Low-dose psychedelics have shown potential in modulating chronic pain in humans, yet their application in veterinary medicine remains unexplored. This study protocol proposes to investigate the therapeutic potential of low-dose oral administration of 1-cyclopropionyl-D-lysergic acid diethylamide (1cp-LSD), a legal LSD analogue in certain countries, for the management of chronic pain in privately owned dogs with osteoarthritis. The study will employ a randomized, placebo-controlled design with caregivers blinded to treatment allocation. A cohort of about 24 dogs previously diagnosed with osteoarthritis, will orally receive sub-perceptual, intermittent doses of 1cp-LSD over a 30-day period, while maintaining their standard analgesic regimens to safeguard animal welfare. Outcome measures will include the Canine Brief Pain Inventory and caregiver-reported assessments, including the Treatment Expectation Questionnaire (TEX-Q), to evaluate both pharmacological efficacy and the influence of caregiver expectations as an indirect indicator of placebo effects as a secondary aim. The study anticipates a reduction in pain scores among treated dogs, potentially modulated by caregiver expectations. However, the sustained effect of 1cp-LSD in osteoarthritis remains uncertain due to interactions with inflammatory mediators. Limitations include the lack of established dose-response relationships, small cohort size, and variability in caregiver perceptions, which will be analyzed descriptively. The protocol establishes a comprehensive and methodologically framework to evaluate both the pharmacological therapeutic effects of low-dose psychedelics in managing chronic osteoarthritic pain and the psychological factors that may influence perceived outcomes.

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.

3-(2-Aminopropyl)benzo[b]thiophene (3-APBT), 5-APBT, and 6-APBT are recently identified psychedelics and entactogens that activate serotonin 2 receptor subtypes and lead to a head-twitch response in mice. The present study characterized their toxicokinetics, metabolism, and monoamine oxidase (MAO) inhibition using liquid chromatography-high-resolution tandem mass spectrometry. Metabolites were tentatively identified in urine from male Wistar rats collected over 24h after oral administration (2mg/kg body weight) and in incubations with pooled human liver S9 fraction (25µM after 1 and 6h). Phase I isoenzyme mapping and MAO inhibition were assessed using individual incubations with 11 human monooxygenases or recombinant human MAO-A and MAO-B. Hydroxylation was the predominant phase I biotransformation, primarily catalyzed by cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A4, and CYP3A5, while N-acetylation, glucuronidation, and sulfation were observed as phase II reactions. The metabolic patterns were similar to those of related 5- and 6-(2-aminopropyl)benzofuran analogues, and the involvement of multiple CYP isozymes suggested a reduced toxicity risk e.g., by CYP-mediated drug-drug interactions. However, all three APBT isomers strongly inhibited MAO-A (IC₅₀ of 5-APBT 0.4µM, 6-APBT 0.6µM, and 3-APBT 4µM) but only weakly MAO-B (IC₅₀ 23-49µM). Given that the MAO-A inhibition strengths of 5-APBT and 6-APBT were in the range of model inhibitors, clinically relevant MAO-A inhibition and associated interaction risks and toxic effects cannot be excluded. These data provide a toxicokinetic basis to support the clinical and forensic interpretation of exposures to APBT and related sulfur-based psychedelics.

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by motor and vocal tics and frequently accompanied by comorbidities such as obsessive-compulsive disorder (OCD) and pathological aggression. Although approved pharmacotherapies often reduce tic severity, they frequently cause adverse effects and are insufficient for managing comorbid symptoms, underscoring the need for improved treatments. Recent evidence indicates that the serotonin 5-HT _2A receptor (5-HT _2A R) antagonist pimavanserin reduces tic severity and improves quality of life, yet its mechanism of action in TS remains unclear. Here, we combine postmortem human and preclinical approaches to gain insight into the role of 5-HT _2A Rs in TS. Western-blot analyses of postmortem prefrontal cortex (PFC) samples obtained from individuals with TS revealed a pronounced, male-specific elevation of 5-HT _2A R protein levels in Brodmann Area (BA) 10. We then tested pimavanserin and the selective 5-HT _2A R antagonist volinanserin in two mouse models of TS: D1CT-7 transgenic mice and mice with early-life depletion of striatal cholinergic interneurons. Systemic administration of pimavanserin (1-2 mg·kg⁻¹, IP) or volinanserin (0.1-0.3 mg·kg⁻¹, IP) robustly reduced tic-like movements and stereotypies in both models. Local infusion of pimavanserin into the medial PFC, but not the dorsal striatum, recapitulated these effects, indicating a cortical locus of action. Pimavanserin also reduced resident-intruder aggression, but not locomotion or anxiety-like behavior. Together, these findings identify elevated prefrontal 5-HT _2A Rs as a key mechanistic contributor to TS and a promising therapeutic target for individuals with TS and pathological aggression.

Classic psychedelic studies involve interpersonal interactions with participants before, during, and after the acute effects of psychedelics. In the field of psychedelic research, there is currently a debate about whether this interpersonal interaction is most accurately considered "psychological support," "psychotherapy," or something else. Proponents of the psychological support label describe the interpersonal interaction in most classic psychedelic studies as aimed at safety, while proponents of the psychotherapy label argue that the interpersonal interaction involves intervening on psychotherapeutic processes that not only support safety, but also contribute to treatment efficacy. However, we believe that the debate has so far been largely unproductive due to a lack of shared definitions or criteria for the relevant interpersonal interactions. Here, we propose definitions and criteria for two viable forms of interpersonal interaction in psychedelic administration: one directed solely towards safety (psychological support) and one directed towards both safety and efficacy (psychotherapy). We then trial our proposed criteria on a sample of 11 published classic psychedelic clinical trials. Our procedure categorized 10 out of 11 studies as being more or less consistent with psychological support or psychotherapy, but achieved clear distinctions in only 4 out of 11 studies. Given these findings, we argue that higher quality data on the interpersonal interaction is needed to clearly distinguish between psychological support and psychotherapy. We conclude by suggesting ways that our criteria can be used in the future to empirically test the relative safety and efficacy of psychological support vs. psychotherapy in psychedelic medicine.

PURPOSE: Cocaine abuse is a major public health concern and is often associated with acute hyperthermia, which can be fatal and has limited pharmacological interventions for its management. Although antidepressants are frequently prescribed to cocaine users, particularly to those with comorbid depression, their safety within this context remains unclear, as some can exacerbate the toxicity of cocaine. This study aimed to evaluate the effects of various antidepressants on cocaine-induced hyperthermia in rats to identify safer treatment options.

SUBJECTS AND METHODS: Adult male Wistar rats received intraperitoneal injections of cocaine (30 mg/kg) following pretreatment with one of the following antidepressants: mirtazapine, fluoxetine, venlafaxine, amitriptyline, or moclobemide. To elucidate the mechanism underlying the effects of mirtazapine, the selective 5-HT2A receptor antagonists ketanserin and ritanserin were also tested. Rectal temperature was measured every 30 min for up to 240 min after cocaine administration.

RESULTS: Cocaine administration significantly elevated body temperature in control rats. However, pretreatment with mirtazapine significantly suppressed this hyperthermic response, presumably via central 5-HT2A receptor antagonism. Ketanserin and ritanserin similarly suppressed hyperthermia, supporting this proposed mechanism. In contrast, moclobemide exacerbated the hyperthermia, venlafaxine prolonged the hyperthermic response, and fluoxetine and amitriptyline had no significant effect on the hyperthermic response.

CONCLUSION: Mirtazapine may be a safer antidepressant option for managing depression in cocaine users because of its capacity to suppress hyperthermia without enhancing monoamine reuptake inhibition. Notably, caution should be exercised when prescribing monoamine oxidase inhibitors and SNRIs to this population. However, further clinical studies are required to validate these findings.

OBJECTIVE: Anxiety is common in patients receiving end-of-life care and significantly impacts their quality of life. However, pharmacological management remains challenging due to complex clinical presentations and potential side effects, emphasizing the need for systematically reviewing existing treatments. Here we aim to systematically evaluate the efficacy and safety of pharmacological treatments for anxiety in end-of-life care.

DESIGN: Systematic review following PRISMA guidelines, prospectively registered in PROSPERO (CRD42024556913). Comprehensive searches were performed in PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. Eligible studies included adults receiving end-of-life care and evaluated pharmacological interventions targeting anxiety.

RESULTS: Five studies met inclusion criteria: two assessing benzodiazepines combined with opioids and three evaluating psilocybin. Both benzodiazepine-opioid combinations and psilocybin reduced anxiety symptoms. Psilocybin studies reported rapid and sustained anxiety relief, with approximately 60%-80% of participants experiencing clinically significant improvements. Both treatment categories showed good tolerability without serious adverse events. However, the evidence base was limited by small sample sizes and narrow study contexts.

CONCLUSIONS: Benzodiazepine-opioid combinations and psilocybin show promise for anxiety relief in end-of-life patients. Nevertheless, limited high-quality evidence highlights an important research gap. Further robust clinical trials are needed to confirm these findings and guide clinical practice in palliative care.

The aging process is associated with gradual cognitive decline resulting from deficits in synaptic plasticity, the brain's natural ability to adapt and reshape its neural circuitry. This review highlights the importance of synaptic plasticity in cognitive function. It provides a full overview of the molecular, cellular, and systemic mechanisms involved in enhanced or diminished synaptic plasticity in the aging brain. We also go over issues in neurotransmitter systems, calcium signaling, neurotrophic support (ex., BDNF-TrkB), cellular signaling pathways (e.g. mTOR, CaMK, CREB, and MAPK/ERK), and neuroinflammation, oxidative stress, and vascular integrity, all of which redirect the trajectory of synaptic failure associated with cognitive decline in aging. Therapeutic approaches toward increasing or restoring synaptic plasticity are evaluated, including pharmacological (e.g., nootropics, cholinesterase inhibitors, NMDA receptor modulators), natural (e.g., curcumin, resveratrol, bacoside A), and new interventions (e.g., psychoplastogens, gene therapy, nanocarriers, and digital therapeutics). Lifestyle approaches, especially physical exercise, cognitive training, intermittent fasting, and mindfulness approaches to stimulation, have highly potent effects on plasticity enhancements and employ multiple neurobiological mechanisms. Despite much promise, there remain substantial translational challenges, including limited clinical efficacy, lack of personalized biomarkers, and ethical considerations concerning cognitive enhancement. As we look ahead, a multidisciplinary integrative approach that includes molecular therapeutics, lifestyle interventions, and next-generation neurotechnologies will be most useful for protecting cognitive health and enhancing brain resilience in aging individuals. This review highlights the immediate necessity for personalized, ethical, and evidence-based approaches to take advantage of synaptic plasticity for healthy cognitive aging.

Psilocybin, a naturally occurring psychedelic compound, has received attention as a novel therapeutic option for major depressive disorder (MDD), particularly in cases where traditional treatments prove ineffective. The study aims to evaluate psilocybin's therapeutic potential by examining its efficacy, safety, and mechanisms of action as well as addressing the societal and regulatory challenges that hinder its broader application. Key objectives include understanding how psilocybin alleviates depressive symptoms, investigating its neurobiological effects, and identifying gaps in current research. The methodology involved analyzing clinical studies conducted between 2014 and 2024, focusing on psilocybin as an intervention, either independently or in conjunction with psychotherapy. Evidence from these studies demonstrates that psilocybin acts on serotonin 5-HT2A receptors, enhancing neuroplasticity and brain connectivity to yield rapid and sustained symptom relief. Despite these promising findings, the use and study of psilocybin remains restricted due to its classification as a Schedule I substance in many countries. Legal prohibitions and societal stigma have significantly delayed progress in exploring psilocybin's therapeutic applications. The findings highlight psilocybin's potential to transform MDD treatment paradigms but emphasize the need to overcome regulatory barriers, conduct larger and more diverse studies, and establish long-term safety and efficacy data. Addressing these challenges is critical for integrating psilocybin into mainstream mental health care and unlocking its full therapeutic potential.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a debilitating condition leading to significant personal and societal burden. Standard treatments frequently demonstrate limited efficacy, leading to persistent symptoms and high dropout rates. Psilocybin has shown promise in treating depression, a condition that is often comorbid with PTSD. We aimed to explore participant experiences of psilocybin treatment for PTSD, emphasising the role of monitoring and support for safety, direct and indirect engagement with trauma-related material during psilocybin treatment, and differences between psilocybin and standard treatments.

METHODS: This qualitative study was nested within a quantitative, open-label phase 2 trial assessing the safety and tolerability of COMP360 psilocybin in adults with PTSD. Eligible participants were adults (18 years or older) who met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria for PTSD secondary to a traumatic event experienced in adulthood. Recruitment was conducted at three sites across two countries: two in the United States and one in the United Kingdom. Enrolled participants underwent standardised preparation, a single psilocybin administration session, and follow-up integration sessions. Semi-structured interviews were conducted before, the day after, and 12 weeks post-treatment. Data were analysed using reflexive thematic analysis, which is a distinct and theoretically grounded approach to co-construction of recurring themes pertaining to participants' preparedness for treatment, how participants' index trauma presented during treatment, and how psilocybin compared to standard treatments. The quantitative phase 2 trial, which the present qualitative study is nested within, is registered with ClinicalTrials.gov, NCT05312151.

FINDINGS: Between June 10, 2022, and Feb 12, 2024, 21 participants were enrolled and participated in this qualitative sub-study and completed the in-person qualitative interviews. The analysis revealed four core themes: (1) non-pharmacological factors for psychological safety and trust, (2) the experiential nature of psilocybin treatment, (3) engagement with trauma-related material during psilocybin treatment, and (4) comparative reflections on prior therapies and psilocybin treatment. Emphasising safety, treatment education, and informed consent, the treatment facilitated an experience of both direct and indirect engagement with trauma-related material during psilocybin treatment. Unlike standard treatments requiring direct confrontation with trauma memories, psilocybin appears to enable a broader, indirect engagement with traumatic material via a range of affective, somatic and self-transcendent experiences (e.g., moments of perceived unity, dissolution of self, or felt connection with a larger whole).

INTERPRETATION: Our qualitative findings suggests that psilocybin treatment, when administered with standardised preparation and treatment support, may offer a meaningful therapeutic opportunity for Patients with PTSD. Future work should include larger controlled studies and use mixed methods to explore how symptom change, functional outcomes, and patient narratives interact.

FUNDING: Compass Pathways, plc.

Psychedelics are a diverse class of psychoactive compounds that profoundly alter perception, cognition, and emotional states. Recently, classical serotonergic agents, such as psilocybin and lysergic acid diethylamide (LSD), along with atypical agents such as methylenedioxymethamphetamine (MDMA, ecstasy) and ibogaine, have attracted renewed attention due to their rapid and sustained clinical effects in psychiatric disorders. Preclinical and clinical studies indicate that serotonergic psychedelics acutely modulate glutamatergic and GABAergic transmission, enhance neuroplasticity, and reorganize brain network connectivity. However, a unified mechanistic framework linking these effects to enduring clinical outcomes remains elusive. Here, we propose a neurodevelopmental hypothesis in which psychedelics restore excitation/inhibition (E/I) balance, a fundamental property of both neurodevelopment and adult brain function. Acutely, psychedelics shift E/I dynamics through serotonergic and nonserotonergic mechanisms, creating a transient state of heightened plasticity similar to developmental sensitive periods. This permissive window facilitates the long-term reorganization of excitatory and inhibitory circuits with GABAergic interneurons as key mediators. By integrating established pharmacological effects with developmental principles, our dual-phase model links initial network excitability with subsequent neuroplasticity and circuit stabilization, providing a coherent framework for the rapid onset and sustained efficacy of psychedelic interventions across psychiatric disorders.

IMPORTANCE: The availability of psychedelic retreats has grown to meet the demand for access to these substances. Despite centuries of use among Indigenous communities, psychedelics can pose serious risks for some users.

OBJECTIVE: To determine safety precautions that retreat organizations that offer psychedelic substances currently use.

DESIGN, SETTING, AND PARTICIPANTS: This qualitative study included structured interviews conducted by phone or email with representatives from 49 organizations publicly advertising psychedelic retreat offerings from July to October 2023. Organizations were eligible if they marketed their services in English, offered at least 1 psychedelic substance, and made contact information available online. Organizations were selected using convenience sampling from a broader pool of organizations identified in a prior study. Data were analyzed from March 2024 to November 2025.

