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The Effectiveness of Microdosed Psilocybin in the Treatment of Neuropsychiatric Lyme Disease A Case Study.

Lyme disease can result in severe neuropsychiatric symptoms that may be resistant to treatment. The pathogenesis of neuropsychiatric Lyme disease is associated with autoimmune induced neuroinflammation. This case report describes an immunocompetent male with serologically positive neuropsychiatric Lyme disease who did not tolerate antimicrobial or psychotropic medications and whose symptoms remitted when he began psilocybin in microdosed (sub-hallucinogenic) amounts. A literature review of its therapeutic benefits reveals that psilocybin is both serotonergic and anti-inflammatory and therefore may offer significant therapeutic benefits to patients with mental illness secondary to autoimmune inflammation. The role of microdosed psilocybin in the treatment of neuropsychiatric Lyme disease and autoimmune encephalopathies warrants further study.

Cannabinoids modulate the microbiota-gut-brain axis in HIVSIV infection by reducing neuroinflammation and dysbiosis while concurrently elevating endocannabinoid and indole-3-propionate levels.

Although the advent of combination anti-retroviral therapy (cART) has transformed HIV into a manageable chronic disease, an estimated 30-50% of people living with HIV (PLWH) exhibit cognitive and motor deficits collectively known as HIV-associated neurocognitive disorders (HAND). A key driver of HAND neuropathology is chronic neuroinflammation, where proinflammatory mediators produced by activated microglia and macrophages are thought to inflict neuronal injury and loss. Moreover, the dysregulation of the microbiota-gut-brain axis (MGBA) in PLWH, consequent to gastrointestinal dysfunction and dysbiosis, can lead to neuroinflammation and persistent cognitive impairment, which underscores the need for new interventions. We performed RNA-seq and microRNA profiling in basal ganglia (BG), metabolomics (plasma) and shotgun metagenomic sequencing (colon contents) in uninfected and SIV-infected rhesus macaques (RMs) administered vehicle (VEHSIV) or delta-9-tetrahydrocannabinol (THC) (THCSIV). Long-term, low-dose THC reduced neuroinflammation and dysbiosis and significantly increased plasma endocannabinoid, endocannabinoid-like, glycerophospholipid and indole-3-propionate levels in chronically SIV-infected RMs. Chronic THC potently blocked the upregulation of genes associated with type-I interferon responses (NLRC5, CCL2, CXCL10, IRF1, IRF7, STAT2, BST2), excitotoxicity (SLC7A11), and enhanced protein expression of WFS1 (endoplasmic reticulum stress) and CRYM (oxidative stress) in BG. Additionally, THC successfully countered miR-142-3p-mediated suppression of WFS1 protein expression via a cannabinoid receptor-1-mediated mechanism in HCN2 neuronal cells. Most importantly, THC significantly increased the relative abundance of Firmicutes and Clostridia including indole-3-propionate (C. botulinum, C. paraputrificum, and C. cadaveris) and butyrate (C. butyricum, Faecalibacterium prausnitzii and Butyricicoccus pullicaecorum) producers in colonic contents. This study demonstrates the potential of long-term, low-dose THC to positively modulate the MGBA by reducing neuroinflammation, enhancing endocannabinoid levels and promoting the growth of gut bacterial species that produce neuroprotective metabolites, like indole-3-propionate. The findings from this study may benefit not only PLWH on cART, but also those with no access to cART and more importantly, those who fail to suppress the virus under cART.

The crosstalk between 5-HT

Schizophrenia is a severe brain disorder that usually produces a lifetime of disability. First generation or typical such as haloperidol and second generation or atypical such as clozapine and risperidone remain the current standard for schizophrenia treatment. In some patients with schizophrenia, antipsychotics produce complete remission of positive symptoms, such as hallucinations and delusions. However, antipsychotic drugs are ineffective against cognitive deficits and indeed treated schizophrenia patients have small improvements or even deterioration in several cognitive domains. This underlines the need for novel and more efficient therapeutic targets for schizophrenia treatment. Serotonin and glutamate have been identified as key parts of two neurotransmitter systems involved in fundamental brain processes. Serotonin (or 5-hydroxytryptamine) 5-HT

A non-hallucinogenic LSD analog with therapeutic potential for mood disorders.

Hallucinations limit widespread therapeutic use of psychedelics as rapidly acting antidepressants. Here we profiled the non-hallucinogenic lysergic acid diethylamide (LSD) analog 2-bromo-LSD (2-Br-LSD) at more than 33 aminergic G protein-coupled receptors (GPCRs). 2-Br-LSD shows partial agonism at several aminergic GPCRs, including 5-HT

Opioid and cannabis co-use The role of opioid use to cope with negative affect.

The opioid epidemic is a significant public health concern, particularly among adults with chronic pain. There are high rates of cannabis co-use among these individuals and co-use is related to worse opioid-related outcomes. Yet, little work has examined mechanisms underlying this relationship. In line with affective processing models of substance use, it is possible that those who use multiple substances do so in a maladaptive attempt to cope with psychological distress. We tested whether, among adults with chronic lower back pain (CLBP), the relation between co-use and more severe opioid-related problems would occur via the serial effects of negative affect (anxiety, depression) and more coping motivated opioid use. After controlling for pain severity and relevant demographics, co-use remained related to more anxiety, depression, and opioid-related problems (but not more opioid use). Further, co-use was indirectly related to more opioid-related problems via the serial effect of negative affect (anxiety, depression) and coping motives. Alternative model testing found co-use was not indirectly related to anxiety or depression via serial effects of opioid problems and coping. Results highlight the important role negative affect may play in opioid problems among individuals with CLBP who co-use opioid and cannabis.

Screening, brief intervention, and referral to treatment (SBIRT) for cannabis A scoping review.

Screening, brief intervention, and referral to treatment (SBIRT) has been used to change substance use behavior. Despite cannabis being the most prevalent federally illicit substance, we have limited understanding of use of SBIRT for managing cannabis use. This review aimed to summarize the literature on SBIRT for cannabis use across age groups and contexts over the last two decades. This scoping review followed the a priori guide outlined by the PRISMA (Preferred Reporting Items for Scoping Reviews and Meta-Analyses) statement. We gathered articles from PsycINFO, PubMed, Sage Journals Online, ScienceDirect, and SpringerLink. The final analysis includes forty-four articles. Results indicate inconsistent implementation of universal screens and suggest screens assessing cannabis-specific consequences and utilizing normative data may increase patient engagement. Broadly, SBIRT for cannabis demonstrates high acceptability. However, the impact of SBIRT on behavior change across various modifications to intervention content and modality has been inconsistent. In adults, patients with primary cannabis use are not engaging in recommended treatment at similar rates to other substances. Results also suggest a lack of research addressing referral to treatment in adolescents and emerging adults. Based on this review, we offer several to improve each component of SBRIT that may increase implementation of screens, effectiveness of brief interventions, and engagement in follow-up treatment.

Patterns of polysubstance use and clinical comorbidity among persons seeking substance use treatment An observational study.

Polysubstance use is common among individuals seeking treatment for substance use disorders (SUD). However, we know less about patterns and correlates of polysubstance use among treatment-seeking populations. The current study aimed to identify latent patterns of polysubstance use and associated risk factors in persons entering SUD treatment. Patients (N 28,526) being admitted for substance use treatment reported on their use of thirteen substances (e.g., alcohol, cannabis, cocaine, amphetamines, methamphetamines, other stimulants, heroin, other opioids, benzodiazepines, inhalants, synthetics, hallucinogens, and club drugs) in the month before treatment and prior to the month before treatment. Latent class analysis (LCA) determined the relationship between class membership and gender, age, employment status, unstable housing, self-harm, overdose, past treatment, depression, generalized anxiety disorder, andor post-traumatic stress disorder (PTSD). Identified classes included 1) Alcohol primary, 2) Moderate probability of past-month alcohol, cannabis, andor opioid use 3) Alcohol primary, Lifetime cannabis and cocaine use 4) Opioid primary, Lifetime use of alcohol, cannabis, hallucinogens, club drugs, amphetamines, and cocaine 5) Moderate probability of past-month alcohol, cannabis, andor opioid use, Lifetime use of various substances 6) Alcohol and cannabis primary, Lifetime use of various substances and 7) High past-month polysubstance use. Individuals who engaged in past-month polysubstance use attended to face elevated risk of screening positive for recent unstable housing, unemployment, depression, anxiety, PTSD, self-harm, and overdose. Current polysubstance use is associated with significant clinical complexity. Tailored treatments that reduce harms resulting from polysubstance use and related psychiatric comorbidity may improve treatment outcomes in this population.

Oral health of recreational ecstasy-users.

In a cross-sectional study, dental records of 149 individuals visiting an Academic Dental Clinic in Amsterdam who reported recreational ecstasy use, defined as no more than twice a week, were systematically analyzed and compared to a group of age- and sex-matched non-drug-users. The parameters retrieved from the dental records were decayed, missing, and filled permanent teeth-index (DMFT-index), number of endodontically treated teeth, presence of active caries lesions, periodontitis, tooth wear, xerostomia, and self-reported use of oral hygiene devices. Periodontitis, active caries lesions, and xerostomia were statistically significantly more present in ecstasy-users. Ecstasy-users brush their teeth significantly less frequent per day than non-recreational-drug-users. There were no significant differences in DMFT-index and in the devices used for brushing and interdental cleaning, and frequency of use of these interdental devices between both groups. We conclude that periodontitis, active caries lesions, and xerostomia, are more frequently present in recreational ecstasy-users compared to age- and sex-matched non-users. De tandheelkundige gegevens van 149 patiënten van een academische tandheelkundige kliniek in Amsterdam, die aangaven op recreatieve basis (niet meer dan 2 keer per week) ecstasy te gebruiken, werden in een cross-sectioneel onderzoek systematisch geanalyseerd en vergeleken met een groep niet-gebruikers (controle) met dezelfde leeftijd en geslacht. Vergeleken werden aantal door cariës aangedane, ontbrekende of gerestaureerde gebitselementen (DMFT), aantal endodontisch behandelde gebitselementen, aanwezigheid van actieve dentinecariës, parodontitis, gebitsslijtage, xerostomie en het gebruik van mondverzorgingsmiddelen. Parodontitis, actieve dentinecariës en xerostomie werden statistisch significant vaker aangetroffen bij recreatieve ecstasygebruikers. Ecstasygebruikers poetsten hun tanden significant minder vaak dan niet-gebruikers. Tussen beide groepen werd geen significant verschil gevonden in DMFT-index, de hulpmiddelen die werden gebruikt voor het tandenpoetsen en de interdentale reiniging en de frequentie hiervan. Uit dit onderzoek bleek dat parodontitis, actieve dentinecariës en xerostomie vaker voorkomen bij recreatieve ecstasygebruikers.

Perceived risk of LSD varies with age and race evidence from 2019 United States cross-sectional data.

Psychedelics are being explored for their potential therapeutic benefits across a wide range of psychiatric diagnoses and may usher in a new age in psychiatric treatment. There is stigma associated with these currently illegal substances, and use varies by race and age. We hypothesized that minoritized racial and ethnic populations, relative to White respondents, would perceive psychedelic use as riskier. Using 2019 cross-sectional data from the National Survey of Drug Use and Health, we conducted a secondary analysis of 41,679 respondents. Perceived risk of heroin was used as a surrogate for overall risk of illegal substance use heroin and lysergic acid diethylamide were the only substances queried this way in the sample. A majority regarded lysergic acid diethylamide (66.7%) and heroin (87.3%) as a great risk if used once or twice. There were clear differences by race, with White respondents and those indicating more than one race having significantly lower perceived risk of lysergic acid diethylamide than respondents from other groups. Perceived risk of use also significantly increased with age. Perceived risk of lysergic acid diethylamide is unevenly distributed across the population. Stigma and racial disparities in drug-related crimes likely contribute to this. As research into potential therapeutic indications for psychedelics continues, perceived risk of use may change.

Diminished prospective mental representations of reward mediate reward learning strategies among youth with internalizing symptoms.

Adolescent internalizing symptoms and trauma exposure have been linked with altered reward learning processes and decreased ventral striatal responses to rewarding cues. Recent computational work on decision-making highlights an important role for prospective representations of the imagined outcomes of different choices. This study tested whether internalizing symptoms and trauma exposure among youth impact the generation of prospective reward representations during decision-making and potentially mediate altered behavioral strategies during reward learning. Sixty-one adolescent females with varying exposure to interpersonal violence exposure ( MVPA demonstrated that rewarding outcomes could accurately be decoded within several large-scale distributed networks (e.g. frontoparietal and striatum networks), that these reward representations were reactivated prospectively at the time of choice in proportion to the expected probability of receiving reward, and that youth with behavioral strategies that favored exploiting high reward options demonstrated greater prospective generation of reward representations. Youth internalizing symptoms, but not trauma exposure characteristics, were negatively associated with both the behavioral strategy of exploiting high reward options as well as the prospective generation of reward representations in the striatum. These data suggest diminished prospective mental simulation of reward as a mechanism of altered reward learning strategies among youth with internalizing symptoms.

Investigation of self-treatment with lysergic acid diethylamide and psilocybin mushrooms Findings from the Global Drug Survey 2020.

Growing numbers of people are using psychedelics for personal psychotherapy outside clinical settings, but research on such use is scarce. This study investigated the patterns of use, self-reported outcomes and outcome predictors of psychedelic self-treatment of mental health conditions or specific worriesconcerns in life. We use data from the Global Drug Survey 2020, a large online survey on drug use collected between November 2019 and February 2020. In all, 3364 respondents reported their self-treatment experiences with lysergic acid diethylamide ( Positive changes were observed across all 17 outcome items, with the strongest benefits on items related to insight and mood. Negative effects were reported by 22.5% of respondents. High intensity of psychedelic experience, seeking advice before treatment, treating with psilocybin mushrooms and treating post-traumatic stress disorder were associated with higher scores on the self-treatment outcome scale after averaging values across all 17 items. Younger age, high intensity of experience and treating with LSD were associated with increased number of negative outcomes. This study brings important insights into self-treatment practices with psychedelics in a large international sample. Outcomes were generally favourable, but negative effects appeared more frequent than in clinical settings. Our findings can help inform safe practices of psychedelic use in the community, and inspire clinical research. Future research can be improved with utilisation of prospective designs and additional predictive variables.

Antidepressants A content analysis of healthcare providers tweets.

