STUDY PROTOCOL published: 19 May 2021 doi: 10.3389/fphar.2021.659644 Protocol for Outcome Evaluation of Ayahuasca-Assisted Addiction Treatment: The Case of Takiwasi Center Brian Rush 1*, Olivia Marcus 2, Sara García 3, Anja Loizaga-Velder 4, Gabriel Loewinger 5, Ariane Spitalier 6 and Fernando Mendive 3 1 Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, Toronto, ON, Canada, 2Department of Anthropology, University of Connecticut, Storrs, CT, United States, 3Takiwasi Center for Rehabilitation of Drug Addicts and Research on Traditional Medicine, Tarapoto, Peru, 4Nierika Institute, National Autonomous University of Mexico, Mexico City, Mexico, 5School of Public Health, Harvard University, Boston, MA, United States, 6Autonomous University of Barcelona, Barcelona, Spain The present study describes the protocol for the Ayahuasca Treatment Outcome Project (ATOP) with a special focus on the evaluation of addiction treatment services provided through Takiwasi Center, the first ATOP study site. The goal of the project is to assess Edited by: treatment outcomes and understand the therapeutic mechanisms of an Ayahuasca- Jia-bo Wang, assisted, integrative treatment model for addiction rehabilitation in the Peruvian Capital Medical University, China Amazon. The proposed intervention protocol highlights the significance of treatment Reviewed by: Nicole Leite Galvão-Coelho, setting in the design, delivery, and efficacy of an addiction rehabilitation program that Federal University of Rio Grande do involves the potent psychedelic tea known as Ayahuasca. After describing the context of Norte, Brazil the study, we put forth details about our mixed-methods approach to data collection and João Carlos Alchieri, Universidade Federal do Rio Grande analysis, with which we seek to gain an understanding of why, how, and for whom this do Norte, Brazil specific ayahuasca-assisted treatment program is effective across a range of outcomes. *Correspondence: The ATOP protocol employs qualitative research methods as a means to determine which Brian Rush brian.rush@camh.ca aspects of the setting are meaningful to clients and practitioners, and how this may correlate with outcome measures. This paper delineates the core principles, methods, and Specialty section: measures of the overall ATOP umbrella, then discusses the role of ATOP in the context of This article was submitted to the literature on long-term residential programs. To conclude, we discuss the strengths Ethnopharmacology, a section of the journal and limitations of the protocol and the intended future of the project. Frontiers in Pharmacology Keywords: ayahuasca, substance use, treatment, outcome, traditional medicine Received: 28 January 2021 Accepted: 04 May 2021 Published: 19 May 2021 INTRODUCTION Citation: Rush B, Marcus O, García S, International research remains focused on finding effective interventions for substance use and other Loizaga-Velder A, Loewinger G, mental disorders that are appropriate for the social contexts in which they are implemented. Due to Spitalier A and Mendive F (2021) the limitations of mainstream addiction medicine and mental health treatments, there is growing Protocol for Outcome Evaluation of interest in interventions based on traditional and complementary medicine, which is widely used by a Ayahuasca-Assisted Addiction Treatment: The Case of majority of the global population and supported by international health initiatives (Sarris et al., 2014; Takiwasi Center. Zhang et al., 2019). Given the tremendous burden of mental health globally (Vigo et al., 2016) and the Front. Pharmacol. 12:659644. limited coverage of mental health services, including substance use services, in most countries around doi: 10.3389/fphar.2021.659644 the world (Kohn et al., 2004; Patel et al., 2010; Whiteford et al., 2013; Vigo et al., 2020), there is a Frontiers in Pharmacology | www.frontiersin.org 1 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP global moral imperative to explore all promising alternatives, treatment efficacy (Labate et al., 2010; Tupper, 2011; including ayahuasca-assisted treatment. The present paper Mercante, 2013; Bouso and Riba, 2014; Dakwar 2015; Nunes describes the implementation and preliminary results of a et al., 2016). Based on the retrospective recall of lifetime alcohol research protocol designed as part of the Ayahuasca and drug use, including severe substance use disorders, the results Treatment Outcomes Project (ATOP), with a goal to assess of observational studies among frequent ayahuasca users who are treatment outcomes and understand the therapeutic members of either the Santo Daime and/or the UDV churches in mechanisms of an ayahuasca-assisted, integrative treatment Brazil have consistently shown either complete remission in some model in the Peruvian Amazon. Data collection commenced cases or considerably reduced substance use in other cases (Grob in 2016 as a mixed-methods longitudinal cohort study with et al., 1996; Fabregas et al., 2010; Halpern et al., 2008; Labate et al., long-term follow-up that will continue until at least through 2010). A qualitative review of other ritual-therapeutic uses of 2023. We report on the formation of the ATOP protocol, ayahuasca also indicates efficacy for addressing problematic preliminary themes that have emerged in data analysis at substance use including substance use disorders (Talin and baseline, and advocate for the strengths of a naturalistic Sanabria, 2017). Thomas et al. (2013) report positive outcomes mixed-methods investigation of a substance abuse treatment on addiction-related measures in a follow-up assessment of program that uses ayahuasca as part of its treatment model. members of an indigenous community participating in a Ayahuasca is the Quechua-language name for a psychoactive structured ayahuasca retreat in Canada. Argento et al. 2019 plant beverage that originated in the Amazon region of several conducted a qualitative analysis of interviews with participants South American countries. For centuries, select indigenous and in that same observational study. They reported reduced mestizo groups have considered ayahuasca a sacred medicine and substance use and cravings as well as several factors one of several plant-based healing agents used by traditional underlying positive outcomes, including the awareness of healers (often referred to in Spanish as curanderos) (Gow, 1994; negative thought patterns and behaviors not previously Luna, 1986; Anderson et al., 2012; Tupper, 2011). In the 20th uncovered through conventional treatment and increased Century, syncretic Christian churches that originated in Brazil, connection with self, others and nature/spirit. Other research namely Santo Daime, Barquinha, and União do Vegetal (UDV), based on qualitative interviews with people engaged with rural or began using ayahuasca as a religious sacrament (Mercante, 2013; urban-based ayahuasca-assisted treatment for substance use Dawson, 2017). The widespread popularity and eventual disorders in several countries and contexts also reports internationalization of Santo Daime, and to a lesser extent positive benefits that are attributed to multiple aspects of the UDV, has been a significant factor in the spread of ayahuasca therapeutic process, including mystical or “peak” experiences, to many other parts of the world, in particular Europe, Australia, insights, emotional processes and body-oriented effects (Harris and North America. The internationalization of Peruvian mestizo and Gurel, 2012; Loizaga-Velder and Loizaga, 2014; Loizaga- shamanism and neo-shamanic practices also continue to influence Velder and Verres, 2014; Horak et al., 2018). the widespread growth of ayahuasca-related practices (Tupper, Alongside the growing literature on treatment effectiveness, 2008; Labate and Jungaberle, 2011; Labate and Cavnar, 2014). toxicity and tolerability issues have also been investigated in Ayahuasca is of growing interest to an international research human subjects. While more research is needed (Barbosa community primarily for its putative therapeutic effects and its et al., 2012), the weight of the evidence suggests that implications for global mental health, local and international drug occasional or long-term use of ayahuasca within well- policy, cross-cultural psychiatry, neuroscience, intellectual property structured ritual contexts carries little health risk and, law, indigenous rights, and intangible cultural heritage, to name just importantly, no addictive potential (Grob et al., 1996; Riba a few domains with keen stakeholders (see, for example, Labate and et al., 2001; Fabregas et al., 2010; Bouso et al., 2012). Cavnar, 2011; Tupper and Labate, 2014). Interest in its therapeutic potential is part of the resurgent research on the use of various hallucinogenic compounds (Tupper et al., 2015; Dakwar, 2016) for Explanatory Mechanisms: Set and Setting the treatment of substance use disorders (Garcia-Romeu et al., 2019; Beyond Neuropharmacology Nielson et al., 2018; Bogenshutz and Johnson, 2016:; Dakwar 2015; It is widely accepted that the underlying mechanisms through Bogenshutz et al., 2015; Ross, 2012; Bogenschutz and Pommy, 2012; which ayahuasca-assisted treatment may exert its therapeutic Hendricks, 2014; Krebs and Johansen, 2012; Johnson et al., 2014) effects are complex and multi-factorial. Psychological and and other mental health challenges within the broad categories of neurobiological mechanisms of ayahuasca are similar to those depression and anxiety (Vollenweider and Kometer, 2010; induced by other psychedelics. While a full review of these Carhart–Harris et al., 2018a; Muttoni et al., 2019; Galvão-Coelho potential mechanisms is beyond the scope of this paper, et al., 2021; Sarris et al., 2021), as well as eating disorders and sufficient evidence has accrued to yield plausible hypotheses protracted grief (González et al., 2017; Lafrance et al., 2017). about underlying psychological and brain mechanisms contributing to treatment efficacy for substance use and other mental disorders. From a neuropharmacological point of view, Ayahuasca and Treatment for Substance the complexity of these hypotheses arises in part through the Use Disorders typical inclusion of two plant species in the ayahuasca brew that Preliminary evidence concerning the therapeutic effects of together implicate a variety of mechanisms for direct and indirect ayahuasca for alcohol and drug use disorders indicates actions on both dopaminergic and serotonergic systems. This Frontiers in Pharmacology | www.frontiersin.org 2 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP would include the general effects of tryptamines (namely, N,N- approach or avoidance to environmental stimuli. The dimethyltryptamine or DMT) contained in the leaves of interoceptive system, closely embedded in the insula region of Psychotria viridis (locally known as Chacruna) as well as the the brain, seems to be particularly important in drug use harmala alkaloids contained in the ayahuasca vine (Banisteriopsis disorders as it processes information about body state and caapi). Dominguez-Clave et al. 2016 as well as Tófoli and de external stimulation, makes a prediction about risk and Araujo, (2016) have reviewed the pharmacology and benefit, and then launches a behavioral response to achieve neuroscience of ayahuasca and Araujo et al. 2015 offers a the desired goal (Paulus et al., 2013). Several neuroimaging summary of mechanisms underlying the hallucinogenic studies also suggest that the altered state of consciousness properties of tryptamines more broadly, including DMT. produced by ayahuasca (and psilocybin) creates a disruption Brierley and Davidson (2012) also reviewed the implicated or interruption of the repetitive, rigid, and pathological pattern neurobiological mechanisms, in particular those related to of negative and compulsive thoughts present in mood, anxiety harmine pharmacology. Findings suggest that harmine can and substance use disorders, contributing to changes in regulate aberrant dopamine reuptake rates. This may be perspective, values and behavior (see summary of this relevant for treatment of substance use disorders as reduced literature by dos Santos et al., 2016). dopamine levels in the mesolimbic pathway interfere with the While it is important to more fully understand the underlying synaptic plasticity associated with the development and neuropharmacological mechanisms, they are only part of a maintenance of addictions. These findings complement an complex interplay between the mechanisms related to the dose earlier contribution by Vollenweider and Kometer (2010) on and quality of the substance ingested and non-pharmacological neurobiological mechanisms underlying psychoactive substances factors such as the individual characteristic of the person (set) and in the same family of psychedelics (e.g., LSD, ketamine) that the therapeutic context of the experience itself (setting) (e.g., impact glutamate neuroplasticity and other mechanisms Loizaga-Velder and Loizaga, 2014; Loizaga-Velder and Verres, implicated in treatment of mood disorders. Dos Santos et al. 2014; Uthaug et al., 2021). The interplay between set, setting, and 2016 further updated this literature through a systematic review neuropharmacology is an important consideration within of clinical trials published in the last 25 years on the anti- psychedelic science that involves analysis of factors that depressive, anxiolytic and anti-addictive therapeutic benefits of influence the user’s general mindset such as motivation for ayahuasca, psilocybin, and LSD, including a review of a wide use, expectation of effects, intentions, and preparation (set) range of potential mechanisms. These mechanisms range from and the social interactions, physical location, and wider commonly accepted pathways related to agonism of the serotonin sociocultural conditions (setting) (Hartogsohn, 2016). Citing 5-HT1A/2A/2C receptors and related modulation of glutaminergic the original ideas postulated by Carhart-Harris and Nutt neurotransmission, as well as anti-inflammatory action (see also (2017), Carhart-Harris et al. (2018b) articulate the Galvão-Coelho et al., 2020). Animal studies suggest that the anti- hypothesized link between these individual and environmental addictive potential of harmine and harmaline appear to involve factors and potential underlying neuropharmacological imidazoline, glutamate, and dopamine pathways. Research with mechanisms, namely increased serotonin 2 A receptor animals has demonstrated that ayahuasca can reduce alcohol signaling mediating cortical plasticity and an associated induced sensitization and inhibit early behavior associated with sensitivity to internal (i.e., endogenous processes and pre- alcohol use disorder, with one study concluding that ayahuasca existing mental context) and external influence (i.e., the can revert long term effects of alcohol dependency without itself environment), is proposed to be the key underlying mechanism. inducing dependency (Oliveira-Lima et al., 2015). Modulation of The role of set and setting has historically been a topic of high cortisol levels has also been implicated (Galvão et al., 2018) as well interest in the exploration of therapeutic models that incorporate as modulation of serum brain-derived neurotrophic factor psychedelic substances, including ayahuasca (Metzner et al., (BDNF), a neurotrophin associated with major depression 1965; Carhart-Harris et al., 2018c; Pollan, 2018). Among the (Almeida et al., 2019). Finally, mechanisms associated with first to advocate for going beyond the mechanistic aspects of the neuroplasticity and neurogenesis have been implicated by neurobiological hypotheses, Liester and Prickett (2012) and several studies of this family of psychedelic compounds (e.g., Prickett and Liester (2014) discuss the role of transcendent Morales-Garcia et al., 2017; 2020). experiences with ayahuasca in the treatment of substance use Based on neuroimaging, comprehensive neuro-psychological disorders, putting forth a ‘psychological theory’ as well as a theory cites the important role of the default mode network ‘transcendental theory.’ Also emphasizing the psychological (DMN) in the so-called entropic brain hypothesis, which aspects, Dominguez–Clave et al. (2016) reviewed research on hypothesizes that under the influence of psychedelics the psychological variables and reported that ayahuasca appears to entropic state of brain activity is heightened, which enhances enhance facets of mindfulness related to acceptance and the sensitivity to set and setting and perceptions of connectedness ability to take a detached view of one’s own thoughts and (Palhano-Fontes et al., 2015; Carhart-Harris et al., 2018b; emotions. They conclude that ayahuasca shows promise as a Carhart-Harris et al., 2018c; Carhart-Harris and Friston, 2019; therapeutic tool by enhancing self-acceptance and allowing safe Pasquini et al., 2020). Important activity in brain regions involved exposure to emotional events, citing its potential usefulness in the in emotional processing and introspection is also implicated treatment of impulse-related, personality, and substance use (Kometer et al., 2012; Kraehenmann et al., 2015), including disorders and also in the handling of trauma. Franquesa et al. the functions of the interoceptive system that modulates (2018) emphasize underpinning psychological variables related to Frontiers in Pharmacology | www.frontiersin.org 3 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP “de-centering” values and self, while Timmermann et al. (2018) functional (e.g., the importance of treatment milieu; therapeutic have focused on the phenomenological relationship between DMT- alliance). induced experiences of ego dissolution (often characterized by ‘ego Some organizations in Brazil (Mercante, 2013) and other death’) and near-death experiences (NDEs), the latter of which are South American countries offer ayahuasca-assisted treatment known to confer long-term positive changes in well-being. for substance use disorders in various structured and semi- Psychological integration of the ayahuasca experience, with structured formats and organizational contexts (Politi et al., psychotherapeutic processes such as group sharing, art therapy 2018). In Peru, Colombia, Ecuador and elsewhere, there are and/or professional psychosocial support and interpretation, are many centers in which curanderos (i.e., local healers) offer also noted to be particularly important for positive outcomes in ayahuasca in ceremonial contexts that differ widely in practice ayahuasca-assisted treatment and rehabilitation for substance use (Holman 2011; Apud 2015; Marcus and Fotiou 2019). These disorders (Loizaga-Velder and Loizaga, 2014). centers cater largely to foreigners who report a range of Among other key elements of the ayahuasca experience such motivations for seeking ayahuasca shamanism, from self- as symbolic aspects related to purging in a non-ordinary state of improvement, to spirituality-oriented and healing experiences, consciousness, psychological insights and emotional processing as well as healing for substance use disorders and other mental of significant life events, the importance of the transcendental, or health issues (Winkelman, 2005; Kavenska and Simonova, 2015). “peak”, mystical experience is emphasized as a strong mediating An additional complex layer of ayahuasca use in this context is factor in treatment outcome for many ayahuasca users. Mystical the phenomenon of ‘ayahuasca tourism,’ which engenders certain experiences have been found to have and important therapeutic perceptions, expectations, and a particularly curated kind of value also in research on the use of psychedelics for alleviating esthetic and relational experience with ayahuasca shamanism. depression and anxiety in terminally ill cancer patients (Griffiths Both benefits and risks associated with ayahuasca tourism have et al., 2016), and other therapeutic processes (Majic et al., 2015). been reported (Kavenska and Simonova, 2015; Prayag et al., 2016; The intensity of mystical-type experiences during psilocybin- Bauer, 2018). assisted therapy has been correlated with treatment outcomes for alcohol dependence (Bogenschutz et al., 2015) and nicotine The Ayahuasca Treatment Outcome Project dependence (Garcia-Romeu et al., 2015; Johnson et al., 2014; ATOP was developed as a multi-site research project with sub- 2017). In an effort to explain such results, Carhart-Harris et al. projects and teams in different countries. Each sub-project is 2018b emphasize the different dimensions of “connectedness” required to secure its own individual research funding and is that arises in the psychedelic experience (e.g., connected to subject to unique timelines, as well as regulatory and cultural nature, to others, or the larger Universe in a mystical way). circumstances. The ATOP team initially anticipated project sites Kjellgren et al. (2009) characterize the stages of the ayahuasca in Peru, Mexico, Brazil and Argentina. There is a potential for experience as often culminating in a deep transpersonal additional sites to be added, each required to share a set of experience and fundamental changes in worldview, personal common principles, methods and measures that will support the development, interests, and orientation to life in general. In a roll-up of key aspects of the resulting data. These common broad-based Internet-based survey, Griffiths et al. (2019) found elements are referred to as the ATOP umbrella. In effect, that ayahuasca users report mystical experiences to be more ATOP aims to tell a story concerning the effectiveness of positive and with more enduring impact on life satisfaction, ayahuasca-assisted treatment for addiction–a story with social relationships, spiritual awareness in everyday life, and separate chapters but a common story line. To this end, it was attitudes about life and self, mood and behavior compared to acknowledged from the outset that the success of ATOP would those using other psychedelics such as LSD, psilocybin, or DMT. depend on the decisions made by a central team on the core With respect to the importance of the therapeutic setting, features of the ATOP umbrella, as well as the commitment of the Griffiths et al. (2019) speculate that the more enduring impact of sub-projects to follow the core principles and protocols. That the ayahuasca experience may be related to its common use in a being said, the ATOP leadership team acknowledges that the structured religious or spiritual group context. Similarly, traditions and cultural/legislative context in each country will ethnographic work reported by Talin and Sanabria (2017) dictate some deviation. concerning substance use-related recovery experiences with The key principles and elements of a common protocol were ayahuasca highlight the importance of collective ritual- identified at a three-day workshop held in October 2013 in ceremonial healing spaces and practices for therapeutic Tarapoto, Peru, hosted by the Takiwasi Center. Participants outcomes, which points to the importance of the therapeutic represented a variety of backgrounds and experience from context. A retrospective qualitative study of ayahuasca use for the different treatment centers, scientific disciplines, and treatment of eating disorders also illustrated the multiple therapeutic orientations, including traditional healing, to form dimensions of the experience that may contribute to efficacy, a protocol in coherence with the intercultural nature of potential including the group ceremonial context (LaFrance et al., 2017). In ATOP project sites and the modern ayahuasca phenomenon. The the more general literature on substance use treatment outcomes, meeting was designed to build upon a strong foundation of there is considerable evidence for the importance of the treatment previous scientific research as well as to foster collaborative environment, both structural (e.g., institutional vs. more initiatives and knowledge exchange between stakeholders from community-oriented services (Urbanoski and Rush, 2013) and different perspectives. Frontiers in Pharmacology | www.frontiersin.org 4 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP As a result of these structured deliberations a core set of treatment (Giovannetti et al., 2020) and on samples of Takiwasi inclusion criteria for study sites, methodological approaches, and patients assessed with selected measures prior to implementation of measures were identified to allow for synthesis of the research the full protocol reported on here (O’Shaughnessy, 2017; Berlowitz across multiple sites. et al., 2019). As described below, the research team is now poized to report on the first cohort of patients followed for a full 12 months after Core Inclusion Criteria discharge. Negotiations continue in Mexico in order to meet • The focus of ATOP was defined as the evaluation of importation and other regulatory requirements for implementing ayahuasca-assisted services for addiction-related the ATOP protocol at Nierika Center. challenges, which may also involve co-occurring mental health challenges such as depression and anxiety Justification for the Study disorders, as well as other physical health challenges. It Among the plethora of options for ayahuasca-assisted healing was also decided to include tobacco use disorders within now available in the Amazonian and global context, the project scope but to exclude “process addictions” such as sex Takiwasi Center, and other potential ATOP sites such as addiction, gambling or video gaming. Nierika in Mexico, are unique in ways which make them of • Program sites would be selected only from Latin American high interest from a treatment research perspective, especially countries and chosen to represent a continuum of the study of treatment outcomes for substance use disorders. approaches that integrate traditional Amazonian plant Takiwasi, for example, is approaching 3 decades of practice in medicine, including ayahuasca as a core element, with a treating problematic substance use and substance use disorders. range of western practices such as psychotherapy and It is officially recognized by the Peruvian Ministry of Health as psychosocial supports. One criterion for site selection an integrative rehabilitation clinic that incorporates rigorous that was hotly debated for the ATOP umbrella was that and frequent medical and psychological pre-treatment there would be no use of other psychoactive substances in assessment, ongoing monitoring, and supervision. This the therapeutic context, including Kambo and cannabis, but clearly sets it apart from the diverse and unregulated excluding tobacco given its core use in Amazonian ayahuasca centers that now proliferate in the Amazon basin, traditional medicine and in the neo-shamanic, as well as the neo-shamanic and New Age ayahuasca groups in naturalistic context as a cleansing and healing agent. urban spaces throughout the world. Takiwasi provides a stable • Last, another key principle for the ATOP umbrella was an organizational environment and infrastructure for the conduct agreement on the study exclusion criteria for individual of a scientifically sound study of treatment outcome, particularly participants, including pregnancy and current use of in its reasonably well-defined and documented assessment and MAO-inhibiting anti-depressants, and other contra- treatment protocol. Client assessment protocols and other indicated medications. program documentation record potentially predictive client characteristics and also facilitate measurement of treatment Core Methods and Measures exposure to help explain treatment outcomes. Further, given The following general aspects of a common study protocol were its longevity and organizational maturity, it is useful to study considered essential features of the ATOP study design. Each of Takiwasi as a longstanding model for contextualized these is described in more detail below. intercultural psychedelic-assisted therapy in light of clinical trials which are now attempting to (re)invent a “new” 1. Contextual Description of Treatment Settings. therapeutic paradigm. From the point of view of examining the complex interplay of set and setting in the determination of • Original and/or existing ethnographic description. treatment outcome, this highly complex treatment protocol • Interviews with program managers, staff, and healers. offers a rich, if not somewhat daunting, opportunity given its syncretic hybrid of Amazonian and Christian cosmologies and 2. Observational design with mixed methods diverse techniques of traditional plant medicine, rituals, psychotherapeutic and self-help approaches offered within • Baseline, discharge and periodic post-discharge the treatment milieu of a therapeutic community. Since its measurement of treatment outcomes with inception, Takiwasi has been supportive of more than 70 validated, quantitative measures, with minimum of research studies, mostly master’s and doctoral theses, across one-year post-discharge follow-up. several disciplines including psychology/psychiatry, • Scheduled semi-structured interviews with study neuroscience, sociology, anthropology, musicology, and art. participants for qualitative analysis. Researchers have investigated the inpatient population (Presser-Velder, 2000; Horák 2013; Cervi et al., 2019; At the present time, the Takiwasi Center remains the first and only Defelippe et al., 2019; Berlowitz et al., 2020; Giovannetti active ATOP study site. The ATOP-Takiwasi study was initiated in et al., 2020), seminar participants (Dupuis, 2018, Dupuis, January 2016 and this paper reports the protocol used in data 2021), and a mix of inpatients, seminar participants, and collection and analysis for the mixed-methods program evaluation, outpatient diet-retreat participants (Håland 2014; Marcus including post-treatment follow-up. Preliminary results have been and Fotiou 2019). Although there are high rates of treatment published on select mental health outcomes achieved during non-completion (Defelippe et al., 2019), preliminary data are Frontiers in Pharmacology | www.frontiersin.org 5 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP suggestive of short-term treatment efficacy (Giove Nakazawa, inpatient options for most clients (Martin et al., 1998; Martin and 2002; Mabit, 2002; Berlowitz et al., 2019; Giovannetti et al., Rehm, 2012; McCarty et al., 2014), thereby mitigating any 2020) and ethnographic inquiry has implicated the various significant improvement in effective treatment coverage of the aspects of the treatment context that may influence treatment overall population in need. In short, such facilities need to be used outcomes (Bustos, 2006; O’Shaughnessy, 2017; Marcus and judiciously. Fotiou, 2019). To summarize, there is a role for long-term residential treatment in well-circumscribed, individual circumstances, and within a stepped-care continuum of services and supports. The Treatment for Substance Use Disorders and extant literature also highlights the complexity of the therapeutic Long-Term Residential Programs community as a treatment intervention and the need for more The interest in studying treatment outcomes at the Takiwasi focused research on critical components and factors associated Center extends beyond the specifics of its treatment model for with treatment completion and positive treatment outcome ayahuasca-assisted healing, to include the potential contribution (Aslan and Yates, 2015). This includes research on to research on long-term residential treatment models, and their motivational and expectancy-based factors associated with place in the overall continuum of services for substance use seeking and completing such a long-term and high intensity treatment. Modern conceptualizations of substance use treatment option. More research is also needed to identify treatment systems articulate a place for residential treatment alternative and innovative treatment models for people with options, including long-term options that extend well beyond complex refractory substance use disorders that have the more common 4–6-weeks treatment models (World Health challenged treatment success in briefer, less intensive options Organization, 2016). That being said, residential treatment within the continuum of care. services must be viewed within a “stepped-care” model whereby they are most effectively and efficiently utilized after other less intensive options (i.e., one might need to “step up” to SUMMARY AND RESEARCH GOALS this option). Alternatively, in a “stepped-down” approach, residential treatment may include a post-discharge transition To summarize, there is considerable anecdotal, as well as to outpatient treatment as part of a well-defined continuing retrospective and prospective quantitative evidence about the care plan (Breslin et al., 1998; Bower and Gilbody, 2005; Rush therapeutic effectiveness of ayahuasca-assisted treatment for and Urbanoski, 2019). These considerations also speak to the problematic substance use, including substance use disorders, need to allocate scarce resources for substance use treatment as well as mood and anxiety disorders. Several plausible wisely, recognizing that the effectiveness of residential treatment neuropharmacological, psychological and other mechanisms of has been judged to be “moderate” at best (Martin and Rehm, action have been