Search Results (240)

Eating disorders (EDs) remain challenging to treat, with high dropout and low remission rates in cognitive-behavioral therapy for EDs (CBT-ED). Psilocybin treatment (PT) demonstrates therapeutic potential to enhance CBT-ED by exerting several neurobiological, psychological, and experiential effects (e.g., antidepressant, neuroplasticity, emotional openness) that are hypothesized to increase psychotherapeutic engagement, reduce dropout, and improve clinical outcomes. This narrative review provides the first consolidation of theoretical evidence for PT/CBT-ED, proposes considerations for a concurrent intervention protocol, and presents clinical and research considerations to empirically test its feasibility, safety, and efficacy. This line of inquiry is expected to advance the development of approaches that improve ED treatment outcomes and, more broadly, advance the study of psychedelics as tools to enhance evidence-based psychotherapy models. 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

In recent years, psychopharmacology has experienced a significant challenge, highlighting a renewed and strong scientific interest in psychedelics as breakthrough therapies for mental disorders. Psychedelics can influence cognitive and emotional processes, showing solid therapeutic potential, particularly in treatment-resistant psychiatric disorders. Amongst the most promising compounds, ayahuasca and its main psychoactive component, N,N-dimethyltryptamine (DMT), have received considerable attention. Ayahuasca is a psychoactive brew traditionally prepared from the liana Banisteriopsis caapi and the leaves of Psychotria viridis. Its psychoactive properties derive mainly from DMT, while β-carbolines, which act as monoamine oxidase-A (MAO-A) inhibitors, prevent the metabolic degradation of DMT, enhancing its bioavailability and allowing oral administration. In contrast, in monotherapy, DMT or its analog 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is generally administered via alternative routes, like inhalation, intranasal, or intravenous delivery. DMT is primarily a serotonin (5-HT)2A receptor partial agonist, whereas 5-MeO-DMT has a higher affinity for the 5-HT1A receptor compared to 5-HT2A, though other receptor targets are engaged, fostering neuroplasticity and a reorganization of brain networks involved in perception, cognition, and mood regulation. Despite limited clinical trials, current evidence offers an optimistic outlook on DMT and 5-MeO-DMT efficacy for treatment-resistant depression (TRD) and major depressive disorder (MDD), whereas evidence for other mental disorders studies is still preliminary. There are four phase II studies with 5-MeO-DMT and one with DMT for TRD, while there are two phase II studies with DMT fumarate for MDD. Beyond their therapeutic potential, psychedelics also represent powerful tools for exploring the human mind, offering valuable insights into brain function and mental health. Full article

Background: The quality and valence of psychedelic experiences are influenced by a range of psychological and contextual factors. This study examines baseline mood and the “relational triad”—comprising social connectedness, mindfulness, and spirituality—as potential predictors of the quality of naturalistic psychedelic experiences. Methods: Data were drawn from the Predicting Responses to Psychedelics dataset, a longitudinal study tracking 654 individuals planning to take a psychedelic substance. Participants completed self-report measures at five time points, before and after ingestion. Baseline mood (depression, anxiety, and wellbeing) and relational triad factors were assessed at Timepoint 1, while acute psychedelic experience quality was measured at Timepoint 3 using validated scales (MEQ-30, CEQ, and ASC). Results: Mystical and challenging experiences were weakly but positively correlated. Baseline depression and anxiety were predictive of more challenging experiences but not of mystical-type experiences, while baseline wellbeing predicted more mystical and less challenging experiences. Mindfulness and spirituality were positively associated with mystical experiences, while social connectedness and mindfulness were inversely associated with challenging experiences. Conclusions: These findings extend previous research by demonstrating that baseline psychological and relational factors shape the nature of psychedelic experiences. Full article