Antidepressants are the primary treatment for depression, and social support from social media may offer another support route. Whilst Twitter has become an interactive platform for healthcare providers and their patients, previous studies found low engagement of healthcare providers when discussing antidepressants on Twitter. This study aims to analyse the Twitter posts of healthcare providers related to antidepressants and to explore the healthcare providers engagement and their areas of interest. Tweets within a 10-day period were collected through multiple searches with a list of keywords within Twitter. The results were filtered against several inclusion criteria, including a manual screening to identify healthcare providers. A content analysis was conducted on eligible tweets where correlative themes and subthemes were identified. Healthcare providers contributed 5.9% of the antidepressant-related tweets ( A relatively low proportion of healthcare providers engagement on Twitter regarding antidepressants (5.9%) was identified, with a minimal increase throughout the COVID-19 pandemic when compared to previous studies. The major clinical topics referred to in the tweets were side effects, antidepressants for the treatment of COVID-19 and antidepressant studies of psychedelics, which have been made publicly available. In general, the findings confirmed that social media platforms are a mechanism by which healthcare providers, organisations and students support patients, share information about adverse drug effects, communicate personal experiences, and share research. It is plausible that this could impact the belief and behaviours of people with lived experience of depression who may see these tweets.

Converging theories on dreaming Between Freud, predictive processing, and psychedelic research.

Dreams are still an enigma of human cognition, studied extensively in psychoanalysis and neuroscience. According to the Freudian dream theory and Solms modifications of the unconscious derived from it, the fundamental task of meeting our emotional needs is guided by the principle of homeostasis. Our innate value system generates conscious feelings of pleasure and unpleasure, resulting in the behavior of approaching or withdrawing from the world of objects. Based on these experiences, a hierarchical generative model of predictions (

Rearing behaviour in the mouse behavioural pattern monitor distinguishes the effects of psychedelics from those of lisuride and TBG.

Psychedelics alter consciousness and may have potential for drug development. As psychedelics are likely therapeutically active, it is important to study their effects and mechanisms using preclinical models. Here, we examined the effects of phenylalkylamine and indoleamine psychedelics on locomotor activity and exploratory behaviour using the mouse Behavioural Pattern Monitor (BPM). DOM, mescaline, and psilocin reduced locomotor activity at high doses and influenced rearings, an exploratory behaviour, in a characteristic inverted U-shaped dose-response function. Pretreatment with the selective 5-HT

The histamine H3 receptor modulates dopamine D2 receptor-dependent signaling pathways and mouse behaviors.

The histamine H3 receptor (H3R) is highly enriched in the spiny projection neurons (SPNs) of the striatum, in both the D1 receptor (D1R)-expressing and D2 receptor (D2R)-expressing populations. A cross-antagonistic interaction between H3R and D1R has been demonstrated in mice, both at the behavioral level and at the biochemical level. Although interactive behavioral effects have been described upon co-activation of H3R and D2R, the molecular mechanisms underlying this interaction are poorly understood. Here, we show that activation of H3R with the selective agonist RAMH mitigates D2R agonist-induced locomotor activity and stereotypic behavior. Using biochemical approaches and the proximity ligation assay, we demonstrated the existence of an H3R-D2R receptor complex in the mouse striatum. Additionally, we examined consequences of simultaneous H3R-D2R agonism on the phosphorylation levels of several signaling molecules using immunohistochemistry. H3R agonist treatment modulated Akt-GSK3β signaling in response to D2R activation via a β-arrestin 2-dependent mechanism in D2R-SPNs, but not in D1R-SPNs. Phosphorylation of MSK1 and rpS6 was largely unchanged under these conditions. As Akt-GSK3β signaling has been implicated in several neuropsychiatric disorders, this work may help clarify the role of H3R in modulating D2R function, leading to a better understanding of pathophysiology involving the interaction between histamine and dopamine systems.

UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice.

The effects of context on the subjective experience of serotonergic psychedelics have not been fully examined in human neuroimaging studies, partly due to limitations of the imaging environment. Here, we administered saline or psilocybin to mice in their home cage or an enriched environment, immunofluorescently-labeled brain-wide c-Fos, and imaged cleared tissue with light sheet microscopy to examine the impact of context on psilocybin-elicited neural activity at cellular resolution. Voxel-wise analysis of c-Fos-immunofluorescence revealed differential neural activity, which we validated with c-Fos

Associations of alternative cannabis product use and poly-use with subsequent illicit drug use initiation during adolescence.

Specific cannabis products may differentially increase risk of initiating non-cannabis illicit drug use during adolescence. To determine whether ever- and poly-use of smoked, vaporized, edible, concentrate, or blunt cannabis products are associated with subsequent initiation of non-cannabis illicit drug use. High school students from Los Angeles completed in-classroom surveys. The analytic sample (N 2163 53.9% female 43.5% HispanicLatino baseline M age 17.1 years) included students who reported never using illicit drugs at baseline (spring, 11th grade) and provided data at follow-up (fall and spring, 12th grade). Logistic regression models assessed associations between use of smoked, vaporized, edible, concentrate, and blunt cannabis at baseline (yesno for each product) and any non-cannabis illicit drug use initiation-including cocaine, methamphetamine, psychedelics, ecstasy, heroin, prescription opioids, or benzodiazepines-at follow-up. Among those who never used non-cannabis illicit drugs at baseline, ever cannabis use varied by cannabis product (smoked 25.8%, edible 17.5%, vaporized 8.4%, concentrates 3.9%, and blunts 18.2%) and patterns of use (single product use 8.2% and poly-product use 21.8%). After adjustment for baseline covariates, odds of illicit drug use at follow-up were largest for baseline ever users of concentrates (aOR 95% CI 5.743.16-10.43), followed by vaporized (aOR 95% CI 3.11 2.41-4.01), edibles (aOR 95% CI 3.43 2.32-5.08), blunts (aOR 95% CI 2.661.60-4.41), and smoked (aOR 95% CI 2.57 1.64-4.02) cannabis. Ever use of a single product (aOR 95% CI 2.34 1.26-4.34) or 2 products (aOR 95% CI 3.82 2.73-5.35) were also associated with greater odds of illicit drug initiation. For each of five different cannabis products, cannabis use was associated with greater odds of subsequent illicit drug use initiation, especially for cannabis concentrate and poly-product use.

The current state of ayahuasca research in animal models A systematic review.

The psychedelic brew ayahuasca is increasingly being investigated for its therapeutic potential. Animal models are essential to investigate the pharmacological effects of ayahuasca since they can control important factors influencing it, such as the set and setting. Review and summarise data available on ayahuasca research using animal models. We systematically searched five databases (PubMed, Web of Science, EMBASE, LILACS and PsycInfo) for peer-reviewed studies in English, Portuguese or Spanish published up to July 2022. The search strategy included ayahuasca- and animal model-related terms adapted from the SYRCLE search syntax. We identified 32 studies investigating ayahuasca effects on toxicological, behavioural and (neuro)biological parameters in rodents, primates and zebrafish. Toxicological results show that ayahuasca is safe at ceremonial-based doses but toxic at high doses. Behavioural results indicate an antidepressant effect and a potential to reduce the reward effects of ethanol and amphetamines, while the anxiety-related outcomes are yet inconclusive also, ayahuasca can influence locomotor activity, highlighting the importance of controlling the analysis for locomotion when using tasks depending on it. Neurobiological results show that ayahuasca affects brain structures involved in memory, emotion and learning and that other neuropathways, besides the serotonergic action, are important in modulating its effects. Studies using animal models indicate that ayahuasca is toxicologically safe in ceremonial-comparable doses and indicates a therapeutic potential for depression and substance use disorder while not supporting an anxiolytic effect. Essential gaps in the ayahuasca field can still be sufficed using animal models.

Psychosocial Factors Associated with Substance Use among Secondary School Students in Ilorin, Nigeria.

Adolescent substance use is a global concern. Identifying factors associated with it can help in preparing prevention programmes. The objectives were to determine the sociodemographic factors associated with substance use and the prevalence of associated psychiatric morbidity among secondary school students in Ilorin. Instruments used were a sociodemographic questionnaire, a modified WHO Students Drug Use Survey Questionnaire, and the General Health Questionnaire-12 (GHQ-12) which was used to determine psychiatric morbidity, using a cut-off score of 3. Substance use was associated with older age groups, male gender, parental substance use and poor relationship with parents, and urban location of school. Reported religiosity did not confer protection against substance use. The overall prevalence of psychiatric morbidity was 22.1% (n 442). Psychiatric morbidity was more common among users of opioids, organic solvents, cocaine and hallucinogens, with current opioid users having ten times the odds of psychiatric morbidity. Factors influencing adolescent substance use serve as a substrate for interventions. A good relationship with parents and teachers are protective factors, while parental substance use calls for holistic psychosocial support. The association of substance use with psychiatric morbidity highlights the need to incorporate behavioural treatment in substance use interventions. La Consommation de Substances Psychoactives chez les Adolescents est une Préoccupation Mondiale. L’Identification des Facteurs qui y sont Associés Peut Aider à Préparer des Programmes de Prévention. Déterminer les facteurs socio-démographiques associés à la consommation de substances psychoactives chez les élèves du secondaire à Ilorin. Déterminer la prévalence de la morbidité psychiatrique chez les étudiants et son association avec la consommation de substances. Les instruments utilisés étaient un questionnaire sociodémographique, un questionnaire modifié de l’enquête de l’OMS sur la consommation de drogues par les étudiants, et le Questionnaire de santé générale-12 (GHQ-12) qui a été utilisé pour déterminer la morbidité psychiatrique, en utilisant un score seuil de 3. La consommation de substances psychoactives était associée à des groupes d’âge plus élevés, au sexe masculin, à la consommation de substances psychoactives par les parents et à une mauvaise relation avec les parents, ainsi qu’à la localisation urbaine de l’école. La religiosité déclarée ne confère pas de protection contre la consommation de substances. La prévalence globale de la morbidité psychiatrique était de 22,1% (n 442). La morbidité psychiatrique était plus fréquente chez les consommateurs d’opioïdes, de solvants organiques, de cocaïne et d’hallucinogènes, les consommateurs actuels d’opioïdes ayant dix fois plus de chances de souffrir de morbidité psychiatrique. Les facteurs qui influencent la consommation de substances psychoactives chez les adolescents servent de substrat aux interventions. Une bonne relation avec les parents et les enseignants sont des facteurs de protection, tandis que la consommation de substances par les parents nécessite un soutien psychosocial global. L’association entre la consommation de substances et la morbidité psychiatrique souligne la nécessité d’intégrer un traitement comportemental dans les interventions en matière de consommation de substances. Santé des adolescents, médecine des adolescents, services de santé mentale en milieu scolaire, consommation d’alcool avant l’âge légal, toxicomanie, oral, pédopsychiatrie. Traduit avec.

Is the Requirement for First-Person Experience of Psychedelic Drugs a Justified Component of a Psychedelic Therapists Training

Recent research offers good reason to think that various psychedelic drugs-including psilocybin, ayahuasca, ketamine, MDMA, and LSD-may have significant therapeutic potential in the treatment of various mental health conditions, including post-traumatic stress disorder, depression, existential distress, and addiction. Although the use of psychoactive drugs, such as Diazepam or Ritalin, is well established, psychedelics arguably represent a therapeutic step change. As

National Institutes of health psilocybin research speaker series State of the science, regulatory and policy landscape, research gaps, and opportunities.

The U.S. National Institutes of Health (NIH) convened a seminal first ever psychedelic drug substance-focused speaker series, from April 22 to June 10, 2021, titled the NIH Psilocybin Research Speaker Series. This speaker series provided evidence-based scientific information to the public and the scientific community. Its aims were to assess the current state of the science and the regulatory and policy landscape, as well as to identify gaps in knowledge and understanding, ultimately serving to define future research needs. The highlights of the lectures and discussion from 26 national and international distinguished experts served as the basis for this special issue of Neuropharmacology.

Pharmacotherapies for Treatment-Resistant Depression How Antipsychotics Fit in the Rapidly Evolving Therapeutic Landscape.

One in three adults with major depressive disorder (MDD) do not experience clinically significant improvement after multiple sequential courses of antidepressants and have treatment-resistant depression (TRD). The presence of TRD contributes to the morbidity and excess mortality associated with MDD and has been linked to significantly increased health care expenses. In the absence of a consensus definition of TRD, this report takes a broad approach by considering inadequate response to one or more courses of antidepressants and focuses on atypical antipsychotics that are approved by the U.S. Food and Drug Administration for treatment of depression (aripiprazole, brexpiprazole, cariprazine, extended-release quetiapine, and olanzapine-fluoxetine combination). While multiple acute-phase studies have demonstrated the efficacy of these medications in improving depressive symptoms, clinically meaningful improvement (i.e., remission) remains limited, with significant concerns about side effects (including weight gain, metabolic dysfunction, extrapyramidal symptoms, and tardive dyskinesia), especially with long-term use. With the rapidly evolving landscape of antidepressant treatments over the past few years, which has witnessed approval of rapid-acting antidepressants (e.g., esketamine nasal spray and dextromethorphan-bupropion combination) and several more in the late-stage pipeline (e.g., zuranolone and psilocybin), it remains to be seen whether the use of atypical antipsychotics will go the way of the older and rarely prescribed antidepressants (such as tricyclics and monoamine oxidase inhibitors). Pragmatic clinical trials are needed to compare the effectiveness of atypical antipsychotics with TRD-specific pharmacotherapies and neuromodulation treatments and to identify the optimal sequencing of these varied approaches for patients with MDD. When using atypical antipsychotics, clinicians and patients are encouraged to use a shared decision-making approach by personalizing treatment selection based on anticipated side effects, tolerability, cost, and feasibility.

Can psychedelics enhance group psychotherapy A discussion on the therapeutic factors.

Despite the growth of psychedelic research, psychedelic-assisted group psychotherapy (PAGP) has received little attention in comparison to individual psychedelic-assisted psychotherapy models. In this article, we aim to discuss the therapeutic potential of PAGP, as well as outline existing models and the challenges of this approach. Using Irvin Yaloms 11 therapeutic factors of group therapy as a basic framework, we analyse current literature from clinical studies and neurobiological research relative to the topic of PAGP. We argue that combining psychedelic substances and group psychotherapy may prove beneficial for increasing group connectedness and interpersonal learning, potentially enhancing prosocial behaviour with direct opportunities to practice newly acquired knowledge about previously maladaptive behavioural patterns. Challenges regarding this approach include a more rigid therapy structure and potential loss of openness from patients, which may be ameliorated by adequate therapeutic training. We hope for this article to support clinical research on PAGP by presenting a therapeutic framework and outlining its mechanisms and challenges.

Off-target activity of NBOMes and NBOMe analogs at the µ opioid receptor.

New psychoactive substances (NPS) are introduced on the illicit drug market at a rapid pace. Their molecular targets are often inadequately elucidated, which contributes to the delayed characterization of their pharmacological effects. Inspired by earlier findings, this study set out to investigate the µ opioid receptor (MOR) activation potential of a large set of psychedelics, substances which typically activate the serotonin (5-HT

Hofmann vs. Paracelsus Do Psychedelics Defy the Basics of Toxicology-A Systematic Review of the Main Ergolamines, Simple Tryptamines, and Phenylethylamines.