proposed, including therapeutic mechanisms 2012; Reif et al., 2014). Outcomes are also highly variable with specific to substance use disorders. Factors associated with respect to therapeutic communities specifically, with more positive treatment outcome have been investigated positive outcomes reported by reviews focused on recovery- quantitatively and qualitatively. Experts in this area agree, oriented outcomes such as legal and employment status and however, that more research is needed with more diverse psychosocial functioning (Magor-Blatch et al., 2014) compared to samples and cultural/therapeutic contexts, as well as more systematic reviews focused on substance use outcomes per se systematic investigation with longer follow-up and comparison (Malivert et al., 2012). Research is unequivocal, however, in samples where possible (Brierley and Davidson, 2012; Bouso and reporting very low rates of treatment completion due to a Riba, 2014). Given the important role of both set and setting in multitude of individual and program-specific factors (Prangley research on psychedelic-assisted treatments in general, more et al., 2018). Previous research data reported for Takiwasi Center, studies are also needed that are aimed directly at the current study site, are consistent with this, with non- understanding this complex interplay. This will require a completion rates measured at 51.8% (Defilippe, et al., 2019). mixed-methods approach that would integrate quantitative Following their systematic review of European therapeutic data on treatment outcome with both an ethnographic communities, Malivert and colleagues (2012) found that, on description of the therapeutic context and qualitative average, participants stayed only a third of the planned time, assessment of the subjective experiences of participants, in with completion rates ranging from 9 to 56%. All studies included particular perceptions and meaning attached to critical in their systematic review showed that substance use decreased ingredients of the treatment experience and the outcomes during treatment and, while relapse was common, treatment attained. completion was the most predictive factor predicting Among the many alternatives available today for those seeking abstinence at follow-up. Relatedly, positive treatment outcomes ayahuasca-assisted treatment for substance-related challenges, appear to be associated with the duration of long-term residential including severe substance use disorders, Takiwasi Center treatment, up to about 18 months, at which point efficacy appears represents a unique opportunity to further our understanding to level off and decline (Zhang et al., 2003). The long duration of of both the therapeutic value as well as the active ingredients of an therapeutic communities also ultimately means that far fewer integrative therapeutic model. The global challenge related to people will be treated compared to outpatient services, which effective treatment coverage, coupled with the rapid growth of research has consistently judged to be more cost-effective than alternative ayahuasca-assisted options in Latin America and Frontiers in Pharmacology | www.frontiersin.org 6 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP globally that incorporate this traditional ethno-medicine, work of Carl Jung, and Gestalt therapy, among other influences increases the urgency of work to document treatment efficacy (Mabit et al., 1996; Dupuis, 2018; O’Shaughnessy 2017). The and explore the underlying mechanisms. Work is also needed on treatment philosophy puts a strong emphasis on spirituality, limitations, potential contraindications, and risks. There are also particularly in the framework of what the institution refers to important opportunities to better understand the role of long- as traditional Amazonian medicine, which reflects a broader term residential treatment alternatives for substance use disorders Andean-Amazonian cosmology in which all plants have a and their place in the overall treatment continuum. In short, the spirit (a madre) that confers a teaching (Jauregui et al., 2011). overarching goal of such work would be to identify effective Takiwasi is not a religious institution; however, there is a notable therapeutic components of ayahuasca-assisted treatment in Catholic influence and presence maintained by its co-founders different communities and cultures and translate these and current leaders of the institution (Dupuis, 2018; Horák, findings into improved treatment for substance use disorders 2013). There is an on-site chapel and a resident Catholic in both traditional medicine and contemporary contexts. priest (padre) who performs Sunday masses, baptisms, and Specifically, the four goals of the ATOP project currently other Christian rites for those who wish to participate underway at Takiwasi Center are to: (O’Shaughnessy, 2017). In the ceremonial maloca,1 the walls are decorated with images representing the Christ, the Virgin • Contribute to the understanding of ayahuasca-assisted Mary, and Saint Michael (Dupuis, 2021), thus the participants treatment for substance use disorders, in particular the inevitably encounter Christian iconography whether or not they understanding of the role of set and setting from the participate in chapel gatherings. The main building also contains perspectives of both staff and patients. iconography from other spiritual traditions as well, such as • Inform other potential ayahuasca-assisted modalities for Buddhism, and linked to practices like yoga and meditation. treatment of substance use disorders, as well as The model of addiction is embedded in a spiritual framework, psychedelic-assisted treatment generally. wherein problematic substance use is conceived as a misguided • Contribute to the body of knowledge on treatment of spiritual ‘self-initiation’ that turns into harmful behaviors (Mabit substance use disorders and factors associated with et al., 1996). According to Mabit et al. 1996, Amazonian positive treatment outcome in long-term residential shamanism offers a ‘true’ initiation that can help individuals treatment alternatives; and reorganize their inner Universe and reconnect with the sacred, • Identify strengths, challenges and limitations within the thus reorienting the relationship with substances, with the self, current Takiwasi treatment model so as to contribute to and with the world (O’Shaughnessy, 2017). The philosophy at ongoing efforts toward quality improvement. Takiwasi acknowledges that the contextual and ritualized use of sacred medicines in an appropriate setting (such as guided ceremonial ayahuasca use) can be highly beneficial for the Research Methods individual. Indeed, the center clearly distinguishes ‘drugs’ and Research Setting ‘drug use’ from ancestral medicines such as ayahuasca and The Takiwasi Center was established in 1992 in the city of mapacho (Nicotiana rustica). The program also recognizes that Tarapoto, located in the Upper Amazonian region of Peru. upon discharge participants may, if they choose, return to Among the programs and facilities known to have selective low-risk substance use. Thus, longer-term treatment incorporated ayahuasca into their treatment protocol for goals are adapted to each individual and this may or may not rehabilitation from substance use disorders, Takiwasi is no include complete abstinence as an indicator of treatment recovery doubt the best-known such facility internationally. The (Giove Nakazawa, 2002). treatment model is referred to internally as a ‘therapeutic The Takiwasi treatment regime is highly structured, following tripod’: traditional Amazonian medicine (including the ritual many common practices of therapeutic communities in general. use of ayahuasca in combination with other plant-based Before entry into the program, in addition to a typical clinical medicines), psychotherapy, and community living (convivencia). assessment, applicants must write a detailed life history that The Center offers a variety of programs and services including describes their childhood, upbringing, life goals, sexual ten-day plant medicine retreats (known as dietas), seminars, and relationships, and relationships with family, romantic partners, a long-term residential treatment program for substance use- and work life, as well as their goals for the program and life in related rehabilitation, which is the main focus of Takiwasi and of recovery. Prospective patients are then interviewed remotely and the present research. The residential program is for men only, encouraged to visit the center. Inpatients sign a contract for a following Peruvian regulations requiring same-sex residential voluntary nine-month internment, divided into three treatment services, modeled in large part after a therapeutic community (TC) model. As a TC there is a heavy emphasis on the role of community living in the therapeutic process, 1 A maloca is a traditional longhouse often constructed of wood with a palm- engendered by sharing work and maintenance duties, thatched roof. In the Peruvian mestizo tradition, ayahuasca ceremonies are recreation, and personal friendships, as well as the inevitable typically conducted in a maloca. This ‘rustic’ structure lends an ambience to interpersonal challenges. The other aspect of the treatment model the setting, demarcating it as a ‘safe’ ritual space. In Takiwasi, in particular, there combines “ancestral healing practices of folk healers and shamans are strict rules about how to exit and enter the maloca once the ceremony with modern psychology” such as transpersonal psychology, the has begun. Frontiers in Pharmacology | www.frontiersin.org 7 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP “trimesters” or treatment phases. As per the contract, once outcomes over time, as well as assessment of interpersonal treatment begins the inpatients must remain on the premises interactions and subjective reports on the significance of for the duration of the program. Each patient is assigned a different treatment components. A mixed-methods approach therapist with whom they will meet weekly for the duration of is consistent with a complexity-based evaluation design as well the program. The first eight days are committed to detoxification, as with trends in the literature on recovery from substance use wherein the patient is isolated from the other inpatients and disorders (e.g., American Society of Addiction Medicine, 2013; attended to by their therapist and the healers, while adhering to a Kaskutas et al., 2014; Costello et al., 2018) that advocate going regime of restricted diet, herbal saunas and baths, and drinking beyond assessment of abstinence to incorporate a broad range of depurative plants. After enduring this initial stage, the individual metrics for positive treatment outcome (see also the officially joins the therapeutic community. In addition to International Consortium for Health Measurement individual psychotherapy sessions, patients participate in Outcomes, 2020). group therapy activities, ergotherapy, a variety of workshops Our research design was also influenced by several practical (which might take the form of yoga, martial arts, dance, or considerations. Although Takiwasi serves our purpose as a sports), and are assigned various plant formulas for daily naturalistic “living research laboratory,” there is not a realistic intake. Patients participate in weekly rituals with purgative opportunity to randomly assign patients to alternative treatment plants, three to four eight-day isolation plant retreats (dietas), conditions, including a no-treatment control group. We also and ayahuasca ceremonies two times a month. The therapists visit recognize that randomized controlled trials are not without patients every two days during their isolation retreats to help their own challenges (Cohen et al., 2004; Rothwell, 2005; integrate the experience. During the dieta, a specialized Melberg and Humphreys, 2010; Hyde and Delphin-Rittmon, Indigenous or mestizo healer or assistant attends to the 2014), especially for complex interventions heavily influenced patient one, two or three times a day to provide the assigned by set and setting (Stame, 2004). Lack of proximity to enhanced plants according to prescription. Throughout the program, medical facilities also precluded incorporating a neuroimaging patients are instructed on the significance of plants-as-teachers component despite early interest among the ATOP team in doing and the importance of the dieta and the ritual shamanic process so. Constraints are also imposed by the length of the Takiwasi now made accessible to non-Indigenous people through the program (typically nine months) as well as anticipated high Center’s psychology-oriented, syncretic and shamanic treatment drop-out rates, which we forecasted would present framework. challenges in recruiting a study population of sufficient sample size for complex multivariate modeling of treatment exposure Study Design and outcome required to identify the most active programmatic Study design is grounded on the premise that the treatment ingredients from a statistic point of view. This further highlighted protocol at Takiwasi is a complex intervention, delivered within the need for a strong qualitative component to the study design a unique organization with multiple mechanisms of action. In and thoughtful integration of the qualitative and Takiwasi, there are many treatment components that include quantitative data. but are not limited to: the ingestion of ayahuasca in syncretic Consistent with the above considerations, a research design shamanic ceremony; traditional use of other key medicinal was formulated that is appropriate and feasible within the plants; ritual ingestion of purgative plants; daily ingestion of Takiwasi context. Figure 1 provides a high-level overview of plantas de contención (containment plants, taken daily in lower the various components of the ATOP protocol implemented at concentration); individual and group therapy sessions; Takiwasi with Figure 2 providing a more detailed timeline for the ergotherapy; and convivencia. All of these components various measurement processes in relation to the various provide the ‘setting’ of treatment and support, which interact elements of the Takiwasi therapeutic processes. Specifically, a with and alter the ‘set; ’ that is, as patients participate in different prospective cohort design using a set of core quantitative rituals and therapies over several months, their expectations and measures at baseline (i.e., program intake), discharge and 3, 6, perceptions of the treatment and their own progress will 12, 18-months and 24-months follow-ups. The baseline necessarily change. Because of the complexity of the assessment includes a research-based, psychiatric interview to intervention and its organizational context, we draw upon define status regarding substance use and other mental disorders the literature on the evaluation of complex interventions by international standards–The MINI International (Sridharan and Nakaima, 2020) and the role of context Neuropsychiatric Interview (Lecrubier et al., 1997; Sheehan (LaFrance et al., 2012; Rog, 2012), so as to ensure critical et al., 1998). The purpose of this structured interview is for attention to the interaction between set and setting. This recruitment (i.e., eligibility depends on a research diagnosis of approach takes into account not just individual elements alcohol/drug abuse or dependence and for purposes of sample such as complexity of patient profiles, previous treatment description and sub-group analysis according to mental health history and level of participation in various aspects of the co-morbidity, e.g., co-occurring depressive or anxiety disorder). program, but the programmatic and organizational context of Following completion of this diagnostic instrument and other Takiwasi as a whole. To better address this complexity, and aspects of eligibility determination (i.e., assessment of cognitive consistent with the overarching ATOP protocol requirements, impairment (Katzman et al., 1983), the remaining baseline the research protocol is based on a mixed-methods approach to measures are administered. These measures cover severity of accommodate measurement of individual health and wellbeing substance use disorder, quantity and frequency of substance Frontiers in Pharmacology | www.frontiersin.org 8 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP FIGURE 1 | Overview of ATOP Study Design. FIGURE 2 | Timeline. Frontiers in Pharmacology | www.frontiersin.org 9 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP TABLE 1 | Quantitative measures used at baseline and post-treatment. Quantitative measure