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Altered brain activity and functional connectivity after MDMA-assisted therapy for post-traumatic stress disorder.

3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) for post-traumatic stress disorder (PTSD) has demonstrated promise in multiple clinical trials. MDMA is hypothesized to facilitate the therapeutic process, in part, by decreasing fear response during fear memory processing while increasing extinction learning. The acute administration of MDMA in healthy controls modifies recruitment of brain regions involved in the hyperactive fear response in PTSD such as the amygdala, hippocampus, and insula. However, to date there have been no neuroimaging studies aimed at directly elucidating the neural impact of MDMA-AT in PTSD patients. We analyzed brain activity and connectivity via functional MRI during both rest and autobiographical memory (trauma and neutral) response before and two-months after MDMA-AT in nine veterans and first-responders with chronic PTSD of 6 months or more. We hypothesized that MDMA-AT would increase amygdala-hippocampus resting-state functional connectivity, however we only found evidence of a trend in the left amygdala-left hippocampus ( Amygdala-insular functional connectivity is reliably implicated in PTSD and anxiety, and both regions are impacted by MDMA administration. These findings compliment previous research indicating that amygdala, hippocampus, and insula functional connectivity is a potential target of MDMA-AT, and highlights other regions of interest related to memory processes. More research is necessary to determine if these findings are specific to MDMA-AT compared to other types of treatment for PTSD. httpsclinicaltrials.govct2showNCT02102802, identifier NCT02102802.

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) 2A 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.

Cyberdelics in context On the prospects and challenges of mind-manifesting technologies.

The concept of cyberdelics emerged in the 1980s and 1990s as an umbrella term denoting the nexus connecting cybernetic (digital) technologies and psychedelic (mind manifesting) drugs. Cyberdelic technologies, in particular the then newly emerging field of virtual reality, were touted by psychedelic cultural icons including Timothy Leary and Terence McKenna as auguring a new era of digital mind-expansion where psychedelic experiences will be recreated online inside virtual worlds. Cyberdelic culture waned in the 2000s. However, recent years have seen the return of the cyberdelic imaginary, following on the heels of a psychedelic resurgence and a renewed interest in virtual reality technologies and their use in therapy. Cyberdelic advocates speak of the necessity of creating transformative technologies that steer humanity away from mindless consumerism and distractedness, and towards expanded states of awe, presence, and transcendence. Nevertheless, much like psychedelics, cyberdelic technologies are seen as running against the grain of current sociocultural arrangements and economic models which threaten to quell their transformative potential. Research on psychedelics within the humanities over the past decade has emphasized the role of cultural set and setting the significance of the cultural embeddedness of these psychoactive agents and the dependence of their effects on surrounding sociocultural conditions. Building on the notion of information technologies as mind-manifesting technologies, this paper sets out to consider what psychedelics can teach us about cyberdelics how the principles of set and setting and current discussions within the psychedelic humanities can inform our understanding of the resurgence of interest in cyberdelic media, its prospects, and challenges.

Distributed harmonic patterns of structure-function dependence orchestrate human consciousness.

A central question in neuroscience is how consciousness arises from the dynamic interplay of brain structure and function. Here we decompose functional MRI signals from pathological and pharmacologically-induced perturbations of consciousness into distributed patterns of structure-function dependence across scales the harmonic modes of the human structural connectome. We show that structure-function coupling is a generalisable indicator of consciousness that is under bi-directional neuromodulatory control. We find increased structure-function coupling across scales during loss of consciousness, whether due to anaesthesia or brain injury, capable of discriminating between behaviourally indistinguishable sub-categories of brain-injured patients, tracking the presence of covert consciousness. The opposite harmonic signature characterises the altered state induced by LSD or ketamine, reflecting psychedelic-induced decoupling of brain function from structure and correlating with physiological and subjective scores. Overall, connectome harmonic decomposition reveals how neuromodulation and the network architecture of the human connectome jointly shape consciousness and distributed functional activation across scales.

Optimizing outcomes in psilocybin therapy Considerations in participant evaluation and preparation.

Recent studies have demonstrated the promise of psilocybin therapies in creating positive changes for those with poor mental health across multiple diagnostic categories, including major depressive disorder (MDD), end-of-life anxiety, and obsessive-compulsive disorder (OCD). While there may be a large population that is eligible to participate in psilocybin therapy based on psychiatric diagnosis and medical clearance, little attention has been given to intrapersonal and interpersonal factors that might influence patients readiness (i.e., eligibility and capacity) for psychedelic interventions. This paper proposes that readiness assessment includes both intrapersonal and interpersonal factors in order to improve safety, patient care, and treatment outcomes. While at the present time a reliable and valid instrument has not been developed, we propose that three specific areas of focus - patient presentation, therapeutic alliance, and patient safety - may be used to establish a patients readiness for psilocybin therapy, thus increasing therapy optimization and personalization.

Cannabis and nicotine co-use among primary care patients in a state with legal cannabis access.

The aim of this exploratory analysis was to evaluate cannabis exposure, reasons for use and problematic cannabis use among adult primary care patients in Washington state (United States) who co-use cannabis and nicotine (tobacco cigarettes andor nicotine vaping) compared to patients who endorse current cannabis use only. As part of a NIDA Clinical Trials Network (CTN) parent study, patients who completed a cannabis screen as part of routine primary care were randomly sampled (N 5,000) to a receive a confidential cannabis survey. Patients were stratified and oversampled based on the frequency of past-year cannabis use and for Black, indigenous, or other persons of color. Patients who endorsed past 30-day cannabis use are included here (N 1388). Outcomes included prevalence of cannabis use, days of cannabis use per week and times used per day, methods of use, THCCBD content, non-medical andor medical use, health symptoms managed, and cannabis use disorder (CUD) symptom severity. We conducted unadjusted bivariate analyses comparing outcomes between patients with cannabis and current nicotine co-use to patients with cannabis-only use. Nicotine co-use (n 352 25.4 %) was associated with differences in method of cannabis use, THCCBD content, days of use per week and times used per day, number of health symptoms managed, and CUD severity (all p < 0.001), compared to primary care patients with cannabis-only use (n 1036). Interventions targeting cannabis and nicotine co-use in primary care are not well-established and further research is warranted given findings of more severe cannabis use patterns and the adverse health outcomes associated with co-use.

Cannabis use patterns in drug-resistant and pharmacoresponsive epilepsy Single tertiary referral center survey investigation.

This study sought to identify differences in cannabis use and perceptions about cannabis in mitigating seizure-related symptoms in patients with epilepsy, and to evaluate differences in these patterns between drug-resistant versus pharmacoresponsive epilepsy. A collection of self-report surveys completed by patients with epilepsy (n 76) were used to retrospectively compare differences in those with drug-resistant versus pharmacoresponsive epilepsy regarding 1) proportion who used cannabis, 2) frequency of use, 3) method of use, and 4) reason for use. A Cochran-Armitage test for trend indicated that of patients who used cannabis, a higher proportion of patients in the drug-resistant group used more frequently than in the pharmacoresponsive group. Almost half (48%) of those in the drug-resistant group reported daily use compared to approximately a third (36%) of those in the pharmacoresponsive group. Additionally, no patient in either group reported that cannabis was harmful in relation to seizure-related symptoms. Results from this study highlight the need for epilepsy providers to formally assess patients perceptions and use of non-prescribed cannabis to inform clinical care decisions, particularly in the drug-resistant epilepsy population.

The association between naturalistic use of psychedelics and co-occurring substance use disorders.

Classic psychedelics (LSD, psilocybin, and peyotemescaline) have been used to support addiction treatment in a variety of contexts ranging from ceremonial use to clinical trials. The aim of this study was to test the hypothesis that past naturalistic use of classic psychedelics would be associated with decreased prevalence of substance use disorder, when controlling for known confounders. This cross-sectional study used 2017 NSDUH survey data to evaluate the association between past use of the classic psychedelics LSD, psilocybin and peyotemescaline and past year substance dependence or abuse. We calculated adjusted odds ratios by multivariate logistic regression, controlling for a range of sociodemographic variables, use of non-psychedelic illicit drugs and mental health related variables. A total of 56,276 participants were included in this study. Past use of LSD and psilocybin were associated with increased odds of substance dependence or abuse compared to those who had never used psychedelics before, and this was more likely for those who had used LSD more recently. However, prior use of peyote or mescaline was associated with lower odds of past year substance dependence or abuse compared to people who had never used psychedelics before (aOR 0.68, Past use of peyotemescaline was associated with decreased odds of substance use disorder compared to people who had never used psychedelics before, while past use of LSD or psilocybin was not. It remains unclear whether this difference is due to pharmacological differences between these compounds or simply due to the context in which peyotemescaline are traditionally taken. Future research should investigate why naturalistic use of different psychedelics is associated with different substance use disorder effects.

The effect of tetrahydrocannabinolcannabidiol oromucosal spray on cognition a systematic review.

Previous studies have shown that tetrahydrocannabinol (THC), the main psychoactive component of cannabis, can impair cognitive abilities. There is also some evidence that cannabidiol (CBD), the most abundant non-intoxicating constituent of cannabis, can attenuate these effects. The purpose of this study was to investigate the effects of THCCBD oromucosal spray (with equal parts THC and CBD) on cognition compared with control conditions in human studies. A systematic literature search was performed on four major bibliographic databases. Studies were included in the present review if they evaluated the cognitive effects of THCCBD oromucosal spray compared with a control condition. Ten studies were identified (7 on patients with multiple sclerosis, 1 on those with Huntington, and 2 on healthy volunteers) with 510 participants in total. There was considerable heterogeneity among the studies in terms of dose and duration of administration. All studies have used an equal or nearly equal dose of THC and CBD. Although the results across studies were somewhat inconsistent, most evidence revealed that there is no significant difference between THCCBD oromucosal spray and control treatments in terms of cognitive outcomes. However, more trials are needed with longer follow-up periods, and dose considerations, particularly comparing lower and higher doses of the spray.

Chronic low-dose Δ

Cognitive functions decline during aging. This decline could be caused by changes in dendritic spine stability and altered spine dynamics. Previously, we have shown that a low dose chronic THC treatment improves learning abilities in old whereas impairs learning abilities in young mice. The mechanism underlying this age-dependent effect is not known. Dendritic spine stability is a key for memory formation, therefore we hypothesized that THC affects spine dynamics in an age-dependent manner. We applied longitudinal 2-photon in vivo imaging to 3- and 18-month-old mice treated with 3 mgkgday of THC for 28 days via an osmotic pump. We imaged the same dendritic segments before, during and after the treatment and assessed changes in spine density and stability. We now show that in old mice THC improved spine stability resulting in a long-lasting increase in spine density. In contrast, in young mice THC transiently increased spine turnover and destabilized the spines.

Psychedelics Science sabotaged by Social Media.

The substantial challenges facing high and low dose psychedelic drug development to achieve regulatory approval have been documented in the scientific literature. These limitations have not deterred drug developers and social media from repeatedly misleading patients, the public and health professionals. Developing micro doses of psychedelics overcomes many of the scientific and regulatory challenges of high dose psychedelics. If micro-dosing could be shown to be efficacious and safe for long term use, it could be administered in the typical model for treatment of mental disorders. Such a model would be more cost effective than the high doseintense psychotherapy model currently described and could be readily available to all individuals who need another medication option. Outpatient psychotherapeutic agents have a clear route for approval and would be unlikely to be burdened by the extensive Risks Evaluation and Mitigation Strategy needed for high dose use. There may be a different therapeutic role for both high and low dose psychedelic agents. This article is part of the Special Issue on National Institutes of Health Psilocybin Research Speaker Series.

Psilocybin sex-dependently reduces alcohol consumption in C57BL6J mice.