Psychedelics are experiencing a strong renaissance and will soon be incorporated into clinical practice. However, there is uncertainty about how much harm they can cause at what doses. This review aimed to collect information on the health-hazardous doses of psychedelic substances, to be aware of the risks to which patients may be subjected. We focused on ergolamines, simple tryptamines, and phenylethylamines. We reviewed articles published in major medical and scientific databases. Studies reporting toxic or lethal doses in humans and animals were included. We followed PRISMA criteria for revisions. We identified 3032 manuscripts for inclusion. Of these, 33 were ultimately useful and gave relevant information about effects associated with high psychedelics doses. Despite having different molecular structures and different mechanisms of action, psychedelics are effective at very low doses, are not addictive, and are harmful at extremely high doses. For LSD and psilocybin, no dose has been established above which the lives of users are endangered. In contrast, MDMA appears to be the most dangerous substance, although reports are biased by recreational missuses. It seems that it is not only the dose that makes the poison. In the case of psychedelics, the set and setting make the poison.

Cannabis-assisted psychotherapy for complex dissociative posttraumatic stress disorder A case report.

A dissociative subtype of posttraumatic stress disorder, known as D-PTSD, has been included in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. In addition to meeting criteria for PTSD, patients endorse prominent dissociative symptoms, namely depersonalization and derealization, or detachment from ones self and surroundings. At present, this population is supported by a highly heterogeneous and undeveloped literature. Targeted interventions are therefore lacking, and those indicated for PTSD are limited by poor efficacy, delayed onset of action, and low patient engagement. Here, we introduce cannabis-assisted psychotherapy (CAP) as a novel treatment for D-PTSD, drawing parallels to psychedelic therapy. A 28-year-old female presented with complex D-PTSD. In a naturalistic setting, she underwent 10 sessions of CAP, scheduled twice monthly over 5 months, coupled with integrative cognitive behavioral therapy. An autonomic and relational approach to CAP was leveraged, specifically psychedelic somatic interactional psychotherapy. Acute effects included oceanic boundlessness, ego dissolution, and emotional breakthrough. From baseline to post-treatment, the patient showed a 98.5% reduction in pathological dissociation, as measured by the Multidimensional Inventory of Dissociation, no longer meeting criteria for D-PTSD. This was accompanied by decreased cognitive distractibility and emotional suffering, as well as increased psychosocial functioning. Anecdotally, the patient has sustained improvements for over 2 years to date. There is urgency to identify treatments for D-PTSD. The present case, while inherently limited, underscores the potential of CAP as a therapeutic option, leading to robust and sustained improvement. Subjective effects were comparable to those produced by classic and non-classic psychedelics, such as psilocybin and ketamine. Further research is warranted to explore, establish, and optimize CAP in D-PTSD, and to characterize its role in the pharmacological landscape.

Therapeutic effect of psilocybin in addiction A systematic review.

Psychedelic-assisted therapy e.g., with lysergic acid diethylamide (LSD) has shown promising results as treatment for substance use disorders (SUDs). Previous systematic reviews assessing the efficacy of psilocybin in SUDs only included clinical trials conducted in the last 25 years, but they may have missed clinical trials assessing the efficacy of psilocybin that were conducted before the 1980s, given much research has been done with psychedelics in the mid-20th century. In this systematic review, we specifically assessed the efficacy of psilocybin in patients with a SUD or non-substance-related disorder with no publication date restrictions in our search strategy. A systematic literature search was performed according to Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines from the earliest published manuscript up to September 2, 2022, in seven electronic databases, including clinical trials in patients with a SUD or non-substance-related disorder evaluating the efficacy of psilocybin. A total of four studies (six articles, of which two articles were long-term follow-up results from the same trial) were included in this systematic review. Psilocybin-assisted therapy was administered to Only one RCT and three small clinical trials were identified assessing the efficacy of psilocybin combined with some form of psychotherapy in patients with alcohol and tobacco use disorder. All four clinical trials indicated a beneficial effect of psilocybin-assisted therapy on SUD symptoms. Larger RCTs in patients with SUDs need to evaluate whether psilocybin-assisted therapy is effective in patients with SUD.

Navigating intensive altered states of consciousness How can the set and setting key parameters promote the science of human birth

The subjective childbirth experience is crucial from a public health standpoint. There is a correlation between a negative childbirth experience and a poor mental state after birth, with effects that go far beyond the postpartum (PP) period. This paper offers a new approach as to how birthing experiences, and birth in general, can be navigated. The theory of set and setting proves that psychedelic experiences are shaped, first and foremost, by the mindset of an individual entering a psychedelic experience (set) and by the surroundings in which the experience happens (setting). In research on altered states of consciousness during psychedelic experiences, this theory explains how the same substance can lead to a positive and life-changing experience or to a traumatic and frightening experience. Because recent studies suggest that birthing women enter an altered state of consciousness during physiological birth (birthing consciousness), I suggest analyzing the typical modern birthing experience in terms of set and setting theory. I argue that the set and setting key parameters can help design, navigate, and explain many psychological and physiological elements of the human birth process. Thus, an operative conclusion that emerges from the theoretical analysis presented in this paper is that framing and characterizing the birth environment and birth preparations in terms of set and setting is a central tool that could be used to promote physiological births as well as subjective positive birthing experiences, which is currently a primary, yet unreached goal, in modern obstetrics and public health.

Development of a computerized adaptive substance use disorder scale for screening, measurement and diagnosis - The CAT-SUD-E.

The Computerized Adaptive Test for Substance Use Disorder (CAT-SUD), an adaptive test based on multidimensional item response theory, has been expanded to include 7 specific Diagnostic and Statistical Manual, 5th edition (DSM-5) defined SUDs. Initial testing of the new measure, the CAT-SUD expanded (CAT-SUD-E) is reported here. 275 Community-dwelling adults (ages 18-68) responded to public and social-media advertisements. Participants virtually completed both the CAT-SUD-E and the Structured Clinical Interview for DSM-5, Research Version (SCID) to assess the validity of the CAT-SUD-E in determining whether participants met criteria for specific DSM-5 SUDs. Diagnostic classifications were based on 7 SUDs, each with 5 items, for current and lifetime SUDs. For SCID-based presence of any lifetime SUD, predictions based on the overall CAT-SUD-E diagnosis and severity score were AUC0.92, 95% CI 0.88, 0.95 for current and AUC0.94, 95% CI 0.91, 0.97 for lifetime. For individual diagnoses, classification accuracy for current SUDs ranged from an AUC0.76 for alcohol to AUC0.92 for nicotinetobacco. Classification accuracy for lifetime SUDs ranged from an AUC0.81 for hallucinogens to AUC0.96 for stimulants. Median CAT-SUD-E completion time was under 4 min. The CAT-SUD-E quickly produces similar results as lengthy structured clinical interviews for overall SUD and substance-specific SUDs, with high precision and accuracy, through a combination of fixed-item responses for diagnostic classification and adaptive SUD severity measurement. The CAT-SUD-E harmonizes information from mental health, trauma, social support and traditional SUD items to provide a more complete characterization of SUD and provides both diagnostic classification and severity measurement.

Interest in receiving psychedelic-assisted therapy among marginalized women Implications and findings from a community-based study in Canada.

Psychedelic-assisted therapies are receiving mounting attention for their therapeutic potential. However, little is known about interest among women who experience elevated risk of mental health and substance use disorders. This study examined interest in receiving psychedelic-assisted therapy and socio-structural factors associated with interest among marginalized women. Data (2016-2017) were drawn from two community-based, prospective open cohorts of >1000 marginalized women in Metro Vancouver, Canada. Bivariate and multivariable logistic regression examined associations with interest in receiving psychedelic-assisted therapy. Among women who used psychedelics, additional data were collected to describe ratings of personal meaningfulness, sense of wellbeing, and spiritual significance. Of 486 eligible participants (aged 20-67 years), 43% ( Several mental health and substance use-related variables that have been demonstrated to be amenable to psychedelic-assisted therapy were associated with interest in receiving psychedelic-assisted therapy among women in this setting. As access to psychedelic-assisted therapies continues to expand, any future approaches to extend psychedelic medicine to marginalized women should integrate trauma-informed care and broader socio-structural supports.

Serotonergic psychedelics for depression What do we know about neurobiological mechanisms of action

Current treatment options for major depressive disorder (MDD) have limited efficacy and are associated with adverse effects. Recent studies investigating the antidepressant effect of serotonergic psychedelics-also known as classic psychedelics-have promising preliminary results with large effect sizes. In this context, we conducted a review of the putative neurobiological underpinnings of the mechanism of antidepressant action of these drugs. A narrative review was conducted using PubMed to identify published articles evaluating the antidepressant mechanism of action of serotonergic psychedelics. Serotonergic psychedelics have serotonin (5HT)2A agonist or partial agonist effects. Their rapid antidepressant effects may be mediated-in part-by their potent 5HT2A agonism, leading to rapid receptor downregulation. In addition, these psychedelics impact brain derived neurotrophic factor and immunomodulatory responses, both of which may play a role in their antidepressant effect. Several neuroimaging and neurophysiology studies evaluating mechanistic change from a network perspective can help us to further understand their mechanism of action. Some, but not all, data suggest that psychedelics may exert their effects, in part, by disrupting the activity of the default mode network, which is involved in both introspection and self-referential thinking and is over-active in MDD. The mechanisms of action underlying the antidepressant effect of serotonergic psychedelics remains an active area of research. Several competing theories are being evaluated and more research is needed to determine which ones are supported by the most robust evidence.

Ethical principles of traditional Indigenous medicine to guide western psychedelic research and practice.

The resurgence of Western psychedelic research and practice has led to increasing concerns from many Indigenous Nations regarding cultural appropriation, lack of recognition of the sacred cultural positioning of these medicines, exclusionary practices in research and praxis, and patenting of traditional medicines. Indigenous voices and leadership have been notably absent from the Western psychedelic field currently widely represented by Westerners. An Indigenous-led globally represented group of practitioners, activists, scholars, lawyers, and human rights defenders came together with the purpose of formulating a set of ethical guidelines concerning traditional Indigenous medicines current use in Western psychedelic research and practice. A global Indigenous consensus process of knowledge-gathering was engaged which identified eight interconnected ethical principles, including Reverence, Respect, Responsibility, Relevance, Regulation, Reparation, Restoration, and Reconciliation. A summary of the work is presented here with suggested ethical actions for moving forward within Western psychedelic research and practice spaces.

Prenatal Exposure to Δ9-Tetrahydrocannabinol Affects Hippocampus-Related Cognitive Functions in the Adolescent Rat Offspring Focus on Specific Markers of Neuroplasticity.

Previous evidence suggests that prenatal exposure to THC (pTHC) derails the neurodevelopmental trajectories towards a vulnerable phenotype for impaired emotional regulation and limbic memory. Here we aimed to investigate pTHC effect on hippocampus-related cognitive functions and markers of neuroplasticity in adolescent male offspring. Wistar rats were exposed to THC (2 mgkg) from gestational day 5 to 20 and tested for spatial memory, object recognition memory and reversal learning in the reinforce-motivated Can test and in the aversion-driven Barnes maze test locomotor activity and exploration, anxiety-like behaviour, and response to natural reward were assessed in the open field, elevated plus maze, and sucrose preference tests, respectively. The gene expression levels of NMDA NR1-2A subunits, mGluR5, and their respective scaffold proteins PSD95 and Homer1, as well as CB1R and the neuromodulatory protein HINT1, were measured in the hippocampus. pTHC offspring exhibited deficits in spatial and object recognition memory and reversal learning, increased locomotor activity, increased NR1-, decreased NR2A- and PSD95-, increased mGluR5- and Homer1-, and augmented CB1R- and HINT1-hippocampal mRNA levels. Our data shows that pTHC is associated with specific impairment in spatial cognitive processing and effectors of hippocampal neuroplasticity and suggests novel targets for future pharmacological challenges.

The Effects of Peripubertal THC Exposure in Neurodevelopmental Rat Models of Psychopathology.

Adolescent exposure to cannabinoids as a postnatal environmental insult may increase the risk of psychosis in subjects exposed to perinatal insult, as suggested by the two-hit hypothesis of schizophrenia. Here, we hypothesized that peripubertal Δ

Characterization of the Antitumor Potential of Extracts of

Cannabis has been used for decades as a palliative therapy in the treatment of cancer. This is because of its beneficial effects on the pain and nausea that patients can experience as a result of chemoradiotherapy. Tetrahydrocannabinol and cannabidiol are the main compounds present in

Aromatic Bromination Abolishes Deficits in Visuospatial Learning Induced by MDMA (Ecstasy) in Rats While Preserving the Ability to Increase LTP in the Prefrontal Cortex.

It has recently been demonstrated that aromatic bromination at C(2) abolishes all typical psychomotor, and some key prosocial effects of the entactogen MDMA in rats. Nevertheless, the influence of aromatic bromination on MDMA-like effects on higher cognitive functions remains unexplored. In the present work, the effects of MDMA and its brominated analog 2Br-4,5-MDMA (1 mgkg and 10 mgkg i.p. each) on visuospatial learning, using a radial, octagonal Olton maze (4 × 4) which may discriminate between short-term and long-term memory, were compared with their influence on in vivo long-term potentiation (LTP) in the prefrontal cortex in rats. The results obtained indicate that MDMA diminishes both short- and long-term visuospatial memory but increases LTP. In contrast, 2Br-4,5-MDMA preserves long-term visuospatial memory and slightly accelerates the occurrence of short-term memory compared to controls, but increases LTP, like MDMA. Taken together, these data are consistent with the notion that the modulatory effects induced by the aromatic bromination of the MDMA template, which abolishes typical entactogenic-like responses, might be extended to those effects affecting higher cognitive functions, such as visuospatial learning. This effect seems not to be associated with the increase of LTP in the prefrontal cortex.

Clinical Epigenomic Explanation of the Epidemiology of Cannabinoid Genotoxicity Manifesting as Transgenerational Teratogenesis, Cancerogenesis and Aging Acceleration.

As global interest in the therapeutic potential of cannabis and its derivatives for the management of selected diseases increases, it is increasingly imperative that the toxic profile of cannabinoids be thoroughly understood in order to correctly assess the balance between the therapeutic risks and benefits. Modern studies across a number of jurisdictions, including Canada, Australia, the US and Europe have confirmed that some of the most worrying and severe historical reports of both congenital anomalies and cancer induction following cannabis exposure actually underestimate the multisystem thousand megabase-scale transgenerational genetic damage. These findings from teratogenic and carcinogenic literature are supported by recent data showing the accelerated patterns of chronic disease and the advanced DNA methylation epigenomic clock age in cannabis exposed patients. Together, the increased multisystem carcinogenesis, teratogenesis and accelerated aging point strongly to cannabinoid-related genotoxicity being much more clinically significant than it is widely supposed and, thus, of very considerable public health and multigenerational impact. Recently reported longitudinal epigenome-wide association studies elegantly explain many of these observed effects with considerable methodological sophistication, including multiple pathways for the inhibition of the normal chromosomal segregation and DNA repair, the inhibition of the basic epigenetic machinery for DNA methylation and the demethylation and telomerase acceleration of the epigenomic promoter hypermethylation characterizing aging. For cancer, 810 hits were also noted. The types of malignancy which were observed have all been documented epidemiologically. Detailed epigenomic explications of the brain, heart, face, uronephrological, gastrointestinal and limb development were provided, which amply explained the observed teratological patterns, including the inhibition of the key morphogenic gradients. Hence, these major epigenomic insights constituted a powerful new series of arguments which advanced both our understanding of the downstream sequalae of multisystem multigenerational cannabinoid genotoxicity and also, since mechanisms are key to the causal argument, inveighed strongly in favor of the causal nature of the relationship. In this introductory conceptual overview, we present the various aspects of this novel synthetic paradigmatic framework. Such concepts suggest and, indeed, indicate numerous fields for further investigation and basic science research to advance the exploration of many important issues in biology, clinical medicine and population health. Given this, it is imperative we correctly appraise the risk-benefit ratio for each potential cannabis application, considering the potency, severity of disease, stage of human development and duration of use.

