Search Results (33)

Background: Understanding the benefits of psychedelic-assisted therapy (PAT) will require scientific attention to the causal interaction between the therapeutic context and process. Measuring what actually happens during PAT in large-scale studies will be an essential component of this work. Objective: We aim to develop and preliminarily evaluate the feasibility and reliability of a direct observation coding system for narrations of awe experiences during PAT, one hypothesized therapeutic mechanism. Methods: We analyzed 32 PAT clinical trial encounter recordings involving eight participants from a Phase 2 clinical trial study of psilocybin-assisted therapy in advanced cancer. Using a conceptually grounded structured codebook, two human coders independently identified start and stop times for moments exhibiting definitional characteristics of awe narration, including expressions of vastness, need for accommodation and ineffability. We used coder agreement and degree of confidence to refine the coding system. Results: During 16,760 total minutes of video, coders collectively recorded 246 moments of awe narration. Of those moments, 42% (104/246) were identified by one coder and 58% (142/246) by two coders. Coders felt substantially more confident in their judgments about a moment of awe when vastness was present compared to when vastness was absent (OR: 4.3; 95% CI: 2.4, 7.8). Iterative refinement of the coding system led to accommodation being operationalized as two distinct components: an initial cognitive disruption followed by variable engagement in the process of accommodation. Conclusions: Awe narration is directly observable using explicit definitional criteria. This work provides the empirical foundation for scalable coding systems of awe narration during PAT. Full article

Background/Objectives: Patients in palliative care frequently experience multidimensional suffering that extends beyond physical symptoms to include existential distress, demoralization, and loss of meaning. Psychedelic-assisted therapies (PAT), including ketamine-assisted psychotherapy (KAP), have re-emerged as promising interventions for these domains. This study aimed to provide a narrative overview and critical evaluation of the existing secondary literature on PAT in palliative care and serious illness and to examine the extent to which emerging best-practice recommendations are reflected in this literature. Methods: An overview of reviews with framework-based narrative synthesis was conducted, including narrative reviews, systematic reviews, scoping reviews, and meta-analyses addressing psychedelic-assisted interventions in patients with life-limiting illness. A comprehensive search of major databases was performed from inception to February 2026. Data extraction and narrative synthesis focused on clinical outcomes, safety, and the incorporation of key domains derived from recent interdisciplinary best-practice recommendations for PAT in palliative care. Results: Twenty-two reviews were included, synthesizing evidence primarily from early-phase clinical trials and observational studies, predominantly in oncology populations. Across reviews, PAT was consistently associated with reductions in depression, anxiety, and existential distress, along with improvements in quality of life and spiritual well-being. Safety profiles were generally favorable under controlled conditions. However, the incorporation of key therapeutic domains—such as preparation and integration, therapeutic setting, clinician training, and relational and biographical factors—was heterogeneous and often incomplete. Most reviews emphasized outcomes over process and context. Conclusions: The current body of secondary literature suggests potential application of PAT to address psychological and existential suffering in palliative care. However, the available evidence remains preliminary and is predominantly derived from small early-phase studies characterized by methodological heterogeneity, limited blinding, and highly selected populations. At the same time, the partial incorporation of emerging best-practice recommendations highlights a gap between evidence synthesis and normative clinical guidance. Full article

Prolonged grief disorder (PGD) affects approximately 10% of bereaved individuals and is now formally recognized in both the DSM-5-TR and ICD-11. Despite its prevalence, PGD often responds poorly to traditional therapeutic approaches. This manuscript outlines the protocol for an early-stage open-label feasibility trial investigating the use of psilocybin, a psychedelic compound, in treating PGD in adults, with a focus on young adults. The study will involve 20 participants diagnosed with PGD. Each participant will undergo a structured therapeutic process that includes a preparatory session, a single 25 mg dose of psilocybin, and post-session integration. Throughout the study, participants will be monitored via symptom assessments, including qualitative and quantitative data, with the main aims related to safety, feasibility and acceptability. Functional MRIs will be obtained pre- and post-dosing and collected during a standardized grief-elicitation methodology. Key outcome measures include changes in the severity of PGD and trauma symptoms, cognitive flexibility, openness to experience, meaning in life and subjective experiences during the psilocybin session. Neural activity will also be evaluated through fMRI to better understand the neurobiological effects of the treatment. This research represents one of the first clinical protocols specifically focused on the potential of psilocybin for treating PGD. The goal is to assess feasibility and safety while laying the groundwork for future randomized controlled trials. Full article