The classical psychedelic psilocybin is of interest as a treatment for alcohol use disorder (AUD). This study investigated the effects of psilocybin on voluntary ethanol consumption in adult male and female C57BL6J mice administered saline or psilocybin intraperitoneally as a single dose of 0.1, 0.5, 1.0 or 2.0 mgkg and provided 20% ethanol utilizing a two-bottle choice alcohol drinking paradigm. Ethanol was provided continuously for 3 days immediately following the administration of psilocybin, then withheld for 2 days, and then provided continuously for two subsequent additional days. A multilevel model (MLM) for repeated measures was used to compare ethanol consumption and preference in psilocybin-treated groups versus controls. Ethanol consumption and preference were reduced in male mice during the 3-day interval that immediately followed psilocybin administration. The effect of psilocybin on ethanol consumption was dose-related and was consistent across the 3-day interval at dosages of 0.5 mgkg or greater. Psilocybin had no effect on consumption or preference when ethanol was subsequently reintroduced after 2 days of withdrawal. In contrast to males, psilocybin had no significant effect on ethanol consumption or preference in female mice at any dosage or time point. The lack of an effect of psilocybin on quinine preference, and its limited interaction with locomotor activity indicated that the observed reduction in voluntary ethanol consumption was not attributable to altered taste perception or motor effects. Total fluid consumption was increased in males at some time points and psilocybin dosages and unchanged in females, and the absence of any decrease in either group at any time point indicated that the observed reduction in ethanol consumption was not mediated by nonspecific effects on consummatory behavior. The finding of a sex-dependent effect of psilocybin on ethanol consumption suggests that the C57BL6J mouse may provide a useful experimental approach to modeling sex differences in vulnerability to AUD in addition to investigation of the neurobiological basis of the effect of classical psychedelics on alcohol drinking behavior.

Psilocybin use patterns and perception of risk among a cohort of Black individuals with Opioid Use Disorder.

There is growing evidence that psilocybin, a serotonergic psychedelic substance, may be useful in the treatment of substance use disorders. However, there is a lack of data on the beliefs and attitudes towards psilocybin amongst Black individuals diagnosed with Opioid Use Disorder (OUD). This study characterized psilocybin use patterns and perception of risk amongst a cohort of Black individuals diagnosed with OUD. Using a convenience sampling approach, patients were recruited from an urban methadone treatment program and paid five dollars to complete an anonymous phone-based survey. Twenty-eight patients participated (mean age 53.8 Many Black individuals with Opioid Use Disorder perceive psilocybin as dangerous and may be hesitant to try psilocybin treatment. Culturally informed treatment models, educational interventions and community outreach programs should be developed to increase racialethnic minority representation in psilocybin research and treatment.

Consciousness alterations in a cohort of young Swiss men Associations with substance use and personality traits.

Substance-induced consciousness alterations (CA) have mainly been studied among users of psychedelics but not among people using street drugs. Explore occurrences of three different types of substance-induced CA ego dissolution (ED), visual pseudo-hallucinations (VPH), anxietyparanoia (AP) and their perceived influences on life, together with their associations with substance use and personality correlates in a general population sample of 25-year-old men. 2,796 young Swiss men lifetime substance users completed a self-report questionnaire including history of use (never, former, and current) of different substances categories (psychedelics, cocaine, psychostimulants, ecstasy, MDMA, and other drugs), substance-induced ego dissolution (ED), visual pseudo-hallucinations (VPH) and anxietyparanoia (AP), the influence of these CA experiences on life, and personality traits (sensation seeking, sociability, anxiety-neuroticism, and aggression-hostility). 32.2% reported at least one CA (i.e., ED, VPH or AP), with 20.5% reporting ED, 16.7% VPH, and 14.6% AP. Former and current use of psychedelics and ketamine was significantly associated with occurrences of all three types of CAs and with a positive influence of CA on life. Associations between the former and current use of other substances and the different types of CA were less consistent, and perceived influences on life were not statistically significant. Sociability was negatively associated with occurrences of all three types of CA. Positive associations were found between anxiety-neuroticism and ED and AP, between aggression-hostility and AP, and between sensation seeking and ED and VPH. This study supports the potential for psychedelics to induce CAs perceived as beneficial to life among people using street drugs, possibly reflecting the mechanism underlying the therapeutic potential of psychedelics.

First episode psychosis with and without the use of cannabis and synthetic cannabinoids Psychopathology, global functioning and suicidal ideation and antipsychotic effectiveness.

Natural Cannabis (NC) and Synthetic Cannabinoids (SCs) use can increase the risk of developing psychotic disorders and exacerbate their course. To examine the differences between psychoses not associated with cannabis use and those associated with NC and SCs use, evaluating psychotic symptoms, global functioning, dissociative symptoms and suicidal ideation. The sample of 61 patients with First Episode Psychosis (FEP) was divided into 3 groups non-Cannabis users (non-users, N 20) NC users (THC-users, N 21) SCs users (SPICE-users, N 20). Each group was assessed at FEP and after 3 and 9 months through specific psychopathological scales. THC-users, and even more SPICE-users, displayed much more severe positive symptoms than non-users. Negative symptoms were higher among non-users. After 9 months the non-users had recovered significantly better than SPICE-users in their global functioning. Dissociative symptoms were significantly greater in substance users. Finally, suicidal ideation was higher in SPICE-users than in both THC-users and non-users. The psychoses induced by NC and SCs showed different symptomatic pictures and outcomes from each other and when compared to the psychoses not associated with the use of substances such knowledge could be relevant in identifying a specific drug treatment.

Menstrual Changes and Reversal of Amenorrhea Induced by Classic Psychedelics A Case Series.

There has been little research on the effects of psychedelics on menstrual and reproductive function, though anecdotal evidence suggests that these compounds may have striking effects on menstrual function in at least a subset of users. Social media and word of mouth were used to seek out individuals who had a history of changes in menstrual function following psychedelic use. Case histories were elicited from three respondents following informed consent. A literature search on the effects of classic psychedelics and related compounds was completed. Three women ranging from 27 to 34 years of age were interviewed and reported three distinct phenomena following the use of classic psychedelics 1) resumption of menses following amenorrhea, 2) early onset of menses, in particular when psychedelics were used in the mid to late luteal period, and 3) improved menstrual regularity in a woman with irregular cycles who was eventually diagnosed with polycystic ovarian syndrome. The mechanisms behind these effects remain unclear, though they may be mediated via direct or indirect effects of 5-HT

The costs and benefits of psychedelics on cognition and mood.

Anecdotal evidence has indicated that psychedelic substances may acutely enhance creative task performance, although empirical support for this claim is mixed at best. Clinical research has shown that psychedelics might have enduring effects on mood and well-being. However, there is no neurocognitive framework that ties acute changes in cognition to long-term effects in mood. In this review, we operationalize creativity within an emerging cognitive control framework and assess the current empirical evidence of the effects of psychedelics on creativity. Next, we leverage insights about the mechanisms and computations by which other psychoactive drugs act to enhance versus impair cognition, in particular to those that act on catecholamines, the neurophysiological consequences of which are relatively well understood. Finally, we use the same framework to link the suggested psychedelic-induced improvements in creativity with enduring psychedelic-induced improvements in mood.

Psilocybin for Depression From Credibility to Feasibility, Whats Missing

Psilocybin has been suggested as a promising transdiagnostic treatment strategy for a wide range of psychiatric disorders. Recent findings showed that psychedelic-assistedpsycholitic psychotherapy should provide significant and sustained alleviation of depressive symptoms. However, to date, there have been several study limitations (e.g., small sample sizes, blinding, limited follow-up, highly screened treatment populations) and some healthpolitical issues, including practitioners experience, lack of standardized protocols, psychedelics legal status, ethical concerns, and potential psychologicalpsychopathologicalmedical untoward effects. The focus here is on a range of clinical and methodological issues, also aiming at outlining some possible suggestions. We are confident that newer evidence, more precise protocols, and eventual reclassification policies may allow a better understanding of the real potential of psilocybin as a transdiagnostic therapeutic molecule.

A Review of Synthetic Access to Therapeutic Compounds Extracted from

Psychedelics are used for various pathologies of the central nervous system and are currently the subject of much research, some of which relates to the compounds contained in various

Comparison of the Cannabinoid and Terpene Profiles in Commercial Cannabis from Natural and Artificial Cultivation.

Interest in cultivating cannabis for medical and recreational purposes is increasing due to a dramatic shift in cannabis legislation worldwide. Therefore, a comprehensive understanding of the composition of secondary metabolites, cannabinoids, and terpenes grown in different environmental conditions is of primary importance for the medical and recreational use of cannabis. We compared the terpene and cannabinoid profiles using gasliquid chromatography and mass spectrometry for commercial cannabis from genetically identical plants grown indoors using artificial light and artificially grown media or outdoors grown in living soil and natural sunlight. By analyzing the cannabinoids, we found significant variations in the metabolomic profile of cannabis for the different environments. Overall, for both cultivars, there were significantly greater oxidized and degraded cannabinoids in the indoor-grown samples. Moreover, the outdoor-grown samples had significantly more unusual cannabinoids, such as C4- and C6-THCA. There were also significant differences in the terpene profiles between indoor- and outdoor-grown cannabis. The outdoor samples had a greater preponderance of sesquiterpenes including β-caryophyllene, α-humulene, α-bergamotene, α-guaiene, and germacrene B relative to the indoor samples.

Solving an Old Puzzle Elucidation and Evaluation of the Binding Mode of Salvinorin A at the Kappa Opioid Receptor.

The natural product Salvinorin A (SalA) was the first nitrogen-lacking agonist discovered for the opioid receptors and exhibits high selectivity for the kappa opioid receptor (KOR) turning SalA into a promising analgesic to overcome the current opioid crisis. Since SalAs suffers from poor pharmacokinetic properties, particularly the absence of gastrointestinal bioavailability, fast metabolic inactivation, and subsequent short duration of action, the rational design of new tailored analogs with improved clinical usability is highly desired. Despite being known for decades, the binding mode of SalA within the KOR remains elusive as several conflicting binding modes of SalA were proposed hindering the rational design of new analgesics. In this study, we rationally determined the binding mode of SalA to the active state KOR by in silico experiments (docking, molecular dynamics simulations, dynophores) in the context of all available mutagenesis studies and structure-activity relationship (SAR) data. To the best of our knowledge, this is the first comprehensive evaluation of SalAs binding mode since the determination of the active state KOR crystal structure. SalA binds above the morphinan binding site with its furan pointing toward the intracellular core while the C2-acetoxy group is oriented toward the extracellular loop 2 (ECL2). SalA is solely stabilized within the binding pocket by hydrogen bonds (C210

Applications of Capillary Electrophoresis for the Determination of Cannabinoids in Different Matrices.

Cannabinoids, terpenophenolic chemicals found only in cannabis, are primarily responsible for cannabis pharmacologic effects nearly 150 distinct cannabinoids have been identified thus far. Among these, the main psychoactive molecule, tetrahydrocannabinol (THC), and the non-psychoactive counterpart, cannabidiol (CBD) are distinguishable. In the past decade, a CBD-containing pharmaceutical preparation was approved by Food and Drug Administration (FDA) for the treatment of drug-resistant epileptic seizures in children, and research trials for a variety of additional medical conditions for which CBD has been suggested as a therapy are being conducted. Additionally, the number of CBD-containing dietary supplements, largely available online, is increasing rapidly. Consequently, the necessity for the development of qualitative and quantitative methodologies for the analysis of the bioactive components of

The Old and the New Cardiovascular and Respiratory Alterations Induced by Acute JWH-018 Administration Compared to Δ

Several new psychoactive substances (NPS) are responsible for intoxication involving the cardiovascular and respiratory systems. Among NPS, synthetic cannabinoids (SCs) provoked side effects in humans characterized by tachycardia, arrhythmias, hypertension, breathing difficulty, apnoea, myocardial infarction, and cardiac arrest. Therefore, the present study investigated the cardio-respiratory (MouseOx Plus EMKA electrocardiogram (ECG) and plethysmography TUNNEL systems) and vascular (BP-2000 systems) effects induced by 1-naphthalenyl (1-pentyl-1H-indol-3-yl)-methanone (JWH-018 0.3-3-6 mgkg) and Δ

Structural Investigation of Beta-Cyclodextrin Complexes with Cannabidiol and Delta-9-Tetrahydrocannabinol in 11 and 21 Host-Guest Stoichiometry Molecular Docking and Density Functional Calculations.

The complexation of β-cyclodextrin (β-CD) with cannabidiol (CBD) and Δ

The Bright Side of Psychedelics Latest Advances and Challenges in Neuropharmacology.

The need to identify effective therapies for the treatment of psychiatric disorders is a particularly important issue in modern societies. In addition, difficulties in finding new drugs have led pharmacologists to review and re-evaluate some past molecules, including psychedelics. For several years there has been growing interest among psychotherapists in psilocybin or lysergic acid diethylamide for the treatment of obsessive-compulsive disorder, of depression, or of post-traumatic stress disorder, although results are not always clear and definitive. In fact, the mechanisms of action of psychedelics are not yet fully understood and some molecular aspects have yet to be well defined. Thus, this review aims to summarize the ethnobotanical uses of the best-known psychedelic plants and the pharmacological mechanisms of the main active ingredients they contain. Furthermore, an up-to-date overview of structural and computational studies performed to evaluate the affinity and binding modes to biologically relevant receptors of ibogaine, mescaline, N,N-dimethyltryptamine, psilocin, and lysergic acid diethylamide is presented. Finally, the most recent clinical studies evaluating the efficacy of psychedelic molecules in some psychiatric disorders are discussed and compared with drugs already used in therapy.