Indole Alkaloids from Psychoactive Mushrooms Chemical and Pharmacological Potential as Psychotherapeutic Agents.

Neuropsychiatric diseases such as depression, anxiety, and post-traumatic stress represent a substantial long-term challenge for the global health systems because of their rising prevalence, uncertain neuropathology, and lack of effective pharmacological treatments. The approved existing studies constitute a piece of strong evidence whereby psychiatric drugs have shown to have unpleasant side effects and reduction of sustained tolerability, impacting patients quality of life. Thus, the implementation of innovative strategies and alternative sources of bioactive molecules for the search for neuropsychiatric agents are required to guarantee the success of more effective drug candidates. Psychotherapeutic use of indole alkaloids derived from magic mushrooms has shown great interest and potential as an alternative to the synthetic drugs currently used on the market. The focus on indole alkaloids is linked to their rich history, their use as pharmaceuticals, and their broad range of biological properties, collectively underscoring the indole heterocycle as significant in drug discovery. In this review, we aim to report the physicochemical and pharmacological characteristics of indole alkaloids, particularly those derived from magic mushrooms, highlighting the promising application of such active ingredients as safe and effective therapeutic agents for the treatment of neuropsychiatric disorders.

Typology of Users of Psychedelics and Alike Psychoactive Substances in Czechia Results of the National Online Survey.

The aim of this study was to define the typical groups of users of psychedelics and alike psychoactive substances in Czechia regarding various variables such as demographics, their patterns of use, or motivation for use. Data from 890 Czech respondents were collected through an online questionnaire as a part of The National Psychedelic Research Project. Subjects reported experience with the use of 29 selected substances by answering 133 questions of the questionnaire. Cluster analysis based on answers on last year use was performed, and descriptive statistics was used for 18 questions from the questionnaire. Six groups of users were identified with distinguished users and demographic characteristics, namely,

Contextual determinants of mass drug administration performance Modelling fourteen years of lymphatic filariasis treatments in West Africa.

Effective mass drug administration (MDA) is the cornerstone in the elimination of lymphatic filariasis (LF) and a critical component in combatting all neglected tropical diseases for which preventative chemotherapy is recommended (PC-NTDs). Despite its importance, MDA coverage, however defined, is rarely investigated systematically across time and geography. Most commonly, investigations into coverage react to unsatisfactory outcomes and tend to focus on a single year and health district. Such investigations omit more macro-level influences including sociological, environmental, and programmatic factors. The USAID NTD database contains measures of performance from thousands of district-level LF MDA campaigns across 14 years and 10 West African countries. Specifically, performance was measured as an MDAs epidemiological coverage, calculated as persons treated divided by persons at risk. This analysis aims to explain MDA coverage across time and geography in West Africa using sociological, environmental, and programmatic factors. The analysis links epidemiological coverage data from 3,880 LF MDAs with contextual, non-NTD data via location (each MDA was specific to a health district) and time (MDA month, year). Contextual data included rainfall, temperature, violence or social unrest, COVID-19, the 2014 Ebola outbreak, road accessisolation, population density, observance of Ramadan, and the number of previously completed MDAs. We fit a hierarchical linear regression model with coverage as the dependent variable and performed sensitivity analyses to confirm the selection of the explanatory factors. Above average rainfall, COVID-19, Ebola, violence and social unrest were all significantly associated with lower coverage. Years of prior experience in a district and above average temperature were significantly associated with higher coverage. These generalized and context-focused findings supplement current literature on coverage dynamics and MDA performance. Findings may be used to quantify typically anecdotal considerations in MDA planning. The model and methodology are offered as a tool for further investigation.

Sperm capacitation and transcripts levels are altered by in vitro THC exposure.

Delta-9-tetrahydrocannabinol (THC) is the primary phytocannabinoid responsible for the psychoactive properties of cannabis and is known to interact with the endocannabinoid system, which is functionally present in the male reproductive system. Since cannabis consumption is the highest among reproductive aged males, the current study aimed to further investigate the effects of THC exposure to phenotypical, physiological, and molecular parameters in sperm. Bull sperm of known fertility were used as a translational model for human sperm and subjected to in vitro treatment with physiologically relevant experimental doses of THC. Sperm parameters, capacitation, apoptosis, and transcript levels were evaluated following treatment. Motility, morphology, and viability of bovine sperm was unaltered from THC exposure. However, 0.32µM of THC caused an increased proportion of capacitating sperm (p < 0.05) compared to control and vehicle group sperm. Transcriptome analysis revealed that 39 genes were found to be differentially expressed by 0.032µM THC exposure, 196 genes were differentially expressed by 0.32µM THC exposure, and 33 genes were differentially expressed by 3.2µM THC. Secondary analysis reveals pathways involving development, nucleosomes, ribosomes and translation, and cellular metabolism to be significantly enriched. Phytocannabinoid exposure to sperm may adversely affect sperm function by stimulating premature capacitation. These findings also show for the first time that spermatozoal transcripts may be altered by THC exposure. These results add to previous research demonstrating the molecular effects of cannabinoids on sperm and warrant further research into the effects of cannabis on male fertility.

Prevalence of psychoactive substance use by adolescents in public schools in a municipality in the São Paulo Metropolitan Area, Brazil.

This study aimed to estimate the prevalence of psychoactive substance use by adolescents from public schools. This is a cross-sectional study that used a random sample of adolescents from five public schools located in a municipality in the central-west region of the São Paulo Metropolitan Area, Brazil. Information on demographic, socioeconomic, and drug use was collected using self-report questionnaires. The sample consisted of 1,460 students, 716 (49%) males, aged 10-19 years (13.19±2.04 years). The prevalence of psychoactive substance use in the last month was 51% for analgesics 48.8% for alcohol 37.3% for tobacco 30.8% for tranquilizers 23.1% for marijuana 22.6% for anabolic steroids 21.6% for ecstasy 15.3% for amphetaminesstimulants 13.4% for phencyclidine 12.9% for cocainecrack 12.6% for inhalantssolvents 11.5% for opiates 11.4% for hallucinogens and 16.2% for other unclassified drugs. Elementary and middle school students were more likely to consume tobacco (OR 2.306 95%CI 1.733-3.068 p < 0.001), and male students were more likely to consume any type of substance. We identified a high use of psychoactive substances among this study participants, with a higher prevalence among male students.

Psilocybin services in Oregon a call for awareness among clinical toxicologists.

In 2023, Oregon enacted laws regulating the manufacture and use of psilocybin products in licensed facilities for supervised sessions with trained facilitators. This commentary summarizes the final rules for psilocybin services in Oregon, and provides perspectives from a clinical toxicologist on some of the issues that may arise. These include the scope of practice for non-clinical facilitators, prevention and management of adverse drug reactions, and toxicological uncertainties with regards to dose considerations for people with mental health and other medical conditions. This commentary addresses some common misperceptions relating to the program, and provides perspective on some of the challenges that clinical toxicologists may encounter as legislative reform initiatives for psilocybin move forward throughout the United States.

Correlates of substance use in a large naturalistic cohort of young people with early and emerging psychosis.

Substance use remains a barrier to recovery for young people accessing early intervention services for psychosis. While correlates of use have been explored in populations experiencing a first episode of psychosis (FEP), sample sizes have been small and less research assesses cohorts at ultrahigh risk of psychosis (UHR). This study uses data from a naturalistic cohort including UHR and FEP participants (N 1252) to elucidate clinical correlates of use in the past 3 months of any illicit substance, amphetamine-type stimulants (ATS), cannabis, and tobacco. Moreover, network analysis based on use of these substances and additionally alcohol, cocaine, hallucinogens, sedatives, inhalants, and opioids was completed. Young people with FEP used substances at significantly higher rates than those at UHR. High concurrence of use was seen between substances. In the FEP group, participants who had used any illicit substance, ATS, andor tobacco had increased positive symptoms and decreased negative symptoms. Young people with FEP who used cannabis had increased positive symptoms. In the UHR group, participants who had used any illicit substance, ATS, andor cannabis in the past 3 months showed decreased negative symptoms compared to those who had not. A distinct clinical picture of more florid positive symptoms and alleviated negative symptoms seen in those who use substances in the FEP group appears muted in the UHR cohort. Treating young people at UHR in early intervention services represents the earliest opportunity to address substance use early to improve outcomes.

Acute psilocybin enhances cognitive flexibility in rats.

Psilocybin has been shown to improve symptoms of depression and anxiety when combined with psychotherapy or other clinician-guided interventions. To understand the neural basis for this pattern of clinical efficacy, experimental and conceptual approaches that are different than traditional laboratory models of anxiety and depression are needed. A potential novel mechanism is that acute psilocybin improves cognitive flexibility, which then enhances the impact of clinician-assisted interventions. Consistent with this idea, we find that acute psilocybin robustly improves cognitive flexibility in male and female rats using a task where animals switched between previously learned strategies in response to uncued changes in the environment. Psilocybin did not influence Pavlovian reversal learning, suggesting that its cognitive effects are selective to enhanced switching between previously learned behavioral strategies. The serotonin (5HT) 2 A receptor antagonist ketanserin blocked psilocybins effect on set-shifting, while a 5HT2C-selective antagonist did not. Ketanserin alone also improved set-shifting performance, suggesting a complex relationship between psilocybins pharmacology and its impact on flexibility. Further, the psychedelic drug 2,5-Dimethoxy-4-iodoamphetamine (DOI) impaired cognitive flexibility in the same task, suggesting that this effect of psilocybin does not generalize to all other serotonergic psychedelics. We conclude that the acute impact of psilocybin on cognitive flexibility provides a useful behavioral model to investigate its neuronal effects relevant to its positive clinical outcome.

An ecological momentary assessment study to examine covariates and effects of concurrent and simultaneous use of electronic cigarettes and marijuana among college students.

The prevalence of concurrent and simultaneous use of e-cigarette and marijuana among college students is high. Yet, the literature was mainly based on cross-sectional surveys with emphasis on the smoking route. This is the first ecological momentary assessment (EMA) study that examined the vaping route of nicotine-marijuana co-use and the associated short-term psychological effects. This study recruited 686 college student e-cigarette users to participate in an on-line survey and 7-day EMA. Frequent marijuana users (247) - using marijuana weekly or daily - were compared with infrequentnon-users (439) on academic performance, e-cigarette use patterns, and dependence and respiratory symptoms. EMA data from the frequent users were used to study the association between marijuana vaping and e-cigarette consumption and the short-term psychological effects of e-cigarette and marijuana use. The results show that e-cigarette users who frequently used marijuana tended to have lower academic performance, be involved in higher-risk use patterns, and have higher levels of e-cigarette dependence, marijuana problems, and respiratory symptoms, compared to infrequentnon-users. Marijuana vaping was associated with a higher level of e-cigarette consumption. E-cigarette use and marijuana use were both associated with higher levels of positive affect, physiological sensation, and craving for e-cigarettes. While marijuana use was linked to a lower level of negative affect, e-cigarette use did not have a significant effect. Further, none of the interaction effects between e-cigarette and marijuana use on psychological states were significant. The results showed additive effects of e-cigarette and marijuana use although the hypothesized synergistic effects were not supported.

An overview of New Psychoactive Substances (NPS) in northeast Brazil NMR-based identification and analysis of ecstasy tablets by GC-MS.

The actual illicit market for synthetic drugs is characterized by a wide variety of psychoactive substances of different chemical and pharmacological classes, such as amphetamine-type stimulants and new psychoactive substances. The knowledge about its chemical composition, as well as the nature and quantity of the active substances present, is important for emergency care in intoxication cases by these substances and to establish adequate chemical and toxicological analysis procedures in forensic laboratories. The aim of this work was to study the prevalence of amphetamine-type stimulants and new psychoactive substances in the states of Bahia and Sergipe, in the northeast region of Brazil, involving samples of drugs seized by the local police forces from 2014 to 2019. In a total of 121 seized and analyzed samples, in which ecstasy tablets predominated (n 101), nineteen substances were identified using GC-MS and

Polysubstance Use Patterns Associated With HIV Disease Severity Among Those With Substance Use Disorders A Latent Class Analysis.

Polysubstance use is common among people with HIV infection (PWH) and with substance use disorder (SUD), but its effects are understudied. We aimed to identify polysubstance use patterns over time and assess their associations with HIV disease severity. In 233 PWH with current or past SUD, latent class analysis identified polysubstance use patterns based on the Alcohol Use Disorders Identification Test-Consumption and past-30-day use of cannabis, cocaine, opioids, and tranquilizers at baseline. We categorized changes in use patterns and tested associations between those changes and CD4 count and HIV viral suppression at 12 months in linear and logistic regressions. Three patterns were identified at baseline 18% did not use any substance (NONE--a priori defined) 63% used mostly cannabis and alcohol (CA) and 19% used opioids along with other drugs, including cocaine, tranquilizers, cannabis, and alcohol (MULTI). At 12 months, 40% moved from a high to a lower substance use class (MULTI to CA, either to NONE) or remained as NONE, 43% were in CA both times and 17% increased (NONE to CA, either to MULTI) or remained as MULTI. The adjusted mean CD4 count (for baseline covariates and baseline CD4 count) was significantly lower among participants increasing or remaining in MULTI (523, 95% CI 448, 598, cellsmm3) compared with those who decreasedabstained throughout (607, 95% CI 552, 663, We identified distinct polysubstance use patterns among PWH with SUD cannabisalcohol and opioids with alcohol and other drugs. Changes over time toward fewer substancesno use were associated with lower HIV disease severity based on CD4 count but not based on HIV viral suppression.

Attitudes Toward Cannabis Use Legalization and Openness to Legal Use Among Young Partygoers in Norway.

The purpose of this study was to examine attitudes toward legalization of cannabis use and openness to legal use among Norwegian partygoers. We examined a combined sample ( Although 46.1% of participants reported having used cannabis at least once, only 13 (32.6%) favored legalization and 14 (25.6%) stated they would themselves use cannabis if legalized. Yet, even among never-users, we observed non-opposition to legalization (16.4% in favor 14.9% dont know) and openness to legal use (8.2% would use 12.4% dont know). Histories of cannabis, tobacco, or any other drug use, sex (male), and age younger than 21 years (vs. 30 or older) were consistently associated with affirmative responses to both questions. Openness to legal use was strongly associated with favorable legalization attitudes and age younger than 21, even after accounting for lifetime cannabis use history. Favoring cannabis legalization and openness to legal use were relatively low in this sample of young Norwegian partygoers. Yet, prevalence of cannabis use may increase after legalization among its supporters and among those younger than 21, especially if dont know responses are considered.