Description Addiction Severity Index—5th Version (ASI-5) ASI scores provide a general profile of problem severity in specific areas (drug use, employment, medical and psychiatric disorders, family/social relationships, legal status) and is a proven international standard for treatment planning and post-treatment outcome evaluation. This project employed the Spanish version of the ASI-5 McLellan et al. (1992) Global Appraisal of Individual Needs –Substance Use Grid This instrument comprises a small set of items and subscales of a much larger tool used for treatment planning and process and outcome evaluation for substance use treatment - the GAIN-I Dennis, (1999); Coleman-Cowger et al. (2013). The tool is needed to supplement the ASI-5, which does not provide sufficient detail on actual drug use, or treatment history. The GAIN-I, including these sub-scales, has been translated into Spanish. The sub-scales measuring drug use have been adapted to reflect street names of various drugs in the peruvian and Latin american context Beck Depression and Anxiety Inventories (BDI and BAI) These are self-administered instruments to measure symptoms of depression and anxiety with 21 items rated on a scale from 0 to 3 Beck et al. (1988); Steer and Beck, (1997). Results are used to classify depression and anxiety as minimal, mild, moderate and severe. They are validated in Spanish Bonicatto et al. (1998); Vega-Dienstmaier et al. (2014) WHOQOL-BREF—Quality of Life The WHOQOL-BREF instrument comprises 26 items, which measure the following broad domains: Physical health, psychological health, social relationships, and environment. The WHOQOL-BREF is a shorter version of the original instrument WHOQOL-100 Saxena et al. (2001); The WHOQOL Group, (1998). It assesses the individual’s perceptions in the context of their culture and value systems, and their personal goals, standards and concerns. The WHOQOL instruments were developed collaboratively in a number of centers worldwide and have been widely field-tested. The Spanish version has shown good psychometric properties Lucas-Carrasca, (2011); Saxena et al. (2001) WHOQOL-SRPB—Spirituality, Religiosity and Personal The WHOQOL-SRPB consists of 32 questions, covering quality of life aspects related to spirituality, Beliefs religiousness and personal beliefs (SRPB). This instrument has been developed from an extensive pilot test of 105 questions in 18 centers around the world. The resulting 32-item instrument represents the finalized version of the WHOQOL-SRPB to be used for field trials. It is available and tested in Spanish Lucas-Carrasco,( 2011) Treatment Entry Questionnaire (TEQ-9) [BASELINE ONLY] This brief nine-item questionnaire measures motivation for treatment based on self-determination theory and contains three separate, validated dimensions that relate to identified motivation (e.g., sought treatment because really identified with goals of the program and wanted to make changes); external motivation (e.g., sought treatment because other people pressured); or introjected motivation (e.g., sought treatment because of internal conflict such as to avoid feeling ashamed) Wild et al. (2006); Urbanoski and Wild, (2012); Wild et al. (2016). The instrument has been translated and back-translated to Spanish use, motivation for treatment, a range of mental health measures, contextual description of the Takiwasi treatment center based quality of life, and spirituality. The specific instruments used are on existing literature (Mabit and Sieber, 2006; Håland, 2014; identified below according to study phase, all but one of which has O’Shaughnessy, 2017; Mercante, 2013; Dupuis, 2018; Dupuis, been validated in Spanish, that being the Treatment Entry 2021; Politi et al., 2019). A sub-project was also initiated part way Questionnaire, which the study team translated and back- through project implementation to identify factors associated translated according to accepted international guidelines. with non-completion of the program. Although initially conducted via telephone on Internet (e.g., The research protocol at Takiwasi was approved by the Comité Skype), the follow-up quantitative data collection was de Ética PRISMA, Lima, Perú. converted to an on-line platform for purposes of cost- efficiency and with personal support available as needed by Measures the respondent. Importantly, all follow-up contacts are Quantitative Table 1 identifies the quantitative measures used to initiated and supported by the Research Coordinator who is establish a baseline and measure change over time, as well as independent of the programmatic structure of the Takiwasi treatment motivation at treatment entry, an important potential treatment program itself. First contact with the follow-up modulator of outcomes. Research Coordinator is immediately after inclusion of the Qualitative Semi-structured interviews are conducted with participant in the study and then regularly thereafter to book recruited program participants at different points: baseline, future appointments and maintain accurate information on the during treatment, discharge, and each point of follow-up, client’s living situation. synchronized with completion of the follow-up quantitative The qualitative component of the mixed methods design measures. The semi-structured interview guides are included includes patient semi-structured interviews undertaken in the in Supplementary Material. same temporal sequence as the quantitative measures: that is at Baseline Information gathered at baseline includes the program entry, during treatment, at discharge, and at each duration/trajectory of substance use problems and previous follow-up point. To improve understanding of the treatment formal and informal treatment experiences within this setting (i.e., environment and interpersonal interactions), trajectory. Life experiences related to overall health and mental patient interviews are complemented by semi-structured health are also explored. Other areas of questioning include interviews with staff, therapists and healers as well as a motivations and expectations for the program experience lying Frontiers in Pharmacology | www.frontiersin.org 10 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP TABLE 2 | The core themes analyzed in the baseline and follow-up qualitative interviews. Data collection phase Core themes explored Baseline interviews Ayahuasca, psychedelics, shamanism (e.g., experience, learnings, worries, expectations before coming to takiwasi) Sociodemographic data History/context of personal and familial substance use Perceptions of mental health and healthcare systems Spirituality/religiosity Takiwasi-related themes (e.g., reasons for coming; concerns and expectations about treatment; initial perceptions of takiwasi) Treatment capital (e.g., previous substance use and/or mental health treatment) During treatment, discharge, and post-discharge Meanings/personal significance (e.g., building upon previous treatment experience) interviews Program experience (e.g., continuity between ayahuasca sessions; effect on craving; perceived addictive potential; frequency of sessions) Recovery process (e.g., perception of benefits, challenges, ability to integrate experiences and learnings into everyday life) Satisfaction with services (e.g., overall perception of services received and suggestions for improvement) ahead, previous experience with ayahuasca, psychedelics, and Study Recruitment and Measuring Treatment religious or spiritual practices. Exposure During treatment and discharge Since Takiwasi uses ayahuasca The status of participant recruitment is summarized below. As of in a manner that draws heavily upon Peruvian practices, the December 17, 2020, a total of 128 participants had completed specific questions in the interviews during the treatment process intake into Takiwasi and were potentially eligible for ATOP. Of reflects these practices. Topic areas for the interview include: these, 42 left the program before participating in any ayahuasca general perceptions of the overall Takiwasi treatment experience; ceremony as part of their treatment. A total of 86 initial the experience with ayahuasca and the importance of subsequent participant interview were undertaken at baseline and, of those integration activities; and the perception that this has led to scheduled for their one-year follow-up (n-60), 48 have completed changes in the person’s current sense of wellbeing or life both the one-year qualitative and quantitative interview, satisfaction. representing an 80% one-year completion rate. The current A framework developed previously by Loizaga-Velder and sample size at 18-months (n  30) and at 24-months (n  25) Loizaga (2014) was used to develop the questions that explore the reflect on-going scheduling and are not reflective of drop  out dimensions of the subjective experience with ayahuasca and its during follow-up. therapeutic context. Following this framework, specific feedback is As shown in Figure 3, a significant proportion of clients who sought on various elements of the overall ceremonial/therapeutic initiated services at Takiwasi during the study period left the process, including elements of the ceremonial experience program before any use of ayahuasca (42 of 128 or 32.8%), and (i.e., ceremonial songs [icaros], energetic interventions by therefore, are not eligible for study inclusion. As noted earlier, curandero/a, purging, ritual blowing of tobacco smoke [sopladas], such high drop-out rates are common in long-term therapeutic perfumes/aromas); activities aimed at integration (e.g., psychotherapy community programs and may include reasons that concern the or other therapeutic assistance, group sharing); other relevant healing program itself (e.g., too long; content didn’t fit with expectations activities such as yoga, exercise or meditation; purgas (i.e., therapeutic and personal values); the program environment (e.g., the nature use of emetic plants); dietas (isolation retreats supported by and type of facility or community context); or personal issues psychoactive plants); shared group experience (e.g., group (e.g., family or employment concerns made it difficult to support, catalyst for group dynamics); and aspects of the continue; psychological issues such as resistance to continued treatment milieu (e.g., activities together, gardening, sharing or inner work or drug cravings). Some leave treatment programs cooking meals). These areas queried with a five-point rating scale against advice of program staff and others leave for such personal in terms of perceived importance followed by an opportunity for reasons. This presents a challenge for any observational study open-ended comment and clarification on the most and least helpful with a follow-up component in substance use treatment services therapeutic elements. The rating scale responses are transferred to since those who finish the program and/or who are located for the quantitative data file for analysis. Although there was one Likert- follow-up may be different in meaningful ways than those who type question concerning the Catholic practices of ‘liberation’ and leave the program prematurely. ‘genealogic tree masses’, there were no focused questions or A related challenge that is important to account for in the qualitative inquiry concerning perceptions and experience of study design and analysis is the level of treatment exposure for religious elements (namely Christianity or other syncretic those formally accepted into the study cohort after the initial elements) woven into ritual-therapeutic treatments. ayahuasca experience. We approach the measurement of The core themes analyzed in the baseline and follow-up treatment exposure in two ways. First, with respect to qualitative interviews are presented in Table 2. treatment completion the study cohort is divided into three Frontiers in Pharmacology | www.frontiersin.org 11 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP FIGURE 3 | ATOP recruitment overview-Takiwasi (as of Dec. 17, 2020). sub-groups: 1) completed treatment; 2) left the program professional formation, their own personal religious and prematurely but voluntarily; and 3) suspended from the spiritual practices, and their use of, and beliefs about, alcohol program. For the current 12-months sample of 48 clients, the or other drugs and related treatment practices. Other questions number in each group is 30 (60%); 14 (29%); and 4 (8%), query their training and experience working with ayahuasca, respectively. While all three sub-groups are included in the narratives about their own ayahuasca experiences as well as discharge and follow-up samples, the number of weeks of those specifically related to possible links between ceremonial treatment participation is calculated for each patient. The experiences and people’s subsequent change in behavior or habits second approach to measuring treatment exposure is based on related to alcohol and other drugs. Narratives also explore their an extract of information from the patient files concerning the beliefs and experiences regarding the relationship between the nature and extent of participation in program activities, for different elements of the Takiwasi ‘therapeutic tripod’ in example, the number of ayahuasca sessions, days of dieta, facilitating behavioral changes related to use of alcohol or integration sessions with staff. A program participation index other drugs. will be calculated from these extracted data, also for inclusion in A total of 17 interviews have been conducted as of December the analysis. 17, 2020. To investigate the potential for response bias in our study sample due to early or subsequent treatment drop-out, a process Contextual Description of Takiwasi Center has been undertaken to locate clients who left prematurely in Consistent with the overall ATOP protocol, the key elements of this order to explore reasons for leaving the program. At the time of contextual description include the program’s physical and this writing, the questionnaire has been drafted (see organizational infrastructure (e.g., physical space, management Supplementary Material) and the survey is being mounted for structure, budget, length of program); staff/personnel (e.g., number on-line completion. Once finalized, those recruited for the study and type of therapists/staff, the training and experience of who have left prematurely will be contacted using the last curanderos/as and therapists); prevailing beliefs and mores about available email address and a request made for completion of addiction (e.g., curanderos/as and therapists beliefs with respect to the questionnaire. Also, characteristics of program completers causes of addiction, the critical ingredients of effective treatment and and non-completers will be compared (e.g., age, country of origin; definition of good outcome as well as the most common success results of the intake psychiatric interview and/or other baseline factors and challenges for people seeking to make changes); data). interventions provided, for example, the combinations of various plants with or without ayahuasca, use of psychiatric medication or Interviews with Managers, Staff and Healers other therapeutic techniques, strategies for safety, integration, follow- In addition to the interviews with program participants, semi- up and/or continuing care; cultural and community context (e.g., structured interviews are conducted with managers, staff, relationship to Indigenous communities, community support and therapists, and healers (see Supplementary Material). This capacity building). See Supplementary Material for guide for site interview captures the person’s role in the center, their description. Frontiers in Pharmacology | www.frontiersin.org 12 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP Analysis Plan • Do participants report incorporating learnings and While the details of the analysis plan differ significantly for the experiences during treatment into their life after discharge? qualitative and quantitative components of the mixed methods, they share several common elements: 1) guided by specific pre- Quantitative analytics—Patients The quantitative analysis determined research questions in support of the broader project team is composed of three team members, aided by an goals identified above; 2) undertaken by two analytic teams external native Spanish-speaking volunteer. Among the formal working independently and according to their area of team members, one is a native Spanish speaker and two speak expertize (i.e., qualitative or quantitative) but meeting bi- Spanish at an intermediate level. The data preparation and weekly as a unified project team to discuss progress, and analysis