Psychotherapeutic and neurobiological processes associated with ayahuasca: A proposed model and implications for therapeutic use

Ayahuasca is a traditional Amazonian decoction combining a DMT-containing plant (commonly Psychotria viridis) with a Banisteriopsis caapi vine that supplies harmala alkaloids. Use of DMT–harmala preparations has expanded from indigenous and syncretic religious settings into international ceremonial and therapeutic contexts, accompanied by increasing anecdotal and scientific reports of mental health and wellbeing benefits. Despite growing interest, the specific psychotherapeutic processes that mediate ayahuasca's reported therapeutic effects and how these map onto neurobiological mechanisms remain incompletely defined in the literature. This paper combines a narrative review of existing empirical and theoretical work with qualitative material drawn from the Global Ayahuasca Project (GAP) to propose a coherent model of psychotherapeutic processes associated with ayahuasca consumption. The stated aim is to identify core experiential elements believed to drive beneficial outcomes, and to discuss implications for clinical treatment models and therapist training, with a view to informing forthcoming clinical trials of ayahuasca-inspired interventions for conditions such as treatment-resistant depression and alcohol use disorder.

The investigators used original qualitative data from the Global Ayahuasca Project (GAP), the largest cross-sectional dataset of ayahuasca drinkers reported to date, together with a narrative review of the literature to develop their proposed model. The GAP survey was an online self-report instrument that collected both quantitative and qualitative information from 10,836 respondents across more than 50 countries. Participants were required to be aged 18 or older and to have used ayahuasca at least once. Recruitment was non-random and achieved via websites, organisations, retreat centres, churches, online groups, social media, and event flyers; no financial incentives were offered. Data cleaning included cross-checking to remove suspected duplicate responses, and partially completed surveys were retained. The study received institutional ethics approval (University of Melbourne HREC number 1545143.3). Reported sample characteristics included wide variation in lifetime exposure: about 8% had used ayahuasca once, 12% two or three times, 19% four to ten times, 8% 11–20 times, 11% 21–50 times, 15% 51–200 times, 13% over 200 times, and 13% over 500 times. More than 75% of respondents provided qualitative accounts of their experiences. The extracted text notes that no dosage information was collected. The methodological approach combined the GAP qualitative material with existing empirical studies and theory to identify recurring psychotherapeutic themes; however, the extraction does not clearly describe a formal qualitative analytic method (for example, whether thematic analysis, coding frameworks, or inter-rater procedures were applied). The authors therefore rely on large-scale self-report data and synthesis of prior research to construct their model rather than on a reported, detailed qualitative-methods pipeline in the extracted text.