Psychotherapeutic and neurobiological processes associated with ayahuasca A proposed model and implications for therapeutic use.

Ayahuasca is a psychoactive Amazonian plant brew. It is usually made from the

Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors.

Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) is essential for psychedelic-induced cortical plasticity, but it is currently unclear why some 5-HT2AR agonists promote neuroplasticity, whereas others do not. We used molecular and genetic tools to demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics these results explain why serotonin does not engage similar plasticity mechanisms. This work emphasizes the role of location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the intriguing possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex.

Possible psychedelic therapeutic mechanism.

Psychedelics act on intracellular serotonin receptors that are not accessible by serotonin alone.

Alleviation of Cocaine Withdrawal and Pertinent Interactions between Salvinorin-Based Antagonists and Kappa Opioid Receptor.

The kappa opioid receptor (KOR) is involved in the regulation of both the reward and mood processes. Recent reports find that the use of drugs of abuse increases the production of dynorphin and the overall activation of KOR. Long-acting KOR antagonists, such as norbinaltorphimine (nor-BNI), JDTic, and 5-guanidinonaltrindole (GNTI), have been shown to stop depressive and anxiety-related disorders, which are the common side effects of withdrawal that can lead to a relapse in drug use. Unfortunately, these prototypical KOR antagonists are known to induce selective KOR antagonism that is delayed by hours and extremely prolonged, and their use in humans comes with serious safety concerns because they possess a large window for potential drug-drug interactions. Furthermore, their persistent pharmacodynamic activities can hinder the ability to reverse unanticipated side effects immediately. Herein, we report our studies of the lead selective, salvinorin-based KOR antagonist (

Psychedelic-Assisted Neuroplasticity for the Treatment of Mental Health Disorders.

The renaissance of research into psychedelics class of drugs has renewed interest for a possible psychedelic clinical therapy for treating psychiatric conditions such as treatment-resistant depression, major depressive-disorder, post-traumatic stress disorder, and other neuropsychiatric diseases. Psychedelics are known to stimulate neurogenesis and gliogenesis, reduce inflammation, and ameliorate oxidative stress, which makes them promising candidates for therapeutics in psychiatric, neurodegenerative, and movement disorders. The patent highlight showcase methods for treating mental health disorders and promoting neural plasticity.

Neural Mechanisms and Psychology of Psychedelic Ego Dissolution.

Neuroimaging studies of psychedelics have advanced our understanding of hierarchical brain organization and the mechanisms underlying their subjective and therapeutic effects. The primary mechanism of action of classic psychedelics is binding to serotonergic 5-HT2A receptors. Agonist activity at these receptors leads to neuromodulatory changes in synaptic efficacy that can have a profound effect on hierarchical message-passing in the brain. Here, we review the cognitive and neuroimaging evidence for the effects of psychedelics in particular, their influence on selfhood and subject-object boundaries-known as ego

Lower-risk substance use guidelines accessible by youth.

Lower-risk substance use guidelines (LRSUGs) are an evidence-based harm reduction strategy used to provide information to people who use drugs so they can reduce harms associated with substance use. This study aimed to identify LRSUGs accessible to youth and to characterize the recommendations within these guidelines. The overall goal is to identify gaps in current LRSUGs and to inform researchers and policymakers of the kinds of health information youth can access. We conducted a digital assessment using the Google search engine to identify LRSUGs that could be identified by youth when searching for official sources of information related to commonly used substances, including cannabis, caffeine, alcohol, hallucinogens, prescription opioids, nicotine, andor prescription stimulants. LRSUGs were coded and data were extracted from them to identify gaps. One hundred thirty LRSUGs were identified most focused on alcohol (n 40, 31%), cannabis (n 30, 23%), and caffeine (n 21, 16%). LRSUGs provided recommendations about dosing (n 108, 83%), frequency of use (n 72, 55%), and when to use (n 86, 66%). Most LRSUGs were published by health (n 51, 39%) and third-sector organizations (n 41, 32%), followed by provincialstate (n 18, 14%), government (n 14, 11%), municipal (n 4, 3%), and academic (n 2, 2%) sources. Only 16% (n 21) of LRSUGs were youth-specific and one-quarter (n 32, 25%) of LRSUGs provided gender-specific recommendations. Most guidelines featured information on short (n 76, 58%) and long-term (n 69, 53%) negative effectives and positive effects of substances (n 56, 43%). Less than half (n 50, 38%) of LRSUGs cited evidence in support of the information they provided. We identified several areas in the current LRSUGs for youth that need to be addressed. Among the gaps are a lack of LRSUGs developed specifically for youth, a lack of youth engagement in developing harm reduction strategies centered around them, and a lack of evidence-based LRSUGs. Youth-oriented, evidence-based LRSUGs are needed to better support youth who use substances and help them manage the negative effects of substance use.

Unblinding and demand characteristics in the treatment of depression.

Blinding of treatment allocation in clinical trials in psychiatry is regarded as an ideal. The potential impact of unblinding chimes with a general concern for psychological research so-called demand characteristics can undermine confidence in findings from experimental and clinical studies. Scepticism can result in nihilism. The reliance on subjective report of symptoms in clinical trials of drug efficacy in depression provides an important example. It is regularly implied that if subjective effects, including specific adverse reactions, unblind participants to an active treatment then evidence for its efficacy is suspect. In fact, the strong association between dose and subjective effects does not translate into a strong relationship with efficacy in randomised controlled trials (RCTs) of conventional antidepressant drugs this observation falsifies the proposition that unblinding is the principal mechanism driving RCT outcomes in studies of depression. Instead, changes in brain function, that occur soon after treatment starts, do predict treatment outcomes and align with our understanding of neurotransmitter effects from neuroscience. Psychedelic experience for the treatment of depression must be unblinding, but the effect results directly from serotonergic receptor activation and changes in brain connectivity. Where such effects are part of a novel mechanism of action, a strong dose response relationship would be expected, irrespective of unblinding. We highlight the importance of exploring blinding as a mechanism, confirming dose-related outcomes, and dissociating unblinding effects from efficacy. Unblinding does not necessarily invalidate the subjective experience of sustained recovery from depression.

Handling prevents and reverses cognitive deficits induced by sub-chronic phencyclidine in a model for schizophrenia in rats.

Treatments for schizophrenia are not effective in ameliorating cognitive deficits. Therefore, novel therapies are needed to treat cognitive impairments associated with schizophrenia (CIAS), which are modelled in rats through administration of sub-chronic phencyclidine (scPCP). We have previously shown that enrichment via voluntary exercise prevents and reverses impairments in novel object recognition (NOR) in this model. The present study aimed to investigate if handling could prevent delay-induced NOR deficits and prevent and reverse scPCP-induced NOR deficits. Two cohorts of adult female Lister Hooded rats were used. In experiment one, handling (five minutesday, five daysweek for two weeks), took place before scPCP administration (2 mgkg, i.p. twice-daily for seven days). NOR tests were conducted at two, four, and seven weeks post-handling with a one-minute inter-trial interval (ITI) and at five weeks post-dosing with a six-hour ITI. In experiment two, rats were handled after scPCP administration and tested immediately in the one-minute ITI NOR task and again at two weeks post-handling. In both handling regimens, the scPCP control groups failed to discriminate novelty, conversely the scPCP handled groups significantly discriminated in this task. In the 6 h ITI test, vehicle control and scPCP control failed to discriminate novelty however, the vehicle handled and scPCP handled groups did significantly discriminate. Handling rats prevented and reversed scPCP-induced deficits and prevented delay-induced NOR deficits. These findings add to evidence that environmental enrichment is a viable treatment for cognitive deficits in rodent tests and models of relevance to schizophrenia, with potential to translate into effective treatments for CIAS.

Assessment of Orally Administered Δ9-Tetrahydrocannabinol When Coadministered With Cannabidiol on Δ9-Tetrahydrocannabinol Pharmacokinetics and Pharmacodynamics in Healthy Adults A Randomized Clinical Trial.

Controlled clinical laboratory studies have shown that cannabidiol (CBD) can sometimes attenuate or exacerbate the effects of Δ9-tetrahydrocannabinol (Δ9-THC). No studies have evaluated differences in pharmacokinetics (PK) of Δ9-THC and pharmacodynamics (PD) between orally administered cannabis extracts that vary with respect to Δ9-THC and CBD concentrations. To compare the PK and PD of orally administered Δ9-THC-dominant and CBD-dominant cannabis extracts that contained the same Δ9-THC dose (20 mg). This randomized clinical trial was a within-participant, double-blind, crossover study conducted from January 2021 to March 2022 at the Johns Hopkins University Behavioral Pharmacology Research Unit, Baltimore, MD. Eighteen healthy adults completed 3 randomized outpatient experimental test sessions that were each separated by at least 1 week. Brownies containing (1) no cannabis extract (ie, placebo) (2) Δ9-THC-dominant extract (20 mg Δ9-THC with no CBD) and (3) CBD-dominant extract (20 mg Δ9-THC 640 mg CBD) were administered to participants 30 minutes prior to administering a cytochrome P450 (CYP) probe drug cocktail, which consisted of 100 mg caffeine, 20 mg omeprazole, 25 mg losartan, 30 mg dextromethorphan, and 2 mg midazolam. Change-from-baseline plasma concentrations for Δ9-THC or Δ9-THC metabolites and scores for subjective drug effects, cognitive and psychomotor performance, and vital signs. The area under the plasma vs concentration vs time curve (AUC) and maximum plasma concentration (Cmax) were determined. The participant cohort of 18 adults included 11 males (61.1%) and 7 females (38.9%) with a mean (SD) age of 30 (7) years who had not used cannabis for at least 30 days prior to initiation of the study (mean SD day since last cannabis use, 86 66 days). The CYP cocktail placebo brownie and the CYP cocktail did not affect any PD assessments. Relative to CYP cocktail Δ9-THC, CYP cocktail Δ9-THC CBD produced a higher Cmax and area under the plasma concentration vs time curve for Δ9-THC, 11-OH-Δ9-THC, and Δ9-THC-COOH. The CYP cocktail Δ9-THC CBD increased self-reported anxiety, sedation, and memory difficulty, increased heart rate, and produced a more pronounced impairment of cognitive and psychomotor performance compared with both CYP cocktail Δ9-THC and CYP cocktail placebo. In this randomized clinical trial of oral Δ9-THC and CBD, stronger adverse effects were elicited from a CBD-dominant cannabis extract compared with a Δ9-THC-dominant cannabis extract at the same Δ9-THC dose, which contradicts common claims that CBD attenuates the adverse effects of Δ9-THC. CBD inhibition of Δ9-THC and 11-OH-Δ9-THC metabolism is the likely mechanism for the differences observed. An improved understanding of cannabinoid-cannabinoid and cannabinoid-drug interactions are needed to inform clinical and regulatory decision-making regarding the therapeutic and nontherapeutic use of cannabis products. clinicaltrials.gov Identifier NCT04201197.

The prescription of psychedelic therapies in Australia and New Zealand A brief survey of psychiatrists.

To explore the knowledge and attitudes of psychiatrists about psychedelics therapies. Access to a cross-sectional survey was distributed to psychiatrists through social media channels. Attitudes and knowledge about psychedelic therapies were recorded using Likert scales and ranking questions. Fifty-eight complete responses were collected (44 fully trained 14 trainee RANZCP members). Greater than 85% of respondents agreed there is a shortfall in effective psychiatric treatments, and greater than 65% agreed that psychedelic therapies might address this shortfall. The psychiatrists did not consider themselves knowledgeable about psychedelic therapies, with 60% showing interest in further training on this topic. About 70% of the sample hold various concerns about psychedelic therapies, and more believe that the prescription of psychedelics should be limited to psychiatrists in the future. Considering these results in the context of a rapidly changing landscape relating to psychedelic research and regulations, we suggest there is scope to develop up-to-date education about psychedelics for psychiatrists.

Crash-involved THC-positive drivers in Norway have a high frequency of polysubstance use.

Tetrahydrocannabinol (THC) is the most frequently detected drug in blood samples from apprehended drug driving suspects in Norway. This investigation aimed to study the extent of polysubstance use among apprehended crash-involved drivers with THC concentrations above the legal limit and explore the importance of THC in polysubstance cases. We selected all drug driving cases where blood samples had been submitted for forensic toxicology testing after involvement in road traffic crashes during 2013-2020, except drivers who were fatally injured. Twenty percent (n 2133) of the 10,520 apprehended crash-involved drivers had concentrations of THC in their blood above the legal limit of 1.3 ngmL, and 84 % of those also had concentrations of alcohol or other drugs above the legal limits 61 % for sedatives, 38 % for stimulants, 33 % for alcohol, and 10 % for opioids. The most frequent substance combination was cannabis together with sedatives and stimulants (22.9 % n 488). Polysubstance use was least common among drivers under 24 years. The proportion of drivers with THC > 5 ngmL was highest if the blood sample was collected within 90 min after the crash, and when only THC was detected. There was a statistically significant inverse association between THC > 5 ngmL and concentrations of alcohol or amphetamines at the highest sanction level. Most apprehended crash-involved THC-positive drivers also tested positive for other psychoactive substances. Drivers with high blood THC concentrations had less often high concentrations of other substances cannabis might then have been a more important contributor to impairment.

Examining associations between MDMAecstasy and classic psychedelic use and impairments in social functioning in a U.S. adult sample.

Impairment in social functioning is a common source of morbidity across many mental health disorders, yet there is a dearth of effective and easily implemented interventions to support social functioning. MDMAecstasy and classic psychedelics (psilocybin, LSD, peyote, mescaline) represent two potential treatments for impairments in social functioning, as evidence suggests these compounds may be supportive for alleviating social difficulties. Using a nationally representative sample of U.S. adults from the National Survey on Drug Use and Health (2015-2019) (N 214,505), we used survey-weighted multivariable ordinal and logistic regression to examine the associations between lifetime use of the aforementioned compounds and impairments in social functioning in the past year. Lifetime MDMAecstasy use was associated with lowered odds of three of our four social impairment outcomes difficulty dealing with strangers (aOR 0.92), difficulty participating in social activities (aOR 0.90), and being prevented from participating in social activities (aOR 0.84). Lifetime mescaline use was also associated with lowered odds of difficulty dealing with strangers (aOR 0.85). All other substances either shared no relationship with impairments in social functioning or conferred increased odds of our outcomes. Future experimental studies can assess whether these relationships are causal.

A scoping review of spirituality in relation to substance use disorders Psychological, biological, and cultural issues.