will proceed through six steps: 1) preparation of a develop a consensus on critical questions and issues brought unified, person-level Excel data file that includes all baseline to the meeting from each team. and subsequent quantitative data points as well as abstracted With respect to the research questions guiding the analysis, information from patient files; 2) descriptive analysis of the these questions were developed by the overall team to create an characteristics of the study sample with frequency overarching analytic framework, with the quantitative and distributions and cross-tabulations (see Supplementary Table qualitative analyses contributing differentially to each question. S1); 3) descriptive analysis of patients’ treatment participation For example, with respect to Takiwasi patients, both quantitative and perceived importance of Takiwasi treatment activities (see and qualitative analyses were aimed at the following questions: Supplementary Table S2); 4) visualization of trends over time across the range plethora outcome measures (See Supplementary • What is the individual’s previous experience with substance Table S3). Importantly, statistical significance testing is not use treatment and what learnings and challenges are being performed on any observed changes over time in these brought into this new experience at Takiwasi? Is previous multiple outcomes so as not to violate the principles on which treatment experience associated with treatment outcomes? the subsequent stage of multivariate modeling is based • What is the individual’s situation at treatment entry with (i.e., mitigating increased odds of Type 1 error across multiple, respect to physical and mental health challenges and overall non-theory driven comparisons) (Kuchibhotla et al., 2020); 5) a life satisfaction? Are baseline physical and mental health team-based, measures minimization process so as to reduce the challenges associated with treatment outcomes? number of predictor and outcome variables based on previous • What meanings are attached to the overall Takiwasi treatment research and a priori conceptual modeling of hypothesized experience as well as key elements (e.g., treatment milieu, relationships. For example, of the many measures of substance specific medicines, dieta, purging, icaros, therapeutic use and problem indicators, one or possibly two primary integration) and how have these meanings evolved during substance use outcomes measures will be identified, and as the course of the program? What ratings attached to the well many potential predictor and moderator variables significance of these experiences are most closely associated associated with mental health, treatment motivation, treatment with treatment outcome? participation and ratings of program experience. Finally, 6) Preparation of DAGs (Directed Acyclic Graphs) to The key questions specific to the quantitative analysis are: conceptually model the hypothesized relationship between predictor and moderating variables and outcome. These DAGs • What are the outcomes achieved at 12 months post-discharge then serve as the basis for multivariate regression modeling (e.g., self-reported reduction in substance use and overall (Herman and Robins, 2020). Regression analyses will start addiction severity; improvements in symptoms of anxiety with less complex, three to five variable DAGS and build from and depression; change in overall quality of life)? there based on variance explained through addition of predictors • What factors are independently associated with these 12- and moderators (Hernan and Robins, 2020) with due months post-discharge outcomes (e.g., treatment consideration for statistical power. See Supplementary Figure motivation; baseline addiction severity or mental health S1 for an example of a hypothesized and relatively complex DAG. status; discharge status on improvements in mood and Post-discharge outcomes relative to baseline will be analyzed anxiety or spirituality). with a generalized linear mixed effects model. Random intercepts (and random slopes where necessary) will be included to account Examples of questions that are the exclusive focus of the for correlation between observations within study participants. qualitative analysis of patient data include: The regression models will also include (potentially time-varying) baseline and within-treatment covariates (e.g., treatment • What is the person’s subjective understanding of their motivation, baseline addiction severity, and number of hours substance use-related challenges and what is the match engaged in non-ayahuasca treatment activities such as between the individual’s perspective and the treatment psychotherapy, group integration, ergotherapy). Statistical provided at Takiwasi? inference will proceed in a manner consistent with the DAGs • How do clients perceive their recovery process at different constructed before any models are fit. The relevant parameter and follow-up points? What outcomes are reported as being the variance estimates associated with all models that are fit will be most meaningful? reported. Frontiers in Pharmacology | www.frontiersin.org 13 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP Qualitative analytics—Patients The qualitative team is relationships with clients (Aim: To explore the subject of composed of four researchers, two of which are native institutional religiosity, including the role of Christianity Spanish-speakers, and the other two speak Spanish at an within the context of spirituality). expert level. Qualitative analysis will employ a grounded • How has Takiwasi affected therapists’ perceptions of care, theory approach (Miles and Huberman, 1994; Strauss and psychology/psychotherapy, and practice? How did their Corbin, 1994), in which the team creates codebooks based time at Takiwasi influence their proximate career goals on themes that emerge from the interview data with inpatients. (Aim: To explore the ’training’ aspect of Takiwasi and Grounded theory approaches work best with relatively open- how it influences practitioners). ended questions and narratives which allow for deep analysis • What are the prevailing views and subjective understanding and emergence of key themes, which ultimately become of addiction and related challenges (Aim: to explore the integral to building a case-specific theory about outcomes match between practitioners and the treatment provided at related to set and setting at Takiwasi. In line with this Takiwasi). approach, the original guiding research questions may be • Do practitioners link their own experiences with ceremonies modified in an iterative process according to significant and dietas to therapeutic efficacy and/or therapeutic alliance themes that emerge in the data. (Aim: To determine the role of ayahuasca in developing a The team selected a cloud-based qualitative data analysis unique kind of therapeutic alliance). program (www.dedoose.com) through which they can • Are there specific aspects of the ayahuasca experience (e.g., remotely cross-code data and conduct collaborative analyses. dietas, icaros, purging, cleansing/limpiezas, visions, death Analysis will focus on several themes guided by the specific experiences) that managers, staff, therapists and healers research questions, including recovery capital, expectations think are particularly helpful for healing? For alcohol and and perceptions of treatment, spirituality, religiosity, and social drug addiction specifically (Aim: To explore potential links influences, among others. between prevailing views on program components and Integrative quantitative and qualitative analytics—Patients A treatment outcomes). framework has been developed to guide the integration of the quantitative and qualitative analysis according to a constant The qualitative analysis team will employ a grounded theory comparative approach to shared evaluation questions. approach, creating codebooks based on themes that emerge from Supplementary Tables S1–S4 illustrate this approach. An the interview data with these Takiwasi stakeholders. In line with important part of this integrative process will involve this approach, the original guiding research questions may be stratifying the study participants into three groups on the modified in an iterative process according to significant themes basis of a consensus rating by the project team of each that emerge in the data. The same Dedoose qualitative analysis patient’s overall treatment outcome. For convenience purposes, program will be employed so as to work remotely and the three groups will be labeled only, as “very poor/poor,” collaboratively. “moderate,” “very good/excellent.” The qualitative themes related to treatment outcome will then be cross-referenced within each of these three groups with the aim being to DISCUSSION identify themes reflecting important predictive or moderating factors. These analyses will complement the multivariate Considerable research has pointed to the therapeutic value of modeling based on the DAGs. ayahuasca and ayahuasca-assisted treatment for substance use Qualitative analytics Managers, staff, therapist and healer disorders (Thomas et al., 2013; Bouso and Riba, 2014; Nunes interviews: As with the patient interviews a set of pre-defined et al., 2016; Argento et al., 2019) as well as other mental health research questions will guide the analysis of these interviews. The challenges, in particular depression and anxiety (Osório et al., primary research focus for these analyses concerns the 2015; Tupper et al., 2015; Palhano-Fontes et al., 2018; Muttoni homogeneity of the therapeutic culture at Takiwasi. Emergent et al., 2019), many of which co-occur with problematic substance themes will also be identified concerning the convergence and use (Chan et al., 2008). This interest in ayahuasca coincides with a divergence of the Takiwasi therapeutic culture over time. The resurgence in interest and research in psychedelic medicine, research questions and their respective aims are: including chemically similar pharmacological compounds such as LSD and pharma-grade psilocybin (Muttoni et al., 2019; • What are therapists’ main theoretical training and has it Brierley and Davidson, 2012). Research on ayahuasca also influenced their work at Takiwasi (Aim: To identify patterns represents a growing interest in traditional medicine in in practical or theoretical background among practitioners general, which includes, but is by no means limited to, other who gravitate toward Takiwasi). entheogens such as peyote, ibogaine, and psilocybin mushrooms. • Do therapists utilize their non-psychotherapeutic skills with Indeed, ayahuasca is poized to be situated on the bridge between clients at Takiwasi (e.g., reiki, yoga, etc) (Aim: To determine ancestral medical traditions and the modern, westernized medical how many alternative healing practices are being applied application of psychedelics. In both ancestral and modern during clients’ residency). applications, the role of set and setting, more recently framed • What are therapists’ views on religion? How do their as the therapeutic “context” (Carhart-Harris et al., 2018c) have personal views relate to practices at Takiwasi or their important relationships to therapeutic benefit as well as risk. Frontiers in Pharmacology | www.frontiersin.org 14 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP Importantly, the role of “context” resonates with developments in pursuing with a more controlled clinical trial design; for example, the science of program evaluation, in particular realist evaluation music, psychotherapeutic integration, and treatment milieu. It and complex interventions (Pawson and Tilley, 1997; Rog, 2012), will be particularly important to explore what aspects of the and summarized succinctly by the phrase: “outcome  treatment model under investigation in this project might intervention + context”. translate to more readily accessible outpatient services using Building upon a strong foundation laid in the ayahuasca- or other psychedelic-assisted interventions, and for multidisciplinary workshop held in Tarapoto, a comprehensive whom they are most appropriate. In translating the findings to evaluation protocol was developed to investigate outcomes other treatment modalities, it will be important to maintain the associated with ayahuasca-assisted treatment for substance use focus on treatment set and setting as critical ingredients of the disorders at Takiwasi Center. This institution was determined to treatment intervention itself, and not viewed as an element of be an excellent starting point for what was envisioned as a multi- potential placebo to be controlled out of the outcome equation. site research project with a common protocol. Advantages Using our study as an illustrative case-in- point, the research is associated with Takiwasi as a study site include its history of conducted in a naturalistic setting and focuses on evaluating support for internally and externally driven research and outcomes of an integral treatment program as a whole. As such, evaluation, and the syncretic nature of its organizational the drinking of ayahuasca intake and subsequent experiences environment and treatment program. This diversity provides occur within a complex setting following the Amazonian fertile ground for testing a protocol designed from the outset tradition, where different practices take place (e.g., singing, to investigate the role of context in the determination of application of perfumes, and perhaps intake of other treatment outcomes. psychoactive medicinal plant preparations like tobacco juice) The research protocol, described above in detail, is poized to during the same session. From a theoretical point of view, make a significant contribution toward each of four study goals. according to the cosmovision inherent in Amazonian Our first goal is to contribute to an understanding of ayahuasca- traditional medicine, as well as the clinical experience of the assisted treatment for substance use disorders. Our mixed Takiwasi Center, the visionary and psychedelic component of methods approach within a longitudinal cohort design, ayahuasca is not the only, nor necessarily the most important, situated in the context of complexity-based evaluation, will be therapeutic mediator. Indeed, Amazonian healers point critical to identifying key elements of set and setting that are most emphasize the importance of the ritual as whole to trigger the closely associated with treatment outcomes. To this end, the healing process. Moreover, in the Amazonian indigenous and major strengths of the protocol include: the use of multiple, mestizo context, patients frequently do not take ayahuasca in the validated measures of predictors, potential moderators, and ceremony and it is rather just the healer who uses the psychedelic- outcomes, which are assessed at multiple time points from visionary effect to facilitate diagnosis and treatment choice. program entry through 24 months post-discharge; multiple With respect to furthering work with ayahuasca or other measures of program participation and satisfaction with psychedelic-assisted interventions for substance use disorders, services; and state-of-the-art statistical testing methods that we also advocate that close consideration be given to our will minimize risks of Type I error that can arise through comprehensive set of measures so as to facilitate cross-study multiple, non-theory-based significance testing. The comparisons. Notably, our measures map well onto the comparative approach to addressing research questions via recommended outcome domains for evaluating substance use complementary quantitative and qualitative analytics is similar treatment (International Consortium for Health Measurement conceptually to that employed by Thomas et al. 2013 and Argento Outcomes, 2020). Further, we aim to demonstrate that situating et al. (2019) in their study of ayahuasca-assisted treatment for this measurement model within a mixed methods study design substance use disorders in Canada, but now advantaged with a will bring significant value for moving the field forward and, to more extensive baseline assessment of patient characteristics, a this end, all measurement tools used in the study protocol are larger sample size and longer follow-up period. As the current provided as easily accessible Supplementary Material, including research progresses toward its first analysis and reporting on one- the semi-structured interview guides. Pending resolution of year follow data, it will prove to be the most rigorous and importation challenges for bringing ayahuasca to Mexico for comprehensive study to date focused exclusively on ayahuasca- research