Psychedelic Law, Science & Policy

EPA is issuing significant new use rules (SNURs) under the Toxic Substances Control Act (TSCA) for certain chemical substances that were the subject of premanufacture notices (PMNs) and are also subject to an Order issued by EPA pursuant to TSCA. The SNURs require persons to notify EPA at least 90 days before commencing the manufacture (defined by statute to include import) or processing of any of these chemical substances for an activity that is designated as a significant new use in the SNUR. The required notification initiates EPA's evaluation of the conditions of that use for that chemical substance. In addition, the manufacture or processing for the significant new use may not commence until EPA has conducted a review of the required notification; made an appropriate determination regarding that notification; and taken such actions as required by that determination.

With the issuance of this final rule, the Drug Enforcement Administration places methyl 3,3-dimethyl-2-(1-(pent-4-en-1-yl)-1H- indazole-3-carboxamido)butanoate (other name: MDMB-4en-PINACA), including its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible, in schedule I of the Controlled Substances Act. This action is being taken, in part, to enable the United States to meet its obligations under the 1971 Convention on Psychotropic Substances. This action imposes regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances on persons who handle (manufacture, distribute, reverse distribute, import, export, engage in research, conduct instructional activities or chemical analysis with, or possess) or propose to handle MDMB-4en-PINACA.

Background: Facial emotion recognition deficits are well defined in depression but understudied in treatment-resistant depression (TRD). Over the past decades, subanesthetic doses of ketamine have emerged as an effective treatment for TRD, but its effect on affective processing is still little known. Approaches from computational psychiatry, such as sequential evidence sampling models of decision making, can provide useful insight into the underlying cognitive processes of facial emotion recognition in TRD patients before and after ketamine antidepressant treatment.Aim: Provide a computational account of facial emotion recognition in TRD and the effects of ketamine treatment using hierarchical drift diffusion modeling (HDDM).Method: In this observational case-control study, 24 TRD patients and 35 healthy controls completed a FER task. TRD patients were assessed before, 2-4 hours after the initial racemic ketamine infusion, and at one week of treatment. Healthy controls were assessed at similar intervals, without intervention, to assess baseline differences and potential learning effects related to task repetition. Accuracy and reaction times were analyzed and fit with an HDDM to formalize correct facial emotion recognition as a noisy evidence-accumulation process. Parameters of the best-fitting model were compared across groups and timepoints.Results: Before treatment, TRD patients were slower but as accurate as controls. Following ketamine, the patients were significantly faster than at baseline and compared with repeated testing in healthy controls. These effects were underpinned by longer nondecision times and wider decision boundaries in patients at baseline, both of which decreased after starting ketamine. There was no behavioral or computational evidence of a negative bias in patients.Conclusions: Results suggest that processes related to psychomotor slowing and response caution, rather than affective processing, underlie deficits observed during facial emotion recognition in TRD and can be restored after starting a ketamine treatment.

Introduction. Limitations of conventional treatments for depression and anxiety, particularly in treatment-resistant cases, have driven interest in alternative therapeutic approaches. Psilocybin, a serotonergic agonist with demonstrated effects on neuroplasticity and large-scale brain networks, has emerged as a promising therapeutic option. Materials and methods: A systematic review of controlled clinical trials published between 2020 and 2025 was conducted in accordance with PRISMA guidelines. Searches were performed in PubMed/MEDLINE, Scopus, PsycINFO, Web of Science, and the Cochrane Library. Eligible studies included adults aged 18-65 years with DSM-5 diagnoses of depression and/or anxiety who received psilocybin-assisted therapy with psychotherapeutic support. Risk of bias was assessed using RoB 2, the Jadad scale, and the Newcastle–Ottawa Scale. Due to methodological heterogeneity, a qualitative narrative synthesis was performed.

Affective biases are important neuropsychological mechanisms by which emotions modulate cognition, behaviour and the subjective experience of mood. Previous studies have shown that the rapid-acting antidepressant, ketamine, and serotonergic psychedelic, psilocybin, modulate affective biases in a translational rat model. Both treatments differ from conventional, delayed onset antidepressants in being able to attenuate negatively biased memories and facilitate re-learning with a more positive affective valence. Psilocybin, but not ketamine, also positively biased new experiences, an effect similar to conventional antidepressants. This study used the different affective bias test protocols, in adult male rats, to investigate the effects of acute treatment with the serotonergic psychedelics N,N-DMT, LSD and 5-MeO-DMT, and MDMA. These drugs have different pharmacology in relation to their effects on serotonin receptor subtypes and we hypothesised this may influence their modulation of affective biases. When comparing the ability to attenuate a negatively biased memory, only MDMA had specific effects although for all drugs tested, retrieval of the FG7142-induced negative affective bias was more variable and less robust statistically. LSD attenuated the negative bias at higher doses but had non-specific effects on memory retrieval. At 24hrs post treatment only N,N-DMT had a sustained effect and none of the treatments facilitated re-learning with a more positive affective valence. However, like psilocybin and conventional antidepressants, N,N-DMT positively biased new experiences. These findings suggest there are divergent affective bias modulating effects associated with different psychedelics which may be relevant to their antidepressant effects.

Abstract Currently, Psychiatric Mental Health Nurse Practitioners (PMHNPs) often defer to electroconvulsive therapy (ECT) for individuals with TRD who fail to achieve resolution of their disorder. However, many individuals do not meet criteria for ECT or decline the treatment due to side effects and associated risks. To synthesize potential alternative treatments and address the current gap in literature that does not include first-line preferred electroconvulsive therapy (ECT), a systematic literature review was conducted using the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA 2020). Databases searched for this review included the Cumulative Index to Nursing and Allied Health Literature (CINAHL Complete), PubMed®, and the Cochrane Central Register of Controlled Trials. Search terms included “treatment resistant depression,” “treatment,” “therapy,” “intervention,” “anti-psychotics,” “antidepressants,” “ketamine,” “esketamine,” “psilocybin,” “vagus nerve stimulation,” and “ECT.” Of the records screened (n = 3,252), eligible reports (n = 559) were further refined to exclude non-English texts (n = 124), not relevant to the research question (n = 81), author(s) opinion (n = 77), and undesired patient population (n = 277). The remaining (n = 5) studies were included in this review. Aripiprazole, a second-generation antipsychotic (SGA) when used as a supplementation to antidepressant therapy decreased TRD symptoms. Extended-release ketamine tablets resulted improvement of TRD symptoms and relapse rates, while intranasal esketamine provided sustained positive effects on TRD symptoms. Single-dose psilocybin provided rapid symptom relief and sustained remission. Lastly, neuromodulation involving surgically implanted vagus nerve stimulation was proven effective in reducing TRD symptoms when compared to sham-participants.

Ketamine-Assisted Therapy (KAT) presents a promising alternative for addressing mental health challenges, particularly in treatment-resistant conditions, yet little exists in the literature guiding its implementation in an Indigenous context, for Indigenous participants, or describing culturally adapted delivery models. This paper presents insights and lessons learned from a collaborative pilot program between Siksika Health Services and ATMA CENA to design and deliver a culturally responsive KAT program within the Siksika First Nation in Alberta Canada. The initiative aimed to explore the feasibility and therapeutic impact of KAT in an Indigenous healthcare setting, while also being conscious of cultural relevance and opportunities for continued clinical and quality improvement of the program. The pilot followed a five-phase approach: collaboration, knowledge acquisition, lived experience, data collection, and follow-up. Recruitment resulted in 6 participants completing care (3 Indigenous and 3 non-Indigenous). Findings demonstrated notable improvements in symptoms of depression, anxiety, and PTSD, with participants reporting increased emotional regulation and stronger cultural connections. Cultural elements including shared meals, traditional decor and blankets, community orientation, and a mid-program break for cultural events, were central to participant reported safety, trust, and meaning making. Notably, the Indigenous and non-Indigenous participant groups, who were treated together, reported comparable gains in safety, trust, and mental, emotional, and spiritual well-being. These shared outcomes suggest the model may hold relevance for reducing inequities in group KAT delivery. Challenges and lessons learned included need to address stigma and systemic influences experienced by Indigenous participants, barriers affecting timely intention setting and integration therapy, and overcoming logistical barriers when working in rural First Nation environments. This pilot program implementation underscores the importance of culturally responsive mental health interventions and highlights key considerations for expanding psychedelic-assisted therapies in Indigenous communities.

Background Obsessive-Compulsive Disorder (OCD) can present significant challenges to individuals mental health, characterized by intrusive thoughts and repetitive maladaptive behaviors. Recent research into alternative treatments has highlighted psychedelics, notably psilocybin, for their potential therapeutic benefits in various psychiatric disorders, including OCD. This case study evaluated the impact of self-administered, low-doses of psilocybin, commonly referred to as microdosing, on symptom reduction and cognitive flexibility in OCD, with a focus on identical twins discordant for the condition. Case presentation The study documents the experiences of one twin diagnosed with OCD who began a regimen of low-doses of psilocybin containing mushrooms, while the other twin, unaffected by OCD, served as a comparison. Case X was diagnosed with OCD by a general practitioner in the Danish healthcare system. Following years of severe OCD, case X began a self-medicated regimen consisting of psilocybin containing mushrooms, corresponding to 1–5 mg of psilocybin, every 3 rd day. The other twin, case Y, who remained unaffected by OCD, and did not take psilocybin containing mushrooms. Cognitive flexibility was evaluated in both cases using a set-shift task. The affected twin reported a notable reduction in OCD symptoms, along with improvements in emotional regulation and overall well-being. However, despite these symptomatic improvements, deficits in cognitive flexibility remained present compared to the unaffected twin. Conclusion This case study underscores the potential of low-doses of psilocybin as a promising avenue for mitigating symptoms of OCD. Nevertheless, the observed disparity in cognitive flexibility highlights the nuanced nature of OCD pathology, suggesting that while low-doses of psilocybin may alleviate certain symptoms, it may not fully address underlying cognitive impairments. Further research employing larger sample sizes and rigorous longitudinal designs is imperative to elucidate the mechanisms underlying the therapeutic effects of psilocybin low-doses in OCD, offering insights into its broader applicability as a treatment modality.