MAIN OUTCOMES AND MEASURES: The main outcomes of interest included the types of drugs offered and presence of polysubstance use, collaboration with health care professionals, presence of health care professionals during retreats, disqualifying conditions, medication washout procedures, and integration practices. Descriptive statistics were used to characterize organizational practices and locations; content analysis was used to categorize medical exclusion criteria, medication washout protocols, involvement of health care professionals, integration offerings, and training of integration facilitators.

RESULTS: Of 48 organizations that reported what substances they offered, all offered either ayahuasca, psilocybin, or both. Nineteen organizations (38.7%) offered more than 1 psychedelic substance. All organizations collected participant medical histories; 36 organizations (73.5%) excluded individuals with certain health conditions. Most (43 organizations [87.8%]) required or recommended medication washout for varying lengths of time, ranging from 1 day to more than 6 weeks. Most (34 organizations [69.4%]) worked with a licensed health care professional or someone with emergency response training, and 32 organizations (65.3%) had someone with those qualifications in attendance at retreats at least some of the time. All organizations offered some sort of integration support.

CONCLUSIONS AND RELEVANCE: This qualitative study of the practices implemented by psychedelic retreat organizations found substantial variability in the implementation of safety precautions. Some practices related to medication washout and polysubstance use may pose increased risks to participants. Best practice guidelines are needed and should be codeveloped with Indigenous and nonclinical communities.

Serotonin (5-hydroxytryptamine, 5-HT) has central roles enabling learning and memory, particularly via serotonin receptor 2A (5-HT_2AR) signaling. Drosophila Fragile X syndrome model (dfmr1 null mutant) studies reveal impaired learning and memory, which may reflect serotonergic signaling deficits. Here, we use classical olfactory T-maze conditioning to assess behavior, combined with imaging to assess 5-HT and 5-HT_2AR levels within the underlying Mushroom Body (MB) brain circuitry. Null dfmr1 mutants exhibit learning and memory deficits that are corrected by elevating 5-HT signaling via 1) overexpression of the serotonin biosynthetic enzyme tryptophan hydroxylase (Trhn) or 2) knockdown of the serotonin reuptake transporter (SERT). Direct comparisons reveal both Trhn and SERT manipulations equally restore learning and memory in dfmr1 null mutants. 5-HT_2AR levels in the MB circuit are reduced relative to controls in dfmr1 mutants, and 5-HT_2AR RNAi phenocopies dfmr1 null behavioral deficits, suggesting these phenotypes are primarily caused by the loss of 5-HT_2AR signaling. Consistently, 5-HT_2AR overexpression in dfmr1 nulls restores normal learning and memory compared to controls. These findings suggest loss of 5-HT_2AR signaling causes learning and memory deficits in this Fragile X syndrome model, and that rectifying this signaling impairment can restore learning and memory, providing a framework for serotonergic intervention strategies.

The resurgence in research with classic psychedelics (e.g. LSD, psilocybin) underscores their potential for improved well-being; however, the interpersonal context and mechanisms of psychedelic impacts remain unknown. In a sample of 798 participants (81 couples), this survey study tested whether use of a psychedelic with a romantic partner (v. not together) was associated with couples' shared understanding (i.e. shared reality) and changes in relational well-being. Multilevel dyadic analyses provided overwhelming support for hypotheses that taking a psychedelic together would be associated with greater shared reality and more positive relational changes (e.g. improved physical intimacy, emotional closeness, satisfaction). Shared reality mediated positive relational changes. Taking a psychedelic alone was indirectly associated with the decision to end a romantic relationship. Although limited by cross-sectional design and low dyadic participation, results emphasize the importance of a socially informed approach to the development of psychedelic therapies, with potential to increase treatment effectiveness and mitigate harms.

Small amounts of stress are thought to have beneficial effects. A new study reports a mechanism by which the psychedelic drug, psilocybin, causes acute release of stress hormones, despite its known long-term anti-anxiety effects.

BACKGROUND: Psilocybin has shown rapid and sustained antidepressant effects in patients with major depressive disorder, yet the neurobiological mechanisms underlying these outcomes remain unclear.

AIMS: This study aimed to bridge clinical and preclinical findings by investigating the relationships between 5-HT_2A receptor occupancy (RO) achieved after administration of psilocybin and its effects on behavior and markers of neuroplasticity in mice.

METHODS: In vivo 5-HT_2A RO was determined via displacement of [³H]MDL-100,907 in the prefrontal cortex (PFC). To relate RO with behavioral outcomes of psilocybin, we assessed the head twitch response (HTR) acutely and investigated behavior in the elevated zero maze (EZM) and forced swim test (FST) 20-24 hours post-drug. Neuroplastic changes were assessed by measuring α-tubulin post-translational modifications (PTMs) and expression of key synaptic proteins in both the PFC and amygdala.

RESULTS: Psilocybin produced dose-dependent 5-HT_2A RO (RO₅₀ = 0.88 mg/kg) and an inverted-U dose-response in HTR, with peak effects occurring between ~44% and 62% RO. Behaviorally, a 1.5 mg/kg dose increased the open areas ratio in the EZM, while 3 mg/kg reduced immobility in the FST, 20 and 24 hours after dosing, respectively. Both dose levels shifted α-tubulin PTMs toward a more dynamic microtubule state and selectively increased synaptic marker expression in the PFC, not in the amygdala.

CONCLUSIONS: These findings suggest that the therapeutic effects of psilocybin could be mediated by dose- and region-specific enhancement of neuronal plasticity, with distinct signatures associated with anxiolytic-like and antidepressant-like properties.

Psychedelics lead to profound changes in subjective experience and behaviour, which are typically conceptualised in psychological terms rather than corresponding to an altered brain state or a distinct state of vigilance. Here, we performed chronic electrophysiological recordings from the neocortex concomitant with pupillometry in freely moving adult male mice following an injection of a short-acting psychedelic 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). We report an acute induction of a dissociated state, characterised by prominent slow oscillations in the cortex and marked pupil dilation in behaviourally awake, moving animals. REM sleep was initially markedly suppressed, but was overcompensated in the subsequent 48 hours, while administration of 5-MeO-DMT immediately after sleep deprivation attenuated the subsequent rebound of sleep slow-wave activity. We argue that the occurrence of a dissociated state combining features of waking and sleep may fundamentally underpin the known and hypothesised effects of psychedelics - from dream-like hallucinations to reopening of the critical period for plasticity.

INTRODUCTION: Psychoactive mushroom edibles are gaining popularity, yet little is known of their clinical effects. These unregulated products are widely available, often with unlisted ingredients and inconsistent formulations, underscoring the need for more research to address public health concerns. We aimed to investigate recent trends in demographics and clinical effects associated with these products.

METHODS: We conducted a retrospective observational analysis of psychoactive mushroom edible exposures reported to the United States National Poison Data System® between 2023 and 2024. We included both single and polysubstance cases from all ages, using the generic codes identifying edible preparations containing Amanita muscaria, psilocybin, or unspecified. We described demographic and clinical characteristics (e.g., management site, related clinical effects) stratified by mushroom type. Our primary outcome was medical admission, and secondary outcomes were the severity of reported toxicity (moderate or worse compared to minimal or non-toxic exposures). Multivariable logistic regression, odds ratios, and 95% confidence intervals were used to measure the association between demographic and clinical factors with each outcome.

RESULTS: Of the 362 total psychoactive mushroom edible exposures identified, the majority were single-substance (78%) and intentional (58%). Factors associated with admission were polysubstance exposures (aOR: 2.58; 95% CI: 1.23-5.40), confusion (aOR: 3.06; 95% CI: 1.36-6.86), and central nervous system depression (aOR: 2.55; 95% CI: 1.29-5.06). These factors were also associated with moderate or worse toxicity (poly-substance exposure [aOR: 2.88; 95% CI: 1.35-6.13], confusion [aOR: 3.05; 95% CI: 1.14-8.13], and central nervous system depression [aOR: 4.92; 95% CI: 2.45-9.88]). No deaths were reported from exposure.

DISCUSSION: The effects of mushroom edible ingestion are unpredictable, and clinical presentations vary widely. Polysubstance exposures involving mushroom edibles are associated with higher hospital admission rates and more severe toxicity.

CONCLUSION: Psychoactive mushroom edibles are an emerging public health concern that necessitates continued epidemiological and clinical monitoring as the trend evolves.

This review aims to evaluate the pharmacological properties, mechanistic selectivity, and early clinical development of zalsupindole, highlighting its potential as a next-generation psychiatric therapeutic. This review was conducted using a structured literature search strategy across PubMed, Google Scholar, ClinicalTrials.gov, and the official Web sites of regulatory bodies and pharmaceutical developers. Searches included combinations of keywords such as "zalsupindole," "DLX-001," "AAZ-A-154," "non-hallucinogenic psychoplastogen," "5-HT₂A receptor," "biased agonism," "neuroplasticity," and "Delix Therapeutics." The inclusion criteria encompassed English-language publications between January 2019 and October 2025. Peer-reviewed articles, preclinical studies, clinical trial data, patents, regulatory documents, and officially released press materials were considered. Sources were excluded if they lacked relevance to zalsupindole's pharmacology, therapeutic positioning, or clinical development pathway. To ensure transparency, all sources have been categorized in-text according to type: Peer-reviewed literature is cited directly and forms the scientific backbone of the review. Gray literature, including press releases, conference posters, patents, and corporate briefings, is clearly identified and used only to provide supplementary context where peer-reviewed data are unavailable. No original research was conducted as part of this review. Peer-reviewed in vitro and in vivo studies confirm that zalsupindole promotes neuritogenesis and dendritic spine growth via 5-HT₂-dependent mechanisms; ketanserin abolishes these effects, and rapamycin-based inhibition studies suggest potential mTOR pathway participation in zalsupindole-induced plasticity. The compound demonstrates rapid brain penetration in rats, with no measurable 5-HT₂B agonism, no glutamate surge, and no head-twitch response, suggesting strong neuroplastic effects without hallucinogenic activity. In the forced swim test and VMAT2-deficient mouse models, single doses produced rapid and durable antidepressant-like effects. In Phase 1 clinical trials, oral zalsupindole was well tolerated across a dose range of 2-360 mg, with no reports of psychotomimetic effects. Pharmacokinetic assessments showed linear absorption/CNS penetration. EEG-based biomarkers revealed dose-dependent increases in power spectra associated with synaptic potentiation. The development of zalsupindole marks a significant step forward in neuropsychiatry. Its unique 5-HT₂A receptor biasing and safety profile position it as a potential treatment for mood disorders. Pending future results, zalsupindole could contribute to evolving treatment strategies in psychiatry.

Psilocybin-containing mushrooms, commonly known as magic mushrooms, strongly affect mood, cognition, and behavior. Psilocybe azurescens is a species of psilocybin mushrooms that contains the main active compounds psilocybin and psilocin. Psilocybin mushrooms have been used since ancient times to improve the quality of life. However, their adverse effects have been less studied. This study aimed to investigate, for the first time, the effect of oral consumption of P. azurescens on social behavior, anxiety- and depressive-like behaviors in rats. The underlying mechanisms of these behaviors were also studied. Male Wistar rats received three doses of P. azurescens (10, 100, and 250 mg/kg) by gavage every other day for 14 days. Social interaction, anxiety- and depressive-like behaviors were assessed using the three-chamber, elevated plus maze, and forced swimming tests, respectively. Protein levels of neurotrophic (BDNF and GDNF), neuroinflammatory (IL-6 and TNFα), and oxidative stress (ROS and SOD) factors were measured in the hippocampus, prefrontal cortex (PFC), and amygdala by ELISA technique. The results showed that P. azurescens significantly increased anxiety- and depressive-like behaviors and disrupted social interaction behavior in rats. These effects were accompanied by increased neuroinflammation and oxidative stress and decreased neurotrophic factors in the hippocampus, PFC, and amygdala. This study suggests that the high doses of P. azurescens can cause mood disorders by increasing inflammatory responses and oxidative stress and decreasing the expression of neurotrophic factors.

Bipolar disorder affects approximately 40 million individuals worldwide, with depression being the most prominent phase of the illness. Owing to limited treatment options, bipolar depression remains a major public health concern, often causing significant functional impairment and increased suicide risk. Current therapies frequently lack rapid effectiveness, highlighting the need for novel approaches. Psilocybin, a psychedelic compound receiving growing interest for its potential rapid antidepressant effects, is under investigation in clinical trials combined with psychotherapy. Early studies in bipolar II disorder (n = 19) show encouraging results, but evidence is still limited, and important safety concerns such as affective switching and pharmacokinetic interactions persist. Additional challenges include regulatory restrictions, infrastructure demands, and uncertainties about the role of the psychedelic experience, especially given possible interference by common bipolar medications. Cautious, rigorous research is essential to determine psilocybin's safety, efficacy, and practical application in bipolar depression, particularly for bipolar I disorder and long-term outcomes.

Psychedelic use has greatly increased within clinical and recreational settings over recent years. While demonstrating a favorable safety profile within certain clinical populations, little empirical research has explored safety of psychedelic use within real-world samples. Using the World Health Organization (WHO) VigiBase, a comprehensive global pharmacovigilance database with voluntary spontaneous reporting of adverse events (AEs) from real-world clinical and recreational populations, we examined reports for classic psychedelics and MDMA. Most reports were made for MDMA (n = 1573) and LSD (n = 394), while psilocybin (n = 56), DMT (n = 18), and mescaline (n = 15) had fewer reports. The most common AEs for all substances were psychiatric in nature, specifically surrounding substance or drug abuse and dependence. Reports of overdose constituted 1.1 to 1.7 % of total AEs. Pregnancy-related and congenital disorders were rare. Compared to the acetaminophen control, LSD and MDMA were associated with significantly greater odds for the reported AEs of alcohol abuse (LSD: ROR=45.7, 95 % CI: 27.2 - 76.9; MDMA: ROR=19.2, 95 % CI: 12.2 - 30.4), substance use disorder (LSD: ROR=71.1, 95 % CI: 36.3 - 139.2; MDMA: ROR=129.9, 95 % CI: 78.4 - 215.5) and substance dependence (LSD: ROR=215.1, 95 % CI: 69.0 - 670.3; MDMA: ROR=76.8, 95 % CI: 25.5 - 231.8). These reports were also greater than those associated with the external positive control, oxycodone. Taken together, this exploratory study provides the first analysis of AEs associated with psychedelics reported to a global pharmacovigilance database and can inform their real-world safety. Findings should be considered in light of limitations surrounding co-use of other substances and potential deterrence towards reporting use of illicit substances.

BACKGROUND AND RATIONALE: Lysergic acid diethylamide (LSD) is a promising therapeutic for psychiatric disorders, but its physiological profile on the nervous system remains elusive. Rodent electrophysiological data has utilized in vivo single-unit electrophysiology recordings, while clinical neurophysiology studies have focused on spectral signatures using electroencephalography (EEG) and magnetoencephalography (MEG). No study to date has examined these spectral signatures in freely moving mice. Studying neural activity when an animal is physically restricted (i.e. head-fixed recordings), is stressful to animals, which informed our decision to avoid this confound of additional physical stress on observed effects. Moreover, how LSD acutely modulates intracranial oscillatory rhythms is not known.

EXPERIMENTAL APPROACH: Here we present the first in vivo electrophysiological investigation of LSD's cortico-hippocampal effects in freely-moving male C57BL/6J mice using intracranial EEG (iEEG) recordings. We did not posit a hypothesis concerning the specific effects of LSD on power spectral density (PSD) due to the lack of preclinical literature as well as LSD's promiscuous pharmacological profile. This study was purely exploratory.

KEY RESULTS: Following intraperitoneal (IP) administration of 30 µg/kg LSD, there was a global decrease in PSD signal power in both broadband and discrete narrow band oscillatory rhythms of the ventral hippocampus CA1 and CA3 regions. Similar but less robust effects were observed in the somatosensory and medial prefrontal cortices. These data confer with the existing clinical neurophysiology data. Lastly, LSD increased between-subject PSD signal power variance, suggesting individual-specific effects.

CONCLUSION AND IMPLICATIONS: Our data lends further credibility to the entropic brain theory of psychedelic drug actions. We conclude that the intracranial acute spectral signatures of LSD coincide with their clinical counterparts. Further work is needed to study cross-regional connectivity, such as frequency coupling.