purposes, we plan for at least one additional ATOP assisted treatment for substance use disorders. site, and more may eventually be added consistent with ATOP The second study goal is to inform other potential ayahuasca- study criteria. The common measurement model and mixed assisted treatment modalities for substance use disorders, as well methods design sets the stage for a multiple case study as psychedelic-assisted therapy more generally. It is anticipated approach, with Takiwasi Center being the first chapter in the that the study results concerning the role of the various non- story of ayahuasca-assisted treatment for substance use disorders pharmacological elements of the treatment context will be useful based on the ATOP protocol. to others that wish to incorporate this medicine into a structured Further with respect to the ATOP measurement model, the treatment process. These critical ingredients may also inform the team elected not to include measures of the immediate development of other psychedelic-assisted treatments for psychedelic (e.g., Hallucinogenic Rating Scale; Strassman et al., substance use and other mental health disorders as well as 1994) or “mystical/peak” experience (e.g., Revised Mystical their evaluation. Following Carhart-Harris et al. (2018c), our Experiences Questionnaire (Barrett et al., 2015) to correlate findings may point to key features of treatment context worthy of with treatment outcomes. While the measurement of mystical Frontiers in Pharmacology | www.frontiersin.org 15 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP experiences has proven valuable in lab-based clinical trials (e.g., Center, to date there is, no clearly documented process by which Rothberg et al., 2021), and many other types of psychedelic this research contributes to service enhancement. Sridharan and research (Johnson et al., 2019), it was determined not to be a Nakaima (2011) speak to the strengths of realist, complexity- good fit for the longitudinal, naturalistic design of ATOP. From a based evaluation in building evaluation capacity within an practical viewpoint, the ayahuasca used at Takiwasi is consumed organization. It is with this spirit that the project team on multiple occasions from different batches, and for this reason anticipates significant knowledge exchange opportunities will undoubtedly vary to some degree in pharmacological among Takiwasi Center managers, staff, therapists, and healers composition and effects. More important, however, is that the to both debate the results and maximize opportunities for purpose of this study is not to assess specific effects of ayahuasca individual and organizational learning and growth. as a dose-response mechanism, nor aim to systematically disentangle pharmacological vs. non-pharmacological factors, Limitations and Conclusion but rather to evaluate an established intervention in a It is important to highlight some of the limitations of the study naturalistic setting. In this naturalistic context the mystical protocol in achieving its ambitious goals. Despite the many experience in any specific ceremony is neither necessary nor strengths of studying ayahuasca-assisted treatment in a sufficient to explain outcomes associated with the multiple naturalistic setting, there are some uncontrolled factors that therapeutic aspects of treatment at Takiwasi for the duration hinder our ability to suggest precise conclusions about efficacy. of a patient’s nine-month participation. For example, the precise composition of the ayahuasca tea and the The third study goal is to contribute to the body of knowledge dosage of consumption (ml/kg) are not available. Similarly, we on treatment of substance use disorders and factors associated could not measure the phenomenological strength of the with positive treatment outcome in long-term residential psychedelic experience (e.g., Barrett et al., 2015). Further, the treatment alternatives. In part, with this protocol we will basic study design precludes strong statements of causality, advance understanding of the effectiveness of the long-term although it’s important to note considerable expert opinion in residential therapeutic community treatment model and its role the field of psychedelic science about the limitations of clinical trials within the overall continuum of treatment and support. In in studying these complex interventions that are so heavily particular, we answer the call for more research on TC’s to dependent on treatment context. And while our protocol may look inside the proverbial “black box” to investigate the role of identify particular aspects of treatment context that could different elements of this complex treatment model in potentially be manipulated in an experimental design, we improving treatment completion and different types of remain very cognizant of the perspective of healers experienced outcomes. Does ayahuasca-assisted treatment within the with this traditional medicine that the healing potential is in the therapeutic community model alter the trajectory of “gestalt” of the practice and the participant’s experience (Berlowitz treatment completion and outcomes, and for whom? How do et al., 2018). participants rate the importance of conventional elements of the Lastly, we note the high rate of program not-completion, a model (e.g., treatment milieu, therapy) as compared to elements factor common to TC’s and clearly a concern with respect to incorporated from traditional medicine and other syncretic Takiwasi Center specifically and a source of potential bias. To sources? What role does spirituality play within the spectrum mitigate this concern to the extent possible, a sub-project has of outcome measures and in sustaining post-discharge been initiated to follow-up with all Takiwasi study patients who improvements? For example, continuation of spiritual have left the program prematurely to explore reasons for leaving practices and related distinctions between safe and harmful the program. The study protocol also includes a variable that use of psychoactive substances. What might we learn from measures length of program participation and which will be used Takiwasi’s spiritual model of addiction, including how it is a potential moderating variable in the multivariate analysis. Aside operationalized through the syncretic integration of from controlling for potential bias, we also view this as an shamanic, Christian and other spiritual practices and their important aspect of the study itself given positive outcomes perceived importance in determining the outcome of that have been obtained with a single dose of ayahuasca treatment? Might information in this area provide insight (Osório et al., 2015; Sanches et al., 2016; Palhano-Fontes et al., into how the TC model, and other treatment models and 2018), and potential implications for Takiwasi and other modalities, could be enhanced within a broad bio-psycho- ayahuasca-assisted treatment modalities. social-spiritual framework? Indeed, the results concerning the These limitations aside, our protocol serves as an important role of spirituality as a potential predictor of outcome, and as an example of the comprehensive approach needed to evaluate outcome in its own right, will have implications for the field of outcomes associated with a context-dependent ayahuasca- substance use treatment writ large, given its long-standing assisted treatment intervention for substance use disorders. interest in spirituality (Geppert et al., 2007; Miller and The protocol may also provide a usable framework for Bogenschutz, 2007). conducting studies with psychedelic-assisted therapy more Fourth, and last, the research protocol aims to identify generally. Applied within the context of a long-term strengths, challenges and limitations within the current residential treatment facility such as Takiwasi Center, the data Takiwasi treatment model so as to contribute to ongoing yielded from this study will also offer insight into the therapeutic efforts toward quality improvement. Although a great deal of community treatment model for substance use disorders as research has been supported by and undertaken by the Takiwasi implemented in a unique and complex environment. Frontiers in Pharmacology | www.frontiersin.org 16 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP AUTHOR CONTRIBUTIONS ATOP workshop held in Tarapoto Peru in October 2013, including the almost 400 individuals globally that supported BR, FM, and AL-V designed the study. BR and OM wrote the a crowd-funding initiative to support that planning workshop. manuscript. FM and AL-V assisted in planning the manuscript Special thanks also go to Celina De Leon and Simon Green and provided significant editorial support. FM and SG assisted in for their insights and encouragement to keep the ATOP project data collection. SG, AS, and GL contributed conceptual support moving forward in its early stages. Our sincere gratitude to the manuscript, organized the data, and provided additional goes out to all managers, staff, therapists and healers at the editorial support. All authors contributed to the article and Takiwasi Center for supporting this work, as well as to the approved the submitted version. patients who have given their time and energy to participate in the project to date. Lastly, a special thank you goes to Jonathan Ramirez at CAMH Toronto for his volunteer support for data FUNDING management. GL was generously supported by the NIH, F31DA052153 as well as the Rose Traveling Fellowship, Harvard School of Public Health. SUPPLEMENTARY MATERIAL ACKNOWLEDGMENTS The Supplementary Material for this article can be found online at: The authors would like to acknowledge the important role in this https://www.frontiersin.org/articles/10.3389/fphar.2021.659644/ work played by participants and financial contributors to the full#supplementary-material Perspectives. Braz. J. Psychiatry 40 (2), 200–209. doi:10.1590/1516-4446-2016- REFERENCES 2117 Berlowitz, I., Walt, H., Ghasarian, C., Mendive, F., and Martin-Soelch, C. (2019). Almeida, R. N. D., Galvão, A. C. D. M., Silva, Da., da Silva, F. S., Silva, E. A. D. S., Short-term Treatment Effects of a Substance Use Disorder Therapy Involving Palhano-Fontes, F., et al. (2019). Modulation of Serum Brain-Derived Traditional Amazonian Medicine. J. Psychoactive Drugs 51 (4), 323–334. doi:10. Neurotrophic Factor by a Single Dose of Ayahuasca: Observation from a 1080/02791072.2019.1607956 Randomized Controlled Trial. Front. Psychol. 10, 1234. doi:10.3389/fpsyg. Berlowitz, I., Walt, H., Ghasarian, C., O’Shaughnessy, D. M., Mabit, J., Rush, B., 2019.01234 et al. (2020). Who Turns to Amazonian Medicine for Treatment of Substance American Society of Addiction Medicine (2013). Terminology Related to Use Disorder? Patient Characteristics at the Takiwasi Addiction Treatment Addiction, Treatment and Recovery. Available at: http://www.asam.org/ Center. J. Stud. Alcohol. Drugs 81 (4), 416–425. doi:10.15288/jsad.2020. docs/default-source/public-policy-statements/1-terminology-atr-7-135f810994 81.416 72bc604ca5b7ff000030b21a.pdf?sfvrsn0 Bogenschutz, M. P., and Johnson, M. W. (2016). Classic Hallucinogens in the Anderson, B. T., Labate, B. C., Meyer, M., Tupper, K. W., Barbosa, P. C. R., Grob, C. Treatment of Addictions. Prog. Neuro-Psychopharmacology Biol. Psychiatry 64, S., et al. (2012). Statement on Ayahuasca. Int. J. Drug Pol. 23(3), 173–175. 250–258. doi:10.1016/j.pnpbp.2015.03.002 doi:10.1016/j.drugpo.2012.02.007 Bogenschutz, M., and Pommy, J. (2012). Therapeutic Mechanisms of Classic Apud, I. (2015). Ayahuasca from Peru to Uruguay: Ritual Design and Redesign Hallucinogens in the Treatment of Addictions: From Indirect Evidence to through a Distributed Cognition Approach. Anthropol. Conscious. 26 (1), 1–27. Testable Hypotheses. Drug Test. Anal. 4 (7-8), 543–555. doi:10.1002/dta.1376 doi:10.1111/anoc.12023 Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A., Wilcox, C. E., Barbosa, P., Araújo, A. M., Carvalho, F., Bastos, M. d. L., Guedes de Pinho, P., de Pinho, P. G., and Strassman, R. J. (2015). Psilocybin-assisted Treatment for Alcohol and Carvalho, M. (2015). The Hallucinogenic World of Tryptamines: an Dependence: a Proof-Of-Concept Study. J. Psychopharmacol. 29 (3), Updated Review. Arch. Toxicol. 89 (8), 1151–1173. doi:10.1007/s00204-015- 289–299. doi:10.1177/0269881114565144 1513-x Bonicatto, S., Dew, A. M., and Soria, J. J. (1998). Analysis of the Psychometric Argento, E., Capler, R., Thomas, G., Lucas, P., and Tupper, K. W. (2019). Exploring Properties of the Spanish Version of the Beck Depression Inventory in Ayahuasca-Assisted Therapy for Addiction: A Qualitative Analysis of Argentina. Psychiatry Res. 79, 277–285. doi:10.1016/s0165-1781(98)00047-x Preliminary Findings Among an Indigenous Community in Canada. Drug Bouso, J. C., and Riba, J. (2014). “Ayahuasca and the Treatment of Drug and Alcohol Review. Drug Alcohol Rev 38 (7), 781–789. doi:10.1111/dar.12985 Addiction,” in The Therapeutic Use of Ayahuasca. Editors B. Labate and Aslan, L., and Yates, R. (2015). Of Therapeutic Community (TC) Methodology and C. Cavnar (Heidelberg: Springer), 95–109. the Subjective Experiences of Residents within TC Structures. Ther. Commun. Bouso, J. C., González, D., Fondevila, S., Cutchet, M., Fernández, X., and Ribeiro Int. J. Ther. Commun. 36 (2), 112. doi:10.1108/tc-04-2015-0014 Barbosa, P. C. (2012). Personality, Psychopathology, Life Attitudes and Barbosa, P. C., Mizumoto, S., Bogenschutz, M. P., and Strassman, R. J. (2012). Neuropsychological Performance Among Ritual Users of Ayahuasca: A Health Status of Ayahuasca Users. Drug Test. Anal. 4 (7-8), 601–609. doi:10. Longitudinal Study. PLoS ONE 7, e42421. doi:10.4324/9781315538501-9 1002/dta.1383/ Bower, P., and Gilbody, S. (2005). Stepped Care in Psychological Therapies: Access, Barrett, F. S., Johnson, M. W., and Griffiths, R. R. (2015). Validation of the Revised Effectiveness and Efficiency: Narrative Literature Review. Br. J. Psychiatry 186 Mystical Experience Questionnaire in Experimental Sessions with Psilocybin. (1), 11–17. doi:10.1192/bjp.186.1.11 J. Psychopharmacol. 29 (11), 1182–1190. doi:10.1177/0269881115609019 Breslin, C., Sobell, M. B., Sobell, L. C., Cunningham, J. A., Sdao-Jarvie, K., and Bauer, I. L. (2018). Ayahuasca: A Risk for Travellers? Trav. Med. Infect. Dis. 21, Borsoi, D. (1998). Problem Drinkers: Evaluation of a Stepped Care Approach. 74–76. doi:10.1016/j.tmaid.2018.01.002 J. Substance Abuse. 10 (3), 217–232. doi:10.1016/s0899-3289(99)00008-5 Beck, A. T., Epstein, N., Brown, G., and Steer, R. A. (1988). An Inventory for Brierley, D. I., and Davidson, C.. (2012). Developments in Harmine Measuring Clinical Anxiety: Psychometric Properties. J. Consulting Clin. Pharmacology—Implications for Ayahuasca Use and Drug-Dependence Psychol. 56 (6), 893–897. doi:10.1037/0022-006x.56.6.893 Treatment. Prog. Neuro-Psychopharmacol. Biol. Psych. 7, 127. doi:10.1016/j. Berlowitz, I., Ghasarian, C., Walt, H., Mendive, F., Alvarado, V., and Martin- pnpbp.2012.06.001 Soelch, C. (2018). Conceptions and Practices of an Integrative Treatment for Bustos, S. (2006). The House that Sings: The Therapeutic Use of Icaros at Takiwasi. Substance Use Disorders Involving Amazonian Medicine: Traditional Healers’ Shaman’s Drum 73, 33–39. doi:10.1093/acrefore/9780199381135.013.3237 Frontiers in Pharmacology | www.frontiersin.org 17 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP Carhart-Harris, R. I., and Friston, K. J. (2019). REBUS and the Anarchic Brain: Fábregas, J. M., González, D., Fondevila, S., Cutchet, M., Fernández, X., and Toward a Unified Model of the Brain Action of Psychedelics. Pharmacol. Rev. Barbosa, P. C. (2010). Assessment of Addiction Severity Among Ritual Users of 71, 317–344. doi:10.1124/pr.118.017160 Ayahuasca. Drug Alcohol Depend. 111 (3), 257–261. doi:10.1016/j.drugalcdep. Carhart-Harris, R. L., and Nutt, D. J. (2017). Serotonin and Brain Function: A Tale 2010.03.024 of Two Receptors. J. Psychopharmacol. 31, 1091–1120. doi:10.1177/ Franquesa, A., Sainz-Cort, A., Gandy, S., Soler, J., Alcázar-Córcoles, M. Á., and 0269881117725915 Bouso, J. C. (2018). Psychological Variables Implied in the Therapeutic Effect of Carhart-Harris, R. L., Bolstridge, M., Day, C. M. J., Rucker, J., Watts, R., Erritzoe, D. Ayahuasca: A Contextual Approach. Psychiatry Res. 264, 334–339. doi:10.1016/ E., et al. (2018a). Psilocybin with Psychological Support for Treatment- j.psychres.2018.04.012 Resistant Depression: Six-Month Follow-Up. Psychopharmacology 235 (2), Galvão, A. C., de Almeida, R. N., Silva, E. A., Freire, F. A., Palhano-Fontes, F., et al. 399–408. doi:10.1007/s00213-017-4771-x (2018). Cortisol Modulation by Ayahuasca in Patients with Treatment Resistant Carhart-Harris, R. L., Erritzoe, D., Haijen, E., Kaelen, M., and Watts, R. (2018b). Depression and Healthy Controls. Front. Psychiatry 9, 185. doi:10.3389/fpsyt. Psychedelics and Connectedness. Psychopharmacology 235 (2), 547–550. 