Progranulin (PGRN) is a neurotrophic and anti-inflammatory factor produced mainly by neurons and microglia in the central nervous system. Progranulin haploinsufficiency causes frontotemporal dementia (FTD). In a previous study we showed that transgenic restoration of progranulin in neurons in progranulin knockout mice (NestinGrn KOBG knockout background) did not prevent the dementia-like phenotype. Here, we assessed if pharmacologic microglia depletion via PLX3397-diet (CSF1R-antagonist) had therapeutic value in these mice. Microglia depletion and spontaneous repopulation was confirmed in immunofluorescence and rtPCR studies. There was no difference in depletion or repopulation efficiency between NesGrn KOBG, PGRN KO and heterozygous (het) PGRN mice, but microglia repopulated faster than in control Grn-flfl mice, and the morphology of primary PGRN deficient microglia during repopulation was closer to homeostatic microglia, and it was accompanied by a remarkable restoration of dendritic spines and synaptic structures. Regardless of these positive effects, NesGrn KOBG and PGRN het mice experienced serious side effects during microglia depletion which peaked around the microglia nadir. Overactivity and excessive grooming escalated and caused serious skin lesions. Bulk transcriptomic and metabolomic studies in the brain taken 8 weeks after the end of PLX-diet clearly revealed differences between genotypes but mostly no lasting impact of PLX-diet, except for a further increase of proinflammatory genes, cathepsins and complement factors in PLX-treated groups. Cell type specific lipidomic studies revealed a time dependent switch not only in microglia but also astrocytes upon PLX3397 treatment. While nadir-microglia were triglyceride-laden, repopulated microglia returned to normal TG levels but were enriched in ether-bound phosphatidylcholines (PC-O) and lysophosphatidylglycerol species which are pro-inflammatory lipids; and astrocytes overtook the TG burden during repopulation. Our data suggest that microglia depletion may cause a deterioration in progranulin-deficiency.

Major depressive episode (MDE) is a common mental disorder that severely impacts patients' lives and carries a high suicide risk. About 30% of patients are resistant to oral antidepressants, necessitating alternative approaches such as neurostimulation. The subcallosal cingulate (SCC), characterized by hyperactivity and altered functional connectivity (FC) in MDE, has emerged as a key target for interventions like deep brain stimulation (DBS) and transcranial focused ultrasound stimulation (TUS). Other techniques, including repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT), may influence SCC activity indirectly via network-level effects. We searched multiple databases for studies investigating changes in SCC connectivity following various neurostimulation techniques in depression. We included 28 studies using resting-state functional MRI to investigate SCC FC changes following neurostimulation for depression with different modalities: ECT, DBS, rTMS, tDCS, TUS. Results showed high variability across studies. rTMS targeting the DLPFC modulated SCC FC with the OFC, precuneus, and default mode network (DMN), while other targets affected connectivity with the hippocampus and supramarginal gyrus. Stronger baseline anticorrelation between SCC and DLPFC predicted better rTMS response. ECT studies reported heterogeneous effects, involving the temporal pole and vmPFC. TUS targeting SCC increased FC with the DLPFC, whereas TUS to the DLPFC enhanced FC between SCC subregions and mPFC or cerebellum. Findings remain heterogeneous, likely due to methodological inconsistencies, including variability in SCC ROI definitions and stimulation protocols. Standardizing analysis methods is essential to improve reproducibility and clarify the SCC's role in treatment response.

Major depressive disorder (MDD) is increasingly understood as a multifactorial psychiatric disorder involving interacting neural, immune, metabolic, and microbial processes. Within this framework, the microbiota–gut–brain axis and mitochondrial bioenergetics have emerged as potentially intersecting contributors to depressive symptomatology. Preclinical studies suggest that microbial metabolites—especially short-chain fatty acids (SCFAs)—can influence oxidative phosphorylation, redox balance, neuroinflammation, and synaptic plasticity, whereas inflammatory signals such as lipopolysaccharide may disrupt mitochondrial dynamics. However, the strength of evidence is uneven: mechanistic support is strongest in cell and animal models, whereas human data remain heterogeneous and largely associative. This narrative review critically synthesizes current evidence on microbiota–mitochondria crosstalk in MDD, distinguishing established findings from emerging hypotheses. It also examines recent psychobiotic trials, metabolomic and biomarker studies, and microglia–mitochondria mechanisms, and discusses the translational limitations that currently constrain clinical application. Overall, this axis represents a plausible and clinically relevant framework for hypothesis generation and adjunctive intervention development, but it should not yet be regarded as a fully validated causal pathway or stand-alone therapeutic target in MDD.

Introduction Psychological trauma is prevalent among beneficiaries of social assistance, posing significant challenges to effective intervention. Traditional psychological support methods are often constrained by limited resources, delayed responses, and insufficient personalization. Against this backdrop, artificial intelligence (AI) offers new opportunities to enhance the efficiency and precision of psychological trauma interventions. This study explores the feasibility and effectiveness of integrating AI technologies into social assistance systems. Methods This study adopts a mixed analytical approach. First, it reviews the current applications of AI in mental health, focusing on natural language processing, emotion recognition, and personalized recommendation systems. Based on this, an AI-driven framework for psychological trauma intervention is proposed, including the development of intelligent auxiliary diagnostic systems and personalized intervention plans. Empirical data are collected through questionnaire surveys to evaluate user experiences and intervention outcomes. Results The findings indicate that AI-assisted interventions significantly improve user satisfaction and mental health outcomes. Specifically, 75% of respondents report being satisfied or very satisfied with the intelligent mental health system. Approximately 60% of participants experience noticeable improvements in their mental health status. Furthermore, 85% of respondents consider the personalized intervention plans to be well-aligned with their individual needs and circumstances. Discussion The results demonstrate that AI technologies can effectively address key limitations of traditional psychological interventions by enhancing accessibility, responsiveness, and personalization. The integration of AI into social assistance systems not only improves intervention outcomes but also offers scalable solutions for resource-constrained settings. This study provides empirical support for the application of AI in social assistance and highlights its transformative potential in advancing mental health governance.

Serotonergic psychedelics such as N,N-dimethyltryptamine (DMT) and 4-phosphoryloxy-N,N-dimethyltryptamine (psilocybin) show therapeutic promise for psychiatric and neurodegenerative disorders but may be limited by liabilities from serotonin (5-HT)-2A mediated psychoactive effects and potential cardiotoxicity via 5-HT2B activation. To address these limitations, we designed and synthesized 2-halogenated derivatives of DMT and psilacetin to reduce 5-HT2A/5-HT2B activity while retaining engagement of therapeutically relevant targets, particularly 5-HT6, 5-HT2C, and 5-HT1B. This study demonstrated that 2-position halogenation decreased affinities, potencies, and efficacies at 5-HT2A and 5-HT1A receptors while preserving potent 5-HT6 agonism, especially for 2-Br-psilocin. The analogues exhibited reduced affinities at 5-HT2B and hERG ion channels, suggesting safer cardiac valve and cardiotoxic profiles. In C57BL/6J mice, 2-Br-psilacetin did not induce the head-twitch response and attenuated 2,5 dimethoxy-4-iodoamphetamine (DOI)-induced head-twitch behavior, suggesting a reduced potential for inducing psychedelic effects. Behavioral assays further revealed improvements in stress-induced affective measures and hippocampus-independent cued learning at intermediate doses. These findings identify 2-halogenated tryptamines as polypharmacological serotonergic ligands with reduced psychoactivity and cardiac valve and toxic liabilities, supporting their potential as next-generation psychedelic-inspired therapeutics.

Abstract Depression in Parkinson’s disease (PD) is often reported as being more debilitating than the motor symptoms and has been shown to accelerate disease progression. Identifying its underlying neurobiology is crucial in the discovery of mechanism-informed treatments. We hypothesize that lower synaptic density in mood circuitry drives symptoms of depression in PD. To test this hypothesis, we used PET imaging and [11C]UCB-J - a radiotracer that binds to synaptic vesicle protein 2A (SV2A) to image synaptic density across patients with PD and depressive symptoms (PDd; n=10), PD patients without depressive symptoms (PDnd; n=20) and healthy controls (HCs; n=18). The primary outcome was binding potential (BPND) in mood circuitry. Participants with PDd exhibited significantly lower synaptic density compared to HC and PDnd in the dorsolateral prefrontal cortex (dlPFC) (-22.0%, p <0.001; -19.9%, p =0.002), anterior cingulate cortex (ACC) (-27.9%, p <0.001; -24.0%, p =0.002), amygdala (-25.1%, p <0.001; -18.9%, p =0.006), and hippocampus (-28.1%, p <0.001; -20.3%, p =0.003). Synaptic density was significantly and negatively correlated with the severity of depressive symptoms across all participants with PD (n=30) in the dlPFC (r=-0.59, p =0.002), ACC (r=-0.68, p <0.001), amygdala (r=-0.53, p =0.004), and hippocampus (r=-0.56, p =0.003). These findings provide the first in vivo evidence that lower synaptic density in mood-related brain regions may contribute to depression in PD. If confirmed, they would support the evaluation of interventions that target synaptic loss/induce synaptic plasticity in individuals with PD and comorbid depression.