The neuropharmacology of psychedelics has traditionally focused on serotonergic mechanisms, particularly 5-HT2A receptor activation. However, this paradigm incompletely explains the diversity of neurobiological and therapeutic effects observed across psychedelic compounds. Non-classical psychedelics such as salvinorin A, the primary active constituent of Salvia divinorum, challenge this framework through direct kappa opioid receptor (KOR) agonism, representing a serotonin-independent pathway to altered consciousness. This review systematically examines the role of the endogenous opioid system in mediating psychedelic effects, with emphasis on salvinorin A’s unique KOR-dependent mechanisms. We synthesized preclinical and clinical evidence from in vitro studies, genetically modified animal models, optogenetic circuit dissection, and human neuroimaging trials. Salvinorin A’s selective KOR activation is characterized by pronounced β-arrestin-biased signaling, distinguishing it from endogenous dynorphins and classical KOR agonists. This produces rapid receptor desensitization, transient functional plasticity, and profound dissociative effects mediated through thalamocortical disruption, mesolimbic dopaminergic suppression, and fragmentation of large-scale brain networks. Classical serotonergic psychedelics indirectly engage opioid systems through downstream 5-HT2A signaling, contributing to analgesic and mood-regulatory effects via secondary MOR/DOR modulation. Despite being a potent opioid agonist, salvinorin A exhibits low abuse potential due to aversive phenomenology, dopaminergic suppression, and absence of positive reinforcement in animal models. Incorporating opioid receptor pharmacology into psychedelic neuroscience expands mechanistic understanding beyond serotonin-centric models, revealing multiple neurochemical pathways capable of inducing therapeutically relevant altered states. This framework enables rational development of biased KOR ligands and establishes salvinorin A as a paradigmatic model for non-serotonergic psychedelia with applications in treatment-resistant depression, addiction, and chronic pain. Full article

This study assessed the correlates of cannabis and psychedelic use and legalization support among young adults in the United States (US). Using 2025 data among adults ages 18–34 (n = 3227), we assessed cannabis and psychedelic message exposure and perceptions, mental health symptoms (Patient Health Questionnaire-4 [PHQ-4]), and adverse childhood experiences (ACEs) in relation to past-6-month cannabis use (40.5%), past-year psychedelic use (11.9%), and legalization support. Relative to cannabis, psychedelics showed less legalization support, promotional and risk-message exposure, and social acceptability and higher perceived addictiveness and harm (p’s < 0.001). Factors associated with cannabis use and greater legalization support included: lower perceived addictiveness (aOR = 0.88, CI = 0.83–0.93; B = −0.04, SE = 0.01) and harm (aOR = 0.75, CI = 0.71–0.80; B = −0.16, SE = 0.01), higher social acceptability (aOR = 1.25, CI = 1.19–1.33; B = 0.19, SE = 0.01), and higher PHQ-4 (aOR = 1.04, CI = 1.01–1.07); more ACEs (aOR = 1.10, CI = 1.06–1.14) and more promotional (aOR = 1.08, CI = 1.01–1.17) and risk-message exposure (aOR = 1.27, CI = 1.17–1.39) were associated with use. Factors associated with psychedelic use and greater legalization support included: more promotional-message exposure (aOR = 1.61, CI = 1.36–1.91; B = 0.09, SE = 0.04), lower addictiveness (aOR = 0.87, CI = 0.78–0.97; B = −0.03, SE = 0.02) and harm (aOR = 0.74, CI = 0.66–0.82; B = −0.19, SE = 0.02), higher acceptability (aOR = 1.59, CI = 1.47–1.73; B = 0.15, SE = 0.01), and higher PHQ-4 (aOR = 1.06, CI = 1.02–1.11; B = 0.02, SE = 0.01); more risk-message exposure (aOR = 1.29, CI = 1.08–1.54) and ACEs (aOR = 1.15, CI = 1.09–1.21) were associated with use. Perceptions and mental health may influence cannabis and psychedelic use and legalization support, and message exposure may be particularly relevant in shaping psychedelic use and legalization support. Thus, information is crucial to ensure population understanding of the risks, benefits, and overall population impacts of cannabis and psychedelic use and legalization. Full article

Glaucoma is increasingly recognized as an ischemic neurodegenerative disorder that extends beyond elevated intraocular pressure (IOP) to involve complex vascular, metabolic, and inflammatory mechanisms. Retinal ganglion cells are particularly vulnerable to ischemia–reperfusion injury, oxidative stress, and chronic neuroinflammation, leading to progressive disconnection from central visual pathways. Current therapies primarily target IOP reduction but fail to address ischemia-driven neurodegeneration or to restore lost neuronal connectivity. Ischemia triggers excitotoxicity, oxidative stress, and a maladaptive inflammatory response involving activated microglia and astrocytes, perpetuating neuronal injury and suppressing intrinsic regenerative capacity. Thus, restoring neural plasticity and mitigating neuroinflammation represent key unmet therapeutic needs. Psychoplastogens are a class of compounds capable of rapidly enhancing structural and functional neuroplasticity and have recently emerged as promising multitarget agents. Compounds such as ketamine, psilocybin, N,N-dimethyltryptamine (DMT), and some newly synthesized non-hallucinogenic analogs act through convergent signaling pathways involving BDNF–TrkB–mTOR, promoting dendritic growth, synaptogenesis, and glial modulation. Beyond their neurotrophic effects, psychoplastogens seem to exert potent immunomodulatory actions. In this review we will explore the interplay between ischemia, neurodegeneration, neuroinflammation, and impaired plasticity in glaucoma, integrating mechanistic insights from cerebral ischemia. We discuss emerging preclinical evidence supporting psychoplastogens as neurorestorative and anti-inflammatory agents, propose their potential application in ocular ischemic neurodegeneration, and outline translational challenges for future studies. Full article