Spirituality is a construct encompassing a diversity of strongly held beliefs and pursuits related to lifes meaning and purpose. Empirical studies in key domains of spirituality related to substance use disorder (SUD) can be valuable in guiding research, and potentially clinical care. To conduct a scoping review of research on the psychological, biological, and cultural dimensions of spirituality and their role in relation to SUD. To identify limitations in empirical findings within these domains and identify promising areas for related research. Illustrative studies available in the empirical literature are reviewed in order to characterize these three key domains. Certain areas of importance stand out On Psychology, attribution of SUD to a spiritual outlook spiritual awakening the relation of spirituality to drug craving and spirituality in the context of psychedelic-assisted psychotherapy. On Biology, heritability of traits related to shared spiritual experience neurophysiologic correlates of spiritually related experiences and correlates in brain imaging On Culture, spiritual aspects of SUD in different cultural settings distinctions between spiritual and religious phenomena roles that international organizations play and context of acquiring recovery capital. The need for further research in each area is defined. There is utility in examining the diversity of findings in the roles of psychology, biology, and culture in the SUD field. Further research, particularly applying randomization and clinical controls, would be useful in improving the effective application of the construct of spirituality in clinical care.

Toxicity of the 3,4-Methylenedioxymethamphetamine and Its Enantiomers to

MDMA (3,4-methylenedioxymethamphetamine) is a chiral psychoactive recreational drug sold in illicit markets as racemate. Studies on the impact of MDMA on aquatic organisms are scarce. While enantioselectivity in toxicity in animals and humans has been reported, none is reported on aquatic organisms. This study aimed to investigate the ecotoxicological effects of MDMA and its enantiomers in

A Colorimetric Method for the Rapid Estimation of the Total Cannabinoid Content in Cannabis Samples.

A colorimetric method for the estimation of the total content of cannabinoids in cannabis samples is proposed. The assay is based on the reaction of these compounds with the reagent Fast Blue B (FBB), which has been immobilized into polydimethylsiloxane (PDMS). The reaction and detection conditions have been established according to the results obtained for the individual cannabinoids Δ

Chiral Separation of Cannabichromene, Cannabicyclol, and Their Acidic Analogs on Polysaccharide Chiral Stationary Phases.

Until recently, chirality has not been a major focus in the study of cannabinoids, as most cannabinoids of interest, such as cannabidiol and tetrahydrocannabinol, exist as a single isomer from natural sources. However, this is changing as more cannabinoids are identified, and compounds such as cannabichromene and cannabicyclol are emerging as potential investigatory candidates for varying indications. Because these molecules are chiral, the separation and study of the individual enantiomers biological and physiological effects should therefore be of interest. The purpose of this study was to identify analytical separation conditions and then adapt those conditions to preparative separation. This was accomplished with a column-screening approach on Daicels immobilized polysaccharide chiral stationary phases using non-traditional mobile phases, which included dichloromethane, ethyl acetate, and methyl tert-butyl ether under high-performance liquid chromatography conditions. CHIRALPAK

Cannabinoids in the Modulation of Oxidative Signaling.

Cannabis sativa-derived compounds, such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), and components of the endocannabinoids system, such as N-arachidonoylethanolamide (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), are extensively studied to investigate their numerous biological effects, including powerful antioxidant effects. Indeed, a series of recent studies have indicated that many disorders are characterized by alterations in the intracellular antioxidant system, which lead to biological macromolecule damage. These pathological conditions are characterized by an unbalanced, and most often increased, reactive oxygen species (ROS) production. For this study, it was of interest to investigate and recapitulate the antioxidant properties of these natural compounds, for the most part CBD and THC, on the production of ROS and the modulation of the intracellular redox state, with an emphasis on their use in various pathological conditions in which the reduction of ROS can be clinically useful, such as neurodegenerative disorders, inflammatory conditions, autoimmunity, and cancers. The further development of ROS-based fundamental research focused on cannabis sativa-derived compounds could be beneficial for future clinical applications.

Analysis of Cannabinoids in Biological Specimens An Update.

Cannabinoids are still the most consumed drugs of abuse worldwide. Despite being considered less harmful to human health, particularly if compared with opiates or cocaine, cannabis consumption has important medico-legal and public health consequences. For this reason, the development and optimization of sensitive analytical methods that allow the determination of these compounds in different biological specimens is important, involving relevant efforts from laboratories. This paper will discuss cannabis consumption toxicokinetics, the most detected compounds in biological samples and characteristics of the latter. In addition, a comprehensive review of extraction methods and analytical tools available for cannabinoid detection in selected biological specimens will be reviewed. Important issues such as pitfalls and cut-off values will be considered.

Substance Use and Attendance Motives of Electronic Dance Music (EDM) Event Attendees A Survey Study.

EDM event attendees are a high-risk population for substance use and associated adverse effects. The aim of this study was to examine substance use at EDM events, focusing on associations between attendance motives and substance use. Sociodemographic characteristics, event specifics, past-year use, and attendance motives were assessed through an online survey. Participants were 1345 Belgian EDM event attendees (69.44% male, M

A novel ego dissolution scale A construct validation study.

Ego dissolution (i.e., ego loss, ego disintegration, ego death, or self-loss) is a conscious state marked by a loss or diminution of ones sense of self and a lack of first-person experience. We developed a novel, valid, and internally consistent ego dissolution scale to both (a) assess trait-like aspects of ego dissolution, which have received scant attention to date, and (b) facilitate future research in a variety of contexts (e.g., personality, psychopathology, substance usepsychedelics, contemplative practices). We determined that the 10-item Ego Dissolution Scale (EDS Cronbachs α 0.80) and its identified subfactors of Ego-Loss (Cronbachs α 0.84) and Unity (Cronbachs α 0.75) were internally consistent, possessed strong convergent (e.g., depersonalizationderealization, mysticism, unusual experiences) and discriminant validity (e.g., neuroticism, social desirability). We found ego dissolution and dissociation to be empirically related yet discriminable on a statistical basis.

The impact of recreational cannabis markets on motor vehicle accident, suicide, and opioid overdose fatalities.

In the U.S., an increasing number of states are legalizing regulated commercial markets for recreational cannabis, which allows private industry to produce, distribute, and sell marijuana to those 21 and older. The health impacts of these markets are not fully understood. Preliminary evidence suggests recreational markets may be associated with increased use among adults, which indicates there may be downstream health impacts on outcomes related to cannabis use. Three causes of death that are linked to cannabis use are motor vehicle accidents, suicide, and opioid overdose. Drawing on data from U.S. death certificates from 2009 to 2019, we conducted a difference-in-differences analysis to estimate the impact of recreational markets on fatalities from motor vehicle accidents, suicide, and opioid overdose in seven states Colorado, Washington, Oregon, Alaska, Nevada, California, and Massachusetts. States with comprehensive medical cannabis programs with similar pre-trends in deaths were used as comparisons. For each outcome, a pooled estimate was generated with a meta-analysis using random effects models. The results revealed substantial increases in crash fatalities in Colorado, Oregon, Alaska, and California of 16%, 22%, 20%, and 14%, respectively. Based on estimates from all seven states, recreational markets were associated with a 10% increase in motor vehicle accident deaths, on average. This study found no evidence that recreational markets impacted suicides. Most states saw a relative reduction in opioid overdose death that ranged between 3 and 28%. On average, recreational markets were associated with an 11% reduction in opioid overdose fatalities.

N,N-dimethyltryptamine affects electroencephalography response in a concentration-dependent manner-A pharmacokineticpharmacodynamic analysis.

N,N-dimethyltryptamine (DMT) is a psychedelic substance and is being used as a research tool in investigations of the neurobiology behind the human consciousness using different brain imaging techniques. The effects of psychedelics have commonly been studied using electroencephalography (EEG) and have been shown to produce suppression of alpha power and increase in signal diversity. However, the relationship between DMT exposure and its EEG effects has never been quantified. In this work, a population pharmacokineticpharmacodynamic analysis was performed investigating the relationship between DMT plasma concentrations and its EEG effects. Data were obtained from a clinical study where DMT was administered by intravenous bolus dose to 13 healthy subjects. The effects on alpha power, beta power, and Lempel-Ziv complexity were evaluated. DMT was shown to fully suppress alpha power. Beta power was only partially suppressed, whereas an increase in Lempel-Ziv complexity was observed. The relationship between plasma concentrations and effects were described using effect compartment models with sigmoidal maximum inhibitory response or maximum stimulatory response models. Values of the concentration needed to reach half of the maximum response (EC

Binding and functional structure-activity similarities of 4-substituted 2,5-dimethoxyphenyl isopropylamine analogues at 5-HT

Certain 4-substituted analogs of 1-(2,5-dimethoxyphenyl)isopropylamine (2,5-DMA) are psychoactive classical hallucinogens or serotonergic psychedelic agents that function as human 5-HT

Preparation of hyaluronic acid-loaded Harmine polymeric micelles and in vitro effect anti-breast cancer.

To prepare hyaluronic acid-loaded Harmine polymeric micelles with CD The carboxyl group on hyaluronic acid is coupled to the amino group on 3,5-bis(trifluoromethyl)benzylamine by an amidation reaction. And the polymeric micelles self-assemble to encapsulate the Harmine in a hydrophobic core, characterized the polymer micelles by IR, The prepared polymer micelles had a uniform particle size of about 200 nm, good dispersion, PDI < 0.3, encapsulation rate up to 87%, drug loading of 4.12±0.03%, and negative charge. Hyaluronidase has a good enzymatic effect on polymeric micelles, with a hemolysis rate of less than 1%. It showed some dose-dependent toxicity to both MDA-MB-231 and MCF-7, with increased uptake of polymer micelles by CD

Ketamine detection in urine samples from patients poisoned by recreational drugs epidemiologic, clinical, and toxicologic profiles.

To describe the epidemiologic, clinical, and toxicologic profiles of patients who used recreational ketamine and experienced acute poisoning. Retrospective observational study of patients attended by several emergency medical services in the Balearic Islands for analytically confirmed acute poisoning after using ketamine between January 2016 and December 2020. Urine samples were analyzed by immunoassay and combined gas chromatography and mass spectrometry. One hundred twenty-two patients were studied. The mean (SD) age was 26.7 (6.5) years. The majority were men (77.9%) and not residents of the Balearic Islands (74.6%). Poisoning cases occurred mainly in the summer and in the island of Ibiza (84.4%). Ketamine use was declared by the patient or clinically suspected in 40.2%. The most common clinical signs were tachycardia (43.4%), hypertension (28.7%), mydriasis (27.0%), altered consciousness (25.4%), agitationaggressiveness (25.4%), and hypothermia (21.3%). Seven patients (5.73%) required admission to the intensive care unit. The drugs most often detected along with ketamine were cocaine, in 93.4%, and 3,4-methylenedioxymethamphetamine (MDMA), in 78.7%. Multiple-drug use combining ketamine, cocaine, and MDMA, or on occasion additional substances, was detected in 98.4%. Detection of ketamine in urine samples from patients poisoned by recreational drugs is associated with a characteristic profile young men who are not residents of the Balearic Islands, who attend electronic music concerts, and who have taken multiple drugs. A substantial percentage of such patients are unaware of drug intake. Identificar el perfil epidemiológico, clínico y toxicológico de los pacientes consumidores de ketamina en el contexto de una intoxicación aguda por drogas recreativas. Estudio observacional retrospectivo en pacientes atendidos en varios servicios de urgencias (SU) en Baleares por intoxicaciones agudas por drogas recreativas con exposición a ketamina confirmada analíticamente, entre enero de 2016 y diciembre de 2020. El análisis toxicológico en muestras de orina se realizó mediante inmunoensayo y cromatografía de gases acoplada a espectrometría de masas. Se incluyeron 122 pacientes. La edad media fue de 26,7 (DE 6,5) años. La mayoría eran hombres (77,9%) y no residentes en las Islas Baleares (74,6%). Los casos se detectaron mayoritariamente en verano y en Ibiza (84,4%). El uso de ketamina solo fue declarado por el paciente o fue clínicamente sospechado por el médico en el 40,2%. Los signos clínicos más frecuentes fueron taquicardia (43,4%), hipertensión (28,7%), midriasis (27,0%), disminución de la consciencia (25,4%), agitaciónagresividad (25,4%) e hipotermia (21,3%). Siete pacientes (5,7%) requirieron ingreso en la unidad de cuidados intensivos (UCI). La cocaína (93,4%) y la 3,4-metilendioximetanfetamina (MDMA) (78,7%) fueron las drogas más detectadas junto con la ketamina. El policonsumo fue habitual (98,4%), combinando ketamina, cocaína y MDMA, en algunos casos asociado a otras sustancias. La detección de ketamina en intoxicaciones por drogas recreativas se asocia a consumidores con un perfil característico (varones jóvenes, no residentes, asistentes a eventos de música electrónica y policonsumo) y un alto porcentaje desconocen de este consumo.

Concentrations of LSD, 2-oxo-3-hydroxy-LSD, and iso-LSD in hair segments of 18 drug abusers.

Lysergic acid diethylamide (LSD) is one of the most widely abused hallucinogens, which can alter consciousness, produce mental disorder, and cause harmful behavior. 1-Propionyl-LSD (1 P-LSD), a novel derivative of LSD, has the similar hallucinogenic effect. It is a control substance in several countries. 1 P-LSD can act as a prodrug for LSD and is rapidly hydrolyzed to LSD in humans. Therefore, LSD use should be confirmed by the absence of 1 P-LSD and in the detection of LSD. Here, we describe a LC-MSMS method for the simultaneous extraction of LSD, iso-LSD, 2-oxo-3-hydroxy-LSD, and 1 P-LSD from hair. Hair samples (25 mg) were pulverized by cryogenic grinding in methanol. The limits of detection were 0.2-1 pgmg and the limits of quantification were 0.5-2 pgmg. This method was validated and applied to hair samples from 18 suspects who may have used LSD. Segmental hair analysis revealed a decrease in the LSD concentrations from the proximal to the distill end, while 1 P-LSD was not detected in any hair segments. The interpretation of hair analysis results of LSD still remains difficult. Nevertheless, concentrations of LSD and iso-LSD in human hair from 18 LSD users were reported. LSD concentrations were from <LOQ to 4.0 pgmg (n 18, median 1.5 pgmg) in the proximal 0-3 cm segment, from <LOQ to 1.8 pgmg (n 8) in the 3-6 cm segment, and from <LOQ to 0.6 pgmg (n 4) in the 6-9 cm segment. Iso-LSD ranged from <LOQ to 1.4 pgmg (n 4) in the 0-3 cm segment and was detectable only in one 3-6 cm segment. To our knowledge, this is the first study to monitor LSD together with 1 P-LSD in hair.

Effects of Δ⁹-tetrahydrocannabinol (THC), cannabidiol (CBD), and THCCBD mixtures on fentanyl versus food choice in rhesus monkeys.