Digital nudges refer to subtle modifications in digital choice architectures that are increasingly applied across domains such as healthcare, human–computer interactions, and behavioral science. However, existing approaches often overlook users’ needs, contextual factors, and ethical considerations related to transparency and autonomy. This systematic literature review, guided by PRISMA 2020, examines the integration of co-design methodologies in digital nudging across four dimensions: participants, application domains, nudge forms, and development methods. The findings show that co-design is primarily driven by end-users, supported by domain experts and technology specialists. Applications are concentrated in health-related contexts, particularly chronic disease management and mental health. The effectiveness of priming varied across studies, with some reporting short-term benefits and others indicating user fatigue, suggesting context-dependent impact and limited long-term effectiveness.

This case report presents the case of a 25-year-old woman who developed ketamine addiction following a single sub-anaesthetic dose of intranasal ketamine in a pilot study investigating intranasal racemic ketamine for acute suicidality. She had a history of depression, obsessive-compulsive disorder, autism spectrum disorder and anorexia nervosa, and she had sporadically used alcohol and cannabis. Following the intervention, she reported a transient reduction in suicidal ideation but later sought illicit ketamine to recreate its calming effects on intrusive thoughts. Subsequently she also started abusing cocaine and 3-methylmethcathinone (3-MMC). Within weeks she had escalated to daily use, which led to financial distress, housing instability and a suicide attempt when access was cut off. Although she initially ceased use, she later relapsed into ketamine and cocaine addiction. This case highlights the addictive risk of ketamine, even in controlled settings. Given ketamine's rising use in psychiatric treatment, careful screening, monitoring and awareness of addiction potential are essential. Future research should evaluate patient-specific risk factors and dosing strategies to minimise abuse liability.

This systematic review and meta-analysis synthesized data from 13 clinical trials (n=606) evaluating psilocybin-assisted psychotherapy for major depressive disorder and treatment-resistant depression. Despite early enthusiasm, the pooled standardized mean difference (-0.79, 95% confidence interval: -3.98 to 2.40, p=0.63) revealed no statistically significant overall antidepressant effect, with extreme heterogeneity (I2=96.9%) across studies. Notably, the type of control group (active comparator vs. placebo/waitlist) accounted for 98.7% of between-study variance, with waitlist and low-dose comparators producing exaggerated effect sizes. Session frequency was a significant moderator: 2 to 5 psilocybin sessions yielded larger effects, while more intensive protocols attenuated benefit. Neither participant age nor follow-up duration significantly influenced outcomes. Evidence of reporting bias and small-study effects was detected (Egger’s test p=0.012). Sensitivity analyses demonstrated that no single study accounted for the non-significant pooled result. Overall, psilocybin’s antidepressant efficacy appears highly context-dependent—shaped by trial design, comparator, and session structure—rather than universally robust. These findings underscore the need for larger, rigorously controlled trials to clarify psilocybin’s therapeutic role in depression.

We read with interest the article entitled ‘Differential effects of ketamine enantiomers on electroencephalogram (EEG) parameters including the gamma-delta shift phenomenon’ (Koncz et al., 2026). The authors provide valuable electrophysiological data showing that esketamine produced stronger wake-promoting and non-rapid eye movement (NREM) sleep-suppressing effects than arketamine in rats and that only esketamine induced the gamma–delta shift. These findings are of interest in ongoing efforts to identify EEG-based biomarkers of rapid-acting antidepressants. However, we believe that several aspects of the authors' interpretation warrant caution. First, the study was conducted in naïve control rats without depression-like phenotypes (Chang & Hashimoto, 2024). This is an important limitation when proposing the gamma–delta shift as a biomarker of antidepressant efficacy. Ketamine exerts robust antidepressant effects in patients with treatment-resistant depression (TRD), whereas its effects in healthy subjects are qualitatively different and may include aversive or depressive-like symptoms, including anhedonia (Nugent et al., 2019). Therefore, EEG changes observed in healthy animals cannot be assumed to reflect mechanisms underlying antidepressant response in disease-relevant states. Validation of the gamma–delta shift as a biomarker of antidepressant action will require demonstration of its association with behavioural improvement in established rodent models of depression or stress susceptibility, and ideally in patients with major depressive disorder or TRD. Second, the conclusion that the absence of a gamma–delta shift after arketamine is consistent with a lack of antidepressant efficacy in TRD appears premature. Although recent placebo-controlled trials of arketamine did not meet their primary endpoints, these studies were limited by very small sample sizes and substantial placebo effects. Accordingly, the currently available clinical data do not definitively exclude antidepressant efficacy of arketamine under alternative dosing regimens, patient stratification strategies or trial designs. Thus, the present EEG findings in healthy rats should not be used to support strong translational claims regarding the clinical inefficacy of arketamine. In our view, the current study demonstrates that esketamine and arketamine produce distinct EEG signatures in normal rats, but it does not establish that the gamma–delta shift is a specific biomarker of antidepressant efficacy. Rather, the findings suggest that esketamine-induced NMDA receptor inhibition may contribute to the observed EEG changes, including the gamma–delta shift (Koncz et al., 2026). Importantly, dissociative symptoms related to NMDA receptor inhibition are not necessarily associated with antidepressant efficacy (Hashimoto, 2025a, 2025b). From this perspective, the EEG changes observed after esketamine administration may reflect neurophysiological effects associated with NMDA receptor-mediated behavioural changes, including dissociative symptoms and other adverse effects, rather than a specific biomarker of antidepressant response. Future clinical studies should therefore examine EEG changes after esketamine administration in patients with depression and determine whether these alterations are associated with antidepressant response or dissociative symptoms. Overall, further studies using depression-relevant animal models and clinically relevant patient populations will be essential before the gamma–delta shift can be considered a translational biomarker of the antidepressant effects of ketamine enantiomers. Key protein targets and ligands in this article are hyperlinked to corresponding entries in the IUPHAR/BPS Guide to PHARMACOLOGY http://www.guidetopharmacology.org and are permanently archived in the Concise Guide to PHARMACOLOGY 2025/26 (Alexander et al., 2025). Kenji Hashimoto: Conceptualization; writing—original draft; writing—review and editing. ChatGPT (OpenAI) was

Elderly colorectal cancer (CRC) patients face high risks of postoperative depression state, inadequately addressed by opioid-based analgesia. Esketamine, an NMDA receptor antagonist with rapid antidepressant effects, offers potential benefits but lacks evidence in this population. This double-blind RCT enrolled 99 elderly (≥ 65 years) CRC resection patients, randomized to three postoperative PCA groups: C: Sufentanil (2 µg/kg) + saline placebo, ES1: Sufentanil + esketamine 1 mg/kg, ES2: Sufentanil + esketamine 2 mg/kg. Primary outcomes were anxiety/depression (HAMA/HAMD scores) at 24 h postoperatively. Secondary outcomes included VAS pain scores, patient satisfaction, and adverse events. Depression/Anxiety: Both esketamine groups showed significantly lower HAMD/HAMA scores vs. control at 24 h and 72 h (e.g., 24 h HAMD: ES1 6.16 ± 2.16, ES2 7.10 ± 2.55 vs. C 9.87 ± 3.67; p < 0.001), with no dose-dependent difference (p > 0.05 ES1 vs. ES2). Pain Control: No intergroup differences in resting/activity VAS scores or rescue analgesia demands (p > 0.05). Satisfaction: Higher satisfaction rates in ES1 (77.4%) and ES2 (90.0%) vs. C (50.0%) (p = 0.002). Safety: Comparable adverse events across groups (p > 0.05). Low-dose esketamine (1 mg/kg) adjunct to sufentanil PCA significantly reduces postoperative depression and anxiety state in elderly CRC patients without enhancing analgesia or increasing adverse events. Its profound psychological benefits and high patient satisfaction support its integration into enhanced recovery protocols for this vulnerable cohort. Registry: Chinese Clinical Trial Registry(chictr.org.cn), TRN: ChiCTR2300070763, Registration date: 23 April 2023.

Psilocybin-assisted therapy shows promise for depression, though current evidence relies on Phase 2 trials with notable methodological limitations. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating psilocybin-assisted therapy for major or treatment-resistant depression up to February 2024. We evaluated depressive symptom severity using random-effects meta-analysis, moderator analyses, Cochrane Risk of Bias 2, and GRADE methodology. Nine RCTs (N=514) were included. Psilocybin therapy demonstrated a large pooled effect size for symptom reduction (SMD = 1.270, 95% CI: 0.865–1.676, p<0.001). However, substantial heterogeneity was observed (I² = 79.1%). Comparator type significantly moderated outcomes, with waitlist controls showing substantially larger effects than active/placebo controls. Overall GRADE certainty of evidence was rated LOW due to risk of bias, heterogeneity, short-term outcomes, and publication bias concerns. In conclusion, while psilocybin-assisted therapy yields a large pooled effect estimate for depression, current findings are preliminary. Results are heavily qualified by methodological constraints, including waitlist-inflated efficacy, compromised blinding from subjective psychedelic effects, and the confounding influence of integrated psychological support. Confirmation through robust Phase 3 trials is required before supporting routine clinical implementation.

