Naturalistic Use of Mescaline Is Associated with Self-Reported Psychiatric Improvements and Enduring Positive Life Changes

Psychiatric disorders such as mood, anxiety-spectrum, and substance use disorders are highly prevalent, contribute substantially to global disease burden, and are often resistant to existing treatments or limited by access disparities. Earlier research on classic serotonergic psychedelics (for example psilocybin, LSD, and ayahuasca) has shown promise for several conditions including major depression, existential distress, PTSD, and addiction, and clinical benefit has been linked to acute psychological factors such as mystical-type experiences and psychological insight. Mescaline is a naturally occurring phenethylamine and serotonin-2A/2C agonist found in peyote and San Pedro cacti; it has a long ceremonial history and has been reported anecdotally to reduce psychiatric symptoms, but systematic research on its therapeutic potential and mechanisms is sparse. Agin-Liebes and colleagues set out to explore whether naturalistic mescaline use is associated with self-reported improvements in depression, anxiety, PTSD, and alcohol or drug misuse, and to examine which acute subjective effects (mystical-type experience, psychological insight, ego dissolution, and challenging experiences) and enduring effects are associated with those reported improvements. The study used an anonymous international online survey to characterise patterns of use, acute phenomenology, and persisting changes following respondents' most memorable mescaline experience, with a particular focus on potential mechanisms that might relate to clinical improvements.

This investigation is a secondary analysis of data from a larger international epidemiological survey of mescaline users. Recruitment occurred via Internet advertisements on social media (e.g., Facebook, Reddit), email invitations to relevant organisations, and word-of-mouth shares; recruitment took place between January and October (the extracted text does not clearly report the year). Participation was anonymous, unpaid, limited to adults (≥18 years) fluent in English, and required at least one prior mescaline ingestion. Ethical approval was provided by the Local Standing Ethical Committee at Maastricht University in The Netherlands. Respondents completed a battery of questionnaires about their most "memorable" mescaline experience. Mental health history was assessed with categorical items asking whether participants had ever had depression, anxiety, PTSD, alcohol misuse/AUD, or drug misuse/DUD and whether each condition became "better", "stayed the same", or "worsened" after the mescaline experience. Acute subjective effects were measured with validated self-report instruments adapted for the survey: the Psychological Insight Questionnaire (PIQ), the Mystical Experiences Questionnaire (MEQ-30), the Challenging Experiences Questionnaire (CEQ), and the Ego Dissolution Inventory (EDI). Enduring changes were assessed with items from the Persisting Effects Questionnaire (PEQ), including ratings of personal meaningfulness, spiritual significance, psychological insight, and a range of lasting changes in well-being, life purpose, attitudes, behaviour, spirituality, and views about reality. Internal consistency for these scales in the sample was reported as excellent (Cronbach's α values ≥ 0.91). Analyses proceeded in stages: descriptive statistics characterised demographics, patterns of use, acute effects, and rates of reported psychiatric conditions. The sample was divided into five psychiatric subgroups based on reported prior conditions (depression, anxiety, PTSD, AUD, DUD) and then into outcome groups within each subgroup (Better versus No Change/Worse after mescaline). Between-group comparisons used chi-square tests and t-tests, with Cohen's d effect sizes reported for mean differences. Logistic regression models were then run to test whether acute subjective effect measures that differed between groups predicted reported improvement in each psychiatric subgroup. A standard alpha of 0.05 was used for significance testing.