BACKGROUND: Several illicit drugs have been reported to be associated with ischemic stroke and myocardial infarction. However, the underlying mechanisms remain poorly investigated. In this study, we focused on N-Ethylpentylone (NEP), a synthetic cathinone with potent hallucinogenic property and explored its role in platelet activation.

METHODS: Platelet function assays and flow cytometry were used to evaluate the effects of NEP on platelet aggregation, spreading, clot retraction, and integrin αIIbβ3 activation. The role of the 5-Hydroxytryptamine2A receptor (5-HT2AR) in NEP-mediated platelet responses was investigated using the selective 5-HT2AR antagonist M100907 in both ex vivo and in vivo. Phosphoproteomics identified NEP-regulated phosphorylation sites, and Western blotting validated mitogen-activated protein kinase (MAPK) pathway activation by targeting key phosphorylation nodes.

RESULTS: NEP significantly potentiated platelet aggregation, spreading, clot retraction, and integrin αIIbβ3 activation in a concentration-dependent manner. The NEP potentiated platelet responses were suppressed by M100907 in both ex vivo and in vivo models, confirming the critical regulatory role of 5-HT2AR. Phosphoproteomics revealed NEP-triggered phosphorylation upregulation, enriched in MAPK pathways. Western blotting confirmed selective ERK and p38 phosphorylation, with no effect on JNK.

CONCLUSION: NEP directly enhances agonist-induced platelet activation by targeting 5-HT2AR on platelet membranes. The findings of this study provide valuable insights for elucidating the hematotoxic mechanisms of NEP and other illicit drugs.

INTRODUCTION: Psilocybin may effectively treat psychological distress in cancer patients. A meta-analysis assessed its safety and effectiveness in this context.

METHODS: A comprehensive search across six databases (Scopus, PsycINFO, PubMed, Cochrane, CINAHL Complete, and Web of Science) was conducted to identify studies on psilocybin's effects on mental health in cancer patients up to November 2024. Both randomized and non-randomized trials were included, assessing anxiety, depression, and other mental outcomes at short-term (2-5 weeks) and long-term (6 months) follow-ups. Study quality was assessed using Cochrane tools, and statistical analyses were performed with Stata version 17.

RESULTS: In randomized controlled trials (RCTs), psilocybin significantly reduced depressive symptoms, with the Beck Depression Inventory (BDI) (standardized mean difference [SMD] = - 2.87, 95% confidence interval [CI]: - 3.99 to - 1.76, p < 0.001) and the Hospital Anxiety and Depression Scale-Depression subscale (HADS-D) (SMD = - 2.97, 95% CI: - 3.60 to - 2.33, p < 0.001) showing strong effects. Anxiety outcomes were mixed: the Hospital Anxiety and Depression Scale-Anxiety subscale (HADS-A) was not significant (SMD = - 3.63, p = 0.11), while the State-Trait Anxiety Inventory (STAI) also showed inconsistent results. Short-term analyses (2-5 weeks) revealed significant improvements in the BDI (SMD = - 1.17), HADS-D (SMD = - 1.58), and HADS-A (SMD = - 1.99), all p < 0.001. Long-term analyses (6 months) demonstrated sustained benefits on the BDI (SMD = - 2.60, p = 0.04) and HADS-D (SMD = - 3.56, p = 0.01). Measures of quality of life (QOL) and spiritual well-being using the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being (FACIT-Sp) scale also improved significantly after psilocybin treatment.

CONCLUSION: Psilocybin may reduce depressive symptoms in cancer patients, with mixed effects on anxiety and time-dependent improvements in spiritual well-being and (in single-arm data) quality of life. Given the small number of studies, high heterogeneity, challenges with blinding/expectancy, and frequent co-intervention with psychotherapy, these findings are preliminary. Larger, rigorously blinded trials are needed to determine clinical effectiveness and safety.

Binge Eating Disorder (BED) is the most prevalent eating disorder and is associated with psychiatric comorbidities, health impairments, and decreased quality of life. Emerging evidence suggests that psilocybin-assisted therapy may promote cognitive and emotional flexibility and disrupt maladaptive behavioral patterns, making it a promising candidate for BED treatment. This open-label pilot study evaluated the feasibility, safety, and preliminary therapeutic effects of a single 25 mg dose of psilocybin administered in the context of Acceptance and Commitment Therapy (ACT)-based psychotherapy in adults with BED (N = 5). Primary outcomes included safety measures, and exploratory outcomes included self-reported binge eating frequency, depression, anxiety, psychological flexibility, anthropometric indices, and neuroimaging biomarkers assessed over a 14-week follow-up. Psilocybin was well tolerated, with no serious adverse events. Reductions in self-reported binge eating frequency were observed across all participants and sustained through week 14. Improvements were also noted in depression, anxiety, and psychological inflexibility. Three participants showed reductions in body mass index and waist circumference. Given the open label design and small sample size, causality cannot be inferred. fMRI analyses generated preliminary signals of change-such as increased functional activation from pre- to post-intervention in the middle frontal gyrus, angular gyrus, and supramarginal gyrus in response to processed versus unprocessed food cues. Psilocybin-assisted therapy was feasible and well-tolerated in individuals with BED. The clinical and neurobiological observations provide directions for future adequately powered trials.

BACKGROUND: Although psychedelics have regained attention as potential treatment tools for various mental disorders, little research has examined their impact on temporal perception.

AIMS: This double-blinded placebo-controlled study aimed to investigate changes in temporal perception under psilocybin, both through performance during the Temporal Bisection Task (TBT) and through subjective self-report scales.

METHODS: Twenty-four healthy volunteers were assessed by comparing their performance on two parameters of the TBT -the Bisection Point (BP) and the Just Noticeable Difference (JND) with subjectively reported changes measured using the Hallucinogen Rating Scale (HRS) and the Altered States of Consciousness (ASC) questionnaires.

RESULTS: We observed a rightward shift in BP under psilocybin compared to placebo (t(23) = 2.27, p = 0.033, g = -0.37). This shift corresponded to reports of subjective time slowing down under psilocybin as measured by HRS and ASC. Psilocybin also increased JND compared to placebo (t(23) = 2.48, p = 0.021, g = -0.47), indicating decreased temporal precision. Consistent with previous findings, these effects were significant for durations longer than 2 seconds.

CONCLUSIONS: Based on Bayesian framework of timing, we emphasised that psilocybin alters time perception through disruptions in cognitive functions, particularly working memory and attention. We also outlined directions for future research, which would allow us to not only understand time perception under psychedelics better, but help elucidate the role of serotonergic system on timing.Research ID:The research was conducted as part of a clinical trial registered at EudraCT database under the number 2012-004579-37.

The distinct subjective effects that define psychedelics such as lysergic acid diethylamide (LSD), psilocybin, or 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) as drug class are causally linked to the activation of the serotonin 2A receptor (5-HT_2AR). However, some aspects of 5-HT_2AR pharmacology remain elusive, such as what molecular drivers differentiate psychedelic from nonpsychedelic 5-HT_2AR agonists. We developed an ex vivo platform to obtain snapshots of drug-mediated 5-HT_2AR engagement of the canonical G_q/11 pathway in native tissue. This nonradioactive methodology captures the pharmacokinetic and pharmacodynamic events leading up to changes in inositol monophosphate (IP₁) in the mouse brain. The specificity of this method was assessed in homogenates from the frontal cortex in DOI-treated wild-type and 5-HT_2AR knockout (5-HT_2AR-KO) animals compared to other brain regions, namely, striatum and cerebellum. The effect of DOI on mouse frontal cortex IP₁ was time-bound, dose-dependent, and was correlated to head twitch response counts. We observed that IP₁ levels in frontal cortex homogenates from mice treated with LSD and lisuride varying in magnitude, consistent with LSD's 5-HT_2AR agonism and psychedelic nature and lisuride's lack thereof. 3,4-Methylenedioxymethamphetamine (MDMA) evoked an increase in the IP₁ signal in the frontal cortex that was not matched by the serotonin precursor 5-hydroxytryptophan or the serotonin reuptake inhibitor fluoxetine. We attribute the differences in the readout primarily to the indirect stimulation of 5-HT_2AR by MDMA via the release of serotonin from its presynaptic terminals. This methodology enables one to capture a snapshot of IP₁ turnover in the mouse brain that can provide mechanistic insights into the study of psychedelics and G_q/11-coupled receptors.

Nicotine dependence remains a leading cause of preventable mortality worldwide. Pharmacotherapy and behavioral interventions offer modest efficacy with limited long-term success. Psilocybin-assisted psychotherapy (PAP) is an emerging approach to nicotine cessation with a growing evidence base. As PAP research expands, understanding how nicotine users' attitudes shape treatment engagement becomes critical. We surveyed daily nicotine users (N = 534) to assess their perceptions and attitudes toward PAP versus standard cessation interventions. Point-biserial correlations and multiple linear regressions examined predictors of treatment interest and credibility. Findings suggest that familiarity with treatment options predicts perceptions of credibility for both interventions (standard: β = 0.16, p < .001; PAP: β = 0.36, p < .001). Credibility in turn predicted willingness to initiate both standard interventions (β = 0.34, p < .001) and PAP (β = 0.71, p < .001). Past psychedelic use influenced perceptions of (β = 0.16, p < .001) and willingness to initiate PAP (β = 0.10, p < .01). Motivation to quit predicted attitudes toward both treatment options (standard: β = 0.25, p < .001; PAP: β = 0.27, p < .001). Providers might leverage these findings to tailor educational materials to increase familiarity, potentially improving adherence and outcomes.

AIM: This study explores the justification for psychedelics use among 40 Finnish interviewees.

METHODS: We conducted and analyzed 40 thematic interviews with Finnish psychedelics users employing justification analysis as an analytical framework. The study investigates justifications as expressed by the users.

RESULTS: We found almost the full spectrum of Boltanski and Thévenot's justification logics represented in the interviewees' use justifications, with the exception of the logics of the market world. We formed an additional 'world of self' to capture justifications connected to various personal experiences, including pleasure, which is often overlooked in clinical research. The participants tended to make a distinction between the use of psychedelics and other drugs or intoxicating substances. The justifications employed ranged from personal level to societal level, and from spiritual to technological justifications. Overall, the justifications appeared largely influenced by the new wave of psychedelic research, self-experienced benefits and ideals of individualism. Reported positive effects included feelings of euphoria and other positive feelings, even when the use was motivated by self-development or self-medication.

CONCLUSIONS: The positive and more recreational aspects of psychedelics use are important for users and could be an essential part of the therapeutic benefits of psychedelics, which is often overlooked in the research.

Anxiety disorders are chronic health conditions affecting the quality of life of millions of people. Psilocin, the active moiety of psilocybin, provides an anxiolytic effect; however, when orally administered as psilocybin, it only offers a moderate level of bioavailability and less predictable pharmacokinetics, potentially making effects after absorption variable and increasing the risk of adverse hallucinations, depending on the dose. As such, we investigated a recently developed stable salt of psilocin, psilocin mucate (L-130), which delivers increased bioavailability and, thus, more precise control of therapeutic levels. We examined factors related to L-130's safety, as well as its effectiveness in addressing anxiety at a commonly used macro dose level, along with dosing schedules similar to those noted in the literature. Clinical assessments and blood analyses suggest psilocin mucate is safe and has no toxicological effects. Compared to vehicle controls, daily dosing of L-130 led to significant reductions in cortisol levels and improved performances on several anxiety-related behavioral tasks: the Elevated Plus Maze, the Open Field Test, and the Novel Object Recognition Task. However, weekly dosing did not generally produce significant results. Overall, daily dosing of L-130 was able to produce anxiolytic behaviors, but larger studies are needed to determine optimal doses and dosing schedules.

Drug repurposing in oncology can reduce the time and cost of new drug development. Studies suggest that depression influences tumor progression, and some antidepressants exhibit anti-tumor effects. This study evaluated the effects of serotonergic antagonists-tropisetron, imipramine, ketanserin, and cyproheptadine-on AGS gastric cancer cells. The half-maximal inhibitory concentration (IC50) values of drugs were determined after 48 h in AGS cells using the MTT assay. Cell cycle distribution and apoptosis were evaluated by flow cytometry. Morphological changes were observed by Acridine Orange/Ethidium Bromide staining. The wound-healing assay was used to assess the effects of the drugs on cell migration. Real-time PCR was used to measure the expression of 5-hydroxytryptamine (5-HT) receptors (5-HT2A, 5-HT2B, 5-HT3A), serotonin transporter (SLC6A4/SERT), apoptosis-related genes (Bcl-2, Bax), and proliferating cell nuclear antigen (PCNA). All drugs significantly inhibited the growth of AGS cell in vitro. All four drugs induced apoptosis and inhibited cell migration with varying efficacies. Imipramine induced G1/S phase arrest, whereas tropisetron, ketanserin, and cyproheptadine increased the sub-G1 cell population. Gene expression analysis revealed decreased Bcl-2 and PCNA levels and increased Bax expression.These findings suggest the potential of tropisetron, imipramine, ketanserin, and cyproheptadine as repurposed therapeutic agents for gastric cancer.

BACKGROUND: Existing tools assess psychedelic experiences, but none specifically measure altered processing of traumatic memories-a key mechanism in trauma-focused therapies and psychotherapy in general. The helioscope effect describes how psychedelics like psilocybin and 3,4-methylenedioxymethamphetamine (MDMA) enable revisiting challenging or traumatic experiences while remaining protected from re-actualization of trauma symptoms. This study introduces and evaluates the Helioscope Questionnaire, a novel scale for assessing memory-related processing during psychedelic experiences.

METHOD: A cross-sectional, Internet-based survey was administered to 468 individuals (mean age = 32.9; 66.7% male) with self-reported psychedelic/MDMA use.

RESULTS: The final Helioscope Questionnaire comprised 21 items across 3 factors: protection, exposure, and avoidant-distress. A composite Helioscope Score (HS) was derived from protection and exposure subscales. Convergent validity was demonstrated through strong correlations with the Psychological Insight Questionnaire. Discriminant validity was evidenced by moderate associations with the Mystical Experience Questionnaire and a lack of significant correlations with the Challenging Experience Questionnaire. Predictive validity was supported by the HS predicting positive changes in mood and attitude on the Persisting Effects Questionnaire, whereas avoidant-distress predicted negative changes. The scale also demonstrated incremental validity by providing explanatory power beyond established psychedelic effect measures. Additionally, the presence of a trip sitter was associated with stronger HS scores, and MDMA use was linked to reduced avoidant distress.

CONCLUSIONS: The Helioscope Questionnaire offers a novel, psychometrically robust tool for assessing therapeutic mechanisms of psychedelic experiences, particularly in relation to processing of difficult memories. Further research in clinical populations is warranted to evaluate its utility in predicting treatment outcomes.

Psilocybin, a tryptamine-derived alkaloid from Psilocybe mushrooms, has emerged as a high-value biopharmaceutical candidate due to its promising applications in mental health. While clinical studies highlight its rapid and sustained antidepressant effects, current challenges lie in achieving scalable, reproducible, and cost-effective production to meet growing research and therapeutic demand. Traditional extraction from fungal biomass yields low concentrations and requires extensive downstream processing, limiting industrial viability. Chemical synthesis ensures purity but is hindered by high costs and multistep complexity. In contrast, biotechnological approaches have demonstrated significant progress toward sustainable production. Heterologous expression of psilocybin biosynthetic genes in Saccharomyces cerevisiae and Aspergillus nidulans has enabled improved metabolic flux and precursor availability, reaching titers over 200 mg/L under optimized conditions. Moreover, recent engineering Escherichia coli strains has further enhanced catalytic efficiency of key enzymes such as PsiH, achieving production levels up to 2000 mg/L, while simplifying fermentation and purification workflows. These advances establish microbial platforms as a promising route for industrial-scale biosynthesis. Beyond production, psilocybin offers an opportunity to integrate biotechnology with socio-cultural context. In regions where diversity of Psilocybe species and ancestral knowledge converge, the development of biotechnological pipelines could foster innovation in drug discovery, sustainable manufacturing, and policy reform. Overall, psilocybin exemplifies a frontier molecule in biotechnology, where metabolic engineering, synthetic biology, and bioresource valorization converge to transform a natural product into a reproducible, scalable, and globally relevant therapeutic.