Introdução: A depressão resistente ao tratamento (DRT) afeta 30% a 40% dos pacientes com transtorno depressivo maior (TDM) e é responsável por mais da metade dos custos totais da depressão. A ausência de definição consensual e a proliferação de opções terapêuticas tornam a escolha do tratamento farmacológico um desafio clínico relevante. Objetivo: Sintetizar sistematicamente as evidências sobre eficácia, segurança e tolerabilidade das principais estratégias farmacológicas para DRT em adultos, comparando-as entre si e em relação ao placebo. Método: Revisão sistemática narrativa com síntese integrativa de metanálises em rede (NMA) e revisões sistemáticas, conduzida conforme as diretrizes PRISMA 2020. Foram consultadas as bases MEDLINE/PubMed, Embase, Cochrane Library, PsycINFO, LILACS e SciELO. A qualidade metodológica foi avaliada pelo RoB 2.0 e GRADE. Resultados: As estratégias de potencialização com antipsicóticos atípicos (aripiprazol, brexpiprazol, quetiapina) e lítio demonstraram eficácia superior ao placebo em taxas de resposta e remissão, sendo os mais bem estabelecidos para uso clínico. Hormônios tireoidianos (liotironina) e compostos dopaminérgicos (modafinila, lisdexanfetamina) também apresentaram resposta significativa. Os compostos glutamatérgicos — cetamina intravenosa (IV) e esketamina intranasal — destacaram-se pela rapidez de ação (horas a dias) e por uma NMA abrangente (72 ECRs, 12.105 participantes) que os posicionou, junto à ECT e à psilocibina, como os tratamentos com melhor balanço de eficácia e tolerabilidade. Meta-análises comparativas head-to-head mostraram que cetamina IV e esketamina intranasal apresentam taxas de resposta e remissão semelhantes (OR=1,26; IC95% 0,92–1,71), com vantagem numérica não significativa para a cetamina IV, que também produz resposta mais rápida. O lítio, embora mais antigo, demonstrou eficácia equivalente à esketamina e ao aripiprazol em NMA recente, com perfil único de redução da mortalidade por suicídio. Ziprasidona, mirtazapina e cariprazina apresentaram maiores taxas de descontinuação. Conclusão: A evidência atual apoia o uso de antipsicóticos atípicos aprovados e lítio como primeira escolha de potencialização, e cetamina/esketamina para casos urgentes ou refratários a múltiplas estratégias convencionais. A escolha deve ser individualizada, considerando rapidez de ação, perfil de eventos adversos, custo e disponibilidade. Lacunas persistem em dados de longo prazo, qualidade de vida e comparações head-to-head robustas.

A manifesto for a non-Laplacian neuropsychopharmacology Contemporary clinical medicine operates with an epistemic apparatus borrowed, largely unrevised, from 19th century inferential statistics and a Laplacian-Cartesian ontology that the systems it proposes to treat — living bodies, nervous systems, minds — have never obeyed. The randomized controlled trial is not questioned here as a method; it is questioned as a so-vereign. Once a drug leaves the averaged patient of the phase-III curve and meets the single patient at the bedside, the tacit metaphysics of the trial collapses: diagnostic categories reveal themselves as soft thresholds on continuous distributions, mechanisms of action prove to be dose-reversing and history-dependent, and the system under intervention — functioning within a strictly non-linear regime — carries the memory of every molecule it has ever met. This essay argues that a mature molecular neuropsychopharmacology must rest on three simultaneous commitments. Epistemically, it must prioritize a non-Laplacian apparatus: one that deploys causal discovery, multivariable Mendelian randomization, and targeted maximum likelihood to dismantle the illusions of observational correlation, while integrating marginal structural models and Lyapunov analysis to map the divergent trajectories of a system where interindividual variability is signal, never noise. Pharmacologically, it must abandon the fiction of equilibrium binding and read receptor occupancy as a hysteretic, path-dependent adaptation: a continuous remapping of the system’s topology where desensitization and differential expression are not noise, but the very language of its non-linear memory. Ontologically, it must break with the Cartesian pilot haunting psychiatric thought and relocate the site of drug action within the phenomenological corps-sujet. Here, consciousness is not a spectator to neural events but the embodied style in which a living body inhabits its world, a realization that the psychotropic effect is not an adjustment of a biological machine, but a topological shift in the patient's very horizon of possibility. Read through this triple commitment, psychotropics — from classical antipsychotics to psychedelics and cannabinoids — cease to be mere items in a therapeutic drawer and become probes into the very architecture of selfhood: chemical perturbations that reveal the fragile, non-linear topology of the mind they modulate. The clinician who emerges is no longer a herald of protocols but an architect of homeostasis, trained to decipher the pharmacological grammar of a molecule and navigate its complex translation into the unique, path-dependent trajectory of an individual life. Conceptual Foundations 📖 Psychotropicā Neuroscience: Molecular neurobiology of consciousness modulation Refusing the reductive comfort of the "chemical imbalance," Psychotropicā Neuroscience re-authors the pharmacological textbook as an architectural map of the human condition, tracing the journey from receptor kinetics to the very threshold of conscious experience. It transposes the drug from a mere clinical corrective into a transformative agent of the subject’s ontology, demanding a rigor that honors the complexity of the mind it seeks to modulate. 📖 The Fractal Brain: Nonlinear dynamics, fractal geometry, and medical epistemology Clinical medicine persists in a pre-Copernican slumber, clinging to a linear mathematics of stasis while the living organism operates as a far-from-equilibrium dissipative structure. The Fractal Brain executes the necessary demolition of this inheritance, relocating health from the dead center of the statistical mean to the vital, normative complexity of a system’s non-linear trajectory.

This brief argues that autism and the psychedelic state share a computational signature — relaxed priors and over-weighted prediction errors, both mediated through the 5-HT2A receptor system — and that much of what is called "autistic distress" is not intrinsic to the neurology but intrinsic to that neurology meeting an environment that refuses to function as good set and setting. Three strands of published research are brought together. First, the endogenous DMT literature, including the 2019 demonstration that DMT is synthesized in mammalian brain at neuromodulator concentrations (Dean et al.) and the 2019 perspective proposing dysregulated endogenous DMT metabolism as a factor in autistic neuroplasticity (Esen-Danaci et al.). Second, the predictive-coding theories of autism — the hypo-priors account (Pellicano & Burr 2012) and HIPPEA (Van de Cruys et al. 2014) — which converge on a lived regime of weak high-level priors and over-weighted prediction errors. Third, the REBUS framework (Carhart-Harris & Friston 2019) and its successor ALBUS (Safron et al. 2025), which describe the psychedelic state in the same computational vocabulary. Placed side by side, the three literatures describe the same regime. The brief then draws on the clinical bad-trip predictor literature (Carbonaro et al. 2016 and decades of psychedelic-assisted therapy protocols) to argue that the everyday social conditions imposed on autistic people — unfamiliar social structure, no preparation, no trusted presence, continual correction and invalidation, punished exit, and pressure to perform normalcy — are, almost line-for-line, the clinical predictors of a difficult or harmful psychedelic experience applied chronically and without consent. Familiar autistic phenomena — meltdowns, shutdowns, stimming, special interests, need for routine, masking — are reframed in trip-language terms, and the accommodations long requested by autistic self-advocates are shown to overlap, nearly point-for-point, with the psychedelic-assisted therapy protocol (prepare, support, do not interfere, integrate). This is an open hypothesis brief, not a clinical or pharmacological recommendation. It is offered as a synthesis for critique from three research communities that rarely read each other, and from the autistic community whose lived observations motivated the synthesis.

Abstract Background Psilocybin is a classic psychedelic that acutely alters brain functional connectivity. These changes are linked to therapeutic doses and subjective effects, with some evidence that changes persist beyond acute drug administration. However, the effects of lower doses on sustained connectivity changes remain unclear. Methods Ten healthy volunteers received three psilocybin doses (between 5 and 20 mg) in a randomized and blinded order, with at least one week between doses. Resting-state functional magnetic resonance imaging was completed at baseline and one week after a single dose. Functional connectivity changes were analyzed in relation to dose and altered conscious states at both the level of individual brain region connections (edges) and resting-state networks. Results Dose-dependent changes in 77 edges (76 increases, 1 decrease, of 1275 possible) were observed, but none survived multiple-comparison correction. At the network level, we observed one dose-dependent between-network increase (of 21 possible), and one dose-dependent within-network increase (of seven possible); the latter surviving correction. Alterations in conscious state were positively associated with widespread connectivity changes (dose-adjusted), with many network-level associations surviving correction. These directional patterns showed that lower doses and smaller conscious state alterations were linked to decreased connectivity, whereas higher doses and greater conscious state alterations were linked to increased connectivity. Conclusions Dose level and acute subjective effects were positively associated with multiple functional connectivity changes one week after a low-to-moderate psilocybin dose. Further research is warranted to characterize these sustained effects and their therapeutic relevance to inform studies adopting similar dosing regimens in clinical cohorts. Trial Registration Australian New Zealand Clinical Trials Registry: ACTRN12621000560897 Date registered: 12 May 2021 URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381526&isReview=true

Major depressive disorder (MDD) is a common mental health disorder and is one of the leading causes of disability. Numerous treatment modalities have been studied for MDD, from interventions to psychotherapies. However, no exhaustive investigation has yet provided an overview of influential research on MDD treatments. Studies do not cover influential efforts occurring in the form of a comprehensive bibliometric review. This bibliometric study aims to fill this gap by thoroughly examining the characteristics of the 50 most cited articles on MDD treatment and providing an essential understanding of the intellectual structure and historical development over time. To guarantee a comprehensive research collection of trends in the treatment of MDD, we reviewed 50 pertinent papers without limiting the search by publication year, and the data collection was performed in a neutral manner. The search focuses on extensive citations from other publications and categorizes them according to their frequencies. Between 1989 and 2018, the top 50 MDD treatment publications received 96-1,837 citations (median 210, IQR 121-299). The 2000s and 2010s had a high level of publication activity (21 articles each, 42% per decade). Geographically, the United States (24, 48%), Canada (12, 24%), and the United Kingdom (5, 10%) dominated the journals. The majority of study types were randomized controlled trials (RCTs) (32, 64%), followed by systematic reviews/meta-analyses (16, 32%) and prospective cohorts (2, 4%). The publications covered a range of treatment modalities, including pharmacological, psychotherapeutic, neurostimulation, and lifestyle/complementary approaches. Elkin et al.'s NIMH Treatment of Depression Collaborative Research Program report (1,738 citations) and Unützer et al.'s IMPACT collaborative care RCT (1,837 citations) were the most referenced publications. Our results shed light on the conceptual framework of MDD treatment research, as current guidelines are shaped by significant randomized trials and systematic reviews. Precision-based and new treatments are growing the field, while traditional therapies continue to play a major role. Global applicability is limited by the geographic concentration of research, underscoring the need for diverse populations, assessment of new treatments, and incorporation of individual patient data to bolster the body of evidence.