Screening System of Cannabis sativa Extracts Based on Their Mitochondrial Safety Profile Using Cytochrome c Oxidase Activity as a Biomarker.

The development of

Transcriptomic Analysis of Glycosylation and Neuroregulatory Pathways in Rodent Models in Response to Psychedelic Molecules.

The potential for psychedelic molecules in impacting cognitive flexibility has long been supported and acknowledged across scientific reports. In the current study, an approach leveraging knowledge-based gene-set information analysis has been adopted to explore the potential impact of psychedelic molecules on both glycosylation, (a post-translational modifications (PTM)) and on neuro-regulatory pathways. Though limitations and restrictions rise from the scarcity of publicly available omics data, targeted analysis enabled us to identify a number of key glycogenes (

Novel Insights into Potential Cannabis-Related Cancerogenesis from Recent Key Whole Epigenome Screen of Cannabis Dependence and Withdrawal Epidemiological Commentary and Explication of Schrott et al.

Whilst the cannabis-cancer link has been traditionally described as controversial recent whole nation and whole continent studies have demonstrated that well documented laboratory-based multimodal cannabinoid genotoxicity is indeed reflected in numerous cancer types in larger epidemiological series. A recent longitudinal human sperm epigenome-wide DNA methylation screen in both cannabis dependence and cannabis withdrawal has revealed remarkable insights into the manner in which widespread perturbations of DNA methylation may lead to cancerogenic changes in both the exposed and subsequent generations as a result of both cannabis exposure and withdrawal. These results therefore powerfully strengthen and further robustify the causal nature of the relationship between cannabinoid exposure and cancerous outcomes well beyond the previously published extensive mechanistic literature on cannabinoid genotoxicity. The reported epigenomic results are strongly hypothesis generating and call powerfully for further work to investigate oncogenic mechanisms in many tissues, organs and preclinical models. These epigenomic results provide an extraordinarily close

A Phase II, Open-Label Clinical Trial of Intranasal Ketamine for Depression in Patients with Cancer Receiving Palliative Care (INKeD-PC Study).

Antidepressants require several weeks for the onset of action, a lag time that may exceed life expectancy in palliative care. Ketamine has demonstrated rapid antidepressant effects, but has been minimally studied in cancer and palliative care populations. Herein, the objective was to determine the feasibility, safety, tolerability and preliminary efficacy of intranasal racemic ketamine for major depressive disorder (MDD) in patients with advanced cancer. We conducted a single-arm, open-label phase II trial at the Princess Margaret Cancer Centre in Toronto, ON, Canada. Participants with advanced cancer with moderate to severe MDD received three flexible doses of intranasal (IN) ketamine (50−150 mg) over a one-week period. The primary efficacy outcome was an antidepressant response and remission rates as determined by the Montgomery−Åsberg Depression Rating Scale (MADRS) from baseline to the Day 8 primary endpoint. Twenty participants were enrolled in the trial, receiving at least one dose of IN ketamine, with fifteen participants receiving all three doses. The Day 8 antidepressant response (MADRS decreased by >50%) and remission (MADRS < 10 on Day 8) rates were high at 70% and 45%, respectively. Mean MADRS scores decreased significantly from baseline (mean MADRS of 31, standard deviation 7.6) to Day 8 (11 − 7.4) with an overall decrease of 20 points (p < 0.001). Antidepressant effects were partially sustained in the second week in the absence of additional ketamine doses, with a Day 14 mean MADRS score of 14 − 9.9. Common adverse effects included fatigue, dissociation, nausea, dysgeusia and headaches almost all adverse effects were mild and transient, resolving within 2 h of each ketamine dose with one dropout related to adverse effects (negative dissociative episode). Given these promising findings, larger, controlled trials are merited.

Effect of Cannabis on Memory Consolidation, Learning and Retrieval and Its Current Legal Status in India A Review.

Cannabis is one of the oldest crops grown, traditionally held religious attachments in various cultures for its medicinal use much before its introduction to Western medicine. Multiple preclinical and clinical investigations have explored the beneficial effects of cannabis in various neurocognitive and neurodegenerative diseases affecting the cognitive domains. Tetrahydrocannabinol (THC), the major psychoactive component, is responsible for cognition-related deficits, while cannabidiol (CBD), a non-psychoactive phytocannabinoid, has been shown to elicit neuroprotective activity. In the present integrative review, the authors focus on the effects of cannabis on the different cognitive domains, including learning, consolidation, and retrieval. The present study is the first attempt in which significant focus has been imparted on all three aspects of cognition, thus linking to its usage. Furthermore, the investigators have also depicted the current legal position of cannabis in India and the requirement for reforms.

Pharmacologic activity of substituted tryptamines at 5-HT

Novel psychoactive substances, including synthetic substituted tryptamines, represent a potential public health threat. Additionally, some substituted tryptamines are being studied, under medical guidance, as potential treatments of psychiatric disorders. Characterizing the basic pharmacology of substituted tryptamines will aid in understanding differences in potential for harm or therapeutic use. Using HEK cells stably expressing 5-HT

Psychedelic discourses A qualitative study of discussions in a Danish online forum.

This study focuses on user-perspectives related to norms, beliefs and practices concerning psychedelic substances as they are articulated in a Danish online forum. The study combines an interest in online drug research with a focus on discourse analysis to account for the dialectical relationship between individual and shared knowledge regarding the use and meaning of psychedelics. A total of 1,865 posts from 154 threads of online discussion were coded and analyzed thematically, inspired by a socio-cognitive approach to the study of discourse. All topics were arranged into 54 categories which were further analyzed to map recurring patterns in the construction of meaning resulting in a limited number of dominant discourses. Five dominant discourses were identified the recreational, the therapeutic, the spiritual, the scientific and the performance discourse. We suggest that these discourses can be seen as the available frameworks which forum users draw upon and reproduce when they describe, discuss, and negotiate their understandings and uses of psychedelics. This study demonstrates the importance of having a nuanced approach to user perceptions. Future drug policy and practice development should take these nuances into account and expect significant variation in the motives and modalities of the use of psychedelics.

LSD and language Decreased structural connectivity, increased semantic similarity, changed vocabulary in healthy individuals.

Language has been explored as a window into the mind. Psychedelics, known to affect perception and cognition, seem to change language, but a systematic, time-dependent exploration is lacking. Therefore, we aimed at mapping the psychedelic effects on language over the time course of the acute and sub-acute effects in an explorative manner. For this, 24 healthy volunteers (age mean±SD, range 35±11, 25-61 years 33% women) received 50 μg lysergic acid diethylamide (LSD) or inactive placebo in a randomized, double-blind, placebo-controlled, crossover study. We assessed different language productions (experience reporting, storytelling), components (structure, semantics, vocabulary) and time points (0 h to 24 h). Language productions included 5-min experience reporting (1.5 h, 6.5 h) and 1-min storytelling (0 h, 2 h, 4 h, 6 h, 24 h). Language structure was assessed by computing speech topology (SpeechGraphs), semantics by semantic distances (FastText), vocabulary by word categories (LIWC). LSD, compared to placebo, changed language structure, including decreased verbosity, lexicon, global and local connectivity (1.5 h to 4 h) decreased semantic distances between neighbouring words and overall words (2 h to 24 h) and changed vocabulary related to grammar, persons, time, space and biological processes (1.5 h to 24 h). In conclusion, low to moderate LSD doses changed language over diverse production types, components and time points. While simpler and disconnected structure and semantic similarity might reflect cognitive impairments, changed vocabulary might reflect subjective perceptions. Therefore, language under LSD might provide a window into the psychedelic mind and automated language quantifications should be better explored as valuable tools to yield more unconstrained insights into psychedelic perception and cognition.

Harmine suppresses the malignant phenotypes and PI3K activity in breast cancer.

Breast cancer remains a serious threaten to the womens health, discovery of potent treatment would help to improve the outcomes of breast cancer patients. Harmine extracted from Peganum harmala L , has been reported to exert tumor suppressive activity in several malignancies. Our objective was to demonstrate the effects of harmine on the malignant phenotypes of breast cancer cells. Breast cancer cell lines (MDA-MB-231, SKBR3, and MCF-7) and human normal breast cell line MCF-10A were employed in the present study. The MTT and colony formation assays were applied to the detection of cell viability and proliferation. Wound healing and transwell assays were performed to evaluate the alterations of cell migration and invasion after harmine treatment. Flow cytometry was applied to assess the effect of harmine in inducing cell apoptosis. Furthermore, western blotting assay was used to detect the biomarkers of epithelial-mesenchymal transition and phosphatidylinositol 3 kinase (PI3K) signaling pathway. The tumorigenesis ability was detected by subcutaneous implantation. Harmine dose-dependently suppressed the viability and proliferative capacity of breast cancer cells. Flow cytometry showed that harmine induced apoptosis in MCF-7 and MDA-MB-231 cells. In addition, harmine effectively inhibited the migration and invasion abilities of breast cancer cells. Western blotting indicated harmine significantly promoted E-cadherin and PTEN expression, while suppressed N-cadherin, vimentin, PI3K, p-mTOR, and AKT levels. Interfering the PTEN expression by siRNA partly rescued the activity of PI3K signaling pathway. Moreover, harmine injection also suppressed the tumorigenesis of breast cancer cells. Our results suggested that Hermine could suppress multiple malignant phenotypes and inhibit PI3K signaling, which supports that harmine might be a potential tumor-suppressive natural compound against breast cancer.

Is psilocybin an effective antidepressant and what is its Mechanism of action

Goodwin et al.

Driving under the influence of cannabis, alcohol, and illicit drugs among adults in the United States from 2016 to 2020.

Driving under the influence (DUI) of substances increases motor vehicle crash risk. Understanding current national trends of driving under the influence of alcohol (DUIA), cannabis (DUIC), and drugs other than cannabis (DUID) can inform public health efforts. Herein, we provide updated trends among United States (US) adults regarding DUIA, DUIC, DUID, and DUI of any substance. We used nationally-representative National Survey on Drug Use and Health (2016-2020) data to derive prevalence estimates of past-year DUIC, DUIA, DUID, and DUI of any substance among non-institutionalized US adults and among those reporting respective past-year substance use. Prevalence estimates and adjusted logistic regressions characterized temporal trends of these behaviors among US adults, among those with respective past-year substance use, and among stratified demographic subpopulations. Over 1 in 10 US adults reported DUI of any substance annually from 2016 to 2020.DUIA was most prevalent among all US adults (8.7% in 2017) however, this behavior is decreasing (AOR0.96 95%CI0.94,0.98). No change in DUIC among the US adult population was found, but a decrease was found among those with past-year cannabis use (AOR0.95 95%CI0.93,0.98), which coincided with a 29.1% increase in past-year cannabis use. There were no significant changes in overall DUID however, females, those ages 26-34 and 65 or older with past-year use displayed increasing trends. DUI of any substance decreased among the US adult population. DUI remains a salient public health concern in the US and results indicate population subgroups who may benefit from impaired driving prevention interventions.

Characterisation of AMB-FUBINACA metabolism and CB

AMB-FUBINACA is a synthetic cannabinoid receptor agonist (SCRA) which is primarily metabolised by hepatic enzymes producing AMB-FUBINACA carboxylic acid. The metabolising enzymes associated with this biotransformation remain unknown. This study aimed to determine if AMB-FUBINACA metabolism could be reduced in the presence of carboxylesterase (CES) inhibitors and recreational drugs commonly consumed with it. The affinity and activity of the AMB-FUBINACA acid metabolite at the cannabinoid type-1 receptor (CB The effect of CES1 and CES2 inhibitors, and delta-9-tetrahydrocannabinol (Δ AMB-FUBINACA was rapidly metabolised by HLM in the presence and absence of NADPH. Additionally, CES1 and CES2 inhibitors both significantly reduced AMB-FUBINACA metabolism. Furthermore, digitonin (100 µM) significantly inhibited CES1-mediated metabolism of AMB-FUBINACA by 56%, while the effects elicited by Δ CES1A1 was identified as the main hepatic enzyme responsible for the metabolism of AMB-FUBINACA to its less potent carboxylic acid metabolite. This biotransformation was significantly inhibited by digitonin. Since other xenobiotics may also inhibit similar SCRA metabolic pathways, understanding these interactions may elucidate why some users experience high levels of harm following SCRA use.