2018.00185 doi:10.1007/s00213-017-4701-y Galvão-Coelho, N. L., de Menezes Galvão, A. C., de Almeida, R. N., Palhano-Fontes, Carhart-Harris, R. L., Roseman, L., Haijen, E., Erritzoe, D., Watts, R., Branchi, I., F., Campos Braga, I., Lobão Soares, B., et al. (2020). Changes in Inflammatory et al. (2018c). Psychedelics and the Essential Importance of Context. Biomarkers Are Related to the Antidepressant Effects of Ayahuasca. J. Psychopharmacol. 32 (7), 725–731. doi:10.1177/0269881118754710 J. Psychopharmacol. 34 (10), 1125–1133. doi:10.1177/0269881120936486 Cervi, F., Friso, F., Saucedo, G., Biolati, R., Torres, J., and Politi, M. (2019). La Galvão-Coelho, N. L., Marx, W., Gonzalez, M., Sinclair, J., de Manincor, M., Perkins, experiencia de la comunidad terapéutica Centro Takiwasi en el contexto de la D., et al. (2021). Classic Serotonergic Psychedelics for Mood and Depressive medicina natural e integrative. Medicina Naturista 13 (2), 12–19. doi:10.15332/ Symptoms: A Meta-Analysis of Mood Disorder Patients and Healthy Participants. tg.mae.2013.00515 Psychopharmacology 238, 341–354. doi:10.1007/s00213-020-05719-1 Chan, Y. F., Dennis, M. L., and Funk, R. R. (2008). Prevalence and Comorbidity Garcia-Romeu, A., Griffiths, R. R., and Johnson, M. (2015). Psilocybin-occasioned Co-occurrence of Major Internalizing and Externalizing Disorders Among mystical experiences in the treatment of tobacco addiction. Current Drug Abuse Adolescents and Adults Presenting to Substance Abuse Treatment. J. Substance Review 7 (3), 157–164. doi:10.2174/1874473708666150107121331 Abuse Treat. 34, 14–24. doi:10.1016/j.jsat.2006.12.031 Garcia-Romeu, A., Davis, A. K., Erowid, F., Erowid, E., Griffiths, R. R., and Cohen, A. M., Stavri, P. Z., and Hersh, W. R. (2004). A Categorization and Analysis Johnson, M. W. (2019). Cessation and Reduction in Alcohol Consumption of the Criticisms of Evidence-Based Medicine. Int. J. Med. Inform. 73, 35–43. and Misuse after Psychedelic Use. J. Psychopharmacol. 33, 1088–1101. doi:10. doi:10.1016/j.ijmedinf.2003.11.002 1177/0269881119845793 Coleman-Cowger, V. H., Dennis, M., Funk, R., Godley, S., and Lennox, R. (2013). Geppert, C., Bogenschutz, M. P., and Miller, W. R. (2007). Development of a Comparison of the Addiction Severity Index (ASI) and the Global Appraisal of Bibliography on Religion, Spirituality and Addictions. Drug alcohol Rev. 26 (4), Individual Needs (GAIN) in Predicting the Effectiveness of Drug Treatment 389–395. doi:10.1080/09595230701373826 Programs for Pregnant and Postpartum Women. J. Substance Abuse Treat. 44, Giovannetti, C., Garcia Arce, S., Rush, B. R., and Mendive, F. (2020). Pilot 34–41. doi:10.1016/j.jsat.2012.02.002 Evaluation of a Residential Drug Addiction Treatment Combining Costello, M. J., Sousa, S., Ropp, C., and Rush, B. R. (2018). How to Measure Traditional Amazonian Medicine, Ayahuasca and Psychotherapy on Addiction Recovery? Incorporating Perspectives of Individuals with Lived Depression and Anxiety. J. Psychoactive Drugs 52 (5), 472–581. doi:10.1080/ Experience. Int. J. Ment. Health Addict. 12, 1–14. doi:10.1007/s11469-018- 02791072.2020.1789247 9956-y Giove Nakazawa, R. (2002). La liana de los muertos al rescate de la vida. Medicina Dakwar, E. (2015). “Evaluating the Therapeutic Utility of Hallucinogens for tradicional amazónica en el tratamiento de las toxicomanias. Siete Anõs de Substance Use Disorders,” in Textbook of Addiction Treatment International Experiencia Del. Centro Takiwasi. Tarapoto: Takiwasi/DEVIDA. Perspectives. SpringerMilanopp. Editors N. el-Guebaly, G. Carrà, and González, D., Carvalho, M., Cantillo, J., Aixalá, M., and Farré, M. (2017). Potential M. Galanter, 713–730. doi:10.1007/978-88-470-5322-9_33 Use of Ayahuasca in Grief Therapy. OMEGA- J. Death Dying. 12, 133. doi:10. Dakwar, E. (2016). The Death and Rebirth of Hallucinogens. Drug and Alcohol 1177/0030222817710879 Dependence 165, 293–297. doi:10.1016/j.drugalcdep.2016.04.003 Gow, P. (1994). “River People: Shamanism and History in Western Amazonia,” in Dawson, A. (2017). “Brazil’s Ayahuasca Religionscomparisons and Shamanism, History, and the State. Editors M. Nicolas and C. Humphrey (Ann Contrasts252,” in Handbook of Contemporary Religions in Brazil.. Editors Arbor: University of Michigan), 90–113. B. Schmidt and S. Engker (Leiden, Netherlands: Brill), 233. Griffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Defelippe, V., Schlütter, A., Meriaan, A., Winkens, B., Kavenská, V., Rojas, G. S., Richards, B., et al. (2016). Psilocybin Produces Substantial and Sustained et al. (2019). Treatment and Outcomes at Takiwasi Center, a Peruvian Decreases in Depression and Anxiety in Patients with Life-Threatening Therapeutic Community: Identifying Patient-Related Indicators. Ther. Cancer: A Randomized Double-Blind Trial. J. Psychopharmacol. 30 (12), Communities: Int. J. Ther. Communities 40 (2), 93–106. doi:10.1108/tc-07- 1181–1197. doi:10.1177/0269881116675513 2018-0016 Griffiths, R. R., Hurwitz, E. S., Davis, A. K., Johnson, M. W., and Jesse, R.. (2019). Dennis, M. (1999). Global Appraisal of Individual Needs (GAIN). Administration Survey of subjective" God encounter experiences": Comparisons among guide for the GAIN and related measures (Version 1299). Bloomington, Il: naturally occurring experiences and those occasioned by the classic Chestnut Health Systems. psychedelics psilocybin, LSD, ayahuasca, or DMT. PloS One 14 (12), Dominguez-Clave, E., Soler, J., Elices, M., Pascual, J. C., Alvarez, E., de la Fuente e0214377. doi:10.1371/journal.pone.0214377 Revenga, et al. (2016). Ayahuasca: Pharmacology, Neuroscience and Therapeutic Grob, C. S., McKenna, D. J., Callaway, J. C., Brito, G. S., Neves, E. S., Overlaender, Potential. Brain Res. Bull. 126, 89–101. doi:10.1016/j.brainresbull.2016.03.002 G., et al. (1996). Human Psychopharmacology of Hoasca: A Plant Hallucinogen Dos Santos, R. G., Osório, F. L., and Crippa, J. A., Riba, J, Zuardi, A. W., and Hallak, Used in Ritual Context in Brazil. J. Nervous Ment. Dis. 184 (2), 86–94. doi:10. J. E. (2016). Antidepressive, Anxiolytic, and Antiaddictive Effects of Ayahuasca, 1097/00005053-199602000-00004 Psilocybin and Lysergic Acid Diethylamide (LSD): A Systematic Review of Håland, R. (2014). Healing with Plants and Spirits: A Phenomenological and Clinical Trials Published in the Last 25 Years. Ther. Adv. Psychopharmacol. 6 Ontological Perspective of the Treatment Practice of Patients and Visitors in (3), 193–213. doi:10.1177/2045125316638008 Takiwasi, Peru,” in Master Thesis Submitted to Department of Social Dupuis, D. (2018). Practicas en busqueda de legitimidad: el uso contemporaneo de Anthropology. Osla: University of Oslo. Retrieved from NBN:no-46773 la ayahuasca, entre reivindicaciones terapeuticas y religiosas. Salud Colectiva 14 Available at: http://urn.nb.no/URN (2), 341–354. doi:10.18294/sc.2018.1539 Halpern, J. H., Sherwood, A. R., Passie, T., Blackwell, K. C., and Ruttenber, A. J. Dupuis, D. (2021). The Socialization of Hallucinations: Cultural Priors, Social (2008). Evidence of Health and Safety in American Members of a Religion Who Interactions, and Contextual Factors in the Use of Psychedelics. J. Transcultural Use a Hallucinogenic Sacrament. Med. Sci. Monitor 14 (8), 15–22. doi:10.1163/ Psychiatry 14, 115. doi:10.15405/epsbs.2020.11.7 1877-5888_rpp_dum_02606 Frontiers in Pharmacology | www.frontiersin.org 18 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP Harris, R., and Gurel, L. (2012). A Study of Ayahuasca Use in North America. Labate, B. C., and Cavnar, C. (2011). The Expansion of the Field of Research on J. Psychoactive Drugs 44 (3), 209–215. doi:10.1080/02791072.2012.703100 Ayahuasca: Some Reflections about the Ayahuasca Track at the 2010 MAPS Hartogsohn, I. (2016). Set and Setting, Psychedelics and the Placebo Response: an “Psychedelic Science in the 21st Century” Conference. Int. J. Drug Pol. 22 (2), Extra-pharmacological Perspective on Psychopharmacology. 174–178. doi:10.1016/j.drugpo.2010.09.002 J. Psychopharmacol. 30 (12), 1259–1267. doi:10.1177/0269881116677852 Labate, B. C., and Cavnar, C. (2014). in Ayahuasca Shamanism in the Amazon and Hendricks, P. S. (2014). Back to the Future: A Return to Psychedelic Treatment beyond. (New York: Oxford University Press). Models for Addiction. J. Psychopharmacol. 28 (11), 981–2. doi:10.1177/ Labate, B. C., and Jungaberle, H. (2011). The Internationalization of Ayahuasca. 0269881114550935 Zurich: Switzerland, Lit Verlag. Hernán, M. A., and Robins, J. M. (2020).Causal Inference: What if/CRC. Boca Labate, B., dos Santos, R. G., Anderson, B., Mercante, M., and Barbosa, P. C. R. Raton: Chapman & Hall. (2010). “The Treatment and Handling of Substance Dependence with Holman, C. (2011). Surfing for a Shaman: Analyzing an Ayahuasca Website. Ann. Ayahuasca: Reflections on Current and Future Research,” in Ayahuasca, Tourism Res. 38 (1), 90–109. doi:10.1016/j.annals.2010.05.005 Ritual, and Religion in Brazil. London. Editors B. C. Labate and E. MacRae, Horák, M. (2013). The House of Song: The Rehabilitation of Drug Addicts by the London: Equinoz Publishing Ltd., 205–227. Traditional Indigenous Medicine of the Peruvian Amazon. Brno, Czech LaFrance, J., Nichols, R., and Kinkhart, K. E. (2012). “Culture Writes the Script: On Republic: Mendel University in Brno. the Centrality of Context in Indigenous Evaluation,” in A Framework for its Hyde, P. S., and Delphin-Rittmon, M. (2014). The Role of EBPs in Behavioral Influence in Evaluative Practice. Editors D. J. Rog, J. L. Fitzpatrick, and Health Treatment. Psychiatr. Serv. 65 (7), 841. doi:10.1176/appi.ps.650707 R. F. Conner, New Dir. Eval. 135, 59–74. doi:10.1002/ev.20027 International Consortium for Health Measurement Outcomes (2020). ICHOM LaFrance, A., Loizaga-Velder, A., Fletcher, J., Renelli, M., Files, N., and Tupper, K. Standard Set—Addiction. Boston: ICHOM. Available at: https://www.ichom. W. (2017). Nourishing the Spirit: Exploratory Research on Ayahuasca org/portfolio/addiction/ Experiences along the Continuum of Recovery from Eating Disorders. Jauregui, X., Clavo, Z. M., Jovel, E. M., and Pardo-de-Santayana, M. (2011). J. Psychoactive Drugs 49 (5), 427–435. doi:10.1080/02791072.2017.1361559 “Plantas con madre”: plants that teach and guide in the shamanic initiation Lecrubier, Y., Sheenan, D. V., Weiller, E., Amorim, P., Bonora, I., Sheehan, K. H., process in the East-Central Peruvian Amazon. J. Ethnopharmacol. 134 (3), et al. (1997). The Mini International Neuropsychiatric Interview (MINI). A 739–752. doi:10.1016/j.jep.2011.01.042 Short Diagnostic Structured Interview: Reliability and Validity According to the Johnson, M. W., Garcia-Romeu, A., Cosimano, M. P., and Griffiths, R. R. (2014). CIDI. Eur. Psychiatry 12 (5), 224–231. doi:10.1016/s0924-9338(97)83296-8 Pilot Study of the 5-HT2AR Agonist Psilocybin in the Treatment of Tobacco Liester, M. B., and Prickett, J. I. (2012). Hypotheses Regarding the Mechanisms of Addiction. J. Psychopharmacol. 28 (11), 983–992. doi:10.1177/ Ayahuasca in the Treatment of Addictions. J. Psychoactive Drugs 44 (3), 0269881114548296 200–208. doi:10.1080/02791072.2012.704590 Johnson, M. W., Garcia-Romeu, A., Johnson, P. S., and Griffiths, R. R. (2017). An Loizaga-Velder, A., and Loizaga, A. (2014). “The Therapeutic Value of Ayahuasca Online Survey of Tobacco Smoking Cessation Associated with Naturalistic for Addiction Treatment from Psychotherapeutic Perspective,” in The Psychedelic Use. J. Psychopharmacol. 31 (7), 841–850. doi:10.1177/ Therapeutic Use of Ayahuasca. Heidelberg. Editors B. Labate and C. Cavnar 0269881116684335 (Germany;Springer), 133–152. doi:10.1007/978-3-642-40426-9_8 Johnson, M. W., Hendricks, P. S., Barrett, F. S., and Griffiths, R. R. (2019). Classic Loizaga-Velder, A., and Verres, R. (2014). Therapeutic Effects of Ritual Ayahuasca Psychedelics: An Integrative Review of Epidemiology, Therapeutics, Mystical Use in the Treatment of Substance Dependence - Qualitative Results. Experience, and Brain Network Function. Pharmacol. Ther. 197, 83–102. J. Psychoactive Drugs 46 (1), 63–72. doi:10.1080/02791072.2013.873157 doi:10.1016/j.pharmthera.2018.11.010 Lucas-Carrasco, R. (2011). The WHO Quality of Life (WHOQOL) Questionnaire: Kaskutas, L. A., Borkman, T. J., Laudet, A., Ritter, L. A., Witbrodt, J., Subbaraman, M. Spanish Development and Validation Studies. Qual. Life Res. 21 (1), 161–165. S., et al. (2014). Elements that Define Recovery: The Experiential Perspective. doi:10.1007/s11136-011-9926-3 J. Stud. Alcohol Drugs 75 (6), 999–1010. doi:10.15288/jsad.2014.75.999 Luna, L. E. (1986). Vegetalismo: Shamanism Among the Mestizo Population of the Katzman, R., Brown, T. K., Fuld, R., Peck, A., Schechter, R., and Schimmerl, H.. Peruvian Amazon. Stockholm: Acta Universitatis Stockholmiensis. (1983). Validation of a Short Orientation Memory Concentration-Test of Mabit, J., Give, R., and Vega, J. (1996). “Takiwasi: The Use of Amazonian Cognitive Impairment. Am. J. Psychiatry, 140, 734–739. doi:10.1176/ajp.140.6.734 Shamanism to Rehabilitate Drug Addicts,” in Yearbook Of Cross-Cultural Kavenská, V., and Simonová, H. (2015). Ayahuasca Tourism: Participants in Medicine And Psychotherapy, International Institute of Cross-Cultural Shamanic Rituals and Their Personality Styles, Motivation, Benefits and Risks. Therapy Research (IIKT). Editor W. Andritzky (Berlin: Deutschland), J. Psychoactive Drugs 47 (5), 351–359. doi:10.1080/02791072.2015.1094590 257–285. Kjellgren, A., Eriksson, A., and Norlander, T. (2009). Experiences of Encounters Mabit, J. (2002). Blending Traditions: Using Indigenous Medicinal Knowledge to with Ayahuasca—“The Vine of the Soul”. J. Psychoactive Drugs 41 (4), 309–315. Treat Drug Addiction. MAPS Bull. 12 (2), 25–32. doi:10.37896/jxu14.5/370 doi:10.1080/02791072.2009.10399767 Mabit, J., and Sieber, C. (2006). The Evolution of a pilot program utilizing Kohn, R., Saxena, S., Levav, I., and Saraceno, B. (2004). The Treatment Gap in ayahuasca in the treatment of drug addictions. Shaman’s Drum 73, 23–31. Mental Health Care. Bull. World Health Organ. 82, 858–866. doi:10.1080/ Magor-Blatch, L., Bhullar, N., Thomson, B., and Thorsteinsson, E. (2014). A 00207411.1990.11449163 Systematic Review of Studies Examining Effectiveness of Therapeutic Kometer, M., Schmidt, A., Bachmann, R., Studerus, E., Seifritz, E., and Communities. Therapeutic Communities: the. Int. J. Ther. Communities 35 Vollenweider, F. X. (2012). Psilocybin Biases Facial Recognition, Goal- (4), 168–184. doi:10.1108/tc-07-2013-0024 Directed Behavior, and Mood State toward Positive Relative to Negative Majić, T., Schmidt, T. T., and Gallinat, J. (2015). Peak Experiences and the Emotions through Different Serotonergic Sub- Receptors. Biol. Psychiatry Afterglow Phenomenon: When and How Do Therapeutic Effects of 72, 898–906. doi:10.1016/j.biopsych.2012.04.005 Hallucinogens Depend on Psychedelic Experiences? J. Psychopharmacol. Kraehenmann, R., Preller, K. H., Scheidegger, M., Pokorny, T., Bosch, O. G., Mar. 29 (3), 241–253. doi:10.1177/0269881114568040 Seifritz, E., et al. (2015). Psilocybin-induced Decrease in Amygdala Reactivity Malivert, M., Fatséas, M., Denis, C., Langlois, E., and Auriacombe, M. (2012). Correlates with Enhanced Positive Mood in Healthy Volunteers. Biol. Effectiveness of Therapeutic Communities: A Systematic Review. Eur. Addict. Psychiatry 78, 572–581. doi:10.1016/j.biopsych.2014.04.010 Res. 18 (1), 1–11. doi:10.1159/000331007 Krebs, T. S., and Johansen, P. O. (2012). Lysergic Acid Dietthylamide (LSD) for Marcus, O., and Fotiou, E.. (2019). Convergent Therapies in Peru’s Amazon: Alcoholism: Meta-Analysis of Randomized Controlled Trials. Enriching Mental Wellness through Ayahuasca and Psychology. In Psychopharmacology 26 (7), 994–1002. doi:10.1177/0269881112439253 Gender, Health, and Society In Contemporary Latin America and the Kuchibhotla, A. K., Brown, L. D., Buja, A., Cai, J., George, E. I., and Zhao, L. H. Caribbean. Editors S. Lerman and R. Shepaerd (Lanham: Lexington (2020). Valid Post-selection Inference in Model-free Linear Regression. Ann. Books), p. 117–137. Stat. 48 (5), 2953–2981. doi:10.1214/19-AOS1917Available at: https:// Martin, G. W., and Rehm, J. (2012). The Effectiveness of Psychosocial Modalities in projecteuclid.org/euclid.aos/1600480938 the Treatment of Alcohol Problems in Adults: A Review of the Evidence. Can. Frontiers in Pharmacology | www.frontiersin.org 19 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP J. Psychiatry-Revue Canadienne De Psychiatrie 57 (6), 350–358. doi:10.1177/ Paulus, M. P., Stewart, J. L., and Haase, L. (2013). Treatment Approaches for 070674371205700604 Interoceptive Dysfunctions in Drug Addiction. Front. Psychiatry 4, 137. doi:10. Martin, G. W., Koski-Jannes, A., and Weber, T. (1998). Rethinking the Role of 3389/fpsyt.2013.00137 Residential Treatment for Individuals with Substance Use Problems. Can. Pawson, R., and Tilley, N. (1997). Realistic Evaluation.. Thousand Oaks, NY: J. Commun. Ment. Health 17, 61–78. doi:10.7870/cjcmh-1998-0004 Guilford Press. McCarty, D., Braude, L., Lyman, D. R., Dougherty, R. H., Daniels, A. S., Ghose, S. S., Politi, M., Friso, F., and Mabit, J. (2018). Plant Based Assisted Therapy for the et al. (2014). Substance Abuse Intensive Outpatient Programs: Assessing the Treatment of Substance Use Disorders- Part 1. The Case of Takiwasi Center and Evidence. Psychiatr. Serv. 65 (6), 718–726. doi:10.1176/appi.ps.201300249 Other Similar Experiences. Revista Cultura y Droga 23 (26), 99–126. doi:10. McLellan, T., Kushner, H., Metzger, D., Peters, R., Smith, I., Grissom, G., et al. 4324/9781315192253-6 (1992). Of the Addiction Severity Index. The fifth edition. J. Substance Abuse Politi, M., Saucedo Rojas, G., Rumlerova, T., Marcus, O., Torres Romero, J., and Treat. 