The therapeutic potential of low, non-psychedelic doses of psilocybin, a fungal tryptamine alkaloid, was investigated in metabolic disorders including obesity, type 2 diabetes mellitus (T2DM), and liver steatosis. Mice fed a high-fat/high-fructose diet received chronic treatment with psilocybin (0.05 mg/kg) for 12 weeks. Body weight, liver histology, insulin sensitivity, and skeletal muscle function were assessed, and hepatic and muscle tissues underwent transcriptomic and lipidomic analyses. The role of three serotonin receptors (5-HT2A, 5-HT2B, and 5-HT2C) in psilocybin-induced metabolic effects was examined in human cell lines using pharmacological and CRISPR/Cas9-based genetic approaches. Low-dose psilocybin reduced body-weight gain, liver steatosis, hyperglycaemia, and insulin resistance without eliciting central nervous system effects. Multi-omics analyses revealed near-complete normalization of disrupted hepatic lipid and carbohydrate metabolism pathways. Psilocybin also improved muscle strength and function, potentially through restoration of leptin sensitivity. Mechanistic studies demonstrated that these metabolic benefits were independent of the canonical psychedelic target 5-HT2A and instead resulted from antagonism of the serotonin 5-HT2B receptor in the liver. Overall, chronic low-dose psilocybin exerts broad metabolic benefits via a hepatic 5-HT2B-dependent mechanism, distinct from its psychedelic effects, supporting its potential as a novel therapeutic strategy for liver steatosis, obesity, T2DM, and sarcopenia.

In this work, the regio- and stereochemistry as well as the molecular mechanism of the cycloaddition reaction of nitrones with (E)-3-(methylsulfonyl)-propenoic acid derivatives were analyzed based on ωb97xD/6-311G(d,p) quantum chemical calculations. In light of these data, it is possible to propose selectivity of the analyzed processes, which was not clearly determined in light of previous experimental studies. Furthermore, the mechanism of the process was diagnosed. CDFT descriptors indicate that the reaction is triggered by a nucleophilic attack of the nitrone oxygen atom on the electrophilic carbon atom of (E)-3-(methylsulfonyl)-propenoic acid derivatives. In turn, PES analysis shows that, despite the nucleophilic-electrophilic character of the reactants, the corresponding transition states are only weakly polar and highly synchronous. IRC calculations rule out zwitterionic or biradical intermediates, confirming a single-step mechanism. The in silico ADME and PASS predictions indicate that the resulting isoxazolidines possess promising biological profiles, showing potential modulation of the serotonin system through 5-HT2A and 5-HT2C antagonism and stimulation of serotonin release, with structural features compatible with P450-mediated metabolism. Considering this attractive application potential, a detailed mechanistic investigation of their formation becomes essential for understanding and ultimately controlling the reaction pathways leading to these heterocycles.

Health-related behaviors are essential determinants of health and well-being, yet unhealthy patterns persist globally. Psychedelics may represent an innovative tool for facilitating positive behavior change. This study investigated retrospective health-related behavior changes attributed to past psychedelic experiences. An online survey was completed by 271 adults who reported on the characteristics of their most impactful psychedelic experience and associated changes across 74 behaviors, including physical activity, and time spent in nature. The most frequently reported changes were in contemplative practices (63%), time spent in nature (55%), and personally meaningful social activities (54%). The majority of changes were reported in a healthy direction. Higher ratings of perceived meaningfulness and having a set intention emerged as significantly associated with overall healthy change. While causality cannot be inferred, these findings highlight the potential of psychedelic experiences as catalysts for health-related behavior change and underscore the role of intention and perceived meaningfulness as candidate mechanisms.

Objective: To scope the available literature on antipsychotic treatment in substance-induced psychotic disorders, summarize evidence across substance categories, and highlight priorities for future research. Methods: This scoping review followed Arksey and O'Malley's framework and PRISMA-ScR guidelines. A systematic search of PubMed, Scopus, Embase, PsycINFO, and Cochrane Library (January 1985-August 2025) identified studies examining antipsychotic treatment in cannabis-, stimulant-, and hallucinogen-induced psychoses. Two reviewers independently screened studies and extracted data using a standardized form. Given marked heterogeneity, findings were synthesized descriptively. Results: Seventeen studies met inclusion criteria: 3 randomized controlled trials (17.6%), 10 observational studies (58.8%), and 4 case series (23.5%). Most evidence involved cannabis-induced (n = 7) and methamphetamine-induced (n = 6) psychosis. Randomized trials showed comparable efficacy between risperidone and haloperidol for cannabis-induced psychosis, and between quetiapine and haloperidol for methamphetamine-induced psychosis. Case series suggested potential benefits of third-generation antipsychotics such as lurasidone and cariprazine. No controlled studies were identified for cocaine- or hallucinogen-induced psychoses. Conclusions: Evidence for antipsychotic treatment in substance-induced psychoses remains scarce and uneven. While conventional antipsychotics appear effective for cannabis- and methamphetamine-related presentations, other substances remain virtually unstudied. Substantial evidence gaps and limited methodological quality highlight urgent research needs.

BACKGROUND: Patients with eating disorders (EDs), particularly anorexia nervosa (AN), experience a complex psychiatric condition often characterized by extreme food restriction, intense fear of weight gain, elevated levels of emotional dysregulation, body image disturbance, and comorbid trauma. Several of these factors can undermine the therapeutic alliance and reduce engagement with treatment, contributing to poorer outcomes. MDMA, a non-classical psychedelic, is being explored as a novel PTSD treatment adjuvans due to its ability to rapidly reduce trauma symptoms and enhance therapeutic alliance. Recent clinical trials and regulatory considerations, as highlighted in emerging research, are shaping its potential therapeutic role, and MDMA may offer a unique mechanism to disrupt maladaptive neural circuits, enhance cognitive flexibility, and facilitate emotional processing in EDs.

OBJECTIVE: To comprehensively evaluate the potential of MDMA-assisted therapy for EDs with a particular focus on the distinct neurobiological and psychological profiles of AN and comorbid PTSD.

METHODS: This paper synthesizes current research literature on MDMA, PTSD, and EDs, with an emphasis on clinical trial outcomes, neurobiological mechanisms, and therapeutic frameworks. Both pharmacological and psychotherapeutic components of MDMA-AT are reviewed.

RESULTS: No clinical trials of MDMA-AT have been conducted in ED populations to date. Findings from clinical trials in patients with PTSD suggest that MDMA's pro-social and fear-reducing and neuroplastic properties may enhance emotional processing, therapeutic alliance, and cognitive flexibility - key factors that often hinder eating disorder treatment. The ability of MDMA to increase emotional openness, reduce fear responses, and promote cognitive flexibility could support deeper engagement with the therapeutic process and improve treatment outcomes in EDs with comorbid trauma.

CONCLUSIONS: The current evidence base suggests that MDMA-AT may hold promise as an adjunctive treatment for EDs echoing its demonstrated therapeutic potential in PTSD. By facilitating deeper emotional processing, enhancing patient-therapist attunement, and fostering openness to change, MDMA may help overcome avoidance, cognitive rigidity, and therapeutic impasses that often hinder progress in EDs. Its integration into clinical practice will require rigorous validation through well powered trials, alongside careful ethical and regulatory oversight, and integration into multidisciplinary treatment frameworks. Tailored dosing, patient selection, and therapist training will be essential for safe and effective implementation. Further research is warranted to fully explore this potential application.

Distinguishing metabolite isomers often relies on comparing relative data, such as relative chromatographic retention times and ion mobility arrival time orders, or relative product ion abundances. These approaches necessitate the need for quality reference data and/or chemical standards. An ideal method for differentiating isomers would leverage one of the absolute physiochemical properties of the isomers, and would have no reliance on instrument vendor, chromatographic column chemistry, or external reference data. For example, the pK_a of an aromatic hydroxy hydrogen changes according to ring position across isomers (e.g., 4- vs 5-hydroxyindole). Herein, we leverage the difference in pK_a to resolve 4- and 5-hydroxy positional isomers of hydroxy-N,N-dimethyltryptamine (psilocin and bufotenine), the structural moiety of compounds with profound effects on the serotonergic system. We first use hydrogen-deuterium exchange (HDX) to rapidly exchange the indole amine hydrogen and gradually exchange the indole hydroxy hydrogen atoms to deuterium atoms. We then back-exchange the indole amine deuterium atom back to a hydrogen atom on the LC column and monitor the kinetic exchange rates of the retained aromatic hydroxy deuterium atom using high resolution mass spectrometry (HRMS). HDX kinetics allow for facile differentiation of the two isomers, with only 4-hydroxy-N,N-dimethyltryptamine exchanging at an appreciable amount within hours. These results could ultimately be used to characterize a variety of unknown structural isomers.

N,N-dimethyltryptamine (DMT) is a fast-acting psychedelic drug that induces a radical reorganization of conscious contents and brain dynamics. However, our understanding of how brain dynamics support psychedelic-induced conscious states remains unclear. We therefore present a repeated-measures dose-dependent study of the subjective and neural dynamics induced through DMT under naturalistic conditions. Nineteen participants received either a 20-mg or a 40-mg dose of freebase DMT across two sessions in a blinded, counterbalanced order. Electroencephalography data and time-resolved measures of subjective experience (Temporal Experience Tracing) were collected. Both doses of DMT induced rapid changes in experience dimensions, with the 40-mg dose inducing more extreme visual hallucinations and emotionally intense experiences. A variety of neural features were computed on the electroencephalography data, with oscillatory alpha power and permutation entropy most strongly associated with continuous subjective experience dimensions. Strikingly, Lempel-Ziv complexity, previously hailed as a robust correlate of subjective experiences within the psychedelic state, yielded the weakest associations. These findings suggest that the relationship between neural complexity and phenomenology in psychedelic states is less clear than originally hypothesized.

PURPOSE OF RESEARCH: Application of psychedelics including ketamine may be important adjuncts in the treatment of alcohol and opioid use disorders. Most patients with alcohol or opioid use disorder (AUD/OUD) may present to the emergency department (ED) seeking care both for substance use and associated complaints. Understanding safety and preliminary efficacy of ketamine and other psychedelics to improve the care and potentially facilitate linkage to long term care for AUD/OUD in the ED is of high importance. Here, we describe our experience conducting rigorous double blind placebo controlled trials to evaluate safety of ketamine in the ED for AUD/OUD and the challenges in conducting this research among this important population.

PRINCIPAL RESULTS: We conducted two studies to evaluate the safety of a single dose ketamine infusion for individuals seeking detox with AUD and those seeking psychiatric care who had OUD. Studies were conducted at an urban community and academic ED with variable pharmacy capabilities. Over the study period study 1 (AUD) screened N = 180 individuals for the study of which N = 3 were preliminarily eligible. None were able to pass full eligibility criteria resulting in no enrollments. Study 2 (OUD) screened N = 234 ED visits were screen of which N = 8 were eligible and N = 4 consented. All four participants were successfully randomized and treated with ketamine or placebo. We were unable to conduct follow up in any of the participants.

MAJOR CONCLUSIONS: Enrollment of ED patients with AUD/OUD for ketamine trials in the ED is difficult and fraught with multiple challenges. Even with enrollment in the ED, follow up can be a significant challenge. This reinforces the need to consider innovative strategies to conduct ketamine and other psychedelic related trials among ED patients with AUD/OUD.

Psilocybin, an indole alkaloid of psychedelic mushrooms, has the potential to sustainably improve the treatment of several psychiatric diseases. So far, the psilocybin demand for clinical trials has been met by chemical synthesis. In this study, we pursued the biotechnological approach to develop a psilocybin production process utilizing an overproduction strain of Aspergillus nidulans. The developed shake flask cultivation regime was characterized rheologically and was evaluated concerning the sensitivity to changes in oxygen availability and power input. Due to the strong impact of power input on viscosity and thus, (oxygen) mass transfer and mixing of the filamentous culture broth, the bioprocess was scaled up from shake flask to 7 L stirred tank reactor according to the specific power input. Utilizing a pressure reactor, the oxygen supply of the viscous culture broth was enhanced. Subsequently, the nitrogen limitation was addressed by supplementing the cultivation medium with additional ammonium sulfate to provide sufficient building blocks for protein biosynthesis. By producing 542 mg L^-1 psilocybin within 68 h from glucose, a robust and efficient batch bioprocess for psilocybin production was developed to potentially contribute to the future supply of psilocybin for pharmaceutical purposes. Moreover, we demonstrated the suitability of pressurized bioprocesses to counteract oxygen limitations for shear-sensitive, filamentous organisms.

Psychedelic compounds significantly reshape conscious perception, yet the implications of these alterations for complex visual-guided behaviors remain poorly understood. We investigated how psilocybin modulates visual salience processing during natural scene perception. Twenty-three participants completed eye-tracking tasks under self-blinded low and high doses of psilocybin, in a naturalistic design with experimental conditions unknown to participants and researchers. Subjects viewed natural scenes while their gaze patterns were recorded and analyzed in relation to normative computational saliency maps generated using a deep learning model of visual attention. Results revealed increased fixation on salient image regions and reduced inter-fixation distance under the high-dose condition, suggesting heightened sensitivity to visual salience and more localized gaze behavior. The Shannon entropy of fixations on high-saliency regions indicated a more exploratory and less predictable visual scanning of the images. Complementary resting-state electroencephalography recordings showed broadband spectral power reductions and increased Lempel-Ziv complexity, with delta power negatively correlating with salience metrics. These findings indicate that psilocybin induces a shift in attentional dynamics, altering gaze behavior, and salience processing during natural scene perception.

OBJECTIVE: The goals of this study were to examine the therapeutic effects and safety of psilocybin given as a pulsed regimen for the prevention of migraine and to consider the blinding integrity of an active control agent.

BACKGROUND: The administration of a single low dose of psilocybin was observed to have lasting therapeutic effects in one small pilot trial in migraine, although the ability of a pulse dose regimen, as practiced by patients with cluster headache, to potentially improve magnitude and/or duration of transitional preventive effects has not been studied. Furthermore, comparison to an active placebo agent that adequately mimics the acute subjective effects of psilocybin is required to improve blinding integrity and measure placebo effects.

METHODS: In an exploratory randomized, double-blind, placebo-controlled, parallel group study, adults with migraine having at least two weekly migraine days at baseline (n = 18) participated in two drug administration sessions separated by 7 days during which they received zero, one, or two doses of psilocybin (10 mg; psi). Whenever participants did not receive psilocybin, they received diphenhydramine (25 mg; diph). Participant recruitment took place between September 2021 and August 2023. The primary outcome measure was a change in migraine frequency using headache diary data collected starting 2 weeks before and continuing through 8 weeks after the second drug session.

RESULTS: In the 2 weeks after completion of the two drug administration sessions, the change from baseline in migraine days/week was not significantly different among groups [diph-diph: -0.7 (95% confidence interval, -1.5 to 0.2); diph-psi: -2.0 (-3.0 to -1.0); psi-psi: -1.7 (-4.1 to 0.7); Χ² ₍₂₎ = 4.56, p = 0.102], despite large effect sizes against the placebo group in the those receiving one (diph-psi; d = 1.66) or two (psi-psi; d = 0.69) doses of psilocybin. Similar reductions in migraine frequency approximating 50% were seen in all groups over the 8 weeks measured. The difference in 50% response rate among groups over 2 weeks, however, approached significance (diph-diph: 17%; diph-psi: 80%; psi-psi: 80%; p = 0.087). Drug confidence ratings (i.e., blinding integrity) suggested that diphenhydramine partially substituted for the acute effects of psilocybin. No correlations were observed between changes in migraine frequency after psilocybin and drug confidence, acute general drug effects, or acute psychedelic effects. No serious or unexpected adverse events occurred.

CONCLUSION: This exploratory study found similar reductions in migraine frequency with single-dose psilocybin, a two-dose pulse of psilocybin, or diphenhydramine placebo. Whereas blinding was incomplete in this study, this important topic is highlighted in the study design and findings. The potential for psilocybin to serve as a transitional treatment in migraine remains but will require careful planning in future studies to separate drug and non-drug effects. Furthermore, the inclusion of headache specialists in the design and execution of these future studies is necessary to preserve the viability of psilocybin treatment in headache medicine.

INTRODUCTION: The subjective effects of psilocybin on obsessive-compulsive disorder (OCD) are under-explored. Therefore, we conducted a qualitative study of participant experiences from the first randomized placebo-controlled trial of single-dose psilocybin combined with unstructured and non-directive support for individuals with treatment-refractory OCD. Our research explored how participants experienced acute and post-dosing effects, the interrelationships between these effects, and participants' perspectives on therapeutic change.