Evaluation of decarboxylation efficiency of Δ

Decarboxylation of Δ Δ The production of Δ These findings indicated that TBA improved the production of Δ

Designer benzodiazepines an update.

Designer benzodiazepines (DBs) are a subclass of novel psychoactive substances (NPS). DBs mimic the properties of approved and prescribed benzodiazepines. A systematic search of literature on DB classification, structure-activity relationships, pharmacologic properties, and adverse effects. The prevalence of DB use has increased substantially over the last decade. All DBs are full-agonist ligands at the gamma-aminobutyric acid type A-benzodiazepine (GABA

Ketamine and serotonergic psychedelics An update on the mechanisms and biosignatures underlying rapid-acting antidepressant treatment.

The discovery of ketamine as a rapid-acting antidepressant spurred significant research to understand its underlying mechanisms of action and to identify other novel compounds that may act similarly. Serotonergic psychedelics (SPs) have shown initial promise in treating depression, though the challenge of conducting randomized controlled trials with SPs and the necessity of long-term clinical observation are important limitations. This review summarizes the similarities and differences between the psychoactive effects associated with both ketamine and SPs and the mechanisms of action of these compounds, with a focus on the monoaminergic, glutamatergic, gamma-aminobutyric acid (GABA)-ergic, opioid, and inflammatory systems. Both molecular and neuroimaging aspects are considered. While their main mechanisms of action differ-SPs increase serotonergic signaling while ketamine is a glutamatergic modulator-evidence suggests that the downstream mechanisms of action of both ketamine and SPs include mechanistic target of rapamycin complex 1 (mTORC1) signaling and downstream GABA

Utility of preclinical models in the study of psilocybin - A comprehensive review.

Interest in the therapeutic potential of psilocybin across a broad range of neuropsychiatric disorders is rapidly expanding. Despite promising clinical data and tremendous public enthusiasm, complimentary basic and translational studies - which are critical for advancing our understanding of psilocybins biological effects and promoting innovation - have been relatively few. As with all work involving the study of complex neuropsychopharmacology, the search for deeper understanding of biological mechanisms, and the need for nuanced behavioral analyses in the context of both normal and diseased states, the roles for preclinical models are clear. A systematic search of the literature identified 57 articles involving the study of psilocybin in preclinical rodent models. A comprehensive review and thematic analysis identified 4 broad areas of investigation - pharmacology, toxicity, effects on disease models, and molecular mechanisms - with pharmacology studies accounting for the majority. Though these papers represent a still remarkably small body of literature, several important conclusions can already be drawn, and several areas of high priority for future work can be identified.

The effects of cannabidiol and Δ9-tetrahydrocannabinol, alone and in combination, in the maximal electroshock seizure model.

In the present study, cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC), and combinations of CBD and THC, were evaluated in the mouse maximal electroshock (MES) seizure test - an animal model of generalized-onset seizures. Male CF-1 mice were injected intraperitoneally (i.p.) with either CBD, THC or a combination of CBD and THC. The MES test was conducted 2 h after the injection of CBD and 1 h after the injection of THC. A wide range of doses was tested to allow the construction of dose-response curves. Toxicity was assessed using a behavioral rating scale. It was found that 1) the ED

The Effects of Acute Cannabis With and Without Cannabidiol on Neural Reward Anticipation in Adults and Adolescents.

Adolescents may respond differently to cannabis than adults, yet no previous functional magnetic resonance imaging study has examined acute cannabis effects in this age group. In this study, we investigated the neural correlates of reward anticipation after acute exposure to cannabis in adolescents and adults. This was a double-blind, placebo-controlled, randomized, crossover experiment. Forty-seven adolescents (n 24, 12 females, ages 16-17 years) and adults (n 23, 11 females, ages 26-29 years) matched on cannabis use frequency (0.5-3 daysweek) completed the Monetary Incentive Delay task during functional magnetic resonance imaging after inhaling cannabis with 0.107 mgkg Δ⁹-tetrahydrocannabinol (THC) (8 mg THC for a 75-kg person) or with THC plus 0.320 mgkg cannabidiol (THCCBD) (24 mg CBD for a 75-kg person), or placebo cannabis. We investigated reward anticipation activity with whole-brain analyses and region of interest analyses in the right and left ventral striatum, right and left anterior cingulate cortex, and right insula. THC reduced anticipation activity compared with placebo in the right (p .005, d 0.49) and left (p .003, d 0.50) ventral striatum and the right insula (p .01, d 0.42). THCCBD reduced activity compared with placebo in the right ventral striatum (p .01, d 0.41) and right insula (p .002, d 0.49). There were no differences between THC and THCCBD conditions and no significant drug by age group interaction effect, supported by Bayesian analyses. There were no significant effects in the whole-brain analyses. In weekly cannabis users, cannabis suppresses the brains anticipatory reward response to money, and CBD does not modulate this effect. Furthermore, the adolescent reward circuitry is not differentially sensitive to acute effects of cannabis on reward anticipation.

The B1080B1192 molecular marker identifies hemp plants with functional THCA synthase and total THC content above legal limit.

In Cannabis sativa L. the presence of delta 9-tetrahydrocannabinolic acid (THCA) above legal limit is a challenging issue that still restricts the industrial exploitation of this promising crop. In recent years, the interest of entrepreneurs and growers who see hemp as a dynamic and profitable crop was joined by the growing knowledge on C. sativa genetics and genomics, accelerated by the application of high throughput tools. Despite the renewed interest in the species, much remains to be clarified, especially about the long-standing problem of THCA in hemp inflorescences, which could even result in the seizure of the whole harvest. Although several hypotheses have been formulated on the accumulation of this metabolite in industrial varieties, none is conclusive yet. In this work, individuals of a population of the hemp cultivar FINOLA obtained from commercial seeds were investigated for total THC level and examined at molecular level. A marker linked to THCA synthase was found at a high incidence in both male and female plants, suggesting a considerable genetic variability within the seed batch. Full-length sequences encoding for putatively functional THCA synthases were isolated for the first time from the genome of both female and male plants of an industrial hemp variety and, using transcriptional analysis, the THCA synthase expression was quantified in mature inflorescences of individuals identified by the marker. Biochemical analyses finally demonstrated for these plants a 100% association between the predicted and actual chemotype.

On blinding and suicide risk in a recent trial of psilocybin-assisted therapy for treatment-resistant depression.

Results from a recent Phase II trial of psilocybin-assisted therapy for treatment-resistant depression

25-hydroxyvitamin D3 inhibits oxidative stress and ferroptosis in retinal microvascular endothelial cells induced by high glucose through down-regulation of miR-93.

The decrease of vitamin D plays a critical role in diabetes mellitus (DM)-induced oxidative stress and vascular endothelial injury. Therefore, we investigated the effect and mechanism of 25-hydroxyvitamin D3 (25 (OH) D3) on oxidative stress and ferroptosis induced by high glucose in human retinal microvascular endothelial cells (hRMVECs). And the objective of this paper was to propose a new strategy for the prevention and treatment of diabetic retinopathy (DR). First, hRMVECs were transfected with mimics NC or miR-93. After that, cells were treated with 100 nM 500 nM 25 (OH) D3 and then cultured in a high glucose (30 mM) environment. Subsequently, qRT-PCR was employed to detect the expression level of miR-93 CCK-8 for the proliferation of cells in each group biochemical tests for the level of intracellular reactive oxygen species (ROS), malondialdehyde (MDA), reduced glutathione (GSH) and ferrous ion (Fe Under a high glucose environment, 25 (OH) D3 at 100 nM500 nM could significantly promote the proliferation of hRMVECs, remarkably decrease the level of intracellular ROSMDA, and up-regulate the level of GSH. Besides, 25 (OH) D3 greatly reduced Fe 25 (OH) D3 may inhibit oxidative stress and ferroptosis in hRMVECs induced by high glucose via down-regulation of miR-93.

THC and CBD Similarities and differences between siblings.

Δ

Risk of depressive disorders associated with medical cannabis authorization A propensity score matched cohort study.

There is an increase in the medical use of cannabis. However, the safety of medical cannabis, particularly for mental health conditions, has not yet been clearly established. Thus, this study assessed the risk of emergency department (ED) visits and hospitalization for depressive disorders among medical cannabis users. We conducted a retrospective longitudinal cohort study of patients who received medical authorization to use cannabis from 2014 to 2019 in Ontario, matched (13 ratio) to population-based controls using propensity scores. Conditional Cox regressions were used to assess the association between cannabis authorization and the outcome. A total of 54,006 cannabis-authorized patients and 161,265 controls were analyzed. Approximately 39% were aged under 50 years, 54% were female, and 16% had a history of anxiety or mood disorders. The adjusted hazard ratio (aHR) for depressive disorders was 2.02 (95%CI 1.83-2.22). The aHR was 2.23 (1.95-2.55) among subjects without prior mental health disorders. The interaction between sex (or age) and exposure was not significant. In conclusion, medical cannabis authorization was associated with an increased risk of depressive disorders. This finding highlights the need for a careful risk-benefit assessment when authorizing cannabis, particularly for patients who seek cannabis to treat a depressive condition.

THC and THC-COOH hair concentrations Influence of age, gender, consumption habits, cosmetics treatment, and hair features.

Evaluation of Cannabis consumption is required for many purposes (i.e., workplace drug testing and driving license renewal). Hair analysis represents the most adopted and reliable approach for the investigation of repeated or chronic exposure to Cannabis. The main markers are the Δ9-tetrahydrocannabinol (THC) and its main metabolite, 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH), as stated by the Society of Hair Testing (SoHT) and the European Workplace Drug Testing Society (EWDTS). In this paper we presented an observational study on the hair concentrations of THC and THC-COOH and influences due to age, gender, consumption habits, and hair features. Data were collected from analysis of scalp hair samples (3-cm proximal segment) provided by subjects tested for THC consumption for personal purposes (i.e., workplace drug testing, personal use proving). The subjects provided an informed consent and a short questionnaire. A new analytical method was previously developed and then adopted. It consisted in a hydrolysis (1 mL of 1 M NaOH at 65 °C, 20 min) and a liquid-liquid extraction (with hexaneethyl acetate,9010, vv in presence of 1.5 mL of H

Pediatric Hospitalizations for Unintentional Cannabis Poisonings and All-Cause Poisonings Associated With Edible Cannabis Product Legalization and Sales in Canada.

Canada legalized cannabis in October 2018 but initially prohibited the sale of edibles (eg, prepackaged candies). Starting in January 2020, some provinces permitted the sale of commercial cannabis edibles. The association of legalizing cannabis edibles with unintentional pediatric poisonings is uncertain. To evaluate changes in proportions of all-cause hospitalizations for poisoning due to cannabis in children during 3 legalization policy periods in Canadas 4 most populous provinces (including 3.4 million children aged 0-9 years). This repeated cross-sectional study included all hospitalizations in children aged 0 to 9 years in Ontario, Alberta, British Columbia, and Quebec between January 1, 2015, and September 30, 2021. Prelegalization (January 2015 to September 2018) period 1, in which dried flower only was legalized in all provinces (October 2018 to December 2019) and period 2, in which edibles were legalized in 3 provinces (exposed provinces) and restricted in 1 province (control province) (January 2020 to September 2021). The primary outcome was the proportion of hospitalizations due to cannabis poisoning out of all-cause poisoning hospitalizations. Data analysis was performed using descriptive statistics and Poisson regression models. During the 7-year study period, there were 581 pediatric hospitalizations for cannabis poisoning (313 53.9% boys 268 46.1% girls mean SD age, 3.6 2.5 years) and 4406 hospitalizations for all-cause poisonings. Of all-cause poisoning hospitalizations, the rate per 1000 due to cannabis poisoning before legalization was 57.42 in the exposed provinces and 38.50 in the control province. During period 1, the rate per 1000 poisoning hospitalizations increased to 149.71 in the exposed provinces (incidence rate ratio IRR, 2.55 95% CI, 1.88-3.46) and to 117.52 in the control province (IRR, 3.05 95% CI, 1.82-5.11). During period 2, the rate per 1000 poisoning hospitalizations due to cannabis more than doubled to 318.04 in the exposed provinces (IRR, 2.16 95% CI, 1.68-2.80) but remained similar at 137.93 in the control province (IRR, 1.18 95% CI, 0.71-1.97). This cross-sectional study found that following cannabis legalization, provinces that permitted edible cannabis sales experienced much larger increases in hospitalizations for unintentional pediatric poisonings than the province that prohibited cannabis edibles. In provinces with legal edibles, approximately one-third of pediatric hospitalizations for poisonings were due to cannabis. These findings suggest that restricting the sale of legal commercial edibles may be key to preventing pediatric poisonings after recreational cannabis legalization.