9 (3), 199–213. doi:10.1016/0740-5472(92)90062-s Mabit, J. (2019). Medicinal Plants Diet as Emerging Complementary Therapy Melberg, H. O., and Humphreys, K. (2010). Ineligibility and Refusal to Participate from the Amazonian Tradition. Data from Centro Takiwasi, a Peruvian in Randomised Trials of Treatment for Drug Dependence. Drug Alcohol Rev. Therapeutic Community. J. Med. Herbs Ethnomedicine 5, 23–28. doi:10. 29, 193–201. doi:10.1111/j.1465-3362.2009.00096.x 25081/jmhe.2019.v5.5692 Mercante, M. (2013). A ayahuasca e o tratemento da dependencia. Mana 19 (3), Pollan, M. (2018). How to Change Your Mind: What the New Science of Psychedelics 529–558. doi:10.1590/S0104-93132013000300005 Teaches Us about Consciousness, Dying, Addiction, Depression and Metzner, R., Litwin, G., and Weil, G. (1965). The Relation of Expectation and Transcendence. New York: Penguin Random House. Mood to Psilocybin. Psychedelic Rev. 5, 3–39. Prangley, T., Pit, S. W., Rees, T., and Nealon, J. (2018). Factors Influencing Early Miles, M. B., and Huberman, A. M. (1994). Qualitative Data Analysis: An Withdrawal from a Drug and Alcohol Treatment Program and Client Expanded Sourcebook. 2nd ed.. Thousand Oaks, CA: Sage. Perceptions of Successful Recovery and Employment: A Qualitative Study. Miller, W. R., and Bogenschutz, M. P. (2007). Spirituality and Addiction. South. BMC Psychiatry 18 (1), 1–11. doi:10.1186/s12888-018-1864-y Med. J. 100, 433–437. doi:10.1097/smj.0b013e3180316fbf Prayag, G., Mura, P., Hall, C. M., and Fontaine, J. (2016). Spirituality, Drugs, and Morales-García, J. A., de la Fuente Revenga, M., Alonso-Gil, S., Rodríguez-Franco, Tourism: Tourists’ and Shamans’ Experiences of Ayahuasca in Iquitos, Peru. M. I., Feilding, A., Perez-Castillo, A., et al. (2017). The Alkaloids of Tourism Recreation Res. 41 (3), 314–325. doi:10.1080/02508281.2016. Banisteriopsis Caapi, the Plant Source of the Amazonian Hallucinogen 1192237 Ayahuasca, Stimulate Adult Neurogenesis In Vitro. Scientific Rep. 7 (1), Presser-Velder, A. (2000). Das therapeutische Potential der rituellen Verwendung 1–13. doi:10.1038/s41598-017-05407-9 sakraler Heilpflanzen. (Diplomarbeit-Master Thesis). Germany: University of Morales-Garcia, J. A., Calleja-Conde, J., Lopez-Moreno, J. A., Alonso-Gil, S., Sanz- Koblenz-Landau. SanCristobal, M., Riba, J., et al. (2020). N, N-Dimethyltryptamine Compound Prickett, J. I., and Liester, M. B. (2014). “Hypotheses Regarding Ayahuasca’s Found in the Hallucinogenic Tea Ayahuasca, Regulates Adult Neurogenesis In Potential Mechanisms of Action in the Treatment of Addiction,” in The Vitro and In Vivo. Translational Psychiatry 10 (1), 1–14. doi:10.1038/s41398- Therapeutic Use of Ayahuasca. Editors B. Labate and C. Cavnar, Heidelberg 020-01011-0 Germany: Springer, 111–132. doi:10.1007/978-3-642-40426-9_7 Muttoni, S., Ardissino, M., and John, C. (2019). Classical Psychedelics for the Reif, S., George, P., Braude, L., Dougherty, R. H., Daniels, A. S., Ghose, S. S., et al. Treatment of Depression and Anxiety: A Systematic Review. J. Affective Disord. (2014). Residential Treatment for Individuals with Substance Use Disorders: 258, 11–24. doi:10.1016/j.jad.2019.07.076 Assessing the Evidence. Psychiatr. Serv. 65 (3), 301–312. doi:10.1176/appi.ps. Nielson, E. M., May, D. G., Forcehimes, A. A., and Bogenschutz, M. P. (2018). The 201300242 Psychedelic Debriefing in Alcohol Dependence Treatment: Illustrating Key Riba, J., Rodríguez-Fornells, A., Urbano, G., Morte, A., Antonijoan, R., Montero, Change Phenomena through Qualitative Content Analysis of Clinical Sessions. M., et al. (2001). Subjective Effects and Tolerability of the South American Front. Pharmacol. 9, 132. doi:10.3389/fphar.2018.00132 Psychoactive Beverage Ayahuasca in Health Volunteers. Psychopharmacology Nunes, A. A., dos Santos, R. G., Osório, F. L., Sanches, R. F., Crippa, J. A. S., and 154 (1), 85–95. doi:10.1007/s002130000606 Hallak, J. E. (2016). Effects of Ayahuasca and its Alkaloids on Drug Rog, D. J. (2012). When Background Becomes Foreground: Toward Context- Dependence: A Systematic Literature Review of Quantitative Studies in Sensitive Evaluation Practice. New Dir. Eval. 135, 25–40. doi:10.1002/ev.20025 Animals and Humans. J. Psychoactive Drugs 48 (3), 195–205. doi:10.1080/ Ross, S. (2012). Serotonergic Hallucinogens and Emerging Targets for Addiction 02791072.2016.1188225 Pharmacotherapies. Psychiatr. Clin. North America 35, 357–374. doi:10.1016/j. Oliveira-Lima, A. J., Santos, R., Hollais, A. W., Gerardi-Junior, C. A., Baldaia, M. A., psc.2012.04.002 WuoSilva, R., et al. (2015). Effects of Ayahuasca on the Development of Ethanol- Rothberg, R. L., Azhari, N., Haug, N. A., and Dakwar, E. (2021). Mystical-type Induced Behavioral Sensitization and on a Post-sensitization Treatment in Mice. Experiences Occasioned by Ketamine Mediate its Impact on At-Risk Drinking: Physiol. Behav. 142 (0), 28–36. doi:10.1016/j.physbeh.2015.01.032 Results from a Randomized, Controlled Trial. J. Psychopharmacol. 35 (2), O’Shaughnessy, D. M. (2017). Takiwasi: Addiction Treatment in the "Singing House. 150–158. doi:10.1177/0269881120970879 PhD Thesis. London: James Cook University. doi:10.7765/9781526115720.00006 Rothwell, P. M. (2005). External Validity of Randomized Controlled Trials: To Osório, F. D. L., Sanches, R. F., Macedo, L. R., Santos Dos, R. G., Maia-de-Oliveira, Whom Do the Results of This Trial Apply? Lancet 365, 82–93. doi:10.1016/ J. P., et al. (2015). Antidepressant Effects of a Single Dose of Ayahuasca in s0140-6736(04)17670-8 Patients with Recurrent Depression: A Preliminary Report. Revista Brasileira de Rush, B. R., and Urbanoski, K. (2019). Seven Core Principles for Substance Use Psiquiatria 37 (1), 13–20. doi:10.1590/1516-4446-2014-1496 Treatment System Design to Aid in Identifying Strengths, Gaps and Required Palhano-Fontes, F., Andrade, K. C., Tofoli, L. F., Santos, A. C., Crippa, J. A. S., Enhancement. J. Stud. Alcohol Drugs Suppl. 11 (S18), 9–21. doi:10.15288/jsads. Hallak, J. E., et al. (2015). The Psychedelic State Induced by Ayahuasca 2019.s18.9 Modulates the Activity and Connectivity of the Default Mode Network. Sanches, R. F., de Lima Osório, F., Santos Dos, R. G., Macedo, L. R., Maia-de- PloS one 10 (2), e0118143. doi:10.1371/journal.pone.0118143 Oliveira, J. P., et al. (2016). Antidepressant Effects of a Single Dose of Ayahuasca Palhano-Fontes, F., Barreto, D., Onias, H., Andrade, K. C., Novaes, M. M., Pessoa, in Patients with Recurrent Depression: A SPECT Study. J. Clin. J. A., et al. (2018). Rapid Antidepressant Effects of the Psychedelic Ayahuasca in Psychopharmacol. 36 (1), 77–81. doi:10.1097/jcp.0000000000000436 Treatment-Resistant Depression: A Randomized Placebo-Controlled Trial. Sarris, J., Glick, R., Hoenders, R., Duffy, J., and Lake, J. (2014). Integrative Mental Psychol. Med. 44 (9), 1–9. doi:10.1017/s0033291718001356 Healthcare White Paper: Establishing a New Paradigm through Research, Pasquini, L., Palhano-Fontes, F., and Araujo, D. B. (2020). Subacute Effects of the Education, and Clinical Guidelines. Adv. Integr. Med. 1, 9–16. doi:10.1016/j. Psychedelic Ayahuasca on the Salience and Default Mode Networks. aimed.2012.12.002 J. Psychopharmacol. 34 (6), 623–635. doi:10.1177/0269881120909409 Sarris, J., Perkins, D., Cribb, L., Schubert, V., Opaleye, E., Bouso, J. C., et al. (2021). Patel, V., Maj, M., Flisher, A. J., Silva, De., Mario, M. J., Koschorke, M., et al. (2010). Ayahuasca Use and Reported Effects on Depression and Anxiety Symptoms: Reducing the Treatment Gap for Mental Disorders: A WPA Survey. World An International Cross-Sectional Study of 11,912 Consumers. J. Affective Psychiatry 9 (3), 169–176. doi:10.1002/j.2051-5545.2010.tb00305.x Disord. Rep. 4, 100098. doi:10.1016/j.jadr.2021.100098 Frontiers in Pharmacology | www.frontiersin.org 20 May 2021 | Volume 12 | Article 659644 Rush et al. Evaluation of Ayahuasca-Assisted Treatment: ATOP Saxena, S., Carlson, C., Billington, R., and Orley, J. (2001). The WHO Quality of Uthaug, M. V., Mason, N. L., Toennes, S. W., Reckweg, J. T., Perna, E. D. S. F., Life Instrument (WHOQOL-Bref). The Importance of its Items for Cross- Kuypers,., K. P. C., et al. (2021). A Placebo-Controlled Study of the Effects of Cultural Research. Qual. Life Res. 10, 711–721. doi:10.1023/a:1013867826835 Ayahuasca, Set and Setting on Mental Health of Participants in Ayahuasca Sheehan, D. V., Lecrubier, Y., Sheehan, K. H., Amorim, P., Janavs, J., Weiller, E., Group Retreats. Psychopharmacology 12, 1–12. doi:10.1007/s00213-021- et al. (1998). The Mini-International Neuropsychiatric Interview (M.I.N.I.): 05817-8 The Development and Validation of a Structured Diagnostic Psychiatric Vega-Dienstmaier, J. (2014). Coronado–Molina and Mazzotti 6Validez de una Interview for DSM-IV and ICD-10. J. Clin. Psychiatry 20 (59 Suppl. l), 22–33. versión española del Inventario de Depresión de beck en pacientes Sridharan, S., and Nakaima, A. (2011). Ten Steps to Making Evaluation Matter. hospitalizados de medicina general. Revista de Neuropsiquitria 77 (2), Eval. Program Plann. 34 (2), 135–146. doi:10.1016/j.evalprogplan.2010.09.003 95–103. doi:10.20453/rnp.2014.1151 Sridharan, S., and Nakaima, A. (2020). Valuing and embracing complexity: How an Vigo, D., Thornicroft, G., and Atun, R. (2016). Estimating the True Global Burden understanding of complex interventions needs to shape our evaluation of Mental Illness. The Lancet Psychiatry 3 (2), 171–178. doi:10.1016/s2215- capacities building initiatives. Eval. Program Plann. 80, 101440. doi:10.1016/ 0366(15)00505-2 j.evalprogplan.2017.05.001 Vigo, D., Haro, J. M., Hwang, I., Aguilar-Gaxiola, S., Alonso, J., Borges, G., et al. Stame, N. (2004). Theory-based Evaluation and Types of Complexity. Evaluation (2020). Toward Measuring Effective Treatment Coverage: Critical Bottlenecks 10 (1), 58–76. doi:10.1177/1356389004043135 in Quality-And User-Adjusted Coverage for Major Depressive Disorder. Steer, R. A., and Beck, A. T. (1997). in Evaluating Stress: A Book of Resources. Editor Psychol. Med. 14, 1–11. doi:10.1017/S0033291720003797 C. P. Wood (Lanham, MD, US: Scarecrow Education), 23–40. Vollenweider, F., and Kometer, M. (2010). The Neurobiology of Psychedelic Drugs: Strassman, R. J., Qualls, C. R., Uhlenhuth, E. H., et al. (1994). Dose-response Study Implications for the Treatment of Mood Disorders. Nat. Rev. Neurosci. 11, of N,N-dimethyltryptamine in Humans. II. Subjective Effects and Preliminary 642–651. doi:10.1038/nrn2884 Results of a New Rating Scale. Arch. Gen. Psychiatry 51, 98–108. doi:10.1001/ Whiteford, H. A., Degenhardt, L., Rehm, J., Baxter, A. J., Ferrari, A. J., Erskine, H. archpsyc.1994.03950020022002 E., et al. (2013). Global Burden of Disease Attributable to Mental and Substance Strauss, A., and Corbin, J. (1994). “Grounded Theory Methodology: An Overview,” Use Disorders: Findings from the Global Burden of Disease Study 2010. The in Handbook of Qualitative Research. Editors N. K. Denzin and Y. S. Lincoln, Lancet 382 (9904), 1575–1586. doi:10.1016/s0140-6736(13)61611-6 Sage Publications, Inc, 273–285. Wild, T. C., Cunningham, J., and Ryan, R. M. (2006). Social Pressure, Coercion, Talin, P., and Sanabria, E. (2017). Ayahuasca’s Entwined Efficacy: An and Client Engagement at Treatment Entry: A Self-Determination Theory Ethnographic Study of Ritual Healing from ‘addiction’. Int. J. Drug Pol. 44, Perspective. Addict. Behav. 31, 1858–1872. doi:10.1016/j.addbeh.2006. 23–30. doi:10.1016/j.drugpo.2017.02.017 01.002 The WHOQOL Group (1998). “Development of the WHOQOL-Bref Assessment& Wild, C., Urbanoski, K., Yuan, Y., Wolfe, J., and Rush, B. R. (2016). Client Division of Mental Health and Prevention of Substance Abuse. (1997). WHOQOL: Engagement in Legally Mandated Addiction Treatment: A Prospective Study Measuring Quality of Life,” in Psychological Medicine, London: World Health Using Self-Determination Theory. J. Substance Abuse Treat. 69, 35–43. doi:10. Organization, 551–559. http://www.who.int/mental_health/media/68.pdf 1016/j.jsat.2016.06.006 Thomas, G., Lucas, P., Capler, R., Tupper, K., and Martin, G. (2013). Ayahuasca- Winkelman, M. (2005). Drug Tourism or Spiritual Healing? Ayahuasca Seekers in assisted Therapy for Addictions: Results from a Preliminary Observational Amazonia. J. Psychoactive Drugs 37 (2), 209–218. doi:10.1080/02791072.2005. Study in Canada. Curr. Drug Abuse Rev. 6 (1), 30–42. doi:10.2174/ 10399803 15733998113099990003 World Health Organization (2016). International Standards for the Treatment of Timmermann, C., Roseman, L., Williams, L., Erritzoe, D., Martial, C., Cassol, H., Drug Use Disorders and United Nations Office on Drugs and Crime. Geneva: et al. (2018). DMT Models the Near-Death Experience. Front. Psychol. 9, 1424. World Health Organization. doi:10.3389/fpsyg.2018.01424 Zhang, Z., Friedmann, P. D., and Gerstein, D. R. (2003). Does Retention Matter? Tófoli, L. F., and de Araujo, D. B. (2016). Treating Addiction: Perspectives from Treatment Duration and Improvement in Drug Use. Addiction 98 (5), 673–684. EEG and Imaging Studies on Psychedelics. Int. Rev. Neurobiol. 129, 157–185. doi:10.1046/j.1360-0443.2003.00354.x doi:10.1016/bs.irn.2016.06.005 Zhang, Q., Sharan, A., Espinosa, S. A., Gallego-Perez, D., and Weeks, J. (2019). The Tupper, K. W., and Labate, B. C. (2014). Ayahuasca, Psychedelic Studies and Health Path toward Integration of Traditional and Complementary Medicine into Sciences: The Politics of Knowledge and Inquiry into an Amazonian Plant Brew. Health Systems Globally: The World Health Organization Report on the Curr. Drug Abuse Rev. 7 (2), 71–80. doi:10.2174/1874473708666150107155042 Implementation of the 2014–2023 Strategy. J. Complement. Altern. Med. 25 Tupper, K. W., Wood, E., Yensen, R., and Johnson, M. W. (2015). Psychedelic (9), 869–871. doi:10.1089/acm.2019.29077.jjw Medicine: A Re-emerging Therapeutic Paradigm. Can. Med. Assoc. J. 187 (14), 1054–1059. doi:10.1503/cmaj.141124 Conflict of Interest: The authors declare that the research was conducted in the Tupper, K. (2008). The Globalization of Ayahuasca: Harm Reduction or Benefit absence of any commercial or financial relationships that could be construed as a Maximization? Int. J. Drug Pol. 19 (4), 297–303. doi:10.1016/j.drugpo.2006.11.001 potential conflict of interest. Tupper, K. (2011). Ayahuasca, Entheogenic Education and Public Policy. Doctoral Dissertation. Vancouver: University of British Columbia. Copyright © 2021 Rush, Marcus, García, Loizaga-Velder, Loewinger, Spitalier and Urbanoski, K., and Rush, B. R. (2013). Does the Redesign of a Psychiatric Inpatient Mendive. This is an open-access article distributed under the terms of the Creative Unit Change Treatment Process and Outcomes? Psychiatr. Serv. 64 (8), Commons Attribution License (CC BY). The use, distribution or reproduction in 804–807. doi:10.1176/appi.ps.004532012 other forums is permitted, provided the original author(s) and the copyright owner(s) Urbanoski, K., and Wild, T. C. (2012). Assessing Self-Determined Motivation for are credited and that the original publication in this journal is cited, in accordance Addiction treatment:Validity of the Treatment Entry Questionnaire. with accepted academic practice. No use, distribution or reproduction is permitted J. Substance Abuse Treat. 43, 70–79. doi:10.1016/j.jsat.2011.10.025 which does not comply with these terms. Frontiers in Pharmacology | www.frontiersin.org 21 May 2021 | Volume 12 | Article 659644