Modern advances in artificial intelligence have accelerated the development of computational tools for protein–ligand structure prediction, yet their real-world performance remains uneven across receptor classes and ligand chemotypes. Recently published cryo-EM structures of several different psychedelics bound to the serotonin 5HT_2A receptor provide a unique opportunity to explore how modern AI-based modeling performs in a pharmacologically important GPCR system. Here, we compare three major approaches: AI-based protein–ligand cofolding (Boltz-2), a leading AI-driven docking module (Uni-Mol Docking v2), and a widely used classical physics-based docking pipeline (AutoDock Vina) across a series of tryptamine and phenethylamine psychedelics. Predicted binding poses were comparatively assessed through structural alignment with these newly available cryo-EM complexes. Additionally, calcium-mobilization assays were performed to provide a coarse functional readout for comparison with computationally predicted binding affinities. This study integrates methodological review with exploratory benchmarking to illustrate how different modeling paradigms behave on a shared receptor–ligand test set. Our results highlight substantial variation between modeling strategies, with AI-based cofolding often producing global binding orientations more closely resembling experimental structures, and classical docking showing greater variability across ligands, while still outperforming AI-driven docking on average. These observations underscore both the growing utility and current limitations of AI-assisted structure prediction in serotonergic drug discovery, and emphasize the importance of careful, experimentally anchored evaluation as such tools continue to advance. 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

Interest in psychoactive substances, including psychedelics, is rapidly expanding in medical, academic, and other popular fields. Despite the classifications established within the psychopharmacological scientific community, certain plants, animals, and fungi, as well as the substances obtained from them, have been misclassified by both the media and academic circles. This opinion piece aims to present arguments to answer the following question: Is CBD a non-psychoactive phytocannabinoid? Hundreds of robust scientific studies published in recent years involving CBD have strengthened its clinical use in the treatment of seizures, anxiety, psychosis, schizophrenia, post-traumatic stress disorder, and addiction. As part of the arguments to answer the question posed, this text provides a historical overview of the classifications of psychoactive substances available to date, and offers reflections on these terminologies and a proposed classification of psychedelics. 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

A total of 250 known and novel compounds—ketamine and serotonergic psychedelics or their analogues—designed to target depression, addictions and/or other mental or neurological disorders and developed as “recreational” (illegal) drugs from three chemical families, ergolines, tryptamines and phenylethylamines, were investigated in the context of their ability to cross the human placenta. Using a novel multivariate model involving compounds’ drug-likeness (according to Lipinski’s Ro5), caco-2 membrane permeability, fraction unbound to plasma proteins, steady-state volume of distribution and the total count of heteroatoms (non-carbon atoms with hydrogens included), it was established that the majority of studied compounds are likely to cross the placenta easily, most probably by the passive diffusion mechanism. Atomic contributions of structural elements of studied compounds were investigated using the Morgan fingerprinting algorithm and it was postulated that the fragments promoting transport of compounds across the placenta are carbonyl, hydroxyl, nitro- and phosphoryloxy groups—rigid polycyclic structures, bulky alkyl/aryl groups and halogen atoms restrict the trans-placental passage. All studied compounds are expected to be relatively easily obtained by synthetic routes, which makes them an interesting target for manufacturers of illegal drugs and warrants the need to pursue pharmacological studies of these compounds in silico. 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

For more than four decades, the emphasis in the academic study of world religions has been on differences over similarities, and comparative analyses allowing for commonalities have become increasingly rare. This article argues that similarities nonetheless exist and should be studied. After disclaiming the judgment of other scholars that Aldous Huxley attempted to describe the “core” or “essence” of mystical experience, the article continues with a description of Huxley’s unitive mystical experience as simply a thread running across the traditions, evidenced by the fact that it is often found in both the primary and secondary literature of mysticism. The essay then goes on to cite descriptions of unitive experiences in research studies with psychedelics. Given that these experiences regularly occur with psilocybin and other drugs, as studies show, the article argues that the use of psychedelics is currently providing a rich source of experiential reports from which scholars of mysticism may glean insights. Furthermore, based on the views of Huxley, and supported by the reports of Roland Griffiths, Jussi Jylkka, David Yaden, William Richards, Julie Holland and others, the article speculates about the possible benefits of unitive mystical experiences triggered by psychedelics for both the individual and society. Full article