Treatment-resistant depression (TRD) remains a major clinical challenge in psychiatric practice and affects a substantial proportion of patients with major depressive disorder (MDD). It is commonly defined as failure to achieve remission after at least two adequately conducted antidepressant trials. TRD is associated with persistent functional impairment, increased morbidity, reduced quality of life, and greater healthcare utilization. This narrative review summarizes current and emerging evidence on the management of TRD, with emphasis on conventional pharmacological strategies, augmentation approaches, ketamine and esketamine, and neuromodulatory approaches. Neuromodulatory interventions discussed include electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and innovative modalities such as theta burst stimulation (TBS), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS). Emerging therapies, including psychedelic-assisted treatments, are also considered as potential future directions in the management of TRD. While conventional therapies remain central to management, newer treatment modalities have expanded available options, particularly for patients with severe or persistent symptoms. Nevertheless, significant limitations remain, including cost, accessibility, durability of response, and uncertainty regarding long-term outcomes and side effects. This review also highlights the importance of individualized selection and clinical sequencing based on patient characteristics, prior treatment response, and illness severity. Continued research is needed to better define treatment sequencing and improve management strategies for patients with TRD.

We propose a three-phase experimental protocol testing whether the radical pair mechanism (RPM) operates during N,N-dimethyltryptamine (DMT)-induced psychedelicstates at the 5-HT2A receptor. Position-specific isotopic substitution of the ligand (13C at C3a, 15N on indole nitrogen) modifies nuclear spin content without altering molecular geometry, receptor affinity, or metabolic half-life.Because the kinetic isotope effect is negligible for 13C (Δm = +8%, KIE < 1.04), any observed phenomenological change constitutes direct evidence for the magnetic isotope effect—and hence for RPM involvement—at the receptor. Structure-guided labelling (PDB: 9AS1), falsification criteria, and a ~$10,000 mouse HTR pilot are described. Version 2: removed speculative theoretical framework, muscled bibliography (46 refs), added quantitative feasibility bounds, integrated as part of a three-document research programme.

Autism Spectrum Disorder (ASD) is a lifelong condition marked by challenges in social communication and repetitive behaviors. Current treatments, primarily behavioral therapies, often fail to address the core symptoms. Recent research has explored the potential of psychedelics, such as LSD, psilocybin, and MDMA, as a new therapeutic approach. While these substances primarily modulate the serotonin 5-HT2A receptor, their therapeutic effects also involve interactions with other serotonergic, dopaminergic, and glutamatergic pathways, collectively promoting neuroplasticity—the brain’s ability to change and adapt. The specific receptors’ activation leads to structural and functional changes in the brain that can enhance social behavior and emotional regulation. Studies show that psychedelics may reduce symptoms of conditions like treatment-resistant depression and PTSD, highlighting their therapeutic potential. For ASD specifically, psychedelics may improve psychological flexibility, reduce distress, and enhance social interaction. While promising, the use of these substances requires careful consideration. Psychedelics can induce intense experiences and altered states of consciousness, necessitating strict monitoring and support during therapy. Ethical guidelines, including informed consent, are crucial, especially for vulnerable populations. In conclusion, psychedelics hold significant promise for treating ASD and other psychiatric disorders by promoting neuroplasticity and modulating complex signaling pathways. Continued research and clinical trials, conducted with strong ethical oversight, are essential to realizing their full therapeutic potential.

Analysis code (Python) and processed results (CSV files) supporting the manuscript: Malone, R.W. (2026). "A Unified Granger-Predictive Influence Pipeline Reveals Drug-Specific Thalamic Dynamic Signatures Across Five Pharmacological Resting-State fMRI Datasets." NeuroImage: Reports (submitted). Contents include: normalized cascade fraction and strength metrics, dynamic functional connectivity variance summaries, layer-specific temporal stability rankings, net directional influence scores, bootstrap confidence intervals, and edge-level statistics across LSD, psilocybin, DMT, ketamine, and propofol conditions. Primary analysis script: normalized_cascade_and_driver_test.py.

Mushroom use dates back to ancient times, and it currently remains significant among indigenous and urban populations as a medicinal option. Psilocybe species are suggested to modify emotions when administered in macro- or microdose form for the treatment of anxiety and depression, both often affected by a delayed onset and adverse effects of current pharmacological therapy. The objective of this study was to evaluate the anxiolytic and/or antidepressant-like effects of P. cubensis mushroom aqueous extract (PcAE) microdosing in mice using open-field and rota-rod tests, followed by plus-maze or forced swimming tests. We also evaluated changes in neuronal activity and dendritic maturation using electrocorticography (ECoG) and immunohistochemical techniques. The outcomes were compared with an effective macrodose of PcAE and antidepressant fluoxetine (FLX). For this study, mice were grouped as follows: (1) vehicle, (2) acute, and (3) repeated (10 days) PcAE microdosing (1 µg/kg); (4) single PcAE macrodose (1 g/kg); and (5) acute and (6) repeated reference drug fluoxetine (FLX, 10 mg/kg).The anxiolytic and antidepressant-like effects using microdosing were similar to those observed with macrodoses of PcAE and FLX; significant dose- and/or time-dependent changes in the ECoG and dendritic maturation of hippocampus neurons were also observed, in addition to altered corticosterone levels. To conclude, P. cubensis mushroom promotes brain effects in mice after micro- and macrodosing, supporting its potential as a therapeutic alternative for mental health.

Glucagon-like peptide-1 (GLP-1) and dual GIP/GLP-1 receptor agonists, originally introduced for the management of type 2 diabetes mellitus and obesity, are increasingly recognized for their broader actions within the central nervous system, with emerging implications in neuropsychiatry and neurodegeneration. This review integrates current preclinical and clinical evidence, emphasizing their pharmacodynamic profile, central receptor distribution, and the molecular pathways linking metabolic signaling to neural function. Evidence suggests that GLP-1 receptor activation across key brain regions involved in energy balance and reward modulates multiple neurotransmitter systems, including dopamine and serotonin, as well as glutamatergic and GABAergic transmission, thereby influencing behavior, affective processes, and cognitive function. In parallel, these agents exhibit neuroprotective properties through improved neuronal insulin sensitivity, attenuation of neuroinflammatory pathways, and support of neuroplasticity, alongside effects on limiting pathological protein aggregation. Dual GIP/GLP-1 agonism may further potentiate these central actions through complementary metabolic and synaptic mechanisms. Although pharmacovigilance data have identified isolated neuropsychiatric adverse events, current clinical evidence does not support a consistent causal association. Collectively, incretin-based therapies represent a promising translational approach at the interface of metabolic and neuropsychiatric disorders, warranting further investigation into their long-term central safety, therapeutic efficacy, and clinical relevance.

This article proposes a research agenda for ketamine treatment in depression, focusing on the glutamatergic-plasticity model and structural synaptic stability.

Introduction In humans, empathy is expressed through various prosocial behaviours between individuals that may be enhanced after intake of the synthetic entactogen MDMA (3,4-methylenedioxymethamphetamine, “Ecstasy”) as the behavioural expression of the so-called entactogenic syndrome. Rodents may also exhibit empathy-like behaviours, such as social interaction and helping behaviour. In this regard, while social interaction has been reported to be enhanced by MDMA, the effects of this drug on helping behaviour remain unexplored. Nevertheless, because helping behaviour is considered as part of the prosocial repertoire, it may be hypothesised that MDMA should enhance it. Methods In the present study, the evaluation of a subtoxic dose range (0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, 5 mg/kg, and 10 mg/kg i.p.) of MDMA on helping behaviour in adult male rats has been conducted using a standardised behavioural setup based on the intrinsic aversion of these animals to water. In addition, as helping behaviour may require a complex interaction between motivational and higher cognitive processes, the neuroplastic effects of MDMA (10 mg/kg i.p.) on cortical and subcortical loci were studied in vivo in anaesthetised rats. Results and discussion Behavioural data indicated that 5 mg/kg and 10 mg/kg of MDMA fully suppressed helping behaviour; 1 mg/kg and 0.5 mg/kg induced partial inhibition only after interchanging roles; and 0.25 mg/kg had no effect. The inhibitions observed at the highest doses (5 mg/kg, and 10 mg/kg) were not reversed after interchanging roles. Electrophysiological data showed that MDMA reinforced long-term depression (LTD) elicited in the nucleus accumbens (NAc) core following stimulation of the dorsal raphe nucleus (DRN). In addition, MDMA increased transcallosal-evoked long-term potentiation (LTP) in the anterior cingulate cortex (ACC) in a serotonin (5-HT)- and oxytocin (OXT)-dependent manner. Taken together, these data support the notion that MDMA disrupts helping behaviour, even though the neuroplastic effects elicited by the drug align with the mechanisms described to promote prosocial/empathic behaviours. The results may suggest a negative modulation of MDMA on neural processes that are essential for the execution of helping behaviour without affecting the willingness to help.