There is considerable interest in utilizing cannabis-based products as adjuvants to opioid agonist therapies as phytocannabinoids like Δ This study examined the effects of THC and cannabidiol (CBD), the two most prominent compounds in cannabis, on the reinforcing effects of fentanyl in rhesus monkeys in a food versus drug choice procedure. Responding on one lever was reinforced by delivery of a sucrose pellet, and responding on another lever was reinforced by delivery of an i.v. infusion of fentanyl. In each monkey, the largest dose of fentanyl that produced less than 20 % drug choice and the smallest dose of fentanyl that produced more than 80% drug choice was determined. Effects of pretreatment with THC and CBD, alone and in mixtures, were then examined. THC, CBD, and THCCBD mixtures did not reliably enhance or diminish choice for fentanyl up to doses that suppressed responding in most monkeys, though some individual differences were observed, with THC and THCCBD mixtures decreasing choice for large doses of fentanyl in one monkey and increasing choice for small doses of fentanyl in another. Phytocannabinoids like THC and CBD, administered alone or in mixtures, do not appear to reliably alter the reinforcing effects of opioids.

A survey of Australian psychiatrists and psychiatry trainees knowledge of and attitudes towards psychedelics in the treatment of psychiatric disorders.

To assess Australian psychiatrists and psychiatry trainees knowledge of and attitudes towards psychedelics as treatment for psychiatric disorders. Australian members of the Royal Australian and New Zealand College of Psychiatrists were invited to participate in an anonymous survey that ran from October 1 to November 30 2021. Participants were asked about their knowledge of the risks and benefits of, and attitudes towards, psychedelics, including the factors that influence those attitudes. Fifty-one doctors responded to the survey, and 38 completed all items. The majority were male, consultants and based primarily in New South Wales. Respondents reported awareness of the evidence demonstrating the benefits of psychedelics for most disorders however most respondents, particularly females, perceived psychedelics as risky. Most considered themselves open-minded and believed psychedelics deserved further research. The poor response rate was a major limitation of this study. Our sample of Australian psychiatrists and trainees were enthusiastic about psychedelics as psychiatric treatment and were aware of some of the evidence demonstrating their efficacy. Safety continues to be a concern, despite growing evidence of their safety in therapeutic settings. Education about the evidence of their efficacy and the risks associated with their use is needed.

Developmental Neurotoxicity Screen of Psychedelics and Other Drugs of Abuse in Larval Zebrafish (

In recent years, psychedelics have garnered significant interest as therapeutic agents for treating diverse neuropsychiatric disorders. However, the potential for these compounds to produce developmental neurotoxicity has not been rigorously assessed, and much of the available safety data is based on epidemiological studies with limited experimental testing in laboratory animal models. Moreover, the experimental safety data available thus far have focused on adult organisms, and the few studies conducted using developing organisms have tested a limited number of compounds, precluding direct comparisons between various chemical scaffolds. In the present study, 13 psychoactive compounds of different chemical or pharmacological classes were screened in a larval zebrafish model for teratological and behavioral abnormalities following acute and chronic developmental exposures. We found that the psychedelic tryptamines and ketamine were less neurotoxic to larval zebrafish than LSD and psychostimulants. Our work, which leverages the advantage of using zebrafish for higher throughput toxicity screening, provides a robust reference database for comparing the neurotoxicity profiles of novel psychedelics currently under development for therapeutic applications.

Microbiota-derived psychedelics Lessons from COVID-19.

Emil Kraepelin believed that dementia praecox, the disorder we now call schizophrenia, was caused by the brain being poisoned with toxins generated in other parts of the body, especially the mouth, intestine or genitals. In this regard, Kraepelin hinted at the microbiome and conceptualized microbial molecules as drivers of severe psychiatric illness. However, it was not until the coronavirus disease (COVID-19) pandemic that Kraepelins paradigm gained traction, particularly because this virus was associated with both gut barrier disruption and new-onset psychosis.Likewise, despite numerous studies linking severe psychiatric illness to genomic damage and dysfunctional DNA repair, this pathogenetic mechanism was underappreciated before the COVID-19 pandemic. The use of the psychotomimetic anesthetic, ketamine, for treatment-resistant depression has reawakened the interest in endogenous serotonergic hallucinogens, especially tryptamine and N,N-dimethyltryptamine (DMT), which are beneficial for depression but associated with psychosis.In this editorial, we take a closer look at the role of the microbiome in psychopathology, attempting to answer 2 questions1. Why may psychosis-predisposing serotonergic hallucinogens alleviate depression2. Are microbiota-derived psychedelics part of an inbuilt antidepressant system similar to endogenous opioids

Recent Progress in Mind-Body Therapies in Cancer Care.

Mind-body therapies (MBTs) are integrative medicine modalities that continue to grow in popularity among people with cancer. MBTs are used to enhance well-being and most commonly include relaxation and imagery, hypnosis, yoga, meditation, Tai Chi and Qigong, and creative therapies. Biofield and psychedelic-assisted therapies are also gaining momentum as MBTs. Herein, recent literature was narratively reviewed to summarize the effectiveness of these MBTs within the context of cancer care. There is growing evidence for the effectiveness of MBTs for addressing a myriad of physical (e.g., pain) and psychosocial (e.g., depression, fatigue) symptoms and biomarkers of stress and immune function in people with cancer. Psychedelic-assisted therapies have robust, sustained effects on symptoms of depression, anxiety, and distress in small clinical trials to date. However, across modalities, MBT studies continue to struggle with methodological issues such as intervention standardization, facilitator training, small sample sizes, and short follow-up. Accumulating evidence supports the use of MBTs for people with cancer. Future research should work to address methodological issues and focus on creating knowledge translation tools these can be leveraged to better educate health care providers and patients regarding evidence-based MBT options to support patients in making informed decisions about their health.

Intoxications with synthetic cannabinoids.

Synthetic Cannabinoid Receptor Agonists (SCRAs) are a group of New Psychoactive Substances. They are used recreationally to mimic the effects of THC in cannabis. However, THC is a partial agonist of the CB1-receptor and SCRAs are full agonists. Because of this specificity and potency serious adverse events may occur among which psychological, cardiovascular, and gastro-intestinal symptoms. Because of the low incidence in the Netherlands clinical information on SCRA intoxications is limited, making diagnosis and treatment difficult. In this clinical lesson, two cases of SCRA intoxications are described followed by treatment recommendations.

Effects of Ketanserin, M100907 and Olanzapine on hallucinogenic like action induced by 2,5-dimethoxy-4-methylamphetamine.

2,5-dimethoxy-4-methylamphetamine (DOM) is a kind of hallucinogen of phenylalkylamine. Psychedelic effects mainly include audiovisual synesthesia, complex imagery, disembodiment etc. that can impair control and cognition leading to adverse consequences such as suicide. By now, there are no specific drugs regarding the management of classic hallucinogen use clinically. We evaluated the effects of three 5-HT 2A receptor antagonists ketanseirn, M100907 and olanzapine on hallucination-like behavior in therapeutic and preventive administration with male C57BL6J mice. Two models were used to evaluate the therapeutic potential of antagonists, one is head-twitch response (HTR) and the other is locomotion. Effects of ketanserin, M100907 and olanzapine on DOM-induced HTR were studied in preventive and therapeutic administration, respectively. In the preventive administration, the ID 50 values of ketanseirn, M100907 and olanzapine were 0.4 mgkg, 0.005 mgkg and 0.25 mgkg. In the therapeutic administration, the ID 50 values of ketanseirn, M100907 and olanzapine were 0.04 mgkg, 0.005 mgkg and 0.03 mgkg. Secondly, locomotor activity induced by DOM was performed to further evaluate the efficacy of three compounds. In locomotion, M100907(0.005 mgkg) whenever in preventive or therapeutic administration, reduced the increase of movement distance induced by DOM. Although ketanserin (0.4 mgkg) in the preventive administration also decreased the movement distance induced by DOM, it was alone administrated to influence the locomotor activity. Through HTR and locomotion, we compared the efficacy and latent side effects of ketanserin, M100907 and olanzapine against hallucinogenic like action induced by DOM. Our study provided additional experimental evidence on specific therapeutic drugs against hallucinogenic behavior induce by representative hallucinogen DOM.

Behavioral, biochemical and histopathological toxic profiles induced by sub-chronic cannabimimetic WIN55, 212-2 administration in mice.

WIN55, 212-2 mesylate is a synthetic cannabinoid (SC) agonist of CB1 and CB2 receptors with much higher affinity to CB1 receptor than tetrahydrocannabinol and many potential therapeutic effects. Few studies have evaluated SCs effects on more complex animal behavior and sex differences in cannabinoids toxicology. The current study was undertaken for determination of behavioral (Open Field test), biochemical (liver and kidney function test plus GABA Glutamate levels), histopathological and CB1 immunohistochemistry risks of sub-chronic administration of SC WIN55, 212-2 mesylate in male and female mice. A total of 40 healthy adult mice were randomly divided into four groups (5 mice each) a negative control group, a vehicle group, a low dose (0.05 mgkg) group and a high dose group (0.1 mgkg) for each gender.Open Field Test revealed dose and gender-dependent anxiogenic effect with reduced locomotor activity in both sexes especially the higher doses with female mice being less compromised. GABA and glutamate levels increased significantly in both dose groups compared to controls alongside female mice versus males. No significant biochemical alterations were found in all groups with minimal histopathological changes. The CB1 receptors immunohistochemistry revealed a significant increase in the number of CB1 positive neurons in both low and high dose groups against controls with higher expression in female brains.ConclusionsThere were sexual dimorphism effects induced by sub-chronic exposure to WIN55, 212-2 with lesser female mice affection and dose-dependent influences.

What good are psychedelic humanities

The revival of psychedelic research has been dominated by the biomedical sciences. Yet it raises questions that cannot be answered by laboratory experiments and clinical trials alone. Among these are questions pertaining to the conceptual and practical frameworks that render experimental and clinical findings meaningful. Psychedelic humanities clarify the historical presuppositions, philosophical blind spots, and political stakes of different approaches to psychedelics. In this emergent field, many scholars evaluate such alternatives epistemologically, ethically, or politically. However, they could just as well refrain from offering normative orientation and instead increase the complexity of the observed phenomena by opening other possible perspectives, leaving it to their readers to reduce the resulting complexity in novel ways. This enables clinical psychiatrists, laboratory scientists, and other practitioners to use (or abuse) psychedelic humanities scholarship for their own purposes. The article concludes with a note on the institutionalization of such collaboration at The New Schools Psychedelic Humanities Lab.

Classic psychedelics do not affect T cell and monocyte immune responses.

Classic psychedelics have been shown to exert therapeutic potential for the treatment of various psychiatric disorders, neuropsychiatric diseases, and neuronal damage. Besides their psychopharmacological activity, psychedelics have been reported to modulate immune functions. There has thus far been a sparse exploration of the direct immune-modulating effect of psychedelics on human immune cells We investigated the effect of the classic psychedelics lysergic acid diethylamide (LSD), psilocin, We did not observe any relevant direct immune-modulatory effects of the tested classic psychedelics in either cell line. We concluded that LSD, psilocin, DMT, or mescaline did not directly stimulate the proliferation or cytokine secretion of primary human T lymphocytes or stimulate NF-κB induction of monocytes. Our findings support the future safe use of classic psychedelics in assisted psychotherapy in patients with life-threatening diseases where immune suppression and diminished immune function would be detrimental.

Association between cannabis use and blood pressure levels according to comorbidities and socioeconomic status.

The associations between blood pressure and cannabis use remain inconsistent. The purpose of our study was to examine gender stratified associations of cannabis use and blood pressure systolic, diastolic blood pressure (BP), pulse pressure (PP) levels among the general UK Biobank population based study. Among 91,161 volunteers of the UK Biobank population, cannabis use status was assessed by questionnaire and range as heavy, moderate, low and never users. Associations between cannabis use and BP were estimated using multiple gender linear regressions. In adjusted covariates models, lifetime heavy cannabis use was associated with decrease in both SBP, DBP and PP in both genders, but with a higher effect among women (for SBP in men, b - 1.09 (0.27), p < 0.001 in women, b - 1.85 (0.36), p < 0.001 for DBP in men, b - 0.50 (0.15), p < 0.001 in women, b - 0.87 (0.17), p < 0.001 and for PP in men, b - 0.60 (0.20), p < 0.001 in women, b - 0.97 (0.27), p < 0.001. Among men, lower SBP and DBP levels were observed with participants without dyslipidemia and lower PP in participants with high income levels. Among women, lower SBP, DBP and PP were observed with current smokers, moderatelow alcohol levels and participants without dyslipidemia. Current cannabis use was associated with lower SBP levels in men (b - 0.63 (0.25), p 0.012) and in women (b - 1.17 (0.31), p < 0.001). Same results were observed for DBP and PP. Negative association between BP in men was found but not in women. The small association in BP differences between heavy users and never users remains too small to adopt cannabis-blood pressure public policy in clinical practice.

A complex systems perspective on psychedelic brain action.

Recent findings suggesting the potential transdiagnostic efficacy of psychedelic-assisted therapy have fostered the need to deepen our understanding of psychedelic brain action. Functional neuroimaging investigations have found that psychedelics reduce the functional segregation of large-scale brain networks. However, beyond this general trend, findings have been largely inconsistent. We argue here that a perspective based on complexity science that foregrounds the distributed, interactional, and dynamic nature of brain function may render these inconsistencies intelligible. We propose that psychedelics induce a mode of brain function that is more dynamically flexible, diverse, integrated, and tuned for information sharing, consistent with greater criticality. This meta perspective has the potential to unify past findings and guide intuitions toward compelling mechanistic models.

Single-dose psilocybin for a treatment-resistant episode of major depression Impact on patient-reported depression severity, anxiety, function, and quality of life.

COMP360 is a proprietary, synthetic formulation of psilocybin being developed for treatment-resistant depression (TRD), a burdensome, life-threatening illness with high global impact. Here, we expand upon the previous report of primary outcomes from a phase 2 study of COMP360 in individuals with TRD-the largest randomised controlled clinical trial of psilocybin-to discuss findings of the exploratory efficacy endpoints. In this phase 2, double-blind trial, 233 participants with TRD were randomised to receive a single dose of psilocybin 25 mg, 10 mg, or 1 mg (control), administered alongside psychological support from trained therapists. Efficacy measures assessed patient-reported depression severity, anxiety, positive and negative affect, functioning and associated disability, quality of life, and cognitive function. At Week 3, psilocybin 25 mg, compared with 1 mg, was associated with greater improvements from Baseline total scores in all measures. The 10 mg dose produced smaller effects across these measures. Interpretation of this trial is limited by the absence of an active comparator and the possibility of functional unblinding in participants who received a low dose of psilocybin. Three weeks after dosing, psilocybin 25 mg and, to a lesser degree, 10 mg improved measures of patient-reported depression severity, anxiety, affect, and functioning. These results extend the primary findings from the largest randomised clinical trial of psilocybin for TRD to examine other outcomes that are of importance to patients.

Reduced emergent character of neural dynamics in patients with a disrupted connectome.

