Search Results (72)

Psychedelic decriminalization has moved from the margins of drug-policy discourse to a mainstream public health and equity conversation. This community survey reveals that people with psychedelic experience who live in areas that have decriminalized psychedelics report greater benefits of psychedelic decriminalization than adverse outcomes. In decriminalized zones, most (84.0%) participants (N = 163) reported feeling improvements in one of the following areas because of decriminalization: legal risks, social acceptance, substance availability, substance safety, diversity of available products, and overall substance quality. Only 5.5% of participants reported worsened conditions in any category. Most (74.8%) participants also reported decriminalization-related improvements related to psychedelic therapy, such as social acceptance, availability, legal risks, safety, and diversity of services available. Notably, no participant reported that legal risk had worsened. Post decriminalization, most (72.4%) participants reported improvements in life conditions including stress and anxiety, worry, depressive symptoms, physical health, addiction, family relationships, other relationships, connection to community, working conditions, and financial status. Only 8.6% of participants reported declines in any category regarding psychedelic therapy or life conditions (2.5%). Although our methodology precludes attributions of causality, this initial study may inspire research with more sophisticated methodologies. Full article

Background/Objectives: Psilocybin-assisted therapy has progressed from early proof-of-concept work to a substantially expanded evidence base, with four pivotal studies published in 2025–2026 that were not incorporated into earlier reviews. This review synthesizes the pharmacological and neurobiological foundations of psilocybin and appraises clinical evidence across major depressive disorder (MDD), treatment-resistant depression (TRD), post-traumatic stress disorder (PTSD), cancer-related distress, and substance use disorders, emphasizing long-term durability, expanding indications, and methodological limitations. Methods: A narrative review was conducted using a targeted search of PubMed/MEDLINE, Embase, Scopus, and Web of Science (January 2000–April 2026), emphasizing 2025–2026 publications. Predefined eligibility principles prioritized randomized controlled trials, long-term follow-up studies, and systematic reviews; formal PRISMA procedures were not applied, consistent with the narrative design. Results: Four 2025–2026 studies extend the evidence base: a 52-week follow-up confirming dose-dependent maintenance of antidepressant benefit after a single 25 mg psilocybin session; the first pilot study in Veterans with severe TRD, reporting a 60% response rate at three weeks; the first safety trial in PTSD, where symptom improvement tracked self-transcendent experience intensity but worsened with session anxiety; and a living review of 15 randomized trials confirming a meaningful antidepressant effect while identifying functional unblinding as a substantial threat to effect estimates. Conclusions: Evidence supports psilocybin-assisted therapy as mechanistically distinct and clinically promising, most strongly in MDD and TRD, with preliminary support in PTSD and Veterans. Functional unblinding, small open-label designs, narrow safety populations, and absent SSRI-integration protocols constrain the current conclusions. Full article

The nature of the psychedelic experience, and the distinctive phenomenological features it generates, leaves it susceptible to an unresolved epistemological tension between first-person phenomenological reports and claims about the fundamental nature of consciousness and reality. This tension is examined through the concept of ontological tourism: the practice of treating phenomenological data as sufficient grounds for ontological conclusions without adequate engagement with alternative mechanistic explanations or the philosophical requirements that such inferences demand. This practice, absent adequate epistemic scaffolding, poses a genuine threat to scientific integrity and clinical ethics. At the same time, reflexively dismissing phenomenological data as mere pharmacological artifacts represents an equally impoverished position. The tourist analogy cuts both ways: the tourist may be an unreliable cartographer, but the tourist has been somewhere. An alternative stance is proposed, one that takes subjective experience seriously as a form of evidence without overclaiming its metaphysical implications or dismissing its epistemic weight, along with a framework for achieving it. Ontological tourism risks bypassing the explanatory work that makes psychedelic phenomenology valuable to consciousness science. Full article

Chronic pain is a complex disorder of central nervous system maladaptation, perpetuated not only by ascending nociceptive transmission but also by entrenched prior expectations. Conventional analgesics typically fail to reverse this cognitive rigidity and the ensuing pathological cycles. Classic psychedelics, however, are emerging as a promising avenue to help address this therapeutic impasse. This narrative review provides a comprehensive overview of the emerging science of psychedelics, encompassing their biological binding targets, potential neural mechanisms and clinical applications, in the context of chronic pain. We synthesize the therapeutic potential of classic psychedelics and critically examine the discrepancies between clinical outcomes and foundational mechanistic research. Furthermore, we evaluate key translational barriers, particularly compromised blinding and expectancy bias, and highlight the necessity for developing novel validation strategies. Ultimately, these new insights compel a fundamental rethinking of how biological neuroplasticity and subjective psychological experiences independently or synergistically drive analgesia, thereby offering a paradigm-shifting perspective for the translation of psychedelics into evidence-based analgesic therapeutics. Full article