Sonogenetics combines genetic tools and low-intensity ultrasound to non-invasively modulate specific neuronal populations and circuits, exhibiting potential for treating brain diseases. This study examines sonogenetics' potential in a mouse depression model, targeting excitatory medial prefrontal cortex (mPFC) neurons projecting to the dorsal raphe nucleus (DRN). Projecting neurons were induced to express a mechanosensitive ion channel (MscL-G22S), and alterations in patterns of neuronal activation and despair-like behaviors upon sonication were evaluated. Sonogenetics selectively activated targeted excitatory mPFC neurons projecting to the DRN, enhancing real-time DRN neuronal activity and serotonin release, with no observed tissue damage or astrocytic/microglial activation. Tail suspension and forced swim tests revealed that sonogenetically activating this pathway rapidly reversed despair-like behaviors in stressed mice, whereas effects observed upon mPFC sonication were abrogated by functionally silencing downstream DRN neurons, and this effect is fully recapitulated by selective inhibition of DRN serotonergic neurons alone. Collectively, this study constitutes the first demonstration of the potential for a circuit-targeted sonogenetic therapeutic approach for relieving despair behaviors.

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Analysis code for Malone (2026), submitted to Human Brain Mapping. Implements thalamic ROI extraction, connectivity, dynamic variance, AR1, and lateralisation metrics across five pharmacological resting-state fMRI datasets (LSD, psilocybin, DMT, ketamine, propofol).

Social cognition is impaired across multiple psychiatric disorders and varies dimensionally in the general population. Studying healthy adults can therefore inform mechanisms relevant for social cognition. This study aimed to extend prior findings of associations between social cognition and serotonin transporter (5-HTT) within autistic and non-autistic controls to healthy adults, and to examine serotonin 1B (5-HT1B) receptor binding. Thirty-one healthy adults (15 males, 16 females) underwent PET imaging with [¹¹C]MADAM to quantify 5-HTT binding. In the replication cohort (n = 17), MASC performance correlated positively with putaminal 5-HTT binding (ρ = 0.61, p = 0.011, BFR = 15.2) and negatively with brainstem binding (ρ = −0.64, p = 0.008, BFR = 6.1). A similar positive association with putaminal 5-HTT binding was observed in the pooled sample (n = 31, ρ = 0.53, p = 0.003). However, no correlations survived correction for multiple comparisons. In a separate sample of 32 healthy adults (13 males, 20 females) examined with [¹¹C]AZ10419369 to assess 5-HT1B receptor binding, no significant associations with measures of social cognition or central coherence were found. Results conceptually replicate an association between putaminal 5-HTT binding and social cognition in healthy adults, supporting a role of 5-HTT—but not 5-HT1B—in social cognitive processes.

Major Depressive Disorder (MDD) is one of the most prevalent and disabling psychiatric conditions worldwide, involving alterations in mood regulation, cognitive function, sleep, and physiological systems. Traditional diagnostic approaches often rely on time-consuming interviews and questionnaires, which are largely based on subjective clinical judgment, and may contribute to misdiagnosis or suboptimal treatment selection. Artificial Intelligence (AI) approaches for MDD detection and monitoring have been studied using various data sources, including clinical data, Magnetic Resonance Imaging (MRI), speech features, and genetics. In this review, we collected evidence on multimodal AI-based methods for MDD-related outcomes, focusing on discriminative and predictive performance, validation practices, and feasibility in clinical settings. A search of four databases (PubMed, Web of Science, Scopus, and Embase) was performed, including 40 original studies published after 2015 divided into two main categories: clinical and translational approaches. Our analysis showed that MRI-based biomarkers frequently provide the best performance, but their high cost and time-consuming acquisition limit scalability; simpler measures (audio-visual, clinical, wearable/smartphone digital biomarkers) may offer a better balance between performance and implementability. Reported accuracies are typically between 65%–85%, however a systematic lack of external validation may imply overfitting, highlighting the need for prospective multi-site validation and stratified analyses before clinical translation. Although the landscape is complex, this review suggests that multimodal AI approaches could help clinicians optimize their clinical practices, support decision-making, and monitor patients, thereby improving the quality of healthcare services.

Psilocybin is a federally illegal psychedelic substance that carries positive (e.g., treatment for mood disorders) and negative (e.g., emotional distress) consequences. In 2020, Oregon legalized psilocybin for adult use (21+) at the state level, restricted to designated service centers. In Fall 2024 and Spring 2026 we summarized and compared Oregon’s legal/regulatory psilocybin context and highlighted public health considerations. We found there are no limits on the number of licenses that can be issued, and there are mandated trainings to obtain facilitator licensure (e.g., 120/128 hours of instruction in 2024/2026, requiring a test score of 75% [unlimited number of testing attempts]). Regulations specify manufacturing rules, including allowable ingredients and testing for contaminants and concentration. One serving includes 25mg of psilocybin analyte; 2 servings per person are allowed. Labeling guidelines are provided (e.g., safety warnings, no youth-oriented wording). We identified the presence of psilocybin-related websites that were not age gated. We found pricing information related to administration ($15-$3,500/person) and facilitator training ($3,000-$14,175). Given the inability to limit the number of psilocybin licensees, numbers of service centers are likely to increase. Since Oregon psilocybin services does not license training programs, and the unlimited number of testing attempts allowed, there may be issues ensuring individuals have adequately acquired the necessary knowledge. Longitudinal research is needed to assess the health impact of these programs and the long-term impacts of psilocybin use.

Neuropsychiatric diseases are characterized by complex molecular underpinnings that remain challenging to fully elucidate. Molecular dynamics (MD) simulations have emerged as a powerful computational tool, providing a crucial bridge between static genetic data and the dynamic functional consequences of molecular alterations. This review offers a comprehensive overview of the application of MD simulations in studying the molecular basis of neuropsychiatric disorders. We highlight key applications, including the assessment of mutation pathogenicity in disease-associated proteins, the influence of post-translational modifications on protein function, folding, misfolding, and aggregation, and the characterization of psychopharmacological drug–target interactions at atomic resolution. Through relevant examples from research on psychiatric and neurodegenerative diseases, we illustrate how these computational methods are implemented to gain mechanistic insights. Importantly, this review traces the historical development of MD simulations in biological applications, critically examines the method’s limitations, and outlines future perspectives for simulating long-timescale physiological processes, large molecular ensembles, and even whole-cell environments. Ultimately, this work highlights MD simulations as a useful and complementary tool for modern neuropsychiatry research, capable of revealing disease mechanisms and guiding the development of novel therapeutic strategies.

Background and Objectives: One of the strongest early factors influencing later psychoactive substance use is adverse childhood experiences (ACEs). Studies investigate a variety of adverse experiences in relation to substance use, yet not all adverse childhood experiences are equal in intensity and harm. Our study aimed to address this gap by examining in detail the associations between individual ACEs, broader ACE categories, and different forms of psychoactive substance use. Materials and Methods: The study included 709 participants who completed self-report questionnaires. ACEs were measured using the MACE questionnaire. Marijuana use was measured using the CUDIT-R, alcohol use using the AUDIT, and heavy psychoactive substance use using the ASSIST. Linear regression analyses were used to predict associations. As expected, only a small part of the sample reported hard drug use; some analyses are limited to substantially fewer observations. Results: All regression models were statistically significant and predicted all three categories of psychoactive substances, but if we count the individual adverse experiences, the results become different. Although the results showed that ACE is a significant predictor of hard drug use and explains 25% of the variance, it is separately only emotional neglect that is associated with hard drug use. The regression analysis also explains 14% of the variance in marijuana use, but when considered separately, we found associations only with emotional neglect. The severity of alcohol use explains 13% of the variance, but only a few ACEs reach statistical significance: peer physical bullying, physical violence, and sexual abuse. Conclusions: The findings of our study suggest that adverse childhood experiences may not be qualitatively equivalent and therefore may not be evaluated only as a cumulative risk score. Separate ACE evaluations, instead of aggregate calculation of ACEs, may be useful to understand better which specific negative experiences have the greatest impact on subsequent use of psychoactive substances. The regression models explain only a small portion of the variance, which suggests that other factors may contribute to a larger share.

This first evaluation of blinding integrity in psychedelic RCTs indicates functional unblinding is pervasive among participants and raters raising concerns about the validity of efficacy findings. Few trials assess blinding or expectancy, highlighting the need for standardized, validated measures and innovative designs to separate true pharmacological effects from expectancy-driven responses.

Psychedelic drugs show promise in facilitating a variety of long-term psychological changes, but they may also lead to unexpected major life changes that have not been captured by measures typically used in clinical trials. The Psychedelic-related Major Life Changes Questionnaire (P-MLCQ) was created to assess psychedelic-related major life changes across 10 different domains and evaluated in a sample reporting naturalistic psychedelic use (N = 581). 482/581 participants (82.96%) reported at least one major life change influenced by their psychedelic use (M = 3.29, SD = 2.60), including changes in Goals (53.70%), Values (53.53%), Religion/spirituality (49.05%), Social activities (37.01%), Eating habits/diet (34.08%), Occupation/Line of work (32.36%), Hobbies (29.43%), Political views (14.97%), Sexuality (13.08%), and Marital status/non-marital partner change (12.22%). Major life changes were rated highly positively (M = 4.64, SD = 0.61 on a 5-point scale). There was a positive relationship between frequency of psychedelic use over the last five years and total number of psychedelic-related major life changes (r = 0.34, p < 0.001). Women were 21% more likely than men to report major life changes, whereas age and education-level were negatively related to major life changes. Although our results support that psychedelic use can be followed by major life changes, future research is needed to examine the generalizability of these results in representative samples that are less susceptible to positive bias.

This proposed rule would revise the Medicare hospital inpatient prospective payment systems (IPPS) for operating and capital- related costs of acute care hospitals; make changes relating to Medicare graduate medical education (GME) for teaching hospitals; update the payment policies and the annual payment rates for the Medicare prospective payment system (PPS) for inpatient hospital services provided by long-term care hospitals (LTCHs); update and make changes to requirements for certain quality programs; and make other policy-related changes.