Background/Objectives: Psilocybin has re-emerged as a promising intervention for neuropsychiatric disorders including major depressive disorder, treatment-resistant depression, anxiety associated with life-threatening illness, obsessive compulsive disorder, and substance use disorders. However, conventional randomized controlled trials (RCTs)—the current gold standard in evidence-based medicine—may not adequately capture the therapeutic complexity of psilocybin, which depends not only on pharmacological action but also on contextual, psychological, and interpersonal factors. This critical narrative review aimed to evaluate the adequacy of existing clinical research frameworks for assessing psilocybin’s therapeutic potential and to explore alternative methodologies that may better reflect real-world clinical conditions. Methods: Using the Web of Science Core Collection database, we identified and analysed the ten most cited clinical studies on psilocybin published between 2015 and 2025 inclusive. Additional literature was included through reference cross-checking, systematic reviews, meta-analyses, and interdisciplinary sources covering neurobiology, history, and real-world evidence (RWE). The review synthesizes clinical outcomes, methodological constraints, and epistemic considerations relevant to psychedelic-assisted therapy. Results: Evidence from highly cited trials demonstrates rapid and sustained antidepressant and anxiolytic effects of psilocybin, with notable benefits also observed in addiction treatment. However, significant methodological limitations were identified, including selection bias, challenges in placebo design and blinding, small sample sizes, and the underrepresentation of diverse populations. Psilocybin outcomes were strongly influenced by subjective experience and contextual factors such as set and setting. Emerging RWE studies revealed heterogeneous patterns of response and provided insights unattainable through RCTs alone. Conclusions: Psilocybin shows considerable therapeutic promise, but current RCT methodologies capture only part of its clinical effects. Comprehensive evaluation will require larger and more diverse clinical trials, long-term follow-up, standardized psychotherapeutic protocols, and the integration of RWE to reflect real-world practice. Psychedelic-assisted therapy should be conceptualized as a complex intervention that combines pharmacological and psychotherapeutic components. Full article

Psychedelic-assisted therapies (PATs) can produce rapid and sustained antidepressant effects, yet variability in response remains substantial. Identifying predictors and moderators is essential for optimising patient selection, preparation, and delivery. To map and synthesise the evidence on the predictors of antidepressant response to classic/serotonergic psychedelics administered with psychotherapeutic support in adults with depressive disorders, including treatment-resistant depression. Following PRISMA-ScR principles, we conducted a scoping review of major biomedical and psychology databases (PubMed (MEDLINE), Embase, PsycINFO, and Web of Science) and trial registries (searches September–October 2025), supplemented by reference-list screening. We included randomised trials, open-label studies, and naturalistic cohorts reporting associations between candidate predictors (baseline traits/clinical features, set/setting variables, acute in-session phenomenology, and biological measures) and validated depression outcomes. We charted study characteristics, analytic approaches (including moderation/mediation where available), and indicators of robustness (e.g., adjustment for overall intensity, preregistration, external validation). A total of 48 studies were included in the review. Across study designs, process-level features during the dosing session were the most consistent correlates of antidepressant improvement. Greater emotional breakthrough, mystical/unitive experiences, and ego dissolution-linked reappraisal/insight generally predicted larger and more durable symptom reductions, whereas anxiety-dominant or dysphoric states tended to attenuate benefit, often independent of overall subjective intensity. Set and setting—particularly a stronger therapeutic alliance and music experienced as resonant—predicted both the emergence of therapeutically salient acute experiences and downstream clinical gains. Baseline moderators showed smaller and mixed effects: PTSD comorbidity sometimes weakened trajectories; extensive prior psychedelic exposure was associated with smaller incremental gains; demographics were typically uninformative. Converging biological findings associated better outcomes with markers consistent with increased neural flexibility and plasticity (e.g., less segregated network dynamics; EEG indices), alongside peripheral changes implicating neurotrophic, inflammatory, and HPA axis pathways. Current evidence suggests that antidepressant response in PATs is driven less by static patient characteristics and more by what occurs during dosing and how the context shapes that experience. Optimising preparation, alliance, and music; facilitating emotional breakthrough and meaning making; and mitigating anxious dysregulation are actionable levers. Future trials should harmonise measures, pre-specify and validate moderators/mediators, intensively sample in-session experience and physiology, and report benefits and harms more consistently. Full article