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

New psychoactive substances (NPS) are a heterogeneous group of recreational drugs that mimic the actions and psychoactive effects of existing pharmaceutical products or recreational drugs. As NPS can be highly potent, even exceeding their template compound’s potency, there are frequent reports of non-fatal and fatal intoxications. One principal target for hallucinogenic and psychedelic drugs, including NPS, is the 5-hydroxytryptamine receptor 2A (5-HT_2A). Since NPS are designed to evade legal restrictions, this drug market is quickly evolving, and researchers are playing catch-up, investigating these novel compounds for their toxicological and pharmacological properties. Receptor binding affinity (Ki) is an important property describing ligand–receptor interactions and is a prerequisite for receptor activation. Competitive in vitro assays can be used to assess Ki; this is a resource-intensive process. We used publicly available Ki data for the 5-HT_2A, calculated molecular descriptors and fingerprints, and trained five classification machine learning models. The predictive performance of the models had precisions and recalls up to 93% and 92%, respectively. We used explainable artificial intelligence, i.e., SHAP values and similarity maps, for model interpretation. The results are in line with previous experiments and support its suitability to predict the binding affinities of possible 5-HT_2A ligands. Full article

Recent studies show that psychedelics such as psilocybin and LSD can reliably occasion spiritual or “mystical-like” experiences under supportive conditions, and the spiritual dimension of these experiences may contribute to their reported mental health benefits. Scholars have begun exploring how such experiences might relate to spiritual growth within Christian frameworks, but most theological engagement has drawn primarily on Western sources. This article addresses that gap by bringing Orthodox Christianity into dialogue with Western Christian theology on questions of psychedelic spirituality. Drawing on traditions beginning in Christianity’s earliest centuries, we argue that Orthodoxy offers distinctive and largely unexplored resources that both challenge and enrich existing approaches. We highlight five themes. First, Orthodoxy’s insistence that profound spiritual experience belongs to the universal Christian vocation rather than a spiritual elite reframes contemporary discussions of mystical experience. Second, the tradition’s recognition of diverse catalysts for spiritual awakening, and its understanding of ascetical preparation as receptive rather than self-generating, provides a framework for evaluating psychedelic experiences that sometimes resemble other mystical experience by their orientation and fruits. Third, the doctrine of the divine energies offers a framework for understanding genuine encounters with God’s real presence and activity in creation, allowing comparison with Western accounts of the Holy Spirit’s activity. Fourth, Orthodoxy’s emphasis on ongoing formation within Christian communities situates spiritual experience within a broader process of transformation. Fifth, Orthodox traditions of spiritual discernment, including the neptic tradition’s caution against acquisitive seeking of mystical states, offer well-developed criteria for evaluating authenticity, a matter of urgency given the diversity of claims surrounding psychedelics. Rather than requiring radical revision of Christian theology, we argue that engagement with psychedelic experiences can occur within established frameworks when guided by discernment, formation, and communal accountability. By placing Orthodox and Western perspectives in constructive dialogue, this study contributes to a richer ecumenical understanding of psychedelic spirituality within Christianity. Full article

While prior research links psychedelic use to improved psychological outcomes, less is known about whether psychedelic exposure relates to engagement with formal mental health care when treatment is recognized as needed. Using publicly available, de-identified pooled data from the National Survey on Drug Use and Health (2008–2019), this study examines whether lifetime psychedelic use is associated with missed needed mental health treatment and whether psychedelic exposure moderates the relationship between psychological distress and unmet care, with attention to gender differences. Regression analyses indicate that psychedelic use is not independently associated with lower odds of missing needed treatment once psychological distress is accounted for. However, psychedelic exposure is associated with a weaker relationship between distress and missed care: as psychological distress increases, individuals with prior psychedelic use—particularly men—exhibit a smaller increase in missed needed treatment compared to non-users. Gender-stratified analyses show that this buffering pattern is evident for men across multiple substances, whereas among women, only MDMA demonstrates a comparable moderating effect. These findings suggest that psychedelic use does not uniformly increase engagement with mental health care but is associated with gendered differences in how psychological distress translates into disengagement. Situated within the Medical Sociological and Social Epidemiological Psychedelics Paradigm, the results highlight how structural inequality shapes the behavioral translation of psychedelic experiences, producing diminished returns for women despite comparable levels of distress. Full article

Mystical experiences are characterized by a profound sense of interconnectedness and transcendence of ordinary reality. These experiences can facilitate feelings of connectedness with oneself and others and have been documented as leading to significant positive changes in thoughts, emotions, and behavior. The purpose of the present study was to evaluate the extent to which the four mindfulness facets of psychological flexibility (i.e., experiential acceptance, present-moment awareness, cognitive defusion, and self-as-context) were associated with self-reported mystical experiences while controlling for established covariates. Using a sample of 150 individuals recruited online, a regularized regression with an elastic net—a computationally efficient machine learning algorithm—was used to model the relationships among mystical experiences, State of Surrender, frequency of psychedelic use, near-death experiences, and facets of psychological flexibility. State of Surrender, experiential acceptance, cognitive defusion, and present-moment awareness emerged as the most robust predictors of mystical experiences. Collectively, these findings underscore the role of psychological processes, including surrender-related processes and facets of psychological flexibility, in predicting mystical experiences. Full article