Single-dose psilocybin-assisted therapy in major depressive disorder A placebo-controlled, double-blind, randomised clinical trial.

Psilocybin has been suggested as a novel, rapid-acting treatment for depression. Two consecutive doses have been shown to markedly decrease symptom severity in an open-label setting or when compared to a waiting list group. To date, to our knowledge, no other trial compared a single, moderate dose of psilocybin to a placebo condition. In this double-blind, randomised clinical trial, 52 participants diagnosed with major depressive disorder and no unstable somatic conditions were allocated to receive either a single, moderate dose (0.215 mgkg body weight) of psilocybin or placebo in conjunction with psychological support. MADRS and BDI scores were assessed to estimate depression severity, while changes from baseline to 14 days after the intervention were defined as primary endpoints. The trial took place between April 11th, 2019 and October 12th, 2021 at the psychiatric university hospital in Zürich, Switzerland and was registered with clinicaltrials.gov (NCT03715127). The psilocybin condition showed an absolute decrease in symptom severity of -13.0 points compared to baseline and were significantly larger than those in the placebo condition (95% CI -15.0 to -1.3 Cohens These results suggest that a single, moderate dose of psilocybin significantly reduces depressive symptoms compared to a placebo condition for at least two weeks. No serious adverse events were recorded. Larger, multi-centric trials with longer follow-up periods are needed to inform further optimisation of this novel treatment paradigm. The study was funded by the Swiss National Science Foundation, Crowdfunding, the Swiss Neuromatrix Foundation, and the Heffter Research Institute.

Psychedelics for Patients With Cancer A Comprehensive Literature Review.

To assess the role of psychedelics in the treatment of anxiety or depression among patients with cancer. PubMed search from inception to March 11, 2022, using the terms anxiety, depression, psychedelics, psilocybin, lysergic acid, methylenedioxymethamphetamine, or ayahuasca. Studies assessing patients with cancer receiving psychedelics for the treatment of anxiety or depression. Five unique randomized, double-blind, placebo-controlled trials were conducted. Significant reductions were found in 2 trials with 2 anxiety scales (State-Trait Anxiety Inventory-State, State-Trait Anxiety Inventory-Trait) and in 1 trial with 2 additional anxiety scales (Hamilton Rating Scale-Anxiety, Hospital Anxiety and Depression Scale-Anxiety). Significant reductions were found in 2 trials in 2 depression scales (Hospital Anxiety and Depression Scale-Depression, Beck Depression Inventory) and in 1 trial with an additional depression scale (Hamilton Rating Scale-Depression). Two studies assessed for clinically relevant reductions in anxiety and depression scores, and they occurred much more commonly in psychedelic-treated patients than those given placebo. There is a new potential option for treating patients with anxiety and depression along with cancer, which is important given the generally lackluster benefits with traditional antidepressants. Only a few sessions may also provide benefits extending out for 6 to 12 months and possibly beyond that. However, the studies were small, had many methodological limitations, and there were increases in blood pressure and heart rate. Psychedelics have a unique mechanism of action that might be well suited for treating anxiety and depression associated with cancer. This offers new promise for patients who are not being sufficiently treated with current antianxiety or antidepressant medications.

Enantioseparation and a comprehensive spectroscopic analysis of novel synthetic cathinones laterally substituted with a trifluoromethyl group.

Recently, the number of structural modifications of synthetic cathinones has been growing making them the second largest group of new psychoactive substances in Europe. Although they are abused because of their various psychoactive effects, some compounds from this group also serve as pharmaceuticals. Since synthetic cathinones are chiral molecules with one chiral center, their biological, toxicological, and pharmacological properties may significantly differ according to their absolute configuration and enantiomeric excess. In this study, we have synthesized two substances bearing a pharmacologically interesting trifluoromethyl group and developed a chiral liquid chromatography method using a polysaccharide chiral stationary phase to separate the corresponding enantiomers of both these drugs. Subsequently, we utilized molecular spectroscopic methods including chiroptical (electronic circular dichroism and vibrational circular dichroism) and non-polarizable (infrared and ultraviolet absorption) spectroscopies. In combination with density functional theory calculations, we have obtained stable conformers of selected enantiomers in solution and their relative abundances, which we used to simulate their spectra. The experimental and calculated data have been used to elucidate the 3D structure of the enantiomerically pure compounds and assign the absolute configuration of all prepared compounds.

Hallucinations and Hallucinogens Psychopathology or Wisdom

Hallucinations are currently associated almost exclusively with psychopathological states. While it is evident that hallucinations can indicate psychopathology or neurological disorders, we should remember that hallucinations also commonly occur in people without any signs of psychopathology. A similar case occurs in the case of hallucinogenic drugs, which have been long associated with psychopathology and insanity. However, during the last decades a huge body of research has shown that certain kinds of hallucinations, exerted by hallucinogenic drugs, may serve to improve mental health. We propose that, in light of historical, epidemiological, and scientific research, hallucinations can be better characterized as a common phenomenon associated sometimes with psychopathology but also with functional and even beneficial outcomes. In the last sections of the manuscript, we extend our argument, suggesting that hallucinations can offer a via regia to knowledge of the mind and the world. This radical shift in the cultural interpretation of hallucinations could have several implications for fields such as drug policy, civil law, and psychiatry, as well as for the stigma associated with mental disorders.

Effects of low-doses of methamphetamine on d-fenfluramine-induced head-twitch response (HTR) in mice during ageing and c-fos expression in the prefrontal cortex.

The head-twitch response (HTR) in mice is considered a behavioral model for hallucinogens and serotonin 5-HT EMD 281014 (0.001-0.05 mgkg) or MA (0.1-5 mgkg) blocked d-fenfluramine-induced HTR dose-dependently during ageing. The 5-HT EMD 281014 suppressed d-fenfluramine-induced HTR but failed to prevent d-fenfluramine-evoked c-fos expression which suggest involvement of additional serotonergic receptors in the mediation of evoked c-fos. The suppressive effect of MA on d-fenfluramine-evoked HTR is due to well-recognized functional interactions between stimulatory 5-HT

Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin.

Psilocybin is a psychedelic with therapeutic potential. While there is growing evidence that psilocybin exerts its beneficial effects through enhancing neural plasticity, the exact brain regions involved are not completely understood. Determining the impact of psilocybin on plasticity-related gene expression throughout the brain can broaden our understanding of the neural circuits involved in psychedelic-evoked neural plasticity. In this study, whole-brain serial two-photon microscopy and light sheet microscopy were employed to map the expression of the immediate early gene, c-Fos, in male and female mice. The drug-induced c-Fos expression following psilocybin administration was compared to that of subanesthetic ketamine and saline control. Psilocybin and ketamine produced acutely comparable elevations in c-Fos expression in numerous brain regions, including anterior cingulate cortex, locus coeruleus, primary visual cortex, central and basolateral amygdala, medial and lateral habenula, and claustrum. Select regions exhibited drug-preferential differences, such as dorsal raphe and insular cortex for psilocybin and the CA1 subfield of hippocampus for ketamine. To gain insights into the contributions of receptors and cell types, the c-Fos expression maps were related to brain-wide in situ hybridization data. The transcript analyses showed that the endogenous levels of

5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines.

Psychedelic compounds have displayed antidepressant potential in both humans and rodents. Despite their promise, psychedelics can induce undesired effects that pose safety concerns and limit their clinical scalability. The rational development of optimized psychedelic-related medicines will require a full mechanistic understanding of how these molecules produce therapeutic effects. While the hallucinogenic properties of psychedelics are generally attributed to activation of serotonin 2A receptors (5-HT2ARs), it is currently unclear if these receptors also mediate their antidepressant effects as several nonhallucinogenic analogues of psychedelics with antidepressant-like properties have been developed. Moreover, many psychedelics exhibit promiscuous pharmacology, making it challenging to identify their primary therapeutic target(s). Here, we use a combination of pharmacological and genetic tools to demonstrate that activation of 5-HT2A receptors is essential for tryptamine-based psychedelics to produce antidepressant-like effects in rodents. Our results suggest that psychedelic tryptamines can induce hallucinogenic and therapeutic effects through activation of the same receptor.

Psilocin suppresses methamphetamine-induced hyperlocomotion and acquisition of conditioned place preference via D2R-mediated ERK signaling.

Psilocin is an active metabolite form of psilocybin and exerts psychoactive effects. Recent studies suggest that psilocin may have regulatory effects on abuse drugs, but the mechanisms remain unclear. In this study, we want to explore the effects of psilocin on methamphetamine (METH)-induced alterations of behavior in mice and its molecular mechanisms. Acute METH administration model and conditioned place preference (CPP) model were used to investigate the effects of psilocin on METH-induced alterations of behavior. Western blot was used to detect the expression of proteins. In the acute 2 mgkg METH administration model, 1 mgkg psilocin counteracted METH-induced elevation of activity. In the 1 mgkg METH-induced CPP model, 1 mgkg psilocin inhibited CPP formation during the acquisition phase. However, psilocin did not impact METH extinction and relapse. Molecular results showed that the regulatory effect of psilocin on METH was underscored by altered expression of dopamine 2 receptor (D2R) and phosphorylated extra-cellular signal-regulated kinase (p-ERK) in the prefrontal cortex (PFC), nucleus accumbens (NAc), and ventral tegmental area (VTA). Trifluoperazine (TFP)-2HCl is a D2R inhibitor, and SCH772984 is a selective extra-cellular signal-regulated kinase (ERK) inhibitor that effectively inhibits ERK12 phosphorylation. The results indicated that 2 mgkg TFP-2HCl and 10 mgkg SCH772984 blocked METH-induced hyperactivity and acquisition of METH-induced CPP. Psilocin has regulatory effects on METH-induced alterations of behavior in mice via D2R-mediated signal regulation of ERK phosphorylation.

Interaction of psychedelic tryptamine derivatives with a lipid bilayer.

Naturally occurring psychedelics have been used for a long time as remedies or in religious ceremonies and recreational activities. Recent studies have proven the therapeutic potential of some psychedelic compounds to safely treat a wide range of diseases such as anxiety, depression, migraine, and addiction. It is hypothesized that psychedelic compounds like tryptamines can exert their effects by two possible mechanisms binding to the transmembrane serotonin receptor andor modifying the properties of the neuronal membrane that can alter the conformational equilibrium and desensitize receptors. The impact of three different tryptamine class compounds with a tertiary amine (dimethyltryptamine, bufotenine, and 5-MeO-DMT) in both neutral and charged forms on a model bilayer lipid membrane are studied using all-atom MD simulations. All compounds partition into the bilayer, and change membrane properties, but to different extents. We determine the tendency of compounds to partition into the membrane by free energy calculations. Neutral tryptamines partition into the bilayer almost completely. Dimethyltryptamine and 5-MeO-DMT cross the membrane spontaneously during the simulation time, but bufotenine does not, although it has the maximum effect on the structural properties of the membrane. However, protonated compounds partition partially into the bilayer and cannot pass through the middle of the membrane during the simulation time. In this way, subtle alteration of chemical structure can play a significant role in the improvement or deterioration of partitioning of these compounds into the bilayer and their passage across the membrane.

Review of systemic and syndromic complications of cannabis use A review.

Prescribed and non-prescribed cannabis use is common. Providers in specialties treating chronic pain - primary care, pain management, and neurology-will be coming across medical cannabis as a treatment for chronic pain, regardless of whether they are prescribers. It is important to be aware of the systemic and syndromic complications of acute and chronic cannabis use in the differential diagnosis of cardiac, cardiovascular, cerebrovascular, gastrointestinal, and psychiatric disorders. Medical cannabis is legal in 36 states. Studies have shown several potentially serious adverse effects associated with cannabis use. Cannabis use has the potential to cause several complications that can be easily overlooked without a preexisting high index of suspicion.

Linking medicinal cannabis to autotaxin-lysophosphatidic acid signaling.