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

For the past half-century, psychiatric drug development has largely focused on tweaking neurotransmitter receptors and chemical pathways. Yet despite billions of dollars invested and major advances in neuroscience, truly innovative treatments for mental illness remain scarce. Disorders like depression, schizophrenia, and post-traumatic stress disorder (PTSD) continue to be managed with drugs discovered decades ago that often provide only partial relief, with remission rates of approximately 30-40% for treatment-resistant depression and 60-70% of schizophrenia patients experiencing persistent symptoms despite medication. This stagnation has prompted a paradigm shift - what if the key to treating mental illness is not just which receptor a drug targets, but how it changes the brain’s processing of sensory information? In this treatise, I propose that many psychiatric conditions stem from breakdowns in the brain’s sensory filtering mechanisms, the neural circuits that gate irrelevant stimuli before they consume valuable processing resources, and that effective therapies must restore these filtering functions. While computational psychiatry has long recognized that mental illness may reflect failures in predictive filtering, the specific neural substrate implementing this gating remains underspecified. Here the cerebellum emerges as a critical hub: neuroanatomically positioned to perform bottom-up sensory gating before cortical processing, housing more than half the brain’s neurons in an architecture ideally suited for distilling signal from noise and showing state-dependent disruption of cerebellar-cortical connectivity during symptom provocation in PTSD. Intriguingly, psychedelic drugs may act as recalibration triggers for these neural filters, acutely disrupting entrenched filtering architectures and reopening windows of plasticity through which maladaptive sensory weightings can be reset. This cerebellar filtering framework offers a neuroanatomically specified extension of predictive processing theory, generates falsifiable predictions, and suggests novel therapeutic targets for conditions that have resisted a half-century of receptor-focused drug development.

The growing demand for accessible mental health support requires training more counselors, yet existing approaches remain resource-intensive and difficult to scale. LLMs can realistically simulate patients and generate actionable feedback for training, but their actual impact on novice counselor skill development remains unknown. We developed an LLM-simulated practice and feedback system and conducted a randomized study with 94 novice counselors, comparing practice alone versus practice with feedback. We evaluated behavioral performance, self-efficacy, and qualitative reflections. Results showed the practice-and-feedback group improved in client-centered microskills (reflections, questions), while the practice-alone group showed no improvements. For empathy, the practice-alone group declined over time and performed significantly worse than the feedback group. Qualitative interviews reinforced these findings: feedback helped participants adopt a client-centered listening approach, while practice-alone participants remained solution-oriented. These results suggest LLM-based training systems can promote effective skill development, and combining simulated practice with structured feedback is critical for meaningful improvement.

Interest in classical psychedelics as potential treatments for ADHD has grown alongside broader psychiatric psychedelic research, but ADHD-specific evidence remains limited. This systematic review examined prospective and experimental studies on whether classical psychedelics, including microdosing-like use and retreat-based exposure, are associated with changes in adult ADHD symptoms and related functioning. A PRISMA-guided systematic review was conducted using a PECO/PICO framework focused on adults (≥18 years) with diagnosed ADHD and/or elevated ADHD symptomatology who were exposed to a classical psychedelic and assessed prospectively with quantitative ADHD outcomes. Major databases were searched, with reference screening and targeted checks for recent or registered trials. Risk of bias was assessed using RoB 2 for the RCT and ROBINS-I for non-randomized studies. Because of heterogeneity and the small number of studies, findings were synthesized narratively. Five studies met the inclusion criteria. Five prospective/experimental studies were included: three naturalistic online microdosing cohorts, one randomized double-blind placebo-controlled phase 2A trial of low-dose LSD, and one pre-post ayahuasca retreat pilot. In uncontrolled naturalistic microdosing studies, participants reported short-term reductions in ADHD symptom ratings together with improvements in well-being and affect-related functioning; however, these studies were highly vulnerable to self-selection, expectancy, attrition, and non-standardized exposure. In contrast, the only randomized placebo-controlled ADHD trial found improvement in both LSD and placebo groups, with no statistically significant advantage for LSD on clinician-rated or self-reported ADHD outcomes. Objective cognitive findings were limited and inconsistent, and safety data outside the supervised trial context were sparse. Naturalistic studies provide, at most, low-certainty signals of perceived short-term improvement, but the strongest controlled evidence does not demonstrate drug-specific efficacy of repeated low-dose LSD for core ADHD symptoms. Current evidence therefore does not allow separation of pharmacological effects from expectancy, setting, self-monitoring, and broader experiential/contextual influences, and is insufficient to support psychedelics as an evidence-based treatment for ADHD.

The Pearson sample correlation between two biomarkers across a group of individuals can sometimes be much stronger than expected by chance. In the context of psychosis risk, we previously analyzed blood plasma protein data from initial presentations as collected in the North American Prodrome Longitudinal Study 2 (NAPLS2). We found enhanced correlation between proteins SERPINE1 and TIMP1, both promoters of coagulation and inhibitors of remodeling of extracellular matrix (ECM). Participants were unaffected community controls vs. others of clinical high risk. The SERPINE1-TIMP1 correlation was consistently higher in individuals at clinical high risk for psychosis who later converted to a psychotic disorder vs. participants who were nonconverters or unaffected community controls. Here, we extend those findings using data from a larger cohort, the North American Prodrome Longitudinal Study 3 (NAPLS3). Again, the correlation between SERPINE1 and TIMP1 remained higher in psychosis high-risk converters vs. the other groups. In NAPLS3 we added an assay for PLAT (anti-coagulation plasminogen activator strongly inhibited by SERPINE1). Comparing the three NAPLS3 groups we found a decreased correlation between SERPINE1 and PLAT in converters. In summary, the increased correlation of SERPINE1 and TIMP1 in converters is consistent with restricted brain circuit remodeling and increased tendency to coagulation. Rigorous application of permutation testing yielded NAPLS2 vs. NAPLS3 consistency of SERPINE1-TIMP1 correlation patterns with empirical p-value 0.03.

Most papers included in this systematic review encompassed multiple SUDs following Rule-Based approaches, "Most common use" NLP methods (e.g. concept extraction), and familiar software applications (e.g. Python). Evaluation metrics for SUD papers utilizing NLP included common performance metrics, with ROC AUC and F1 scores achieving acceptable-to-outstanding discrimination between classes and good-to-excellent balance between precision and recall, respectively. The future direction of NLP for SUD information extraction could make use of Machine- or Deep-Learning approaches, advanced methods including Regular expressions or Sentiment analysis, and/or advanced software packages designed specifically for NLP endeavors, to better inform public health research and clinical decision making.

The psychedelic psilocybin has shown therapeutic potential, yet underlying neural mechanisms remain poorly understood. We investigated the impact of psilocin-the active metabolite of psilocybin-on basal activity and reactivity within the paraventricular nucleus of the thalamus (PVT) and PVT projections to central amygdala (CeA) in rats. Psilocin administration increased PVT c-Fos expression and selectively engaged PVT→CeA neurons in females, but not males. Psilocin enhanced PVT reactivity to an aversive air-puff stimulus, with effects primarily driven by passive responders. In PVT→CeA neurons, psilocin prevented time-dependent reductions in stimulus-evoked activity and maintained reactivity across timepoints in females but not males. The sustained engagement of PVT→CeA circuitry was driven by active responders. These findings identify sex-specific modulation of thalamic-limbic circuitry and behavior by psilocin, implicating PVT→CeA circuitry in the neural and behavioral effects of psychedelic compounds, advancing our understanding of how psychedelics modulate emotional brain circuits to further inform potential therapeutic mechanisms.

Este artículo presenta una revisión narrativa sobre las variables extrafarmacológicas que influyen en la terapia asistida con psicodélicos (TAPs). A partir del análisis de literatura reciente, se destaca la importancia de la persona (set) y el ambiente (setting) en la modulación de los efectos subjetivos y terapéuticos de sustancias como la psilocibina o el MDMA. El objetivo principal fue sintetizar los principales hallazgos sobre cómo estas variables influyen en los resultados del tratamiento y en la experiencia de bienestar. Se revisaron artículos conceptuales y empíricos publicados en las últimas dos décadas, considerando criterios de inclusión relacionados con el abordaje clínico y la descripción contextual del uso terapéutico de psicodélicos. Los hallazgos se organizan en tres niveles: la preparación terapéutica previa, el ambiente durante la sesión y la integración posterior. Se concluye que las variables extrafarmacológicas son fundamentales para maximizar el potencial terapéutico de las TAPs, y se propone un modelo comprensivo para su aplicación clínica y de investigación.

Self-compassion is theorized to play a central role in promoting mental health and wellbeing, including for individuals with social anxiety disorder (SAD). One proposed mechanism of MDMA-assisted therapy (MDMA-AT) for SAD is the cultivation of self-compassion. Across five aims, we will characterize self-compassion experiences during MDMA-AT and evaluate its role as a potential mechanism of therapeutic change. Specifically, we will examine whether trait self-compassion increases over the course of treatment and whether state self-compassion experienced during MDMA dosing sessions contributes to these changes and to clinical outcomes: Aim 1 establishes whether trait self-compassion significantly increases over treatment and explores its trajectory of change. Aim 2 examines whether state self-compassion experienced during dosing sessions translates to enduring changes in trait self-compassion over the course of MDMA-AT. Aims 3 and 4 evaluate whether changes in trait self-compassion (Aim 3) and levels of state self-compassion during dosing (Aim 4) are associated with changes in mental health, wellbeing and functional outcomes, including: (a) social anxiety symptoms, (b) global functional impairment, (c) depressive symptoms, (d) internalized shame, and (e) sense of belonging. Aim 5 evaluates whether the intensity of state self-compassion differs across the two MDMA dosing sessions.