Evidence from animal and human studies reviewed by the authors indicates potential therapeutic effects of DMT–harmala alkaloid preparations across mood, anxiety, and substance-use domains, though the clinical literature remains limited and heterogeneous. Small clinical trials and non-clinical studies have reported antidepressant, anti-addictive, and anxiolytic signals. The authors cite a study of 17 inpatients with depression that reported significant reductions in depressive symptoms after a single ayahuasca dose, with the largest Cohen's d of 1.83 at day 7; a secondary analysis reported reduced suicidality with Hedges's g = 1.75 at day 21. A broader systematic review of 28 human ayahuasca studies found acute administration to be generally well tolerated and associated with improved mood and cognition, increased spirituality, and reduced impulsivity. The authors emphasise, however, that many studies are open-label or small, and that expectancy, contextual factors (for example, community support in retreat or church settings), concurrent psychosocial care, and difficulties with blinding limit causal inference. Observational and qualitative evidence in the GAP dataset and prior studies identified a cluster of psychological and wellbeing changes associated with ayahuasca use. Reported cognitive‑affective changes include improved decentring, aspects of mindfulness (acceptance, non-judgemental processing), cognitive flexibility, and emotional regulation. Broader outcomes include increased confidence, optimism, life satisfaction, openness to therapy, reduced harm avoidance, and changes in interpersonal relationships, sense of self, creativity, somatic perception, and health behaviours. Personality-level shifts reported across studies included increases in agreeableness, openness to experience, and extraversion, alongside reductions in neuroticism and negative emotionality. The authors outline multiple neurobiological mechanisms proposed to underlie acute and longer-term effects. These mechanisms arise from combined actions of DMT and harmala alkaloids and include serotonergic 5-HT2A agonism (shared with classic psychedelics), modulation of dopaminergic and glutamatergic systems, increased neurogenesis and neuroplasticity, MAOI effects of harmala alkaloids, sigma-1 receptor activation by DMT, decreased default mode network (DMN) connectivity, reduced pro-inflammatory cytokines, and altered reactivity in limbic and interoceptive regions such as the amygdala and right anterior insula. From a network perspective, ayahuasca is proposed to transiently relax high-level cognitive control and facilitate bottom-up information flow, thereby enabling emotional access and revision of entrenched beliefs. From synthesis of the literature and GAP qualitative reports, the authors propose a five-element psychotherapeutic model associated with ayahuasca consumption: (1) somatic effects; (2) introspection and emotional processing; (3) increased Self‑connection (a compassionate, authentic core Self); (4) increased spiritual connection and awareness; and (5) gaining of insights and new perspectives. Key empirical observations supporting these elements include: strong acute somatic and interoceptive changes (including nausea and vomiting traditionally framed as 'the purge'), reports of improved bodily presence and reduced dissociation, and neuroimaging evidence of engagement of interoceptive/emotional processing systems. Introspective processes commonly involved vivid life‑review sequences, accelerated recognition and reframing of maladaptive patterns, and access to suppressed memories; around 90% of participants in one study reported rapid thought clarity or “Aha!” experiences. Regarding Self‑connection, over 70% of GAP respondents selected concepts such as a “higher” or “true” self as the source of insights during the acute experience. Spiritual effects were prominent: roughly 70% of GAP participants rated the ayahuasca experience among the top five most spiritually significant life events, over 75% reported insights about sacredness or a higher power, and almost 90% indicated these experiences had a very positive effect on their life; more than half reported enhanced connection with nature or lasting connection with a plant spirit. Insights and new perspectives were frequent and consequential: most common insights related to personality, family dynamics, life purpose, childhood events, and health; more than 50% of participants reported these themes, and almost 80% of single‑occasion drinkers reported at least three personal insights. Behavioural changes attributed to these insights included reductions in substance use and healthier diet or other health behaviours (about 30–50% reported life changes such as healing relationships, reduced drug/alcohol use, or vocational shifts), with around 50% saying they took much better care of their physical health and diet post‑ayahuasca. The authors stress that these processes are typically interconnected and reinforced by the proposed neurobiological window of plasticity, facilitating integration of somatic, emotional, cognitive, and spiritual material. They also identify potential harms and integration challenges: vivid re‑experiencing of trauma can risk re‑traumatisation in vulnerable individuals or without sufficient support, intense death‑related spiritual experiences or extreme fear can complicate integration, and some recipients may develop rigid or grandiose interpretations, impulsive major life decisions, or spiritual narcissism. The extracted text reiterates that no dosing data were recorded in GAP and that contextual variables and concurrent therapies confound causal attributions.

The authors situate their model within the current 'psychedelic renaissance', noting promising early trial signals for compounds such as MDMA and ayahuasca but emphasising that therapeutic frameworks for DMT–harmala preparations remain underdeveloped. They argue that explicitly defining psychotherapeutic processes associated with ayahuasca use can inform the design of manualised treatment models and therapist training, thereby helping to maximise benefit and minimise harm in clinical applications. In particular, the paper highlights the likely importance of incorporating somatic practices into preparation and integration phases because somatic awareness and embodied processing are unusually prominent in ayahuasca experiences relative to other classic psychedelics. A further pragmatic implication identified by the authors is the value of psycho‑spiritual support: because ayahuasca often elicits deep spiritual experiences, integrating culturally sensitive, non‑doctrinal spiritual counselling before and after sessions has been associated with greater insights, fewer integration difficulties, and better psychological outcomes in naturalistic contexts. The authors recommend therapeutic approaches that foster ongoing connection with an inner core Self, suggesting Internal Family Systems (IFS) as a promising candidate given its emphasis on a compassionate Self, somatic elements, and a non‑pathologising stance; they acknowledge, however, that other therapies may also be adapted to address the five processes in their model. Key limitations acknowledged in the extracted text include the non-random, self-selected nature of the GAP sample, potential overrepresentation of individuals favourable to ayahuasca, and underrepresentation of Indigenous drinkers. The authors concede that their synthesis cannot establish causal links between the proposed processes and clinical outcomes and that the highly subjective nature of ayahuasca experiences produces substantial inter- and intra‑individual variability. They therefore call for future controlled clinical research to operationalise and test the five psychotherapeutic processes, and note ethical considerations around recognition and reciprocal relationships with Indigenous communities from whom ayahuasca knowledge originates. Finally, the investigators report they are developing therapist training and planning a Phase II clinical trial using lyophilised whole‑plant material, and they caution that synthetic or non‑hallucinogenic analogues may not reproduce all plant‑based subjective or biochemical constituents implicated in therapeutic processes.