Autotaxin is primarily known for the formation of lysophosphatidic acid (LPA) from lysophosphatidylcholine. LPA is an important signaling phospholipid that can bind to six G protein-coupled receptors (LPA

Alleviating anxiety and taming trauma Novel pharmacotherapeutics for anxiety disorders and posttraumatic stress disorder.

Psychiatric disorders associated with psychological trauma, stress and anxiety are a highly prevalent and increasing cause of morbidity worldwide. Current therapeutic approaches, including medication, are effective in alleviating symptoms of anxiety disorders and posttraumatic stress disorder (PTSD), at least in some individuals, but have unwanted side-effects and do not resolve underlying pathophysiology. After a period of stagnation, there is renewed enthusiasm from public, academic and commercial parties in designing and developing drug treatments for these disorders. Here, we aim to provide a snapshot of the current state of this field that is written for neuropharmacologists, but also practicing clinicians and the interested lay-reader. After introducing currently available drug treatments, we summarize recentongoing clinical assessment of novel medicines for anxiety and PTSD, grouped according to primary neurochemical targets and their potential to produce acute andor enduring therapeutic effects. The evaluation of putative treatments targeting monoamine (including psychedelics), GABA, glutamate, cannabinoid, cholinergic and neuropeptide systems, amongst others, are discussed. We emphasize the importance of designing and clinically assessing new medications based on a firm understanding of the underlying neurobiology stemming from the rapid advances being made in neuroscience. This includes harnessing neuroplasticity to bring about lasting beneficial changes in the brain rather than - as many current medications do - produce a transient attenuation of symptoms, as exemplified by combining psychotropiccognitive enhancing drugs with psychotherapeutic approaches. We conclude by noting some of the other emerging trends in this promising new phase of drug development.

Perceived effects of cannabis Generalizability of changes in driving performance.

The objective of this analysis was to determine the generalizability of the relationship between different samples of a drivers perceived state after cannabis use and related performance while operating a motor vehicle. Data were collected from 52 subjects in a study examining the effects of cannabis on driving performance. Data were analyzed using the SAS GLM Select procedure, using stepwise selection, with subjective effects, dosing condition (placebo vs. 6.18% delta-9-tetrahydrocannabinol THC), and driving context as independent measures. Correlation matrices of measures of driving performance against subjective responses and dosing condition used Pearsons and Spearmans test statistics, respectively. Results were compared to a prior study from a sample of 10 subjects. Subjective perceptions of acute cannabis impairment remain significant predictors of driving performance and explain individual variability in driving performance degradation as well as the data, beyond that which can be explained by acute use of cannabis alone. However, the significant subjective predictors of driving performance differ between the current and prior studies. To better understand these differences, correlations between subjective effects and performance measures were evaluated, which revealed that most correlations matched directionally (e.g., an increase in good drug effect was correlated with an increase in standard deviation of lane position SDLP). When there was a mismatch, 1 or more correlations were insignificant. Dosing condition and stoned were perfectly consistent high and sedated contained 1 mismatch and anxious, good drug effect and restless contained 3 or more mismatches. The results indicate that across both studies, differences in the perceived effects of cannabis are reflected in changes in both lateral and longitudinal control beyond the acute effects of cannabis, which may help explain individual variability in response to acute intoxication. However, the generalizability of these findings is lacking, as shown by inconsistencies in when and where subjective effects were significant. Other factors such as frequency of use, usage type, the evolving profile of a cannabis user, as well as other individual differences should be considered to explain this additional variability.

Valorization of Wild-Type Cannabis indica by Supercritical CO2 Extraction and Insights into the Utilization of Raffinate Biomass.

Supercritical CO

The management of orofacial pain to alleviate the quality of life of affected patients is becoming increasingly challenging for scientific research and healthcare professionals. From this perspective, in addition to conventional therapies, new alternatives are being sought, increasingly looking at the use of both natural and synthetic products.

Synaptoproteomic Analysis of the Prefrontal Cortex Reveals Spatio-Temporal Changes in SYNGAP1 Following Cannabinoid Exposure in Rat Adolescence.

The regular use of cannabis during adolescence has been associated with a number of negative life outcomes, including psychopathology and cognitive impairments. However, the exact molecular mechanisms that underlie these outcomes are just beginning to be understood. Moreover, very little is known about the spatio-temporal molecular changes that occur following cannabinoid exposure in adolescence. To understand these changes, we exposed mid-adolescent male rats to a synthetic cannabinoid (WIN 55,212-2 mesylate WIN) and, following drug abstinence through late adolescence, we subjected the synaptosomal fractions of the prefrontal cortex (PFC) to proteomic analyses. A total of N 487 differentially expressed proteins were found in WIN-exposed animals compared to controls. Gene ontology analyses revealed enrichment of terms related to the gamma-aminobutyric acid (GABA)-ergic neurotransmitter system. Among the top differentially expressed proteins was the synaptic Ras GTPase-activating protein 1 (SYNGAP1). Using Western blotting experiments, we found that the WIN-induced upregulation of SYNGAP1 was spatio-temporal in nature, arising only in the synaptosomal fractions (not in the cytosol) and only following prolonged drug abstinence (not on abstinence day 1). Moreover, the SYNGAP1 changes were found to be specific to WIN-exposure in adolescence and not adulthood. Adolescent animals exposed to a natural cannabinoid (Δ

Indolethylamine N-methyltransferase (INMT) is not essential for endogenous tryptamine-dependent methylation activity in rats.

Indolethylamine N-methyltransferase (INMT) is a transmethylation enzyme that utilizes the methyl donor S-adenosyl-L-methionine to transfer methyl groups to amino groups of small molecule acceptor compounds. INMT is best known for its role in the biosynthesis of N,N-Dimethyltryptamine (DMT), a psychedelic compound found in mammalian brain and other tissues. In mammals, biosynthesis of DMT is thought to occur via the double methylation of tryptamine, where INMT first catalyzes the biosynthesis of N-methyltryptamine (NMT) and then DMT. However, it is unknown whether INMT is necessary for the biosynthesis of endogenous DMT. To test this, we generated a novel INMT-knockout rat model and studied tryptamine methylation using radiometric enzyme assays, thin-layer chromatography, and ultra-high-performance liquid chromatography tandem mass spectrometry. We also studied tryptamine methylation in recombinant rat, rabbit, and human INMT. We report that brain and lung tissues from both wild type and INMT-knockout rats show equal levels of tryptamine-dependent activity, but that the enzymatic products are neither NMT nor DMT. In addition, rat INMT was not sufficient for NMT or DMT biosynthesis. These results suggest an alternative enzymatic pathway for DMT biosynthesis in rats. This work motivates the investigation of novel pathways for endogenous DMT biosynthesis in mammals.

Biomarkers of 4-hydroxy-

4-Hydroxy- 4-OH-MPT was incubated with 10-donor-pooled human hepatocytes to simulate Three phase I and four phase II metabolites were identified, including 4-OH-MPT metabolic fate was consistent with the human metabolism of tryptamine analogues we suggest 4-OH-MPT-

Removal of residues of psychoactive substances during wastewater treatment, their occurrence in receiving river waters and environmental risk assessment.

Continuous consumption combined with incomplete removal during wastewater treatment means residues of psychoactive substances (licit drugs, medications of abuse and illicit drugs) are constantly introduced into the aquatic environment, where they have the potential to affect non-target organisms. In this study, 17 drug residues of psychoactive substances were determined in wastewater influent, effluent and in receiving rivers of six Slovene municipal wastewater treatment plants employing different treatment technologies. Variations in removal efficiencies (REs) during spring, summer and winter were explored, and ecotoxic effects were evaluated using in silico (Ecological Structure-Activity Relationships software-ECOSAR) and in vivo (algal growth inhibition test) methods. Drug residues were detected in influent and effluent in the ngL to μgL range. In receiving rivers, biomarkers were in the ngL range, and there was good agreement between measured and predicted concentrations. On average, REs were highest for nicotine, 11-nor-9-carboxy-∆9-tetrahydrocannabinol (THC-COOH), cocaine residues, and amphetamine (>90 %) and lowest for methadone residues (<30 %). REs were comparable between treatments involving activated sludge and membrane bioreactors, while the moving biofilm bed reactor (MBBR) removed cotinine, cocaine, and benzoylecgonine to a lesser extent. Accordingly, higher levels of nicotine and cocaine residues were detected in river water receiving MBBR discharge. Although there were seasonal variations in REs and levels of drug residues in receiving rivers, no general pattern could be observed. No significant inhibition of algal growth (Chlamydomonas reinhardtii) was observed for the tested compounds (1 mgL) during 72 h and 240 h of exposure, although effects on aquatic plants were predicted in silico. In addition, environmental risk assessment revealed that levels of nicotine, methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), morphine, and 3,4-methylenedioxymethamphetamine (MDMA) pose a risk to aquatic organisms. Since nicotine and EDDP can have acute and chronic effects, the authors support regular monitoring of receiving surface waters, followed up by regulatory actions.

SnapShot Psychedelics and serotonin receptor signaling.

Serotonin (5-hydroxytryptamine 5HT) signaling regulates processes in every major organ system, but it is most widely known for its role as a neurotransmitter in modulating a plethora of human behaviors. Psychedelics target the 5HT

Smoked cannabis reduces peak cocaine plasma levels and subjective effects in a controlled drug administration study of polysubstance use in men.

Despite the high prevalence of polysubstance use, outcomes and potential risks associated with common drug combinations are not well characterized. Many individuals who use cocaine also use cannabis, yet little is known about how interactions between the two drugs might contribute to continued co-use. The aim of this double-blind, placebo-controlled study was to determine the physiological and subjective effects of smoked cannabis with smoked cocaine, to identify variables that may contribute to the continued use of this drug combination. Healthy, non-treatment seeking volunteers who reported smoking both cocaine and cannabis (N 9, all males) completed a 13-day inpatient protocol. On session days, cannabis 0.0 or 5.6 % tetrahydrocannabinol (THC) was administered 28 min prior to cocaine (0, 12, or 25 mg). Dependent measures included pharmacokinetic assessment of THC and cocaine and their respective metabolites, in addition to subjective and cardiovascular effects. Active cannabis (5.6 % THC) increased plasma levels of THC and the metabolite 11-nor-9-carboxy-Δ9-THC (THCCOOH), as well as subjective ratings of cannabis effects and heart rate relative to inactive cannabis. Cocaine dose-dependently increased plasma cocaine and metabolites and subjective ratings of cocaine effects. Active cannabis pre-treatment decreased plasma levels of cocaine and metabolites. Furthermore, active cannabis attenuated cocaine-related reductions in Hunger and Calm. Cannabis pre-treatment altered the subjective experience of smoked cocaine and reduced peak plasma levels of cocaine. Future studies should explore additional doses of each drug and whether these changes also impact cocaines reinforcing effects.

Use of Cannabis and Other Pain Treatments Among Adults With Chronic Pain in US States With Medical Cannabis Programs.

This cross-sectional study uses a survey to estimate use of cannabis and other pain treatments among adults with chronic pain in areas with medical cannabis programs in 36 US states and Washington, DC.

Interval delivery of 5HT

There is an urgent unmet medical need to develop therapeutic options for the 50% of depression patients suffering from treatment-resistant depression, which is difficult to treat with existing psycho- and pharmaco-therapeutic options. Classical psychedelics, such as the 5HT

Eating disorders and substance use Examining associations among US college students.

To investigate associations between reported eating disorder (ED) diagnosis and substance use disorder (SUD) diagnosis, substance misuse, and illicit drug use among US college students. Data consisting of n 414,299 students responses to the National College Health Assessment survey conducted by the American College Health Association between fall 2015 and spring 2019 were utilized for this study. Unadjusted and adjusted odds ratios were used to determine the association of reported ED diagnosis with reported SUD diagnosis, misuse of cigarettes, e-cigarettes, alcohol, marijuana, cocainemethamphetamine, sedatives, hallucinogens, opiates, inhalants, MDMA, and other club drugs, as well as illicit use of prescription pain killers, prescription sedatives, and prescription stimulants. A sensitivity analysis investigating associations between reported anorexia nervosa (AN), bulimia nervosa (BN), and each substance use outcome was also conducted. Among all in our analytic cohort, 7.15% reported receiving an ED diagnosis or being treated for an ED in the last 12 months. Students with ED indications were significantly more likely to report each of the substance use outcomes investigated in this study, including SUD diagnosis (aOR 7.43 95% CI 6.98, 7.92 p < .0001), opiate misuse (aOR 8.35 95% CI 7.38, 9.45 p < .0001), and misuse of other club drugs (aOR 10.37 95% CI 9.10, 11.81 p < .0001) than peers without reported EDs. Both AN and BN were associated with an increased likelihood of SUD diagnosis. These findings demonstrate strong associations between EDs and the most extensive list of substance use outcomes explored in the context of college setting ED research to date.