Substance Use Disorder (SUD) constitutes a major and persistent global public health burden, accounting for approximately 600,000 deaths annually, largely driven by opioid use. Despite substantial advances in addiction neuroscience, currently approved therapeutic strategies remain limited in efficacy, as they predominantly target isolated neurobiological processes and fail to concurrently address core mechanisms such as glutamatergic hyperactivity, mesolimbic hypodopaminergic, and dysfunction of cortical and executive control networks. This mechanistic fragmentation contributes to persistently high relapse rates and underscores the need for integrative and multitarget therapeutic approaches. Within this context, ibogaine has re-emerged as a clinical candidate due to its distinctive multimodal neuropharmacological profile and its reported capacity to modulate multiple pathways implicated in addictive behaviours. However, the clinical translation of ibogaine remains substantially constrained by fragmented and heterogeneous evidence, the absence of regulatory frameworks in several jurisdictions, limited phytochemical validation and standardization of available formulations, and unresolved concerns regarding cardiac safety. This scoping review critically synthesizes the available preclinical and clinical literature on ibogaine in the treatment of SUD, with particular emphasis on reported effects on withdrawal symptoms and craving, dose–response relationships, and the occurrence of cardiac adverse events. By clarifying the current state of the evidence and delineating key translational constraints, this review defines the conditions under which ibogaine, an indole alkaloid isolated from Tabernanthe iboga Baill. (Apocynaceae), may warrant continued investigation. The hypothesis of a neurobiological “reset”, supported by emerging preclinical and clinical data, positions ibogaine as a compound of relevance in addiction research and highlights the need for rigorous pharmacological, toxicological, and regulatory evaluation to inform safer and more standardized clinical pathways. Full article

Shelter environments frequently expose dogs to chronic stress and anxiety, which can compromise their welfare and reduce their chances of adoption. Recent interest in psychedelic-assisted approaches has suggested potential therapeutic applications in veterinary behavioral medicine, although empirical evidence remains scarce. This study aimed to evaluate the combined effects of low-dose 1-cyclopropionyl lysergic acid diethylamide (1cp-LSD), a legal lysergamide prodrug of LSD in several countries, and ethological intervention (EI) on the behavior and welfare of shelter dogs. Twenty dogs were randomly assigned to four groups: pharmacological intervention, ethological intervention, combined treatment, or control. The ethological sessions were conducted by veterinary behaviorists, and pharmacological treatment consisted of 10 µg of 1cp-LSD administered orally for three weeks. Blinded evaluators assessed animals using validated anxiety and welfare scales, including a treatment expectation scale, before, during and after the intervention. Results showed that the combined condition consistently outperformed single interventions, significantly enhancing sociability, calmness, and positive emotional reactivity. Importantly, these improvements persisted for three weeks following treatment cessation, indicating sustained benefits beyond the active intervention phase. These findings provide preliminary evidence for the potential of integrating low doses of psychedelics with behavioral therapy in shelter settings. Future studies with larger cohorts and refined pharmacokinetic data are required to confirm safety, elucidate mechanisms, and optimize protocols for clinical application in veterinary practice. Full article

Adolescent mental health conditions, particularly treatment-resistant depression (TRD), represent a growing public health challenge associated with high morbidity, functional impairment, and elevated suicide risk. Psychedelic-assisted therapies have shown robust antidepressant and transdiagnostic effects in rigorously controlled adult trials. Extending this work to adolescents is scientifically compelling yet ethically complex, given neurodevelopmental vulnerabilities and the paucity of pediatric data. This review examines the historical context of psychedelic use, summarizes adult efficacy and mechanistic insights, explores adolescent-specific opportunities and risks, and considers applications in co-occurring neurodevelopmental disorders. Conventional treatments, including selective serotonin reuptake inhibitors and psychotherapy, are often inadequate for a narrow but substantial subset of clinical phenotypes, prompting interest in novel and rapid-acting interventions. Psychedelic-assisted therapies have shown promising results in adults with refractory mood disorders, yet their applicability to adolescents remains uncertain due to ongoing neurodevelopment and ethical constraints. This review critically examines evidence from adult psychedelic and psychedelic-adjacent interventions, including esketamine, and evaluates their potential relevance to adolescent populations through a developmental, mechanistic, and ethical lens. Rather than advocating for premature clinical adoption, we highlight translational gaps, developmental risks, and research priorities paramount to responsibly assess these approaches in youth. Full article