The final analytic sample comprised 452 respondents after exclusions for missing mescaline-type information and age <18. Participants were predominantly White (83%), male (76%), and heterosexual (82%), with a mean age of 38 (SD = 14.4). Almost half (46%) reported lifetime mescaline use of 1–3 occasions, and 70% reported using mescaline yearly or less frequently. Approximately one-third of the full sample characterised their most memorable mescaline session as among the top five or the single most personally meaningful or spiritually significant experience of their life. Reported prevalence of conditions at the time of the most memorable experience was: depression 41% (n = 184), anxiety 46% (n = 210), PTSD 16% (n = 72), alcohol misuse/AUD 16% (n = 72), and drug misuse/DUD 19% (n = 85). Among respondents who reported a prior condition, the majority reported that the condition improved after their mescaline experience: depression 86% (of those with depression), anxiety 80% (of those with anxiety), PTSD 76% (of those with PTSD), AUD 76% (of those with AUD), and DUD 68% (of those with DUD). Only a small minority (2–5%) reported an explicit intention to address or resolve their psychiatric condition during the mescaline session. Between-group comparisons showed that respondents who reported improvement in their psychiatric condition had significantly higher ratings of acute mystical-type experience (MEQ-30), psychological insight (PIQ), and ego dissolution (EDI) than those who reported no change or worsening; reported effect sizes for these differences ranged approximately from d = 0.7 to d = 1.5. Enduring positive effects measured on the PEQ (for example, life satisfaction, sense of purpose and meaning, social relationships, attitudes about life and self, relationship to nature, positive behavioural changes, spirituality, and views of reality) were also higher among improvers, with Cohen's d ranging roughly from 0.6 to 2.2. Ratings of psychologically challenging experiences (CEQ) did not differ between improvers and non-improvers except in the PTSD subgroup, where those who improved reported lower intensity of acute challenging experiences. Logistic regression analyses examined which acute effects independently predicted reported improvement. Greater intensity of psychological insight (PIQ) was associated with increased odds of reporting improvement in depression (OR = 2.60, 95% CI 1.43–4.58), alcohol misuse/AUD (OR = 3.25, 95% CI 1.91–5.54), and drug misuse/DUD (OR = 3.34, 95% CI 1.47–7.59) after controlling for mystical-type and ego dissolution effects. For PTSD, intensity of mystical-type experience (MEQ-30), but not PIQ or EDI, was associated with increased odds of symptom improvement (OR = 3.72, 95% CI 1.20–11.51). Demographic differences were minimal across psychiatric subgroups, although within the anxiety subgroup improvers were younger on average, and within the DUD subgroup a larger proportion of White respondents reported no improvement compared with those reporting improvement.

The investigators interpret the findings as preliminary evidence that naturalistic mescaline use is associated with self-reported improvements across multiple psychiatric domains, and they highlight psychological insight during the acute psychedelic experience as a potential transdiagnostic mechanism linked to sustained benefit. They note that while mystical-type and ego dissolution experiences were higher among improvers, psychological insight—as measured by the PIQ—emerged in regression models as the strongest and most consistent predictor of improvement for depression and substance use outcomes, whereas mystical-type intensity was the predictor for PTSD improvement. The researchers situate these observations within evolving process-oriented models that propose access to transpersonal states may be necessary but that assimilation of those states into personal psychological insight and behavioural change may be critical for durable therapeutic effects. Agin-Liebes and colleagues acknowledge parallels and contrasts with other psychedelic-assisted paradigms: for example, they contrast the apparent association of mystical-type experience with PTSD improvement here against MDMA-assisted psychotherapy models in which mystical phenomena are less prominent and mechanisms proposed include enhanced fear extinction and reconsolidation. The authors also underscore the potential importance of set, setting, preparation, and integration—factors that may be more consistently provided in controlled human laboratory trials and could account for larger proportions of participants reporting highly meaningful experiences in those settings. Key limitations are emphasised. The cross-sectional, retrospective survey design precludes causal inference and is subject to selection bias, recall bias, and expectancy effects; recruitment via social media and community networks may have attracted respondents favourable to psychedelic use. Mental health history was assessed with single-item, self-reported categorical questions rather than standardised clinical instruments, so reported conditions and improvements could not be independently verified and do not constitute confirmed diagnoses. The study did not assess psychiatric comorbidity systematically and the sample was demographically homogeneous (predominantly young White males), limiting generalisability. The authors therefore caution that findings are preliminary and recommend prospective, longitudinal, controlled trials to systematically evaluate mescaline's efficacy, safety, and underlying psychological and neurobiological mechanisms. They also call for improved diversity in future research samples and for investigation of structured preparation and integration practices to optimise therapeutic outcomes.