Seeking the Psilocybiome Psychedelics meet the microbiota-gut-brain axis.

Moving towards a systems psychiatry paradigm embraces the inherent complex interactions across all levels from micro to macro and necessitates an integrated approach to treatment. Cortical 5-HT

An Integrative Review of Measures of Spirituality in Experimental Studies of Psilocybin in Serious Illness Populations.

Among psychedelic-experienced users, only past use of psilocybin reliably predicts nature relatedness.

Past research reports a positive relationship between experience with classic serotonergic psychedelics and nature relatedness (NR). However, these studies typically do not distinguish between different psychedelic compounds, which have a unique psychopharmacology and may be used in specific contexts and with different intentions. Likewise, it is not clear whether these findings can be attributed to substance use per se or unrelated variables that differentiate psychedelic users from nonusers. The present study was designed to determine the relative degree to which lifetime experience with different psychedelic substances is predictive of self-reported NR among psychedelic-experienced users. We conducted a combined reanalysis of five independent datasets ( Among people experienced with psychedelics, only past use of psilocybin (versus LSD, mescaline, Results suggest that experience with psilocybin is the only reliable (and strongest) predictor of NR. Future research should focus on psilocybin when investigating effects of psychedelic on NR and determine whether pharmacological attributes or differences in user expectationsuse settings are responsible for this observation.

Psychedelics in Psychiatry - Development and Current State in Germany.

Clinical research on the therapeutic efficacy of psychedelics is currently experiencing a renaissance. Available scientific evidence on their efficacy in various psychiatric conditions, as well as their legally approved use in some countries of the world, show the possibility of their future application in clinical practice also in Germany. The field is facing substantial challenges that have to be addressed, such as defining and setting a suitable clinical frame. This manuscript deals with the historical background of the clinical application of psychedelics, as well as the psycho-phenomenology, modes of action, possible indications and aspects of safety. The current research status in Germany and the organization of professional societies are discussed in a historical and international context and attention is drawn to unresolved critical issues in the field. In den letzten Jahren erlebte die klinische Forschung zur therapeutischen Wirksamkeit von Psychedelika eine Art Renaissance. Der aktuelle Stand wissenschaftlicher Erkenntnisse zur Wirksamkeit bei verschiedenen psychiatrischen Indikationen, wie auch die bereits unter bestimmten Voraussetzungen genehmigungsfähige Anwendung einiger psychedelischer Substanzen in der klinischen Praxis in manchen Ländern der Welt, legen die Möglichkeit einer zukünftigen Anwendung im klinischen Setting auch in Deutschland nahe. Dabei steht das Feld noch vor großen Herausforderungen inklusive der Notwendigkeit einer kritischen Gestaltung der Rahmenbedingungen für einen möglichen klinischen Einsatz. In diesem Artikel wird auf die historischen Hintergründe der klinischen Anwendung von Psychedelika eingegangen, um dann Aspekte wie Psychophänomenologie, Wirkmodelle, mögliche Indikationen und Pharmakosicherheit zu beleuchten. Anschließend wird der aktuelle Stand der Forschung und auch der Organisation von Fachgesellschaften in Deutschland im historischen und internationalen Kontext betrachtet, wie auch kritische Aspekte und noch zu klärende Fragen in dem Themenfeld.

Effect of four-week cannabidiol treatment on cognitive function secondary outcomes from a randomised clinical trial for the treatment of cannabis use disorder.

Chronic cannabis use is associated with impaired cognitive function. Evidence indicates cannabidiol (CBD) might be beneficial for treating cannabis use disorder. CBD may also have pro-cognitive effects however, its effect on cognition in people with cannabis use disorder is currently unclear. We aimed to assess whether a 4-week CBD treatment impacted cognitive function. We hypothesised that CBD treatment would improve cognition from baseline to week 4, compared to placebo. Cognition was assessed as a secondary outcome in a phase 2a randomised, double-blind, parallel-group and placebo-controlled clinical trial of 4-week daily 200 mg, 400 mg and 800 mg CBD for the treatment of cannabis use disorder. Participants had moderate or severe DSM-5 cannabis use disorder and intended to quit cannabis use. Our pre-registered primary cognitive outcome was delayed prose recall. Secondary cognitive outcomes were immediate prose recall, stop signal reaction time, trail-making task performance, verbal fluency and digit span. Seventy participants were randomly assigned to placebo (n 23), 400 mg CBD (n 24) and 800 mg CBD (n 23). A 200 mg group was eliminated from the trial because it was an inefficacious dose at interim analysis (n 12) and was not analysed here. For the primary cognitive outcome, there was no effect of CBD compared to placebo, evidenced by a lack of dose-by-time interaction at 400 mg (0.46, 95%CIs - 1.41, 2.54) and 800 mg (0.89, 95%CIs - 0.99, 2.81). There was no effect of CBD compared to placebo on secondary cognitive outcomes, except backwards digit span which increased following 800 mg CBD (0.30, 95%CIs 0.02, 0.58). In this clinical trial for cannabis use disorder, CBD did not influence delayed verbal memory. CBD did not have broad cognitive effects but 800 mg daily treatment may improve working memory manipulation. The trial was registered with ClinicalTrials.gov (NCT02044809) and the EU Clinical Trials Register (2013-000,361-36).

Are psychedelics the answer to chronic pain A review of current literature.

We aim to provide an evidence-based overview of the use of psychedelics in chronic pain, specifically LSD and psilocybin. Chronic pain is a common and complex problem, with an unknown etiology. Psychedelics like lysergic acid diethylamide (LSD) and psilocybin, may play a role in the management of chronic pain. Through activation of the serotonin-2A (5-HT2A) receptor, several neurophysiological responses result in the disruption of functional connections in brain regions associated with chronic pain. Healthy reconnections can be made through neuroplastic effects, resulting in sustained pain relief. However, this process is not fully understood, and evidence of efficacy is limited and of low quality. In cancer and palliative related pain, the analgesic potential of psychedelics was established decades ago, and the current literature shows promising results on efficacy and safety in patients with cancer-related psychological distress. In other areas, patients suffering from severe headache disorders like migraine and cluster headache who have self-medicated with psychedelics report both acute and prophylactic efficacy of LSD and psilocybin. Randomized control trials are now being conducted to study the effects in cluster headache Furthermore, psychedelics have a generally favorable safety profile especially when compared to other analgesics like opioids. In addition, psychedelics do not have the addictive potential of opioids. Given the current epidemic use of opioids, and that patients are in desperate need of an alternative treatment, it is important that further research is conducted on the efficacy of psychedelics in chronic pain conditions.

Delta-9 tetrahydrocannabinol (THC) effects on the cortisol stress response in bovine granulosa cells.

Maternal stress can result in changes in the hypothalamic-pituitary-adrenal (HPA) axis and lead to stress-related behaviours in offspring. Under physiological conditions, delta-9 tetrahydrocannabinol (THC) appears to be detrimental for fertility. However, cannabis is also commonly used for stress-relief. THC acts on the endocannabinoid receptors in granulosa cells (GCs), which affect oocyte competency. The objective of this study was to evaluate the effects of THC on in vitro bovine granulosa cell viability, apoptosis, and stress response pathway. GCs were cultured in vitro in the presence of clinically relevant therapeutic and recreational plasma doses of THC. Cortisol doses reflecting normal and elevated plasma levels were used to evaluate the effects of THC under induced stress in vitro. No effect of THC was observed on cell viability or apoptosis. High and low cortisol concentrations caused significant increases in 11β-HSD1 mRNA expression (n 6, p < 0.0001). Interestingly, when combined with high THC, there was a significant decrease in 11β-HSD1 expression compared to high and low cortisol treatments alone (p < 0.001, p < 0.05). GR expression was unaffected by cortisol treatments, and low THC treatment maintained increased expression in the presence of high and low cortisol treatments (n 6, p < 0.01, p < 0.0001). Our findings represent a foundation to obtain useful data for evaluating THC potential therapeutic benefit.

Contextualizing prescription opioid misuse and heroin use within dimensional models of drug involvement.

Prescription opioid misuse (POM) is often implicated in heroin initiation, despite evidence that POM does not predict heroin initiation any better than other drug use. Additionally, prescription misuse and illicit use behaviors tend to respectively cluster together. This study aimed to test a series of theory-driven factor models to explore how POM and heroin use are situated within the broader constellation of drug use that typically occurs alongside opioid (mis)use. 36,309 individuals from NESARC-III (56.31% female mean age45.63 SD17.53) reported their lifetime (mis)use of prescription opioids, prescription stimulants, prescription sedatives, heroin, cannabis, cocainecrack, illicit stimulants (e.g., methamphetamine), club drugs, hallucinogens, and inhalants, and were administered a DSM-5 substance use disorder (SUD) assessment. Bifactor, correlated factors, and one-factor confirmatory factor models were fit using all drug useSUD variables and subsequently compared. POM was most strongly correlated with prescription sedative misuse heroin use was most strongly correlated with cocainecrack use. All factor models fit the data well. Highly correlated factors and patterns of factor loadings suggested that POM and heroin use were most parsimoniously captured within a general factor alongside all other forms of drug use. This was also the case for SUD. Additional analyses testing an alternate factor structure provided further support for unidimensionality. POM and heroin use, as well as prescription- and heroin-based SUDs, were neither separable nor distinctly associated. Future research should account for other drug use more comprehensively rather than isolating POM as a primary risk factor in heroin use and use disorder.

On the realness of people who do not exist The social processing of artificial faces.

Today more than ever, we are asked to evaluate the realness, truthfulness and trustworthiness of our social world. Here, we focus on how people evaluate realistic-looking faces of non-existing people generated by generative adversarial networks (GANs). GANs are increasingly used in marketing, journalism, social media, and political propaganda. In three studies, we investigated if and how participants can distinguish between GAN and REAL faces and the social consequences of their exposure to artificial faces. GAN faces were more likely to be perceived as

Psychedelic drug abuse potential assessment for new drug applications and controlled substance scheduling A United States perspective.

Psychedelics are an increasingly active area of research and pharmaceutical development. This includes abuse potential assessment to better understand their pharmacological mechanisms and effects and guide controlled substance regulation. Psychedelics pose challenges to abuse assessments to ensure valid, reliable, and generalizable outcomes and safe study conduct. Key nonclinical techniques, for example, receptor binding and functional assays in vitro, and nonclinical physical dependence determinations, are easily adaptable to psychedelics. However, the entactogens (weak reinforcers) and hallucinogens (non-reinforcers) require more flexible approaches than typically recommended by regulatory agencies. Phase 1 pharmacokineticpharmacodynamic safety studies and Phases 23 efficacysafety trials with systematic monitoring of abuse-related adverse events are readily applicable to psychedelics. Human abuse trials require modification because supratherapeutic doses may not be safe and procedures, for example, personal monitors to manage serious adverse events, might bias outcomes. Abuse-related studies for psychedelics requiring approval by Food and Drug Administration and other agencies should take into consideration existing knowledge that will vary from extensive, for example, psilocybin, to zero for novel hallucinogens and entactogens. Many abuse assessments can be reasonably applied to animals and humans without compromising scientific integrity. Modification of existing techniques and incorporating a broader range of nonclinical tests should ensure generalizable outcomes. Human abuse studies merit reconsideration and possible modification to ensure safety and validity for psychedelic drug evaluation. Other nonclinical and clinical methods can provide evaluations of the pharmacological equivalence of test drugs to known drugs of abuse to provide context to the abuse assessment and guide drug scheduling.

Genome sequencing progenies of magic mushrooms (Psilocybe subaeruginosa) identifies tetrapolar mating and gene duplications in the psilocybin pathway.