Background: Psychedelic-assisted therapy is gaining renewed attention as a potential treatment for various mental disorders. Despite increasing numbers of randomized controlled trials (RCTs) and meta-analyses, a comprehensive synthesis of the evidence across different substances and indications is lacking. This umbrella review aims to evaluate the effectiveness and safety of psychedelic-assisted therapy—primarily psilocybin, MDMA, and LSD—across major psychiatric disorders, including depression, post-traumatic stress disorder (PTSD), and substance use disorders. Methods: We systematically identified and synthesized data from 23 meta-analyses encompassing over 100 primary studies. Outcomes were standardized and re-expressed as Hedges’ g to enable cross-study comparisons. Study quality was assessed using AMSTAR2, and certainty of evidence was evaluated via the GRADE framework. Results: The number of identified meta-analyses differed markedly depending on the substance and clinical indication: psilocybin for depression (n = 9) and MDMA for PTSD (n = 10) had the strongest evidence base, while fewer meta-analyses were available for LSD in alcohol use disorder (n = 2) and depression (n = 2), ayahuasca in depression (n = 2), and MDMA in autism spectrum disorder (n = 2). Psilocybin demonstrated large effect sizes in major depression (Hedges’ g ≈ 1.05), with some evidence of sustained benefits up to six months. MDMA showed very large effects in reducing PTSD symptoms (Hedges’ g ≈ 1.24), often after 2–3 sessions. LSD yielded short-term benefits for alcohol use disorder (OR ≈ 2.0), though effects declined over time. Across studies, adverse events were generally mild and transient, with no consistent signal for serious harm. Considerable methodological variability was observed, including small and sometimes overlapping samples, heterogeneity, risk of bias, and limited long-term data. These constraints should be taken into account when interpreting the overall findings. Conclusions: Current evidence supports the short-term efficacy and safety of psychedelic-assisted therapy for selected psychiatric disorders, particularly depression and PTSD. However, the low methodological quality of studies and most meta-analyses, as well gaps in long-term safety data highlight the need for high-quality studies. Full article

The CAnadian Network for Psychedelic-Assisted Cancer Therapy (CAN-PACT) was launched in 2025 to address urgent gaps in supportive care for Canadians with cancer experiencing demoralization syndrome (loss of meaning, dysphoria, disheartenment, helplessness, a sense of failure) and related psychosocial distress. CAN-PACT has six major objectives: (1) to develop a national interdisciplinary research and practice network; (2) to set research priorities through structured stakeholder engagement; (3) to develop and provide PAT training and education for clinicians, researchers, and patients; (4) to pilot test the feasibility of intervention and assessment procedures; (5) to conduct a multi-center, randomized controlled trial of PAT for people with advanced cancer; and (6) to inform and influence healthcare policy on PAT in Canada. We discuss the background and need for PAT in cancer, describe challenges currently limiting its use, and outline CAN-PACT’s strategy for building capacity, generating Canadian evidence, and preparing the oncology healthcare environment for potential implementation. This manuscript presents a summary overview of CAN-PACT as a multi-objective research program; detailed protocols for each discrete study component will be published separately as the research program progresses. Through environmental scans, national engagement, targeted training, rigorous research, and ongoing collaboration with policymakers, CAN-PACT aims to enable equitable access to safe, evidence-based PAT for people with advanced cancer in Canada’s publicly funded cancer centers. Full article

Today’s research highlights the therapeutic potential of the hallucinogen psilocybin in the treatment of pathologies associated with mood, cognitive, and affective dysregulation. These domains of function are regulated by the serotonergic system, which can be influenced by sex hormones, like estrogen and testosterone, and psychedelic compounds including psilocybin. Current evidence supports a higher prevalence of affective disorders in females, and a growing awareness of sex-based differences in response to drug therapy. Estrogen’s influence on serotonin physiology is an aspect that must be accounted for when planning a treatment regimen that includes a psychoactive drug such as psilocybin. A review of the current literature was conducted, and an analysis of how the fluid hormonal states in females across their different reproductive phases may impact serotonin dynamics, synaptic plasticity, and therapeutic timing of psilocybin use is discussed. Future research should focus on the influence of sex hormones on psychedelic-assisted therapy in the effort to further personalize treatment plans for these pathologies. Full article

Psychedelic-assisted therapy offers rapid and profound benefits for treatment-resistant psychiatric conditions but remains constrained by the need for intensive, clinic-based administration. Concurrently, advances in digital health technologies have introduced scalable tools. This systematic review evaluates the safety, efficacy, and implementation of digitally enabled psychedelic-assisted therapy delivered in non-clinical settings. A comprehensive search of five databases, registered in PROSPERO (CRD420251020968) and conducted in accordance with PRISMA guidelines, identified six eligible studies including real-world analyses, clinical trials, qualitative research, and case reports, representing a total of 12,731 participants. Most studies examined at-home ketamine or esketamine therapy supported by telehealth platforms or mobile applications. Data were synthesized narratively given the heterogeneity of designs and outcomes. Digital enablement was associated with high response rates (ranging from 56.4% to 62.8% for depression) and rapid symptom improvement, particularly in depression and anxiety. Remote monitoring and digital tools demonstrated feasibility and acceptability, but serious safety concerns—including psychiatric adverse events and one unintentional overdose—underscore the need for strict oversight. Risk of bias was moderate to serious across non-randomized studies, limiting confidence in the findings. One study on virtual ayahuasca rituals highlighted the sociocultural potential and limitations of online practices. Despite promising preliminary findings, the field is marked by low methodological rigor and absence of controlled trials. Digitally supported at-home psychedelic therapy represents a transformative but high-stakes frontier, requiring robust research and safeguards to ensure safe, equitable, and effective implementation. No funding was received for this review, and the authors declare no conflicts of interest. Full article