MATERIALS AND METHODS: We conducted qualitative interviews with 12 participants approximately one month after psilocybin dosing; (six who received psilocybin in the initial randomized placebo-controlled phase, six who received open-label psilocybin following unblinding). We analyzed interview transcripts via interpretative phenomenological analysis (IPA) and engaged in consensus decision-making to arrive at 100% intercoder agreement in the process of abstracting codes into higher-order themes.

RESULTS: Four major themes (and several subthemes) emerged from our analysis: 1) Influences on Psilocybin Experience (i.e., Set, Setting); 2) Acute Effects (i.e., Acute perceptual effects, Acute [meta]cognitive effects, Acute emotional effects, Acute impact of OCD, Other acute effects); 3) Post-Dosing Changes in OCD (i.e., Post-dosing changes in symptoms, Post-dosing changes in perceptions of OCD); as well as 4) Post-Dosing Changes Beyond OCD Symptoms (i.e., Post-dosing [meta]cognitive changes, Other post-dosing changes). Meaningful interrelationships among codes, subthemes, and themes were the norm.

DISCUSSION: Our findings highlight the moderate to strong influences of set and setting in the nature and trajectory of participants' psilocybin experiences. We also uncovered acute, synergistic visual/perceptual, emotional/psychological, and physiological/somatic effects that map onto those commonly reported in prior psilocybin trials for other closely related indications. However, these acute effects tended to occur at lower intensities (i.e., 'partial' experiences) potentially due to acute interference by OCD symptoms. Certain acute and post-dosing (meta)cognitive and behavioral effects also map onto putative mechanisms of action in evidence-based psychotherapy for OCD (e.g., exposure and response prevention [ERP] and acceptance and commitment therapy [ACT]). These findings yielded hypotheses for future investigation, and point toward potential integration of psilocybin with structured psychotherapy approaches for OCD.

BACKGROUND: The Altered States of Consciousness Scale (3/5D-ASC or 11-ASC) is widely used to assess non-ordinary states of consciousness, particularly for psychedelic research. However, its original dimensional model (3D-ASC within 5D-ASC) and later 11-subscale structure (11-ASC) have a hierarchically incompatible higher/lower-order structure. Although the 11-ASC offers superior model fit, the 3D-ASC remains widely used for summarizing broader experiential domains.

AIMS: We wanted to provide an updated, psychometrically revalidated version of the ASC. We tested whether the 42-item 11-ASC could be integrated into a coherent three-dimensional framework. We further hypothesized that this revised model would outperform the original 66-item 3D-ASC while preserving its conceptual clarity.

METHODS: Data from 901 5D-ASC questionnaires from 398 healthy participants across 16 randomized, mostly placebo-controlled psychedelic (lysergic acid diethylamide, psilocybin, mescaline, and N,N-dimethyltryptamine) studies were split for exploratory and confirmatory factor analysis. We compared the 3D-ASC and 11-ASC in terms of reliability and model fit, and tested whether the 11-ASC could be summarized within a three-dimensional model.

RESULTS: Ten of the 11 subscales formed three higher-order dimensions-Positive (PosE), Distressing (DisE), and Perceptual (PerE) effects-mirroring the 3D-ASC but with improved fit. We propose this as the 3D-ASCr scale. The Anxiety subscale could not be integrated due to consistent floor effects (low anxiety in the sample), but given its clinical relevance, it is retained within 3D-ASCr (as part of DisE or a standalone subscale).

CONCLUSION: The 3D-ASCr is an updated version of the ASC and is recommended for use with classic serotonergic psychedelics in both clinical practice and research.

OBJECTIVE: To investigate the reporting of harms in systematic reviews (SRs) focused on hallucinogen use.

METHODS: A search was conducted in May 2022 using MEDLINE, Embase, Epistemonikos, and Cochrane databases to retrieve SRs focused on the use of hallucinogens. Investigators screened the titles and abstracts from the search for study inclusion in a masked, triplicate fashion. Investigators analyzed the included SRs for reported harms linked to hallucinogen use via a pre-established harms reporting assessment. Methodological quality of SRs was graded using the A MeaSurement Tool to Assess Systematic Reviews-2 (AMSTAR-2) in a masked, duplicate manner. Study characteristics for each review were extracted in duplicate. The corrected covered area was measured for SR dyads.

RESULTS: Our search returned 908 articles, and 32 SRs met eligibility criteria for final harms reporting analysis. Of the included reviews, 28 SRs (56.2%) indicated harms as a primary or secondary outcome, 2 SRs (6.3%) reported predetermined methods to grade, collect harms data, or statistically analyze harms. A significant relationship was found between completeness of harm reporting and whether harms were listed as a primary or secondary outcome.

CONCLUSION: Harms were largely underreported in scientific literature regarding hallucinogen use, despite many studies designating them as a primary or secondary outcome. Inadequate reporting is unlikely to provide credible evidence used to evaluate the benefit-harm trade-off. Therefore, steps should be taken to improve the reporting of harms in studies concerning hallucinogen use.

Psychedelics are gaining attention as putative treatments for a range of psychiatric conditions, and evidence suggests that they produce sustained behavioural and clinical change. Enhanced learning is an emerging candidate mechanism mediating these sustained effects. This narrative review synthesises evidence across behavioural, neural and computational levels to examine the current evidence base for how psychedelics may alter learning mechanisms. We propose that viewing psychedelic mechanisms through the lens of learning unifies context-dependent outcomes, increased environmental sensitivity and neuroplastic change. We discuss how persistent changes in top-down and bottom-up information processing at a systems-level may account for both the therapeutic and adverse effects of psychedelics, and highlight a mechanistic convergence between such systems-level changes and the recently identified psychedelic-mediated reopening of critical learning periods. This systems-level framework may explain why psychedelic outcomes vary widely and hinge critically on the context: it is the learning environment, including psychological support and therapeutic insights, which shapes the lasting effect. If the post-psychedelic period is characterised by a vulnerable neuroplastic state in combination with increased environmental sensitivity, usually observed uniquely during childhood, this would offer a window of opportunity for revision of entrenched beliefs. Understanding these mechanisms has important translational relevance for the design and implementation of psychedelic-assisted psychotherapy.

The sense of self is a multidimensional feature of human experience. Different dimensions of self-experience can change drastically during altered states of consciousness induced through meditation or psychedelic drugs, as well as in a variety of mental disorders. Some experienced meditation practitioners are able to modulate their sense of self deliberately, which allows for a direct comparison between an active and suspended sense of self. Meditation therefore has the potential to serve as a model-system for alterations in the sense of self. The current study aims to identify a neural marker of such meditation-induced alterations in the sense of self based on magnetoencephalography (MEG) recordings of meditation practitioners (N = 41). Participants alternated between a state of reduced sense of self, termed self-boundary dissolution, a resting state and a control meditation state of maintaining their sense of self. Machine learning methods were used to find multivariate patterns of brain activity which distinguish these states on a single-trial basis. Source band power and Lempel-Ziv complexity features allowed to predict the mental state from MEG recordings with significantly above-chance accuracy (> 0.5). The highest performance was obtained for the self-boundary dissolution versus rest classification based on Lempel-Ziv complexity, which showed an average accuracy of ~0.64 when training and testing were performed on data from the same individual (within-participant prediction) and ~0.57 when models trained on one group of individuals were tested on different participants (across-participant prediction). Potential applications include decoded neurofeedback, for example, for clinical treatments of disorders of the sense of self, or for assistance in meditation training.

AIMS: To identify the functional brain connectivity patterns that were correlated with headache and mental conditions in migraineurs and then to elucidate their neurotransmitter basis and explore the potential clinical implications.

METHODS: Eighty patients with migraine without aura (MwoA) and 94 healthy controls (HCs) were included. Firstly, we employed partial least-squares correlation (PLSC) to identify a set of resting-state functional connectivity (RSFC) that was co-related with headache symptoms and mental conditions in MwoA patients. Then, we investigated the specific neurotransmitter basis underlying headache-mental disorders-related RSFC patterns. Finally, we explored the potentials of these RSFC patterns in discriminating patients from HCs, interpreting patient symptoms, stratifying patients into subgroups, and predicting treatment outcomes.

RESULTS: The PLSC analysis revealed one robust latent component linking RSFC between the subcortical nuclei (in particular the thalamus and basal ganglia) and the occipital/temporal cortex to the headache-mental conditions in MwoA patients. These RSFC patterns were spatially correlated with the distribution of several neurotransmitters including 5HT1a, 5HT2a, and mGluR5 receptors. The third part of the analysis indicated that the RSFC patterns could discriminate MwoA patients from HCs with an accuracy of 0.793, differentiate patients into two subtypes, and to some extent predict the efficacy of acupuncture treatment.

CONCLUSION: This was the first "doubly" multivariate analysis identifying functional brain connectivity patterns underlying headache-mental disorder comorbidity in migraineurs. These findings reveal a neurobiological substrate for migraine-mental disorder comorbidity and highlight the potential of these connectivity patterns as biomarkers for diagnosis and treatment prediction.

Ketamine is a unique anesthetic agent that induces dissociative anesthesia, characterized by perceptual detachment, analgesia, and altered states of consciousness. Beyond its widespread use in anesthesia, subhypnotic ketamine dosing has emerged as a rapid-acting antidepressant and a valuable model for probing the neural mechanisms underlying consciousness and neuropsychiatric disorders. At the core of its effects are actions on cortical circuits, primarily through NMDA receptor and HCN1 channel antagonism, disinhibition of pyramidal neurons, and altered thalamocortical connectivity. This review brings together emerging findings from ketamine pharmacology, cell type-resolved and region-specific in vivo imaging, and systems neuroscience to define how ketamine alters cortical circuit dynamics to drive dissociation. We further explore the intriguing possibility that ketamine freely diffuses into and concentrates within intracellular compartments and, in doing so, modulates neuronal excitability, intracellular signaling, and an epigenetic state, even following a single dose. A deeper mechanistic understanding of these cortical and cellular processes will not only advance our knowledge of ketamine's complex pharmacology but may also inform new therapeutic strategies for treatment-resistant depression and facilitate the study of diverse states of consciousness.

2,5-dimethoxy-4-iodoamphetamine (DOI) is a phenethylamine psychedelic with high affinity for 5-HT₂ receptors. In 2022 and 2023, the US Drug Enforcement Administration proposed to place DOI, along with a similar compound, 2,5-dimethoxy-4-chloroamphetamine, in Schedule I of the Controlled Substances Act based on their psychoactivity and alleged abuse potential. Here, we describe the history of DOI, its utility in preclinical neuroscience research, and how it has significantly advanced the study of 5-HT_2A and 5-HT_2C receptors. Finally, we suggest alternative compounds for studying 5-HT₂ receptors, should obtaining DOI for research become restricted. SIGNIFICANCE STATEMENT: 2,5-Dimethoxy-4-iodoamphetamine, the key pharmacological tool for studying 5-HT_2A receptor function and localization, has been used in more 1200 publications across 5 decades. This review covers its utility, research barriers if the Drug Enforcement Administration schedules it, and alternatives for continued investigation of serotonin receptors.

BACKGROUND: People with a history of psychotic disorders are excluded from contemporary trials of psychedelic-assisted therapy. Although survey studies have explored the impact of naturalistic psychedelic use on people with a history of psychotic disorders, a qualitative study has yet to examine the subjective effects of psychedelic use in this population during both the acute effects and perceived long-term impacts.

METHOD: Two semi-structured in-depth interviews were conducted with participants (n = 19) who had used psychedelics after the diagnosis of non-affective psychotic disorders (NAPD). Interviews probed the perceived positive and negative effects of psychedelic use. Data were analyzed using reflexive thematic analysis.

RESULTS: We constructed three major themes: 1) common challenges during the acute effects of psychedelics; 2) psychosis-specific psychedelic experiences; and 3) post-acute and long-term effects. In the common challenges of psychedelic use theme, participants often described experiences with transient anxiety, which sometimes resulted in brief self-reported hospitalizations. In the psychosis-specific psychedelic experiences theme, the subthemes consisted of psychedelics during and after psychosis, self-compassion and reduced self-stigma, and insight into hallucinations and delusions. The post-acute and long-term effects theme included subthemes of positive effects, negative effects, and a lack of long-term effects. Overall, most participants described some benefits of psychedelics, but the durability of perceived benefits varied widely.

CONCLUSION: Psychedelics might have heterogeneous impacts on people with NAPD, including both risks for harm and potential benefits. Our findings may assist in the development of safety and tolerability trials, highlighting the need for more nuanced work that examines how psychedelics impact people with NAPD.

The 5-HT_1A receptor is a critical target in the treatment of depression and anxiety. Bufotenine derivatives, such as 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT), and 5-hydroxy-N,N,N-dimethyltryptamine-derived from traditional Chinese medicine-have shown antidepressant potential. However, the structural basis of their interaction with 5-HT_1A and their pharmacological profiles remain incompletely understood. This study investigated bufotenine derivatives acting on multiple serotonin receptors, highlighting 5-HT_1A as a key mediator of antidepressant effects while recognizing 5-HT_2A as primarily responsible for hallucinogenic outcomes, to identify candidates with therapeutic efficacy but reduced hallucinogenic liability. We determined the cryo-electron microscopy structures of 5-HT_1A bound to selected bufotenine derivatives. Functional assays in mice, including behavioral tests and receptor activation studies, were used to evaluate the antidepressant of each compound. Structural analysis revealed that all bufotenine derivatives engage conserved motifs within the 5-HT_1A binding pocket, with 5-OH-DMT displaying a distinct interaction pattern. Behavioral assays showed that 5-OH-DMT and 5-MeO-DMT retained strong antidepressant and anxiolytic effects. These pharmacological differences correlate with their unique receptor binding conformation. This study delineated the structural pharmacology of bufotenine derivatives at the 5-HT_1A receptor, identifying 5-OH-DMT and 5-MeO-DMT as promising antidepressant and anxiolytic candidates. The findings establish a molecular framework for the development of next-generation nonhallucinogenic therapeutics aimed at 5-HT_1A.

BACKGROUND: Although the dorsal raphe nucleus (DRN) serotonergic neurons-which play a key role in consciousness-send dense projections to the basolateral amygdala (BLA), the electrophysiological mechanisms underlying their role in general anesthesia regulation remain elusive.

METHODS: Fiber photometry was used to monitor DRN serotonergic activity changes in the BLA during sevoflurane anesthesia and arousal process. Optogenetics and neuropharmacology were taken advantage to study the effects and receptor mechanisms. Additionally, in vivo electrophysiology was applied to elucidate the neurophysiological mechanisms underlying DRN serotonergic modulating BLA during sevoflurane anesthesia and arousal process.

RESULTS: DRN serotonergic afferents in the BLA exhibited decreased activity during sevoflurane anesthesia compared to wakefulness. Optogenetic activation of DRN serotonergic terminals in BLA accelerated arousal from sevoflurane anesthesia, as evidenced by electroencephalographic (EEG) signatures and behavioral recovery. Microinjection of 5-hydroxytryptamine (5-HT)1A receptors agonist (but not 5-HT2A or 5-HT2C agonists) into the BLA similarly promoted anesthetic emergence. Mechanistically, DRN serotonergic input inhibited GABAergic neurons while exciting glutamatergic neurons in the BLA, with these effects persisting across both wakefulness and anesthetic states.

CONCLUSIONS: Our findings establish a functional role for the DRN serotonergic-BLA neural pathway in promoting arousal from sevoflurane general anesthesia. These results provide novel mechanistic insights into the neural circuitry underlying consciousness recovery.

BACKGROUND: Treatment-resistant depression (TRD) is a complex and heterogeneous condition affecting a considerable subset of patients who do not respond to conventional antidepressants. Given the limitations of traditional treatment strategies, there is a growing need for alternative and personalized approaches.

OBJECTIVE: This review explores the neurobiological underpinnings of TRD and examines the efficacy of emerging pharmacological and neuromodulatory interventions. We also highlight the potential role of the bipolar spectrum in TRD and the need for tailored treatment strategies.

METHODS: A systematic review of literature from 2015 to 2025 was conducted using PubMed and Scopus. Studies on TRD treatment modalities, including augmentation strategies, mood stabilizers, atypical antipsychotics, and neuromodulation techniques, were analyzed.