Background: Incorporating sex as a biological variable (SBV) is recognized as essential for improving the reliability, reproducibility, and generalizability of pharmacological research. This principle is codified in international policies and guidelines, yet implementation remains uneven, especially in phytomedicine. Phytomedicines are a major component of healthcare worldwide, with 65% of the global population relying on them in both regulated and traditional contexts. Globally, phytomedicines are used by males, females, intersex and non-cis gender persons, all of whom may present specific safety and efficacy considerations and warrant full inclusion in pre-clinical to clinical research pipelines. However, in contemporary settings, phytomedicine lags in SBV best practices relative to Western allopathic standards for research design. Methods: We conducted a non-systematic review and in silico data mining to quantify sex/gender representation in recent preclinical and clinical phytomedicine studies, complemented by targeted case studies of sexually dimorphic safety/efficacy. We also summarize the historical role of women and gender-diverse people as users and providers within Traditional and Integrative Medical Systems (TIMSs). Results: Across rodent and human studies, females are under-represented relative to males, and sex is rarely reported for cell lines. Intentional inclusion of intersex and other gender-diverse populations is largely absent. Case studies illustrate plausible sex-associated differences in pharmacokinetics, pharmacodynamics, and adverse event profiles. TIMSs historically address women’s health needs and include substantial participation by female practitioners; however, contemporary SBV practices remain less standardized than in Western allopathic pipelines. Conclusions: SBV integration in phytomedicine is needed to strengthen safety, efficacy, and regulatory-grade evidence. Practical barriers include legacy datasets without sex metadata, limited intersex animal models, and uneven resources across settings. We outline feasible, stepwise practices to improve SBV adoption in a manner compatible with TIMS contexts and recommend expanding current guidelines to better support diverse research environments while maintaining scientific rigor.

Post-Traumatic Stress Disorder (PTSD) continues to be a significant mental health concern among U.S. military veterans. This quantitative study examines the interrelationships among PTSD symptom severity, alcohol use, and psychological resilience using three standardised instruments: the PTSD Checklist for DSM-5 (PCL-5), the Alcohol Use Disorders Identification Test (AUDIT), and the Connor-Davidson Resilience Scale (CD-RISC). A cross-sectional correlational design was implemented with a convenience sample of 150 American military veterans, recruited through online platforms and veteran-focused organisations from all branches. Participants completed an anonymous online survey that assessed trauma-related symptoms, alcohol consumption behaviours, and resilience levels. Statistical analysis included descriptive statistics, Cronbach alpha to evaluate internal consistency, Pearson’s correlation to examine bivariate relationships, and PTSD regression analysis to determine the predictive power of alcohol use and resilience on PTSD symptoms. Additionally, to test the moderating effect of resilience, moderation analysis was conducted using Hayes’ PROCESS macro for SPSS. It was hypothesised that alcohol use would positively correlate with PTSD symptoms, while resilience would show a negative correlation and act as a protective moderating factor. The results of this study suggest implications for trauma-informed clinical practices and intervention strategies by elucidating the protective role of resilience and the compound effect of substance use in American military veterans with PTSD.

Altered states of consciousness (ASC) represent a universal human capacity for accessing and transforming the subconscious mind, employed across cultures and millennia through diverse contemplative, somatic, pharmacological, ritual, and technological modalities. This comprehensive review synthesizes evidence from over 25 distinct disciplines spanning five clusters: (A) contemplative and meditative practices (yoga, hypnotherapy, qigong, Tibetan meditation, mindfulness); (B) breathwork and somatic practices (holotropic breathwork, pranayama, somatic experiencing, trauma-release exercises, Wim Hof method); (C) plant-based and psychedelic practices (ayahuasca, psilocybin, MDMA, ketamine, ibogaine, peyote, cannabis); (D) ritual, cultural, and energetic practices (shamanic drumming, Sufi whirling, sound therapy, sweat lodge, lucid dreaming); and (E) neurotechnology and sensory modulation (neurofeedback, TMS, tDCS, float therapy, VR therapy, EMDR). We provide the first in-depth scholarly treatment of transpersonal hypnotherapy modalities—Life Between Lives (LBL) hypnotherapy and Past Life Regression (PLR) therapy—as legitimate therapeutic frameworks warranting rigorous empirical investigation. Comparative neurobiological analysis reveals converging mechanisms across all disciplines: default mode network (DMN) suppression or modulation, autonomic nervous system regulation via vagal tone and heart rate variability, neuroplasticity enhancement through brain-derived neurotrophic factor (BDNF) upregulation, memory reconsolidation enabling schema revision, interoceptive predictive coding that updates maladaptive priors, theta and alpha brainwave entrainment facilitating subconscious access, and ego dissolution permitting self-transcendence. Clinical evidence demonstrates strongest support for MDMA-assisted therapy in PTSD (Phase 3 RCTs, 67% response rate), psilocybin therapy in treatment-resistant depression (60-70% response in multiple RCTs), EMDR for trauma (WHO and APA endorsed), mindfulness-based interventions for depression relapse prevention and anxiety (multiple meta-analyses), and neurofeedback for ADHD and anxiety disorders (systematic reviews). Transpersonal modalities including LBL and PLR show preliminary evidence for existential distress, grief, depression, and life-purpose confusion in case series and open trials, though rigorous controlled trials are lacking. Philosophical frameworks from Vedantic (atman, samskaras, moksha), Buddhist (alaya-vijnana, anatta), Jungian (collective unconscious, archetypes), Platonic (anamnesis), transpersonal (Assagioli, Wilber), and neuroscientific (predictive coding, Bayesian brain) traditions offer complementary conceptualizations of the subconscious mind as the universal therapeutic target. All ASC disciplines converge on temporarily suspending ordinary critical consciousness to enable direct access to subconscious patterns—conceptualized variously as samskaras, unconscious complexes, predictive priors, conditioned schemas, or soul memories. LBL hypnotherapy uniquely targets the superconscious or Higher Self dimension, representing the only modality explicitly accessing soul-level knowing and between-lives experiences. Significant research gaps include absence of head-to-head comparative trials, lack of standardized ASC phenomenological and neurophysiological measurement protocols, limited mechanistic neuroimaging studies during deep transpersonal trance states, insufficient integration protocols, and need for personalized matching algorithms. We propose an integrative framework positioning ASC as a spectrum from subconscious (conditioned patterns) to superconscious (transpersonal wisdom), with diverse modalities as complementary vehicles for consciousness transformation. Future research priorities include rigorous RCTs for LBL and PLR, neurophenomenological studies combining EEG/fMRI with first-person phenomenology, replication of reincarnation research with modern methodology, quantum cons

Post-traumatic stress disorder (PTSD) is a chronic mental illness that occurs following exposure to traumatic stressors such as combat, disasters, or assault. It is characterized by a triad of reexperiencing of the trauma, avoidance of triggers for such recollections, and increased vigilance towards threats (1). In 1992, Judith Herman described a variant of PTSD that occurred in persons who had undergone prolonged or repeated traumatic stress, such as hostages, prisoners of war, concentration camp survivors, or victims of chronic familial abuse or violence. Apart from the classical "triad" seen in PTSD, these patients experienced somatic, dissociative, and mood symptoms, alterations in identity, and disturbed interpersonal relationships. She proposed the term "complex PTSD" to describe such cases (2).A syndrome akin to "complex PTSD" was proposed for inclusion in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) under the name "Disorders of extreme stress, not otherwise specified" (DES-NOS). The alterations in mood, identity and relationships described by Herman were also included in the tenth edition of the World Health Organization (WHO)'s International Classification of Diseases and Disorders (ICD-10) with the label "Enduring personality change after catastrophic experience (F62.0)." However, DES-NOS was not included in the final version of DSM-IV, and ICD-10 category F62.0 was rarely used in practice (3). Based on research over the next two decades, the concept of complex PTSD was refined and validated in diverse settings. Complex PTSD (C-PTSD) was redefined as a syndrome consisting of both the PTSD triad, and a second triad of disturbances in self-organization (DSO), characterized by disturbances of mood (numbing or increased reactivity), difficulties in interpersonal relationships, and a negative self-image. Such symptoms were defined as occurring in the context of complex trauma -that is, trauma which is repeated or prolonged. This definition of complex PTSD has been included in the most recent WHO classification of mental disorders (ICD-11). It is estimated that about 2-8% of the world's population suffers from C-PTSD, with much higher rates observed in vulnerable groups such as refugees and survivors of childhood abuse (4)(5)(6).Optimal treatment strategies for C-PTSD are still in development. Pharmacological treatments for PTSD may improve symptoms in the PTSD triad, but do not have proven benefits for DSO. Trauma-focused psychotherapies improve PTSD triad symptoms, depression, anxiety, and insomnia, but their effect on overall quality of life -a measure of DSO -is low (7). There are also significant variations in efficacy between psychotherapies based on different theoretical models and techniques (8). Novel therapies such ketamine and psilocybin have been suggested as alternatives, but though they have some benefits in PTSD, their efficacy in C-PTSD has not been evaluated (9,10). The development of more effective treatments for this chronic and disabling condition would require a better understanding of the neurobiology of C-PTSD, particularly in relation to symptoms of DSO, which do not appear responsive to currently available treatments (11).The past four years have seen remarkable advances in our understanding of the pathophysiology of PTSD. Initial work focused on dysregulation of monoamine neurotransmitters such as serotonin (5-HT, and on altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis (12). It is now known that a host of complex physiological and biological alterations occur in PTSD, including alterations in glutamatergic and peptidergic transmission, increased oxidative stress, immuneinflammatory dysregulation, and accelerated cellular aging. These changes appear to arise from an interaction between genetic variants influencing these pathways, "sensitizing" experiences such as childhood adversity, and exposure to one or more traumatic stressors (5,1

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