropsychological evaluations to corroborate self- and informant-report measures. However, we note that previous work in pharmacotherapies for depression suggests that objective measures capture larger effect sizes relative to less objective measures such as the self-report surveys used in this study (Joffe et al., 1996). Additionally, our use of an extensive mental health battery provides assurance of broad range improvements across multiple domains including mood/affect, social relationships, Self-connection, impulse control, and spirituality.

While we enrolled only participants naive to ayahuasca consumption, some participants reported previous psychedelic use (e.g., psilocybin, LSD, ketamine, etc) which may influence outcomes compared to individuals with no prior psychedelic experience and who are non-ayahuasca naïve. However, previous psychedelic use was not associated with behaviour change in this study, suggesting both psychedelic-naïve and psychedelic-experienced participants may benefit from ayahuasca. Additionally, chemical analysis of the ayahuasca brew was not performed, limiting knowledge of psychoactive concentrations and ratios and dose effects. The volume of ayahuasca liquid administered was generally consistent, although was adjusted in some cases such as very high/low weight or more acute mental health symptoms. Exploratory correlation analyses showed no relationship between the number of dosing sessions and mental health and alcohol/marijuana use outcomes, which should be interpreted with caution since the study was not poised to address dose response questions. Long-term follow-up is also necessary to assess the durability of treatment effects identified. Sustained improvements have been reported 6-month posttreatment in one study, and a large cross-sectional study identified little diminishing of reported improvements in mental health or reductions in drug and alcohol use over time (Jiménez-Garrido et al., 2020; Ruffell et al., 2021). However, another study found that at a 4–7-year follow-up, treatment gains from ayahuasca were lost after a single administration, suggesting repeated administration may be necessary (dos Santos et al., 2016). It would also be useful for ayahuasca research to examine treatment trajectories for specific diagnostic groups to develop long-term treatment plans.

In this naturalistic observational study of facilitated ayahuasca consumption in naïve participants, we identified improvements on a myriad of mental health and wellbeing measures, in addition to changes in personality structure. Our mental health results are in congruence with previous research, and we also report novel findings relating to change in self-beliefs, self-connection, and impulsivity, in addition to predictors of therapeutic response to ayahuasca identifying a range of factors that should be considered in the context of mental health treatment. While the findings are preliminary and require confirmation using randomised clinical trial designs, they mark a useful step towards developing personalised medicine approaches for the treatment of complex psychiatric conditions. Moreover, the detection of therapeutic improvements on novel instruments warrants consideration of these measures in more rigorous designs.

Finally, we note that while studies conducted in laboratory and hospital settings provide excellent internal validity, it is also important to understand therapeutic changes as a function of the naturalistic ceremonial settings in which these practices evolved. Such contexts encompass a radically different worldview than Western medical approaches and may provide new insights to enable enhanced clinical treatments.