RESULTS: Our findings indicate that novel interventions, such as ketamine, esketamine, psychedelics, and neuromodulation therapies (e.g., repetitive transcranial magnetic stimulation, magnetic seizure therapy) show promise in addressing TRD. Additionally, biomarker-driven and pharmacogenetic approaches may enhance treatment selection and improve outcomes. Evidence suggests that a subset of patients with TRD could fall within the bipolar spectrum, requiring mood stabilizers and antipsychotics rather than standard antidepressant regimens.

CONCLUSION: A multidisciplinary and precision-based approach is essential for optimizing TRD management. Future research should focus on biomarker-driven treatment selection, artificial intelligence-assisted decision making, and large-scale trials to refine personalized therapeutic strategies.

The complete mitochondrial genome of Ophiorrhiza guizhouensis has not previously been reported, hindering insights into its genetic makeup and evolutionary history. In this study, we assembled and annotated this genome, revealing a single loop structure containing 36 protein-coding genes (GenBank accession number: PX058827). The total length of the genome was found to be 476,177 bp, and its GC content was 43.55%. Phylogenetic analysis based on mitochondrial genes indicated that Ophiorrhiza guizhouensis shared close evolutionary relationships with Psychotria viridis, Psychotria serpens, and Damnacanthus indicus.

The saprotrophic genera Deconica and Psilocybe exhibit broad geographic distributions across temperate and subtropical biomes globally. Despite China's rich fungal diversity, taxonomic studies of these genera remain limited, with few species previously documented. In this study, 64 specimens of Deconica and Psilocybe from China were examined using an integrative taxonomic approach combining detailed morphological characterization with multilocus phylogenetic analyses (ITS, nrLSU, rpb2, and tef1-α). We identified six known Psilocybe species, three known Deconica species, and three species new to science, i.e., Deconica lignicola, D. shannanensis, and Psilocybe striata. In addition, at least six not yet described taxa were identified as members of the two genera. Psilocybe striata is distinguished by a white pileus covered with distinctive striate veils and exhibits a bluing reaction, which was discovered in Chongqing, representing the expansion of the known geographic range of Psilocybe in China. Deconica lignicola is characterized by pleurocystidia of the chrysocystidia type and narrowly lageniform cheilocystidia with short necks, and it is a typical lignicolous fungus, which grows on decaying wood. Deconica shannanensis produces small, reddish-brown to dark brown basidiomata, with abundant narrowly lageniform to lageniform cheilocystidia and does not have pleurocystidia; it is a coprophilous species inhabiting high-altitude meadows. These findings not only enrich the recorded species diversity of Deconica and Psilocybe in China but also deepen the understanding of their ecological adaptations and geographical distribution.

In recent decades, there has been a significant increase in the diversification and global commercialization of new psychoactive substances (NPS). This study assessed changes in the chemical profile of blotter papers and ecstasy tablets seized in the state of Paraná, Brazil, between 2014 and 2024. A total of 4911 samples (1656 blotter papers and 3255 tablets) were analyzed using GC-MS NMR, and FTIR techniques. These samples originated from synthetic drug seizures conducted across the state. A total of 64 chemical substances were identified, of which 50 were classified as NPS. The number of forensic requests for the analysis of blotters and tablets varied over the years, with peaks in 2016 and 2023. The most frequently identified compounds were central nervous system stimulants, especially phenethylamines. In ecstasy tablets, the most frequently identified substance was 3,4-methylenedioxyamphetamine (MDA), whereas among blotters, the NBOH series predominated. Additionally, a progressive increase in lysergic acid diethylamide (LSD) identifications was observed in blotters, while NPS identifications decreased over time. Most synthetic drug seizures occurred in Curitiba, the state capital, while a lower incidence was observed in border regions. The data indicate that the chemical profile of synthetic drugs identified in Paraná is diverse and resilient. Moreover, the observed decrease in the number of NPS in the state coincides with the implementation of national and international legislative measures aimed at stricter control of psychoactive substances.

The lifetime prevalence of mood disorders such as major depressive disorder (MDD) is thought to approach up to 50% of the world's population. Traditionally, research into the mechanisms of these disorders has focused on neurotransmission, but emerging evidence highlights neuroimmune interactions-the molecular signaling between immune and brain cells-as key regulators of brain plasticity, affective behavior, and potential vulnerability to mood disorders. Chronic stress models have unearthed how immune cell responses modify neural circuit activity, synaptic connectivity, and behaviors relevant for mood disorders by acting on brain-resident cell types. This perspective synthesizes basic principles of neuroimmune communication derived from animal studies relevant for mood disorders and assesses their relevance in MDD and post-traumatic stress disorder (PTSD). We describe cellular neuroimmune interactions important for behavior as well as the molecular mechanisms that govern immune-brain plasticity across different cell types. We also explore how therapeutic interventions, including anti-inflammatory biologics and psychedelics, can target these pathways. Finally, we chart how the field could dissect neuroimmune interactions across biological scales in the near future by highlighting the conceptual frontiers and emerging technologies. Understanding the modulation of neuroimmune interactions promises to inform next-generation treatments for mood disorders.

Double-blind, randomized, controlled trials (DB-RCT), if designed and conducted well, are widely considered the gold standard in medical research for purposes of establishing causal efficacy. Their logic is compelling: by balancing out all confounding variables through the research design, DB-RCTs are thought to reveal whether a proposed treatment-by virtue of its characteristic constituents-causes therapeutic effects. Many studies on psychedelic-assisted therapy (PAT) follow this ostensible gold standard and use a DB-RCT design. But several authors have already noted that conducting psychedelic DB-RCTs is particularly challenging: due to the psychoactive effects of psychedelics, participant awareness of condition assignment is likely; this awareness may then interact with response expectancy and experimenter behavior, introducing systematic bias into the trial. For this reason, these authors have suggested ways to rescue DB-RCTs for PAT. This paper takes a different direction. It argues that we should abandon the DB-RCT design as the assumed gold standard in PAT research, because its logic is largely undermined by the intervention(s) in question, and the design in its standard form neglects potentially important aspects of PAT (i.e., extrapharmacological factors and their interaction(s) with the psychedelic). Abandoning DB-RCT opens the door to a more holistic study of PAT, in which DB-RCTs are still useful for certain ends but are considered to produce results that are not per se superior but complementary to those of other research designs.

AIMS: Neuroinflammation complicates traumatic brain injury predisposing to long-lasting neurologic impairment. The aim of the present study was to test whether parenteral administration a small peptide mimic (SN..8) of the receptor- activating- region of the human serotonin 2A receptor (1-, 3- and 5-days) after traumatic brain injury suppresses hippocampal inflammation in the rat compared to a scrambled peptide sequence of the same eight amino acids.

METHODS: Adult male Sprague-Dawley rats were exposed to lateral fluid percussion (LFP)-induced, traumatic brain injury (TBI) vs. sham injury. An identical 2 mg/kg concentration of SN..8 vs LD..8 (scrambled peptide) was administered via intraperitoneal route 1-, 3- and 5-days after injury. Two weeks post injury, the bilateral hippocampal, dorsal and ventral brain regions were examined by RT-PCR for altered gene expression. Comparisons were made between TBI vs sham injury; and active vs scrambled peptide treatment.

RESULTS: Two weeks after injury, the novel SN..8 peptide (vs scrambled peptide) significantly reduced (more than 3-fold) CD68 mRNA relative expression in ventral hippocampus in adult male Sprague-Dawley rats subjected to TBI (N=22) (1.65 ± 0.83 vs 5.27 ± 4.1; P=0.012).

CONCLUSION: These results suggest that the neuroprotective effects of SN..8 peptide may be due in part to its ability to substantially suppress subacute inflammation in the ventral hippocampus.

High-grade gliomas are lethal brain cancers that are powerfully regulated by glutamatergic neurons through activity-dependent paracrine factors and functional neuron-to-glioma synapses. Here, we report that serotonergic neurons promote the proliferation of high-grade gliomas throughout the brain. Serotonergic neuronal activity drives circuit-specific increases in high-grade glioma proliferation, calcium transients, and reduced survival. This growth-promoting effect is chiefly mediated by activation of the serotonin (5-hydroxytryptamine; 5HT) receptor 5HT_2A on glioma cells. Knock out or pharmacological blockade of 5HT_2A receptors in glioma abrogated the glioma growth-promoting effects of serotonergic neuronal activity, while serotonergic psychedelic drugs robustly promote malignant cell proliferation. Gliomas alter serotonergic neuronal activity patterns, resulting in elevated serotonin release into the tumor microenvironment. Together, these findings uncover pathogenic, feed-forward interactions between serotonergic neurons and glioma cells.

Alzheimer's disease (AD) remains a significant challenge in diagnosis and treatment, with current methods insufficient for early detection. A major obstacle is the lack of effective imaging agents targeting the Tau protein, which plays a key role in AD pathology. To address this, we developed a computational methodology for selecting F-18 labeled drug candidates from a library of CNS-penetrant compounds curated from literature and databases. The library, consisting of 977 compounds, was evaluated based on clinical data, target proteins, pathways, toxicity, and other relevant factors. We implemented Python-based algorithms to select the top 39 compounds from virtual screening results, prioritizing those with optimal Tau binding affinity and BBB permeability. Additionally, we developed an algorithm to identify F-18 labeling candidates that maintain their biological activity post-labeling. We then performed virtual screening of an F-18 labeled drug library and selected the top 3 compounds based on stability and imaging potential. The selected compounds exhibited molecular weights of 350-520 Da, favorable logP values (2.05-2.72), and high BBB permeability. Our findings indicate that Drug 388 (BI-D1870), binds to Tau with a binding free energy of ΔG = -8.79 kcal/mol. Drug 416 (reported BRAF inhibitor, RG6344) shows a binding free energy of ΔG = -7.91 kcal/mol, while Drug 610 (Iloperidone/HP 873), a D2/5-HT2 receptor antagonist, exhibits a predicted binding free energy of ΔG = -6.88 kcal/mol with the target Tau protein respectively. Molecular dynamics simulations confirmed stable Tau-drugs interactions, with minimal RMSD fluctuations, indicating strong binding. The F-18 label enabled real-time PET imaging, allowing non-invasive tracking of the drug's binding to Tau in the brain. Our approach provides a comprehensive solution to the current limitations in Alzheimer's diagnosis by offering F-18 labeled drugs that effectively target Tau protein without compromising their biological activity, advancing both diagnostic and therapeutic strategies for AD.

BACKGROUND: Offspring of parents with alcohol use disorder (AUD) have elevated risk of substance use. However, few studies have comprehensively assessed risks associated with different substances. This study investigated the risk of substance use disorders (SUDs) in adult children with severe parental AUD over four decades, contributing information on the risk of each disorder, the roles of important risk factors, and the general versus substance-specific nature of SUD risk.

METHODS: Swedish national register data were used to follow children with and without ≥ 1 parent with an inpatient diagnosis of AUD from 1973 to 2018 to investigate risk of alcohol, opioid, cannabinoid, sedative/hypnotic, cocaine, other stimulant, hallucinogen, volatile solvent, and multiple drug use disorder. The composite outcomes any SUD, 1 SUD, and ≥ 2 SUDs including and excluding AUD were also investigated. Severe parental AUD and outcomes were defined with hospital inpatient diagnoses (ICD codes). Hazard ratios (HRs) were calculated with Cox regression. Model 1: unadjusted. Model 2: adjusted for child’s sex, parental education, and parental mortality. Model 3: Model 2 plus parental SUD. Model 4: Model 3 plus parental psychiatric disorder.

RESULTS: Risks of all outcomes were higher in those with (n = 99,723) than without (n = 2,321,756) severe parental AUD. For SUD diagnoses, the highest unadjusted risks were for other stimulant (HR 5.33, 95% CI 5.03–5.64), volatile solvent (HR 4.95, 95% CI 3.98–6.15), and opioid (HR 4.62, 95% CI 4.37–4.87) use disorders. After full adjustment, risks declined, and HRs of the different diagnoses converged to approximately twice as high in the adult children of parents with AUD. Risks of any SUD and of ≥ 2 SUDs were more elevated (95% CIs did not overlap) when AUD was included than when AUD was excluded. Risk of ≥ 2 SUDs was higher than risk of 1 SUD, but only when AUD was included.

CONCLUSIONS: Severe parental AUD was associated with elevated risk for all SUDs. After full adjustment, SUD risks declined and converged but remained doubled. Sociodemographic factors, parental SUD, and parental psychiatric disorder explained much of the excess risk. Drug combinations that included alcohol elevated the risk of ≥ 2 SUDs and any SUD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12889-025-24900-9.

BACKGROUND AND AIMS: There is an urgent unmet need for novel treatments for methamphetamine (MA) use disorder. We explored the qualitative experiences of people participating in a study of psilocybin-assisted psychotherapy (PAT) to treat MA use disorder.

DESIGN AND SETTING: Qualitative study of participants enrolled in a single arm, open-label pilot study of PAT for MA use disorder delivered in an outpatient stimulant treatment program setting in Sydney, Australia.

PARTICIPANTS: Twelve participants were interviewed before starting PAT and then again one month following PAT.

MEASUREMENTS: Pre-PAT interviews explored participants' experiences of MA use and expectations of receiving PAT. Post-PAT interviews explored participants' experiences of PAT, with a focus on phenomena related to the acute subjective effects of psilocybin, the perceived effects of PAT on MA use, self-perception, beliefs, values, behaviours, interpersonal relationships and spirituality, and acceptability of the intervention. Interviews were audio recorded, transcribed verbatim and analysed using an inductive qualitative approach.

FINDINGS: While participants generally hoped to have positive outcomes from study participation, their expectations were generally tempered and realistic. Their trial experiences of PAT were often characterised by new understandings of themselves, their narrative histories and interpersonal relationships, all of which were frequently prompted by leaning into vividly presented challenging experiences within the psychedelic experience. This volitional attitude of 'leaning into the obstacle' emerged as a key theme, meriting exploration for its potential to expose the subjective dimension of the psychedelic mechanism of effect. Resolution of this obstacle was associated with a reduction in the salience of methamphetamine. Therapeutic alliance was seen as critical to positive outcomes and was achieved through high levels of concentrated therapeutic attention and intersubjective intimacy between participant and therapist.

CONCLUSIONS: Interviewed participants in a study of psilocybin-assisted psychotherapy (PAT) for methamphetamine use disorder perceived PAT as an acceptable intervention. Transformation in understandings of self and interpersonal relationships and subsequent reduced salience of methamphetamine use often occurred through confronting psychic obstacles in the context of high levels of therapeutic support from study therapists.

BACKGROUND: Hallucinogen use among justice-involved youth presents an understudied public health problem. Variation in cognitive development of impulse control and sensation-seeking may be relevant for predicting this behavior. That said, there remains a dearth of research which has examined these relationships from a life-course perspective. The present study addresses this gap in the literature by examining sensation-seeking and impulse control as predictors of hallucinogen use and whether these relationships are moderated by age among a sample of justice-involved youth.

METHODS: The Pathways to Desistance data were analyzed. Mixed effects modeling was used to assess direct and moderated relationships of interest. Results: Findings indicated that lower impulse control predicted greater hallucinogen use likelihood and that this effect diminished in magnitude as youth aged through adolescence. Greater sensation-seeking predicted increased likelihood of hallucinogen use, but effects were not moderated by age. However, the direct effect of sensation-seeking was attenuated when interaction effects were included.

CONCLUSIONS: These results suggest that programming within juvenile correctional settings may benefit from focusing on impulse control as a mechanism to reduce hallucinogen use among justice-involved youth. Implications are relevant primarily for prevention programming within juvenile justice systems rather than general youth populations.

Clinical research in psychedelic-assisted therapies is flourishing following the resumption of human trials exploring classic psychedelics and their therapeutic application to a range of mental health conditions. Translation from research to the clinic is underway in Australia and appears imminent in several other countries. Classic psychedelics function primarily as agonists of a subgroup of serotonin (5-HT) receptors but also act to varying degrees at other receptor and transporter systems. Some physiological responses to psychedelics may present risks to susceptible individuals that must be weighed against the potential neuropsychological benefits afforded by psychedelic therapies. Hence, an important rationale for eligibility criteria in clinical trials is to ensure participant safety by minimizing risks of adverse events. The analysis presented here focuses on physiological considerations associated with psychedelic therapies. We conducted a critical evaluation of medical exclusion criteria applied in clinical studies of psychedelic-assisted therapy listed on international clinical trials registries. The criteria were interrogated for their rationale and medical basis; informed by this analysis, the evolution of medical exclusion criteria over twenty-five years of psychedelic clinical research was considered. Finally, the applicability of medical exclusion criteria in psychedelic therapies is discussed in the context of hospital-based psychiatry as the global transition from clinical trials to clinical practice gathers pace.

