set and setting

Background Clinical research on psychedelic-assisted therapy (PAT) has expanded substantially in recent years, particularly for post-traumatic stress disorder (PTSD) and depressive disorders. Contemporary studies have generally evaluated psychedelic administration within controlled therapeutic settings that include psychological support, preparation, and integration. However, variability in clinical response and methodological challenges have highlighted the importance of individual, relational, and contextual factors, often described as “set and setting,” in understanding therapeutic outcomes. The role of psychotherapy and the broader therapeutic context therefore remains an important area of investigation. Objective This scoping review aimed to map the contemporary evidence on PAT, characterize the clinical and psychotherapeutic approaches used with psilocybin, MDMA, LSD, and DMT, summarize reported clinical and safety findings, and identify methodological, mechanistic, ethical, and implementation considerations across existing protocols. Methods A structured search of PubMed, PsycINFO, Scopus, and ClinicalTrials.gov was conducted on 23 February 2026. Sources published or publicly available between January 2020 and November 2025 were eligible. The review included peer-reviewed and relevant non-peer-reviewed sources addressing psychedelic-assisted interventions, including primary clinical studies, reviews, clinical trial registrations, regulatory documents, and other relevant contextual sources. Records were managed using Zotero and screened against predefined Population, Concept, and Context criteria. Findings were synthesized descriptively according to source type and evidence domain. Results The mapped evidence was most developed for MDMA-assisted therapy in PTSD and psilocybin-assisted interventions for depressive disorders. Randomized clinical trials reported reductions in PTSD and depressive symptoms following MDMA- and psilocybin-based interventions, respectively, while emerging clinical evidence also investigated LSD-based treatment for generalized anxiety disorder. Evidence for DMT-assisted therapy remained comparatively preliminary, with several available sources consisting of trial registrations or industry-reported information. Across the literature, preparation, supervised psychedelic administration, and integration were common therapeutic components, although the structure and intensity of psychotherapy varied substantially. Functional unblinding, expectancy effects, heterogeneity of psychotherapeutic approaches, and limitations in long-term safety data were recurring concerns. Ethical issues included informed consent during altered states of consciousness, therapist competence and boundaries, cultural considerations, and equitable access. Conclusion PAT represents a rapidly developing area of clinical research, but the evidence base remains heterogeneous across compounds, indications, therapeutic models, and levels of evidential maturity. Future research should improve the standardization and reporting of psychotherapeutic interventions, strengthen methods for assessing blinding and expectancy, establish consistent long-term safety monitoring, and develop robust ethical and equity frameworks. Clear distinction between peer-reviewed clinical findings and preliminary or contextual evidence will also be essential as PAT research progresses toward broader clinical implementation.

While psychedelic experiences are often reported as positive, adverse psychological reactions can occur. We present the case of a 19-year-old Caucasian male who presented to the ER with suicidal thoughts after taking lysergic acid diethylamide (LSD) alone. He was diagnosed with anxious state associated with panic attacks, and suicidal thoughts without ideation or behaviors. He was admitted to the psychiatric ward and treated with trazodone, a serotonin antagonist and reuptake inhibitor antidepressant, and brexpiprazole, an atypical antipsychotic. He responded well and was discharged after 12 days with recommendations to continue therapy with brexpiprazole and attend follow-up at the territorial mental health services. Five days later, he engaged in alcohol consumption with a roommate met during the psychiatric admission, and suicidal thoughts re-emerged. He presented again to the ER but was not admitted to the inpatient unit, since he improved with supportive conversation and medication. One month later, he returned to the ER a third time due to pervasive doubt and confusion that distressed him to the point of triggering unstructured suicidal thoughts. After one week of hospitalization, he was discharged and citalopram (a selective serotonin reuptake inhibitor [SSRI]) was added to the therapy. Following the third admission, the clinical suspicion strengthened that he may have an underlying obsessive functioning pattern that became clinically apparent following LSD use, although the contribution of other vulnerability factors could not be excluded. This case highlights the importance of set and setting, underscores the relevance of harm reduction strategies for both recreational and clinical users, and highlights a potentially negative interaction between serotonergic psychedelics and alcohol.

اگرچه تجربه‌های روان‌گردان اغلب به‌عنوان تجربه‌هایی مثبت گزارش می‌شوند، واکنش‌های روان‌شناختی نامطلوب نیز می‌توانند رخ دهند. در این مقاله، مورد یک مرد قفقازی ۱۹ ساله ارائه می‌شود که پس از مصرف لیسرجیک اسید دی‌اتیل‌آمید (LSD) به‌تنهایی، با افکار خودکشی به بخش اورژانس مراجعه کرد. او با وضعیت اضطرابی همراه با حملات پانیک و افکار خودکشی بدون تمایل یا رفتار تشخیصی شد. وی در بخش روان‌پزشکی بستری و با ترازودون، یک داروی ضدافسردگی آنتاگونیست سروتونین و مهارکننده بازجذب، و برکسپیپرازول، یک داروی ضدروان‌پریشی غیرمعمول، درمان شد. او به درمان پاسخ مناسبی داد و پس از ۱۲ روز با توصیه ادامه درمان با برکسپیپرازول و پیگیری در خدمات سلامت روان منطقه‌ای ترخیص شد. پنج روز بعد، او با هم‌اتاقی‌ای که در مدت بستری با او آشنا شده بود، الکل مصرف کرد و افکار خودکشی مجدداً ظاهر شد. او بار دیگر به اورژانس مراجعه کرد اما به دلیل بهبود با گفت‌وگوی حمایتی و دارو بستری نشد. یک ماه بعد، برای بار سوم به دلیل شک و تردید فراگیر و سردرگمی که او را تا حد بروز افکار خودکشی بدون ساختار آزار می‌داد، به اورژانس مراجعه کرد. پس از یک هفته بستری، ترخیص شد و سیتالوپرام (یک مهارکننده انتخابی بازجذب سروتونین [SSRI]) به درمان او افزوده شد. پس از سومین بستری، ظن بالینی تقویت شد که ممکن است او الگوی عملکرد وسواسی زمینه‌ای داشته باشد که پس از مصرف LSD به‌صورت بالینی آشکار شده است، اگرچه نقش سایر عوامل آسیب‌پذیری نیز قابل رد نیست. این مورد اهمیت شرایط ذهنی و محیطی، لزوم راهبردهای کاهش آسیب برای مصرف‌کنندگان تفریحی و بالینی، و همچنین احتمال تعامل منفی بین روان‌گردان‌های سروتونرژیک و الکل را برجسته می‌کند.