High-level brain functions are widely believed to emerge from the orchestrated activity of multiple neural systems. However, lacking a formal definition and practical quantification of emergence for experimental data, neuroscientists have been unable to empirically test this long-standing conjecture. Here we investigate this fundamental question by leveraging a recently proposed framework known as Integrated Information Decomposition, which establishes a principled information-theoretic approach to operationalise and quantify emergence in dynamical systems - including the human brain. By analysing functional MRI data, our results show that the emergent and hierarchical character of neural dynamics is significantly diminished in chronically unresponsive patients suffering from severe brain injury. At a functional level, we demonstrate that emergence capacity is positively correlated with the extent of hierarchical organisation in brain activity. Furthermore, by combining computational approaches from network control theory and whole-brain biophysical modelling, we show that the reduced capacity for emergent and hierarchical dynamics in severely brain-injured patients can be mechanistically explained by disruptions in the patients structural connectome. Overall, our results suggest that chronic unresponsiveness resulting from severe brain injury may be related to structural impairment of the fundamental neural infrastructures required for brain dynamics to support emergence.

Effect of acrolein on the formation of harman and norharman in chemical models and roast beef patties.

Harman and norharman were the most abundant β-carboline-type heterocyclic amines (HCAs) detected in various foodstuffs. Unsaturated fatty acids in foods may undergo rapid oxidative deterioration during transportation, storage and heat treatment, forming reactive carbonyl species (RCS). This work studied the effects of acrolein, a highly reactive RCS, on the formation of harman and norharman in the tryptophan model system. Results showed that 0.005, 0.01, 0.015, 0.02, 0.05, 0.1 and 0.2 mmol of acrolein led to harman production increased by 528 %, 752 %, 981 %, 1172 %, 1375 %, 1288 % and 768 % respectively, and led to norharman formation increased by 116 %, 129 %, 152 %, 169 %, and 197 %, 185 % and 157 %, respectively. Furthermore, acrolein addition reduced the residue of tryptophan (up to 63.19 %), but increased the level of the intermediates including formaldehyde (up to 352 %), acetaldehyde (up to 491 %), (1S,3S)-1-Methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (MTCA, up to 1936 %), and 1,2,3,4-tetrahydro-β-carboline-3-carboxylicacid (THCA, up to 2142 %) in the tryptophan model system. Acrolein might react with tryptophan, harman and norharman to eliminate them directly. These data suggested that acrolein may contribute to harman and norharman formation through participating in the above complex chemical reactions. In addition, the content of harman and norharman produced in roast beef patties made of minced beef oxidized for 2, 4, 6, 8, and 10 days increased by 118 %, 188 %, 267 %, 137 %, and 48 %, respectively, and led to norharman formation increased by 140 %, 132 %, 90 %, 86 %, and 74 %, respectively compared with those made of fresh minced beef, which further illustrated that lipid oxidation products potentially contributed to harman and norharman formation.

Adult use of highly-potent Δ9-THC cannabis concentrate products by U.S. state cannabis legalization status, 2021.

Compared to plantflower cannabis products, cannabis concentrates have higher average potency of delta-9-tetrahydrocannabinol (Δ9-THC), which may be associated with greater likelihood of cannabis-related harms. Information on factors associated with use of cannabis concentrates is needed. Respondents were 4,328 adult past-7-day cannabis users from all 50 U.S. states and Washington DC (DC) who participated in an online 2021 survey. Using logistic regression to generate adjusted odds ratios (aOR), we investigated whether participants in states that enacted recreational cannabis laws (RCL, 12 states plus DC treated as a state, n 1,236) or medical cannabis laws (MCL-only, 23 states, n 2,030) by December 31, 2020 were more likely than those in states without cannabis laws (no-CL, 15 states, n 1,062) to use cannabis concentrate products in the prior 7 days. Most participants (92.4%) used plant material in the prior 7 days 57.0% used cannabis concentrates. In RCL, MCL and no-CL states, concentrate use was reported by 61.5%, 56.6%, and 52.5%, respectively. Compared to participants in no-CL states, odds of using cannabis concentrate products were greater among those in RCL states (aOR 1.47 CI 1.17-1.84) and MCL-only states (aOR 1.29 CI 1.08-1.55). Whether states had legally-authorized dispensaries had little effect on results. Results suggest that individuals in MCL-only and RCL states are more likely to use cannabis concentrate products. Determining mechanisms underlying these results, e.g., commercialization, could provide important information for prevention. Clinicians should be alert to patient use of concentrates, especially in MCL-only and RCL states. Continued monitoring is warranted as additional states legalize cannabis use.

LSD-induced increase of Ising temperature and algorithmic complexity of brain dynamics.

A topic of growing interest in computational neuroscience is the discovery of fundamental principles underlying global dynamics and the self-organization of the brain. In particular, the notion that the brain operates near criticality has gained considerable support, and recent work has shown that the dynamics of different brain states may be modeled by pairwise maximum entropy Ising models at various distances from a phase transition, i.e., from criticality. Here we aim to characterize two brain states (psychedelics-induced and placebo) as captured by functional magnetic resonance imaging (fMRI), with features derived from the Ising spin model formalism (system temperature, critical point, susceptibility) and from algorithmic complexity. We hypothesized, along the lines of the entropic brain hypothesis, that psychedelics drive brain dynamics into a more disordered state at a higher Ising temperature and increased complexity. We analyze resting state blood-oxygen-level-dependent (BOLD) fMRI data collected in an earlier study from fifteen subjects in a control condition (placebo) and during ingestion of lysergic acid diethylamide (LSD). Working with the automated anatomical labeling (AAL) brain parcellation, we first create archetype Ising models representative of the entire dataset (global) and of the data in each condition. Remarkably, we find that such archetypes exhibit a strong correlation with an average structural connectome template obtained from dMRI (r 0.6). We compare the archetypes from the two conditions and find that the Ising connectivity in the LSD condition is lower than in the placebo one, especially in homotopic links (interhemispheric connectivity), reflecting a significant decrease of homotopic functional connectivity in the LSD condition. The global archetype is then personalized for each individual and condition by adjusting the system temperature. The resulting temperatures are all near but above the critical point of the model in the paramagnetic (disordered) phase. The individualized Ising temperatures are higher in the LSD condition than in the placebo condition (p 9 × 10-5). Next, we estimate the Lempel-Ziv-Welch (LZW) complexity of the binarized BOLD data and the synthetic data generated with the individualized model using the Metropolis algorithm for each participant and condition. The LZW complexity computed from experimental data reveals a weak statistical relationship with condition (p 0.04 one-tailed Wilcoxon test) and none with Ising temperature (r(13) 0.13, p 0.65), presumably because of the limited length of the BOLD time series. Similarly, we explore complexity using the block decomposition method (BDM), a more advanced method for estimating algorithmic complexity. The BDM complexity of the experimental data displays a significant correlation with Ising temperature (r(13) 0.56, p 0.03) and a weak but significant correlation with condition (p 0.04, one-tailed Wilcoxon test). This study suggests that the effects of LSD increase the complexity of brain dynamics by loosening interhemispheric connectivity-especially homotopic links. In agreement with earlier work using the Ising formalism with BOLD data, we find the brain state in the placebo condition is already above the critical point, with LSD resulting in a shift further away from criticality into a more disordered state.

Individualized fMRI connectivity defines signatures of antidepressant and placebo responses in major depression.

Though sertraline is commonly prescribed in patients with major depressive disorder (MDD), its superiority over placebo is only marginal. This is in part due to the neurobiological heterogeneity of the individuals. Characterizing individual-unique functional architecture of the brain may help better dissect the heterogeneity, thereby defining treatment-predictive signatures to guide personalized medication. In this study, we investigate whether individualized brain functional connectivity (FC) can define more predictable signatures of antidepressant and placebo treatment in MDD. The data used in the present work were collected by the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study. Patients (N 296) were randomly assigned to antidepressant sertraline or placebo double-blind treatment for 8 weeks. The whole-brain FC networks were constructed from pre-treatment resting-state functional magnetic resonance imaging (rs-fMRI). Then, FC was individualized by removing the common components extracted from the raw baseline FC to train regression-based connectivity predictive models. With individualized FC features, the established prediction models successfully identified signatures that explained 22% variance for the sertraline group and 31% variance for the placebo group in predicting HAMD

Reduced death anxiety as a mediator of the relationship between acute subjective effects of psychedelics and improved subjective well-being.

Research over the past several decades suggests that meaningful psychedelic experiences can engender long-term effects on subjective wellbeing. However, less research has investigated the psychological mechanisms through which these effects may emerge. In the present study, participants (

Reconsidering dissociation as a predictor of antidepressant efficacy for esketamine.

The relationship between subjective drug experience and antidepressant outcomes for ketamine derivatives is poorly understood but of high clinical relevance. Esketamine is the patented (S)-enantiomer of ketamine and has regulatory approval for psychiatric applications. We examined the relationship between acute dissociation, as measured by the Clinician-Administered Dissociative States Scale (CADSS), and antidepressant efficacy, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), for esketamine across the 4-week induction phase of treatment. This post hoc analysis combined data (N 576) from the TRANSFORM-1 and TRANSFORM-2 clinical trials of esketamine for treatment-resistant depression. Linear mixed models were performed using total MADRS score as the outcome variable with the following independent variables baseline MADRS score, treatment condition × time interaction, and CADSS × time interaction. To assess whether initial dissociation predicted rapid antidepressant benefit with esketamine, a separately planned regression was performed with day 2 MADRS as the outcome variable with the following dependent variables baseline MADRS, treatment condition, and day 1 CADSS. The linear mixed model did not show any effect of a CADSS × time interaction (p 0.7). Looking solely at the effect of day 1 CADSS on day 2 MADRS revealed that each additional CADSS point was associated with a - .04 95% CI - .08, - .002 (p .04) decrease in MADRS score. We found no evidence of a clinically significant positive or negative association between dissociation and antidepressant effect for esketamine. Our findings suggest that subsequent inquiry in this area will benefit from improved characterization of drug experiences relevant to therapeutic outcomes.

The high frequency oscillation in orbitofrontal cortex is susceptible to phenethylamine psychedelic 25C-NBOMe in male rats.

Serotoninergic psychedelics induced extensive alterations in perception and cognition, which has been attributable to its disruptive effect on oscillatory rhythms of prefrontal cortex. However, there is a lack of information how serotoninergic psychedelics affect the intra-prefrontal network, which intrinsically interact to accomplish perceptual processing. Uncovering the altered neural network caused by psychedelics helps to understand the mechanisms of their psychoactive effects and contribute to develop biological markers of psychedelic effects. In present study, we investigated the effects of substituted phenethylamine psychedelic 25C-NBOMe on neural oscillations in the intra-prefrontal and hippocampal-prefrontal network. The effective dose of 25C-NBOMe (0.1 mgkg) disrupting sensorimotor gating in male Sprague-Dawley rats was used to observe its effects on neural oscillations in the prelimbic cortex, anterior cingulate cortex, orbitofrontal cortex (OFC) and hippocampus CA1. The power of high frequency oscillation (HFO, 120-150 Hz) was potentiated by 25C-NBOMe selectively in the OFC, with peaking at 20-30 min after treatment. 25C-NBOMe strengthened HFO coherence within the intra-prefrontal, rather than hippocampal-prefrontal network. Potentiated HFO in the OFC had a strong positive correlation with the strengthened inter-prefrontal HFO coherence by 25C-NBOMe. The 25C-NBOMe-induced alterations of rhythmic patterns were prevented by pre-treatment with selective serotonin 2A receptor antagonist MDL100,907. These results demonstrate that OFC rhythmic activity in HFO is relatively susceptible to substituted phenethylamine and potentially drives drug-induced rhythmic coherence within intra-prefrontal regions. Our findings provide additional insight into the neuropathophysiology of the psychoactive effects of psychedelics and indicate that the altered HFO might be applied as a potential biological marker of psychedelic effect.

Prevalence and associations of challenging, difficult or distressing experiences using classic psychedelics.

Previous studies have investigated challenging, difficult, or distressing classic psychedelic experiences, but little is known about the prevalence and associations of such experiences. Using nationally representative data of the US adult population (N 2822), this study examined the prevalence and associations of challenging, difficult, or distressing experiences using classic psychedelics, in a subsample of respondents who reported lifetime classic psychedelic use (n 613). Of the 613 respondents who reported lifetime classic psychedelic use, the majority of them (59.1 %) had never had a challenging, difficult, or distressing experience using a classic psychedelic, but 8.9 % of respondents reported functional impairment that lasted longer than one day as a result of such experiences. Notably, 2.6 % reported seeking medical, psychiatric, or psychological assistance in the days or weeks following their most challenging, difficult, or distressing classic psychedelic experience. In covariate-adjusted regression models, co-use of lithium, co-use of other mood stabilizers, and six set and setting variables (no preparation, disagreeable physical environment, negative mindset, no psychological support, dose was too large, major life event prior to experience) were associated with the degree of difficulty and co-use of lithium, co-use of other mood stabilizers, and three set and setting variables (negative mindset, no psychological support, major life event prior to experience) were associated with overall risk of harm. In summary, this study provides insight into the prevalence and associations of challenging, difficult, or distressing classic psychedelic experiences. The findings broadly correspond with findings from previous studies and can inform harm reduction efforts and future experimental research designs.

Quantifying the Root-to-Shoot Transfer of 4,4-Methylenedianiline Using Pressure Chamber and Intact Plant Methods.

The high-production-volume chemical 4,4-methylenedianiline (4,4-MDA) is an aromatic amine used to manufacture 4,4-methylenedianiline diisocyanate for polyurethane production. Based on 4,4-MDAs octanolwater partition coefficient (K

Towards mapping neuro-behavioral heterogeneity of psychedelic neurobiology in humans.

Precision psychiatry aims to identify markers of inter-individual variability that allow predicting the right treatment for each patient. However, bridging the gap between molecular-level manipulations and neural systems-level functional alterations remains an unsolved problem in psychiatry. After decades of low success rates in pharmaceutical RD for psychiatric drugs, multiple studies now point to the potential of psychedelics as a promising fast-acting and long-lasting treatment for some psychiatric symptoms. Yet, given the highly psychoactive nature of these substances, a precision medicine approach is essential to map the neural signals related to clinical efficacy in order to identify patients who can maximally benefit from this treatment. Recent studies have shown that bridging the gap between pharmacology, systems-level neural response in humans and individual experience is possible for psychedelic substances, therefore paving the way for a precision neuropsychiatric therapeutic development. Specifically, it has been shown that the integration of brain-wide PET or transcriptomic data, i.e. receptor distribution for the serotonin 2A receptor, with computational neuroimaging methods can simulate the effect of psychedelics on the human brain. These novel computational psychiatry approaches allow for modeling inter-individual differences in neural as well as subjective effects of psychedelic substances. Collectively, this review provides a deep dive into psychedelic pharmaco-neuroimaging studies with a core focus on how recent computational psychiatry advances in biophysically based circuit modeling can be leveraged to predict individual responses. Finally, we emphasize the importance of human pharmacological neuroimaging for the continued precision therapeutic development of psychedelics.