Background/Objectives: This study examines the development of clinical trials investigating psilocybin for the treatment of psychopathologies, with a comparative focus on the United States (US) and the European Union (EU). The objective is to identify regional differences in trial progression, research infrastructure, and regulatory frameworks. Methods: A mixed-methods approach was applied, combining case studies, qualitative and quantitative research. Key variables included trial phase, geographical distribution, demographic factors, funding, governmental support, and public health policies. Results: The US demonstrated a substantially higher number of psilocybin trials across both early and advanced phases. This reflects a strong research infrastructure, growing financial investment, and increasing interest in psychedelic-assisted therapies. In contrast, the EU showed fewer trials and slower advancement, reflecting a more cautious stance that emphasizes patient safety and therapeutic efficacy. These divergences are shaped by differences in regulation, funding mechanisms, and sociocultural attitudes toward psychedelics in psychiatry. Conclusion: This comparative analysis highlights the uneven pace of psilocybin research across different regions. It also emphasizes the importance of international collaboration, harmonization of public health policies, and the development of standardized procedures prioritizing safety and effectiveness. Integrating psilocybin-assisted interventions into psychiatric practice has the potential to expand treatment options and strengthen mental health care, but coordinated global efforts are essential to ensure both scientific rigor and patient protection. Full article

Addiction remains a persistent public health crisis, marked by poor treatment retention and limited pharmacotherapy options. Emerging treatments, such as psychedelic-assisted psychotherapy and neuromodulation, offer promising avenues for circuit-level interventions in behavioral addictions. This narrative review synthesizes the current landscape of psychedelic compounds and neuromodulation techniques with a focus on their mechanisms of action, applications in specific behavioral addictions, and translational potential. By targeting disrupted reward, executive control, and stress regulation networks, these interventions may facilitate meaningful recovery and long-term remission in otherwise treatment refractory cases. We highlight key findings, current research limitations, and future directions in integrating these novel therapies into the treatment of gambling disorder; internet gaming disorder/gaming disorder, predominantly online; internet use disorder; and compulsive sexual behavior disorder. Full article

Background: Evidence is growing that psychedelic substances have positive effects in the setting of Palliative Care (PC), focusing on special needs in this patient population. After a scoping review of the literature, no published expert recommendations guiding best practice for psychedelic-assisted therapy (PAT) towards the end of life were identified. Objective: To draw conclusions from first-hand experienced professionals on PAT in PC (PATPC). Setting, Design, Participants: An international workshop with experts was held in Wasserfallen, Switzerland. A thematic analysis of a semi-structured, questionnaire-based qualitative study with 13 experts in PC, oncology, psychiatry/psychology, and PAT from Europe, the United States, and Oceania was made. Measurements: The questionnaire was designed to elicit the participant’s perspectives on (A) special considerations on PATPC, (B) specific characteristics of PATPC (versus mental illness), and (C) the relevance of these differences during preparation, substance dosing session, and integration in PATPC. Results: (A) Special Considerations included (non-medicalized) setting, potential need, and possibility to reduce preparation time. (B) Distinguishing characteristics included the patient’s intrinsic motivation for treatment success, the importance of anxiety, depression, and spiritual distress as indications for PATPC, and the importance of sufficient integration of the psychedelic experience into life in the face of limited time due to the life-limiting illness. (C) Flexibility in setting and timing of preparation, choosing the appropriate dosage of the psychedelic substance depending on the patient’s intended focus, low/medium (relational issues), higher for transcendental experiences, considering mental capacity and vulnerability for the individual. In addition, respondents noted that for therapists, knowledge about transcendental states, such as mystical experiences, existential aspects of life-threatening illness, and the role of therapists’ own self-experience/inner work, as well as good knowledge of the theoretical basis for treatment, was highlighted. Conclusions: This study highlights special considerations for PAT PC and could be a first step towards specific treatment recommendations (guidelines) for PATPC. Full article