Recent studies highlight the promising use of psychedelic therapies for psychiatric disorders, including depression. The persisting clinical effects of psychedelics such as psilocybin are commonly attributed to activation of the serotonin 2A receptor (5-HT2AR) based on its role in the acute hallucinatory effects. However, the active metabolite of psilocybin binds to many serotonin receptor subtypes, including the serotonin 1B receptor (5-HT1BR). Given the known role of 5-HT1BR in mediating depressive phenotypes and promoting neural plasticity, we hypothesized that it mediates the effects of psilocybin on neural activity and behavior. We first examined the acute neural response to psilocybin in mice lacking 5-HT1BR. We found that 5-HT1BR expression influenced brain-wide activity following psilocybin administration, measured by differences in the patterns of the immediate early gene c-Fos, across regions involved in emotional processing and cognitive function, including the amygdala and other subcortical limbic structures. Functionally, we demonstrated that 5-HT1BR mediates some of the acute and persisting behavioral effects of psilocybin. Although there was no effect of 5-HT1BR expression on the acute head twitch response, mice lacking 5-HT1BRs had attenuated hypolocomotion to psilocybin. We also measured the persisting effects of psilocybin on anhedonia and anxiety-like behavior using transgenic and pharmacological 5-HT1BR loss-of-function models. Although there were effects of sex and stress paradigms, we found that 5-HT1B is involved in mediating some of the longer-lasting behavioral responses to psilocybin. Finally, using a network analysis, we identified neural circuits through which 5-H1BR may modulate the response to psilocybin. Overall, our research implicates the 5-HT1BR, a non-hallucinogenic serotonin receptor, as a mediator of the behavioral and neural effects of psilocybin in mice.

Nitrous oxide (N2O), the colorless, odorless gas known as "laughing gas", has gained recent attention for its misuse as a recreational drug. As an anesthetic, N2O produces sedation, euphoric and possible hallucinogenic effects. Adverse effects may include disorientation, psychomotor retardation, hypoxia, and asphyxia. N2O misuse has grown due to its ease of availability, rapid onset of effects, and increased social media attention, leading to anticipated increases in forensic testing needs. Due to its short half-life and volatility, analytical detection can be challenging. From January 2022 through September 2025, over 1700 cases were analyzed for N2O using headspace-gas chromatography-mass spectrometry (HS-GC-MS) over a calibration range of 1.8-180 mcg/mL. Total test requests and percent positivity increased during this timeframe for both driving (DUID) and postmortem (PM)/clinical casework. Blood, brain, liver, lung, and urine yielded positive detections. Attempts at repeat testing indicate significant losses in analyte concentrations. Consideration of pre-analytical and analytical factors are critical for suspected inhalant casework. Overwhelmingly, both DUID and PM casework noted N2O canisters present at the scene. Common driver behaviors included disorientation, slow reaction times, struggling with speech, inability to follow directions, and difficulty maintaining balance. DUID blood draws should be collected as close as possible to the suspected incident. Further review of case histories and testing practices generated handling recommendations for suspected inhalant case samples: fill containers to limit headspace; glass containers and tight-fitted closures are preferred; avoid transferring volume to alternate containers; limit container ingresses; and avoid repeat testing within the same container. Multiple matrices/containers should be collected and preserved, whenever possible, with inhalant testing prioritized over other drugs and/or alcohol. Laboratories should also consider qualitative reporting and/or testing as a one-time analysis. By employing these best practices, an inhalant gas may be better collected and preserved, increasing the chances of detection.

This qualitative study of how successful Psychedelic Assisted Psychotherapy (PAP) transforms the way of life of terminally ill subjects provides new knowledge for researchers and clinicians contemplating its use. Using an interpretive phenomenological approach (IPA) and interviews with subjects before and after PAP from a recent randomised control trial, we find that participants with extreme death anxiety have become displaced from their own life, afraid and alone in an all-encompassing present. PAP can enable them to fully inhabit their life in a more abundant and joyful present, even in the face of death. The psilocybin component is found to be necessary but not sufficient for this achieving this outcome. These novel findings expand our conceptualisation of death anxiety and of the personal transformation that constitutes successful PAP. Clinical trial details Australian New Zealand Clinician Trials Registry. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378101&isReview=true registration: ACTRN12619001225101.

Psilocybin, a naturally occurring hallucinogenic substance present in certain mushrooms, has drawn growing attention as a therapeutic breakthrough for several mental and psychiatric conditions. Psilocybin originated in spiritual and cultural traditions and has become the focus of extensive scientific research. This meta-analysis and systematic review aggregate results from the literature to evaluate the therapeutic function of psilocybin following PRISMA 2020. Although it is now used to treat addiction, end-of-life anxiety, and treatment-resistant depression, new research indicates that it could additionally be used to treat obsessive-compulsive disorder, eating disorders, and neurodegenerative diseases. Psilocybin's regulation of serotonin 5-HT2A receptors, which improves neuroplasticity, disrupts maladaptive cognitive processes and encourages emotional integration, is the backend of its therapeutic benefits. The meta-analysis results indicate that psilocybin has an outstanding capacity to reduce the symptoms of anxiety/MDD (SMD = -1.438, 95 % CI: -1.729 to -1.146, p < 0.001) and mood disorders (SMD = -1.476, 95 % CI: -1.773 to -1.178, p < 0.001). Sustained improvements are frequently observed after a single therapy session. The results of this meta-analysis and systematic review highlight psilocybin's potential as a potent and immediate treatment for mental health issues that are difficult to treat. Although the results are resistant to publication bias (fail-safe N > 5500), they highlight the significance of addressing unsolved hurdles to clinical adoption and customizing therapies for particular groups. Psilocybin has the potential to transform psychiatry and give millions of people suffering from crippling mood disorders fresh hope as research progresses and regulations change.

N,N-dimethyltryptamine (DMT) is a serotonergic psychedelic that is being investigated clinically for the treatment of psychiatric disorders. Although the neurophysiological effects of DMT in humans are well-characterized, similar studies in animal models and data on the neurochemical effects of DMT are generally lacking, which are critical for mechanistic understanding. In the current study, we combined behavioral analysis, high-density (32-channel) electroencephalography, and ultra-high-performance liquid chromatography-tandem mass spectrometry to simultaneously quantify changes in behavior, cortical neural dynamics, and levels of 17 neurochemicals in medial prefrontal and somatosensory cortices before, during, and after intravenous administration of three different doses of DMT (0.75 mg/kg, 3.75 mg/kg, 7.5 mg/kg) in male and female adult rats. All three doses of DMT produced head twitch response with most twitches observed after the low dose. DMT caused dose-dependent increases in serotonin and dopamine levels in both cortical sites and a reduction in EEG spectral power in theta (4-10 Hz) and low gamma (25-55 Hz), and increase in spectral power in delta (1-4 Hz), medium gamma (65-115 ), and high gamma (125-155 Hz) bands. Functional connectivity decreased in the delta band and increased across the gamma bands. We detected cortical DMT in baseline wake condition in 80% of the animals tested at levels comparable to serotonin and dopamine, which together with a previous study in occipital cortex, motivates cross-species studies to confirm endogenous presence of DMT. This study represents one of the most comprehensive characterizations of psychedelic drug action in rats and the first to be conducted with DMT.Significance Statement N,N-dimethyltryptamine (DMT) is a serotonergic psychedelic with potential as a tool for probing the neurobiology of consciousness and as a therapeutic agent for psychiatric disorders. However, the neurochemical and neurophysiological effects of DMT in rat, a preferred animal model for mechanistic studies, are unclear. We demonstrate that intravenous DMT caused a dose-dependent increase in serotonin and dopamine in medial prefrontal and somatosensory cortices, and simultaneously increased gamma functional connectivity. Similar effects have been shown for other serotonergic and atypical psychedelics, suggesting a shared mechanism of drug action.

In clinical trials for mental health treatments, functional unmasking (unblinding) is a widespread challenge wherein participants become aware of their assigned treatment. Unmasking is especially concerning with psychedelics, due to the near unmistakable acute effects (the "trip"), resulting in uncertainty about whether outcomes following treatment reflect true therapeutic properties of the interventions, or placebo-like effects. We present a counterfactual conceptualization of unmasking that 1) formalizes the shortcomings of many existing statistical and experimental design solutions (e.g., dose-response, active controls), and 2) demonstrates how modern causal inference approaches can be applied to isolate effects devoid of this "contamination." Our results reveal feedback mechanisms between perceived therapeutic benefits and expectancies that can render traditional methods prone to obscuring or exaggerating therapeutic benefits. Our proposal motivates trial designs and statistical methods that can be implemented to mitigate the impacts of functional unmasking.

The subacute period following the use of classic psychedelics is often marked by an "afterglow" - a state characterized by elevated mood; enhanced psychological well-being; increased emotional openness toward self, others, and nature; and sometimes a heightened sense of clarity and existential meaning. From a neurobiological perspective, subacute psychedelic states have been associated with changes in brain network connectivity, amygdala reactivity, and neuroplasticity.However, individual responses to psychedelics vary considerably, and not all users experience positive aftereffects. Some struggle to make sense of their psychedelic experiences or to integrate them into daily life. Others report psychological instability, including mood swings, anxiety, panic attacks, sleep disturbances, depressive symptoms, feelings of alienation, depersonalization, derealization, persisting perceptual changes, flashbacks, prolonged psychosis, mania, or suicidal ideation.Many of these issues can be mitigated through interventions commonly referred to as "psychedelic integration," often practiced individually or provided by peers within the psychedelic community or through other forms of social support. In cases of severe or persistent symptoms, however, professional mental health care may be required. Key components in managing subacute complications include establishing safety, mobilizing internal and external resources, supporting the psychological processing of the experience, addressing maladaptive interpretations, monitoring symptom progression, and, when indicated, pharmacotherapy. Persistent complications may furthermore warrant established disorder-specific treatment to prevent further chronification.This chapter outlines and discusses strategies for managing clinically significant subacute complications, with the aim of advancing a nuanced harm-reduction framework relevant to research, clinical, and non-clinical contexts.

INTRODUCTION: Many military Veterans who experienced blast-related traumatic brain injuries (TBI) in the conflicts in Iraq and Afghanistan currently suffer from chronic cognitive and mental health problems including post-traumatic stress disorder (PTSD). Rats exposed to repetitive low level blast injury exhibit chronic PTSD-related behavioral traits. Inflammation has long been suspected of playing a role in blast-induced brain injury and rats exposed to repetitive low-level blast develop chronic inflammatory changes. Minocycline is a tetracycline antibiotic that besides having antibacterial properties has anti-inflammatory activity. The aim of this study was to determine whether minocycline could reverse PTSD related behavioral traits in rats exposed to repetitive low level blast exposure.

METHODS: Rats were exposed to three 74.5 kPa blast exposures administered one per day for three consecutive days. We tested two cohorts of blast-exposed rats at 8-8.5 months after blast exposure. Rats were tested in a novel object recognition (NOR) task, elevated zero maze (EZM) and cued fear learning paradigm. In one experiment rats were treated with five doses of minocycline over a 9-day period. In the second experiment blast-exposed rats were treated with a 4-week course of minocycline with the drug administered 11 times. After the second experiment blast-induced effects on expression of the serotonin receptor 2A (5-HT2AR) and the post-synaptic density protein-95 (PSD-95) were examined by Western blotting. Microglial morphology was examined by Iba1 immunostaining.

RESULTS: In both experiments, cognitive changes in NOR and anxiety in an EZM were reversed by minocycline. However, in neither experiment was exaggerated fear learning rescued. Minocycline did not reverse blast induced effects on expression of 5-HT2AR or PSD-95 although it did appear to modulate blast-induced effects on microglial morphology.

CONCLUSIONS: These studies have implications for understanding the nature of blast-induced behavioral traits, some of which may be the direct result of inflammatory effects, while others may be independent of inflammation or if the result of inflammation, not reversible once downstream structural or neurochemical changes are established.

OBJECTIVES: Interest in psilocybin as a treatment for depression has risen over the past decade, fuelled by promising clinical trials and a rapidly evolving regulatory landscape. Media coverage plays a critical role in shaping public perceptions, yet little is known about how psilocybin is portrayed in global anglophone online news for the treatment of depression.

METHODS: This study examines the comprehensiveness and sentiment of English-language online news articles (n = 125) discussing psilocybin as a treatment for depression from January 2000 to May 2024. Articles were sourced from the top 30 global anglophone news outlets, assessed using a 13-item instrument for comprehensiveness, and analysed for sentiment across five thematic categories. A separate sub-analysis was completed for Irish media.

RESULTS: Findings indicate a significant increase in coverage over time, with 43.2% of articles published between 2022 and 2024, predominantly from the USA (68%). While 90.4% of articles cited researchers, fewer addressed risks (47.2%), long-term evidence (46.4%), or patient perspectives (25%). Sentiment analysis revealed a very positive sentiment across articles which was 2.27 on a scale from -5 (most negative) to + 5 (most positive) (SD 1.33), with no significant changes over the time period. Reporting on psilocybin's onset and duration of effects increased significantly, reflecting growing clinical evidence. However, coverage remains concentrated in prominent outlets, with limited attention to patient experiences and long-term safety.

CONCLUSIONS: These findings highlight the media's role in shaping discourse on emerging treatments and suggest a need for more balanced reporting to align public understanding with scientific evidence. This study provides a foundation for future research on media portrayals of psilocybin and implications for public perception and policy.

BACKGROUND: Palliative Care is concerned with relieving suffering and improving the quality of life of patients and their families. Currently, questions arise about how to provide patients with good end-of-life care. There has been increasing interest in the beneficial effects of using psilocybin-assisted therapy in patients with severe chronic illnesses near the end of their lives and who present symptoms of depression and/or anxiety.

AIM: Explore the role of psilocybin-assisted therapy in palliative care, synthesizing evidence from clinical trials and longitudinal studies.

DESIGN: Systematic review.

DATA SOURCES: A bibliographic search was performed in April 2024 in B-on, PubMed, Web of Science, and Scopus. Eligible studies included peer-reviewed quantitative research (RCTs, longitudinal, and observational designs) with adult participants in palliative care settings, examining the efficacy and safety of psilocybin-assisted therapy. Reviews, gray literature, and studies outside the scope of palliative care were excluded.

RESULTS: Of the 215 articles found, six studies (n = 74 participants; age range 22-75 years) met the inclusion criteria. Across randomized and open-label trials, psilocybin-assisted therapy produced clinically significant reductions in depression and anxiety, with 57-79% of participants achieving ⩾ 50% symptom reduction on standardized scales (e.g. HAM-D, HAM-A, BDI, STAI). Improvements were sustained for up to 6-8 months in most trials, and in one follow-up study, for up to 4.5 years. Reported adverse effects were generally mild and transient, including nausea, vomiting, and temporary increases in blood pressure and heart rate; no serious adverse events were observed.

CONCLUSIONS: Psilocybin-assisted therapy consistently demonstrated efficacy and safety in the reduction of depressive and anxiety symptoms. However, more studies exploring integrating psilocybin-assisted therapy into existing palliative care healthcare systems are needed. This includes investigating the feasibility, acceptability, and cost-effectiveness of integrating psilocybin-assisted therapy into routine clinical practice.