Autism Spectrum Disorder (ASD) is a lifelong condition marked by challenges in social communication and repetitive behaviors. Current treatments, primarily behavioral therapies, often fail to address the core symptoms. Recent research has explored the potential of psychedelics, such as LSD, psilocybin, and MDMA, as a new therapeutic approach. While these substances primarily modulate the serotonin 5-HT_2A receptor, their therapeutic effects also involve interactions with other serotonergic, dopaminergic, and glutamatergic pathways, collectively promoting neuroplasticity—the brain’s ability to change and adapt. The specific receptors’ activation leads to structural and functional changes in the brain that can enhance social behavior and emotional regulation. Studies show that psychedelics may reduce symptoms of conditions like treatment-resistant depression and PTSD, highlighting their therapeutic potential. For ASD specifically, psychedelics may improve psychological flexibility, reduce distress, and enhance social interaction. While promising, the use of these substances requires careful consideration. Psychedelics can induce intense experiences and altered states of consciousness, necessitating strict monitoring and support during therapy. Ethical guidelines, including informed consent, are crucial, especially for vulnerable populations. In conclusion, psychedelics hold significant promise for treating ASD and other psychiatric disorders by promoting neuroplasticity and modulating complex signaling pathways. Continued research and clinical trials, conducted with strong ethical oversight, are essential to realizing their full therapeutic potential. 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

The use of ketamine for the management of neuropsychiatric conditions outside clinical settings has rapidly expanded, creating a critical need to understand diverse individual experiences. We conducted a qualitative content analysis of posts from the r/TherapeuticKetamine subreddit. From 3302 threads, the 500 highest-engagement threads (12,852 comments) were analyzed by independent coders across six domains: perceived positive effects, adverse effects, reasons for use, route of administration, polydrug use, and dose amounts. Mood-related concerns were the primary reason for use (53%). Users reported positive effects, most often improvements in emotional well-being (65%). Adverse effects were predominantly psychological or mood-related (56%). A total of 70% of reported doses exceeded 149 mg, suggesting a trend toward higher dose use. Intravenous administration (40%) and sublingual troches (23%) were the most frequently reported routes. Concurrent use of prescribed psychotropics, cannabis, and psychedelics was also reported. This analysis identified substantial heterogeneity in individual-reported experiences. Frequent high-dose use, dose escalation, and polydrug exposure underscores the importance of clinical monitoring and attention to addiction potential and drug–drug interactions. The findings should be interpreted with caution, as follow-up and clinical verification were not possible; however, the data provide an unfiltered view of individual experiences in relation to ketamine use outside the clinical setting. Full article

The clinical renaissance of psychedelic medicine has highlighted the therapeutic potential of rapid-acting neuroplastogens, or “psychoplastogens,” for psychiatric disorders. However, the widespread application of classical psychedelics—such as psilocybin and LSD—and the atypical dissociative ibogaine is severely limited by their hallucinogenic properties and, particularly in the case of ibogaine, life-threatening cardiotoxicity. Addressing these limitations, Tabernanthalog (TBG) has emerged as a frontrunner in the field. This non-hallucinogenic analog of ibogaine was rationally designed to eliminate interactions with the human ether-à-go-go-related gene (hERG, KCNH2) potassium channel, thereby mitigating cardiotoxic risks. While initially characterized for its anti-addictive and antidepressant-like properties, recent data from 2024–2025 have significantly expanded its therapeutic horizon. TBG demonstrates robust efficacy in preclinical models of neuropathic and visceral pain, as well as in the rescue of cognitive deficits associated with cancer-related cognitive impairment (CRCI). TBG has shown efficacy in reversing cognitive impairments induced directly by the presence of a tumor in preclinical models, rather than by chemotherapy-specific neurotoxicity. Crucially, emerging evidence suggests that TBG’s mechanism extends beyond simple 5-HT2A receptor agonism. New findings point to a multi-target profile involving the inhibition of nicotinic acetylcholine receptors (nAChRs), positive modulation of NMDA receptors, and functional crosstalk with mGlu2 receptors. Furthermore, TBG appears to induce structural neuroplasticity without the widespread induction of immediate early genes (IEGs) seen with classical hallucinogens, suggesting a decoupling of therapeutic rewiring from the subjective psychedelic experience. This review synthesizes current preclinical evidence to discuss TBG as a promising chemical scaffold for next-generation neurotherapeutics targeting the intersection of psychiatry and neurology. Full article