Rodent studies have shown that psychedelic drugs can enhance fear extinction. However, investigations to date have relied on normative aversive conditioning procedures, which limit their relevance to trauma-related memories, as these tend to be overgeneralized and resistant to extinction. Fear extinction depends on activity and plasticity within the infralimbic (IL) region of the medial prefrontal cortex and is regulated by brain-derived neurotrophic factor (BDNF). Ayahuasca (AYA), a brew containing the serotonergic psychedelic N,N-dimethyltryptamine (DMT), facilitates fear extinction in rodents and increases BDNF levels/signaling. Here, we investigated whether AYA attenuates extinction deficits and generalized fear induced by preconditioning restraint stress or high-intensity contextual fear conditioning, and whether these effects depend on BDNF-TrkB receptor signaling in the IL cortex. Adult male and female rats underwent the protocols above and received oral AYA one hour before each of the two extinction sessions conducted on consecutive days. Repeated administration of AYA containing 0.3 mg/kg of DMT enhanced extinction learning and its retention, effects that were abolished by bilateral intra-IL cortex infusion of an anti-BDNF antibody or the TrkB receptor antagonist ANA-12. AYA treatment also reduced fear generalization, an action that was BDNF-dependent in the IL cortex of females but not males. Overall, these findings indicate that AYA can modulate maladaptive fear memories through cortical mechanisms involving BDNF signaling, highlighting the potential of psychedelics as enhancers for extinguishing difficult-to-treat memories like those underlying post-traumatic stress disorder.

Party drugs are frequently used in social settings such as festivals. The changing dynamics of the party scene and drug market require up-to-date information on current drug use to support law enforcement, public health and policymakers. This study provides an overview of psychoactive substances seized at 2 international dance festivals in Belgium. In total, 1151 samples were analysed on-site using ATR-FT-IR and Raman. Selected samples were confirmed with GC-MS and quantified using GC-FID. Overall, 28 different psychoactive substances were registered in various physical forms, predominantly ecstasy-like tablets (44.3 %) and powders (34.1 %). MDMA remains the most prevalent drug, followed by cocaine and ketamine. In addition, 7 different types of synthetic cathinones (mainly MMC and CMC analogues) were detected. Notably, 33 "pink powder" samples, commonly referred as "pink cocaine", were analysed, revealing 16 distinct combinations in their composition. A new phenomenon involves colored liquids, often containing combinations of 2 or more synthetic drugs, such as amphetamine analogues and synthetic cathinones. Based on the analysis results, it can be concluded that there is a diversification of the drug market by the detection of 28 psychoactive substances used at a party scene. Additionally, alongside the rise of polydrug formulations, users take drugs with diverse pharmacological effects, including stimulants ("uppers"), sedatives ("downers") and psychedelics. The majority of the substances had high purity and were identified on-site using 2 complementary spectroscopic techniques with optimized settings and up-to-date libraries. The on-site detection of polydrug formulations (in powders, tablets and liquids) and low-dosed psychoactive substances (< 10 % w/w) is challenging, resulting in the necessity of lab confirmation for unambiguous identification.

Classical psychedelics, like lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), and psilocybin, can alter perception, emotion, and cognition, and have shown promise as 're-purposed' treatments for some psychiatric disorders. Recent trials have, e.g., demonstrated rapid and sustained symptom relief in treatment-resistant depression. While promising as a treatment, the neurobiological mechanisms underlying both the subjective and clinical effects remain incompletely understood. Also, their broader influence on (intra) cellular processes, neural circuits, and brain-wide connectivity is less well documented. Here, we review the molecular and network-level alterations induced by classical serotonergic psychedelics through a systematic review of experimental and (pre)clinical studies from 1990 onward. We focus on the short-term impact on receptor activity, intracellular signaling, and functional brain connectivity underlying the psychedelic experience. Most psychedelics primarily act as serotonin 5‑HT₂A receptor agonists, initiating intracellular signaling pathways that modulate neuroplasticity, glutamate release, and cortical excitability. Psychedelics disrupt functional network connectivity, particularly within the default mode network, while enhancing global integration across brain regions. These effects are associated with subjective experiences of 'ego dissolution' and altered perception, which may contribute to their therapeutic effects. This review synthesizes findings at the molecular and systems level and their interaction during the psychedelic state. While no single model explains all effects, several overlapping theories begin to bridge receptor-level activity with large-scale brain connectivity changes. Improving our understanding of their neurobiological basis may help clarify how psychedelics act and allows for more tailored opportunities to enhance their therapeutic effects and clinical application in a stratified manner.

BACKGROUND: Antidepressants are the primary treatment for major depressive disorder (MDD), yet their precise neurobiological mechanisms remain incompletely understood. This study aimed to elucidate neural differences between medicated and unmedicated MDD patients by analyzing resting-state functional magnetic resonance imaging data.

METHODS: We conducted a coordinate-based meta-analysis, complemented by behavioral, genetic, and neurotransmitter-level evaluations to identify potential therapeutic targets and diagnostic biomarkers. Using seed-based d-mapping with permutation of subject images (SDM-PSI), we assessed brain activation changes associated with antidepressant treatment. The identified regions were further characterized using large-scale molecular and functional brain databases.

RESULTS: A total of 59 studies on unmedicated MDD (2,618 patients, 2,486 controls) and 15 studies on medicated MDD (541 patients, 483 controls) were included. The meta-analysis revealed significantly increased activation in the left striatum among medicated patients, a region linked to cognitive functions such as memory and perception. Gene expression analysis highlighted SLC5A7 and prolactin (PRL) as key genes in this region, while neurotransmitter mapping showed associations with serotonin (5-HT1a, 5-HT2a) and dopamine (D1, D2) receptors. Additionally, reduced activation in the left middle occipital gyrus (MOG) was observed across both medicated and unmedicated groups. This region, implicated in recognition and face processing, showed high expression of TFAP2B and PRL and was associated with serotonin and norepinephrine transporter distributions.

CONCLUSIONS: These findings suggest that the left striatum may represent a core neurofunctional target of antidepressant treatment, while the left MOG may serve as a stable neurobiological marker for MDD diagnosis, independent of pharmacological status.

The 5-HT2A and 5-HT2C receptors are key therapeutic targets for CNS disorders. We investigated whether a nonhallucinogenic dual 5-HT2A/5-HT2C agonist could offer novel treatment potential. Large screening of in-house structurally diverse compounds revealed centhaquin, an FDA-approved hypovolemic shock drug, as a selective 5-HT2C agonist (EC50: 35 nM). We then synthesized 22 aza-aryl analogs with modified piperazine groups, and identified two dual agonists, 3ci and 3dh (EC50 < 1 μM), with no 5-HT2B activity up to 10 μM. Molecular docking highlighted critical interactions with Ser159 (5-HT2A) and Ser138 (5-HT2C) on the upper side of the orthosteric binding pocket. Pharmacokinetic studies in mice demonstrated that 3ci was rapidly absorbed in the plasma and brain (T _max = 0.08 h; C _max = 936.4 ng/mL plasma, 2446.8 ng/g brain). Both compounds (3ci and 3dh, 20 mg/kg, i.p.) triggered a head-twitch response but were less potent than the hallucinogenic control 2,5-dimethoxy-4-iodoamphetamine, suggesting a reduced hallucinogenic liability. These results highlight 3ci as a promising lead for developing 5-HT2A/2C dual agonists to treat CNS disorders.

Recent patents unveil a new wave of psychedelic analogs optimized for 5-HT₂A receptor modulation, reduced adverse effects, and tunable duration of action. By refining DMT and psilocin scaffolds through prodrug design, fluorination, and structure-activity exploration, these innovations promise safer, shorter-acting psychedelic medicines that align with clinical workflow and improve therapeutic predictability for psychiatric disorders.

BACKGROUND: Ibogaine is a naturally occurring hallucinogenic alkaloid originally used in ritualistic ceremonies by West Central African tribes for centuries. Ibogaine's rise in popularity in the 1960s was fueled by reports from those with a heroin addiction that claimed ibogaine stemmed their addiction. Currently, there is a renewed interest in ibogaine's potential for treating opioid dependence.

METHODS: We reviewed ibogaine's mechanism of action, potential drawbacks associated with its use, and recent progress in clinical trials.

RESULTS: Ibogaine acts on several neurotransmitters in the brain such as μ and κ opioid receptors, dopamine, serotonin, N-methyl-D-aspartate, and nicotinic acetylcholine receptors. Ibogaine's anti-addictive effects are thought to be related to its activity on nicotinic acetylcholine receptors in the ventral tegmental region of the midbrain. Regarding its cardiotoxicity, ibogaine has shown to cause QTc prolongation leading to polymorphic ventricular tachycardia with cardiac arrest in one case. However, in an observational cohort study that included 30 participants, no serious adverse events occurred while taking ibogaine. Currently, there is a phase 1/2a study that has been completed, but no results regarding adverse events have been reported.

CONCLUSION: Ibogaine is an interesting candidate that needs further study to determine its safety and potential for treating opioid dependence.

Australia's reclassification of psilocybin as a Schedule 8 substance for treatment-resistant depression represents a significant shift in psychiatric policy. While this regulatory change positions Australia as a global leader in psychedelic medicine, its implementation has revealed substantial challenges. This article critically examines the regulatory, ethical and operational complexities surrounding the provision of psilocybin-assisted therapy in clinical practice. Key issues include limited prescriber access, absence of Australian Register of Therapeutic Goods-listed products, lack of standardised training pathways and significant cost barriers. Ethical considerations such as informed consent, cultural safety and therapeutic fidelity are also discussed, particularly in the context of trauma-informed care. This article proposes a series of structural recommendations to support safe and equitable deployment, including national training accreditation and fidelity monitoring tools. In addition, to maximise the efficacy of psilocybin-assisted therapy, we recommend that research explores the potential of neurobiologically informed stratification models to assist with treatment recommendations. These recommendations aim to enhance clinical integrity through evidence-based patient selection, improved safety, and to ensure that emerging psychedelic treatments are integrated responsibly within Australia's mental health system. By addressing these foundational gaps, Australia can move beyond regulatory novelty ensuring the therapeutic potential of these products is realised in a manner which is scientifically sound and upholds the integrity of psychiatric practice.

OBJECTIVE: Unipolar and bipolar depression severely impact millions of individuals worldwide, with a significant subset of cases remaining unresponsive to conventional treatments. Psilocybin-assisted psychotherapy (PAP) has demonstrated therapeutic efficacy; however, the optimal psychotherapeutic approach remains undefined, ranging from unstructured models rooted in historical practices to modern frameworks that are structurally tailored for depression. This narrative review proposes a conceptualization of psychotherapeutic models employed in existing interventional trials of PAP for depression and provides a preliminary comparison of their main characteristics and evidence for efficacy.

METHODS: The online databases PubMed, PsycINFO, and Google Scholar were searched for interventional trials evaluating PAP for individuals with unipolar or bipolar depression.

RESULTS: A total of 38 publications were reviewed, contributing to the conceptualization of two main types of psychotherapy models: 1) 'Specific' approaches (most commonly Acceptance and Commitment Therapy and Perceptual-Control Therapy) and 2) 'Non-specific' models of psychological support. Both models emphasize the critical role of the therapeutic alliance, yet differ in mechanistic focus, with specific models being developed to enhance psychological flexibility and non-specific models emphasizing the concept of the 'inner-healer.' Importantly, critical gaps in the literature were identified, including methodological limitations of current evidence and the need for standardized reporting guidelines.

CONCLUSION: Although each PAP model differs, both may have clinical relevance in depression treatment. Future work should explore the standardized reporting of psychological interventions in PAP and comparative study designs to better evaluate non-specific and specific models and inform treatment guidelines.

Schedule-induced polydipsia (SIP) arises when subjects consume excessive amounts of water during interval responding on operant tasks, a paradigm introduced and mostly developed in rats. Neuropharmacological studies conducted on SIP have mainly shown a prominent role of dopamine and 5HT in this adjunctive behavior. In particular, D₁/D₂ receptor antagonists decrease SIP, whereas low doses of dopamine reuptake blockers increase SIP. There is more specific evidence of a decline in SIP after lesions of the mesolimbic dopamine pathway. A decline in SIP is likewise observed after the injection of 5HT reuptake blockers and modulated by 5HT_2A/5HT_2C receptor agonists and antagonists. Despite more limited studies with other neurotransmitter systems, SIP has so far been shown to decline after the injection of muscarinic or NMDA receptor antagonists as well as benzodiazepine receptor agonists. Under some conditions, the role of neuroendocrine factors is shown by alterations in blood corticosterone levels during the course of SIP, indicative of its stress-reducing properties.

The quick and accurate identification of the powerful psychoactive compound Dimethyltryptamine (DMT) is still a significant drawback in forensic science and investigation concerning clinical toxicology. To overcome the issues associated with classical analytical instrumentation, a novel class of innovative highly sensitive nanosensors based on pristine and doped C₂₀ fullerenes is presented. Using a heavy computational workflow grounded in Density Functional Theory (DFT) at the computational level B3LYP-D3/6-311G(d, p) in the CPCM solvation model (water phase), we systematically examined the sensing properties of pristine C₂₀, and the boron (BC₁₉), germanium (GeC₁₉), and silicon-doped (SiC₁₉) C₂₀ fullerenes to DMT. We use calculated values based on theoretical properties relating to the performance (adsorption energy (Eads), HOMO-LUMO gap (HLG), electrical conductivity (σ), and recovery time (τ)). According to the data, each nanomaterial will have its own unique and promising applications. The BC₁₉ and SiC₁₉ nanostructures presented extremely strong adsorption energies for DMT of -40.78 kcal.mol^{- 1} and - 18.82 kcal.mol^{- 1}, respectively, and recovery times that indicated effectively irreversible binding. The combination of high Eads and negligible responsibility change in electrical conductivity of BC₁₉ and SiC₁₉ suggests they would work well as candidates for adsorption and removal applications where stable analyte capture is desired. On the other hand, the GeC₁₉ nanosensor showed an unprecedented and selective response, with adsorption of DMT leading to remarkable increases in the electrical conductivity of the nanomaterial of over 16 orders of magnitude, from 3.4 × 10^{- 15} S.m^{- 1} to 1.9 × 10² S.m^{- 1} while exhibiting a relatively strong adsorption energy of -25.75 kcal.mol^{- 1}. This unique alteration identifies GeC₁₉ as the top-performing disposable electrochemical sensor for fast, sensitive, and selective detection of DMT. These interactions were also confirmed by NBO, NCI, and QTAIM analyses, which indicated strong charge transfer (NBO), attractive non-covalent interactions (NCI), and medium strength hydrogen bonding (QTAIM) in the BC₁₉@DMT, GeC₁₉@DMT, and SiC₁₉@DMT complexes, respectively. This work not only provides the first theoretical evidence for C₂₀-based DMT detection, but also provides a clear pathway for experimental imagining of novel, task-specific nanosensors with important implications for future applications in forensic and point-of-care diagnostics.

Psychedelic substances and meditation can elicit personally meaningful experiences that support well-being, yet their relative and combined contributions remain unclear. Meditation typically produces gradual improvements through sustained practice, whereas psychedelics may induce acute shifts. To examine these dynamics, we re-analysed data from two cross-sectional online surveys using multiple regression models. In Study 1 (N = 679), we assessed associations of cumulative psychedelic use and meditation practice with well-being, ill-being, and psychological flexibility. When examined separately, both practices were associated with greater well-being and flexibility. However, when considered jointly, the associations for psychedelics were reduced or became nonsignificant, whereas meditation remained consistently associated with the outcomes. Weak evidence also emerged for a potential synergy effect via an interaction between the two practices. In Study 2 (N = 137), we examined perceived well-being changes following a personally meaningful experience facilitated by psychedelics alone, meditation alone, or both combined. Participants in the combined and meditation groups reported significantly greater improvements compared with the psychedelic-only group, although all groups showed positive change on average. Together, these findings suggest that meditation may enhance the benefits of psychedelic experiences and that meditation practice can confound associations between psychedelic use and well-being. More broadly, they highlight the importance of considering both practices together when evaluating their contributions to mental health outcomes.

Psychedelics and meditation are known for their potential to induce personally meaningful and even transformative experiences. However, it is unclear how similar these experiences are, or how they differ from each other. This explorative study used natural language processing (NLP) methods to compare reports of personally meaningful subjective experiences facilitated by either psychedelic substances or meditation. Participants (N = 197) wrote open-ended narrative reports about their most meaningful experience facilitated either with psychedelics (n = 134) or meditation (n = 63). These reports were analysed with text similarity analyses, topic modeling and sentiment analysis. The semantic and lexical contents of the reports were highly similar and both groups expressed positive emotions on average. However, psychedelic experience reports were more emotionally charged, showing higher levels of positive and negative sentiments compared to more neutral meditation experiences. These results suggest that the two types of subjective experiences might be quite similar in general, but emotional intensity could be a distinguishing factor between them. Challenges with the NLP methods and the dataset limit the conclusions that can be drawn from the study. However, it offers new hypotheses and suggestions for future research on transformative experiences.