Knowledge of breeding systems and genetic diversity is critical to select and combine desired traits that advance new cultivars in agriculture and horticulture. Mushrooms that produce psilocybin, magic mushrooms, may potentially be used in therapeutic and wellness industries, and stand to benefit from genetic improvement. We studied haploid siblings of Psilocybe subaeruginosa to resolve the genetics behind mating compatibility and advance knowledge of breeding. Our results show that mating in P. subaeruginosa is tetrapolar, with compatibility controlled at a homeodomain locus with one copy each of HD1 and HD2, and a pheromonereceptor locus with four homologs of the receptor gene STE3. An additional two pheromonereceptor loci homologous to STE3 do not appear to regulate mating compatibility. Alleles in the psilocybin gene cluster did not vary among the five siblings and were likely homozygous in the parent. Psilocybe subaeruginosa and its relatives have three copies of PsiH genes but their impact on production of psilocybin and its analogues is unknown. Genetic improvement in Psilocybe will require access to genetic diversity from the centre of origin of different species, identification of genes behind traits, and strategies to avoid inbreeding depression.

Malpractice and Other Civil Liability in Psychedelic Psychiatry.

Psychedelics have the ability to fundamentally alter the consciousness of individuals who take them and thus pose unique legal risks for psychiatrists interested in incorporating them into their practice. Several issues related to malpractice may be relevant, including absence of standards of care, risk of harm, inappropriate treatment, and the doctrine of

Canalization and plasticity in psychopathology.

This theoretical article revives a classical bridging construct, canalization, to describe a new model of a general factor of psychopathology. To achieve this, we have distinguished between two types of plasticity, an early one that we call TEMP for Temperature or Entropy Mediated Plasticity, and another, we call canalization, which is close to Hebbian plasticity. These two forms of plasticity can be most easily distinguished by their relationship to precision or inverse variance TEMP relates to increased model variance or decreased precision, whereas the opposite is true for canalization. TEMP also subsumes increased learning rate, (Ising) temperature and entropy. Dictionary definitions of plasticity describe it as the property of being easily shaped or molded TEMP is the better match for this. Importantly, we propose that pathological phenotypes develop via mechanisms of canalization or increased model precision, as a defensive response to adversity and associated distress or dysphoria. Our model states that canalization entrenches in psychopathology, narrowing the phenotypic state-space as the agent develops expertise in their pathology. We suggest that TEMP - combined with gently guiding psychological support - can counter canalization. We address questions of whether and when canalization is adaptive versus maladaptive, furnish our model with references to basic and human neuroscience, and offer concrete experiments and measures to test its main hypotheses and implications. This article is part of the Special Issue on National Institutes of Health Psilocybin Research Speaker Series.

Subtypes of the psychedelic experience have reproducible and predictable effects on depression and anxiety symptoms.

Subjective experiences seem to play an important role in the enduring effects of psychedelic experiences. Although the importance of the subjective experience on the impact of psychedelics is frequently discussed, a more detailed understanding of the subtypes of psychedelic experiences and their associated impacts on mental health has not been well documented. In the current study, machine learning cluster analysis was used to derive three subtypes of psychedelic experience in a large (n 985) cross sectional sample. These subtypes are not only associated with reductions in anxiety and depression symptoms and other markers of psychological wellbeing, but the structure of these subtypes and their subsequent impact on mental health are highly reproducible across multiple psychedelic substances. Data were obtained via retrospective self-report, which does not allow for definitive conclusions about the direction of causation between baseline characteristics of respondents, qualities of subjective experience, and outcomes. The present analysis suggests that psychedelic experiences, in particular those that are associated with enduring improvements in mental health, may be characterized by reproducible and predictable subtypes of the subjective psychedelic effects. These subtypes appear to be significantly different with respect to the baseline demographic characteristics, baseline measures of mental health, and drug type and dose. These findings also suggest that efforts to increase psychedelic associated personal and mystical insight experiences may be key to maximizing beneficial impact of clinical approaches using this treatment in their patients.

Cannabidiol and Δ8-Tetrahydrocannabinol Cannabinoids of Rising Interest and Concern.

Although much is known about Δ9-tetrahydrocannabinol and its inactive open ring isomer, cannabidiol, far less is known about the effects, metabolism, and pharmacodynamics of Δ9-tetrahydrocannabinols double-bond isomer, Δ8-tetrahydrocannabinol. With the passage of the so-called United States Farm Bill, which was made law in order to allow legal hemp cultivation in the United States, more needs to be known about the effects of Δ8-tetrahydrocannabinol, a double-bond isomer of Δ9-tetrahydrocannabinol, and cannabidiol (CBD), which is an open-ring isomer of Δ8-tetrahydrocannabinol. It is the aim of the review to summarize current knowledge of Δ8-tetrahydrocannabinol and CBD, including the pharmacodynamics and pharmacokinetics of CBD. Also, plant genetics, the effect of cannabinoids on the current topic of viral entry into mammalian cells, and the current practice of vaping, dabbing, and dripping are covered.

Aging, circadian disruption and neurodegeneration Interesting interplay.

The circadian system is an intricate molecular network of coordinating circadian clocks that organize the internal synchrony of the organism in response to the environment. These rhythms are maintained by genetically programmed positive and negative auto-regulated transcriptional and translational feedback loops that sustain 24-hour oscillations in mRNA and protein components of the endogenous circadian clock. Since inter and intracellular activity of the central pacemaker appears to reduce with aging, the interaction between the circadian clock and aging continues to elude our understanding. In this review article, we discuss circadian clock components at the molecular level and how aging adversely affects circadian clock functioning in rodents and humans. The natural decline in melatonin levels with aging strongly contributes to circadian dysregulation resulting in the development of neurological anomalies. Additionally, inappropriate environmental conditions such as Artificial Light at Night (ALAN) can cause circadian disruption or chronodisruption (CD) which can result in a variety of pathological diseases, including premature aging. Furthermore, we summarize recent evidence suggesting that CD may also be a predisposing factor for the development of age-related neurodegenerative diseases (NDDs) such as Alzheimers disease (AD), Parkinsons disease (PD), and Huntingtons disease (HD), although more investigation is required to prove this link. Finally, certain chrono-enhancement approaches have been offered as intervention strategies to prevent, alleviate, or mitigate the impacts of CD. This review thus aims to bring together recent advancements in the chronobiology of the aging process, as well as its role in NDDs.

Neural Correlates of the DEEPP (Anti-suicidal Response to Ketamine in Treatment-Resistant Bipolar Depression) Study Protocol for a Pilot, Open-Label Clinical Trial.

Suicide is among the top 10 leading causes of death worldwide. Of people who died by suicide, the majority are diagnosed with depression. It is estimated that 25%-60% of people with bipolar depression (BD) will attempt suicide at least once, and 10%-15% will die by suicide. Several treatments, such as lithium, clozapine, electroconvulsive therapy, and cognitive behavioral therapy, have been shown to be effective in treating suicidality. However, these treatments can be difficult to tolerate or may take months to take effect. Ketamine, a glutamate N-methyl-D-aspartate antagonist, has been shown to have rapid antisuicidal effect and antidepressant qualities, and is thus a promising intervention to target acute suicidality in patients with BD. However, the biological mechanism underlying its therapeutic action remains poorly understood. Enhancing our understanding of underlying mechanisms of action for ketamines effectiveness in reducing suicidality is critical to establishing biological markers of treatment response and developing tailored, personalized interventions for patients with BD. This is an open-label clinical trial to test the safety and feasibility of repeated ketamine infusions to treat acute suicidality. The primary objective is to test the safety and feasibility of ketamine intervention. The secondary objective is to examine ketamines potential neurophysiological mechanisms of action by assessing cortical excitation and inhibition to determine potential biomarkers of clinical response. Other objectives are to evaluate the effect of ketamine on acute suicidality and other clinical outcomes, such as depressive symptoms and quality of life, to inform a future larger trial. This open-label clinical trial aims to test the safety and feasibility of repeated ketamine infusions in patients with BD for suicidality and to assess ketamines neurophysiological effects. A sterile form of racemic ketamine hydrochloride will be administered over a 40-minute intravenous infusion 2 times per week on nonconsecutive days for 4 weeks (8 sessions). We will recruit 30 adults (24-65 year olds) over 2 years from an academic psychiatric hospital in Toronto, Canada. This study is currently ongoing and actively recruiting participants. So far, 5 participants have completed the trial, 1 is currently in active treatment, and 8 participants are on the waitlist to be screened. We anticipate initial results being available in the fall of 2023. This proposal was presented as a poster presentation at the Research to Reality Global Summit on Psychedelic-Assisted Therapies and Medicine, held in May 2022 in Toronto, Canada. Developing effective interventions for acute suicidality in high-risk populations such as those with BD remains a major therapeutic challenge. Ketamine is a promising treatment due to its rapid antidepressant and antisuicidal effects, but its underlying neurophysiological mechanisms of action remain unknown. ClinicalTrials.gov NCT05177146 httpsclinicaltrials.govct2showNCT05177146. DERR1-10.219641013.

Effect of MAOA DNA Methylation on Human in Vivo Protein Expression Measured by 11Charmine Positron Emission Tomography.

Epigenetic modifications like DNA methylation are understood as an intermediary between environmental factors and neurobiology. Cerebral monoamine oxidase A (MAO-A) levels are altered in depression, as are DNA methylation levels within the MAOA gene, particularly in the promoterexon Iintron I region. An effect of MAOA methylation on peripheral protein expression was shown, but the extent to which methylation affects brain MAO-A levels is not fully understood. Here, the influence of MAOA promoterexon Iintron I region DNA methylation on global MAO-A distribution volume (VT), an index of MAO-A density, was assessed via 11Charmine positron emission tomography in 22 patients (14 females) suffering from seasonal affective disorder and 30 healthy controls (17 females). No significant influence of MAOA DNA methylation on global MAO-A VT was found, despite correction for health status, sex, season, and MAOA variable number of tandem repeat genotype. However, season affected average methylation in women, with higher levels in spring and summer (Puncorr .03). We thus did not find evidence for an effect of MAOA DNA methylation on brain MAO-A VT. In contrast to a previous study demonstrating an effect of methylation of a MAOA promoter region located further 5 on brain MAO-A, MAOA methylation of the region assessed here appears to affect brain protein levels to a limited extent at most. The observed effect of season on methylation levels is in accordance with extensive evidence for seasonal effects within the serotonergic system. NCT02582398 (httpsclinicaltrials.govct2showNCT02582398).

Repeated use of 3,4-methylenedioxymethamphetamine is associated with the resilience in mice after chronic social defeat stress A role of gut-microbiota-brain axis.

3,4-Methylenedioxymethamphetamine (MDMA), the most widely used illicit compound worldwide, is the most attractive therapeutic drug for post-traumatic stress disorder (PTSD). Recent observational studies of US adults demonstrated that lifetime MDMA use was associated with lower risk of depression. Here, we examined whether repeated administration of MDMA can affect resilience versus susceptibility in mice exposed to chronic social defeat stress (CSDS). CSDS produced splenomegaly, anhedonia-like phenotype, and higher plasma levels of interleukin-6 (IL-6) in the saline-treated mice. In contrast, CSDS did not cause these changes in the MDMA-treated mice. Analysis of gut microbiome found several microbes altered between saline CSDS group and MDMA CSDS group. Untargeted metabolomics analysis showed that plasma levels of N-epsilon-methyl-L-lysine in the saline CSDS group were significantly higher than those in the control and MDMA CSDS groups. Interestingly, there were positive correlations between plasma IL-6 levels and the abundance of several microbes (or plasma N-epsilon-methyl-L-lysine) in the three groups. Furthermore, there were also positive correlations between the abundance of several microbes and N-epsilon-methyl-L-lysine in the three groups. In conclusion, these data suggest that repeated administration of MDMA might contribute to stress resilience in mice subjected to CSDS through gut-microbiota-brain axis.

Psilocybin as a Treatment for Psychiatric Illness A Meta-Analysis.

Psilocybin is an emerging potential therapy for the treatment of psychiatric illnesses. Microdosing has been shown to result in an overall improvement in patients with anxiety, depression, obsessive-compulsive disorder, post-traumatic stress disorder, and substance abuse. This meta-analysis explores and compiles prior research to make further inferences regarding psilocybin and its use for the treatment of psychiatric illness along with its safety and efficacy. Database searches were conducted to identify peer-reviewed randomized controlled trials and clinical trials mentioning psilocybin use and psychiatric illness. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram was created and analysis was run on the nine articles that met all established inclusion criteria. An event is defined as a participant who showed improvement, in a quantitative method, from baseline after the use of psilocybin. Another analysis was done using depression severity (Quick Inventory of Depressive Symptomatology 16-Item Self Report, QIDS-SR16) at baseline and after the use of psilocybin. Analyses of the original data and the nine articles showed a great deal of heterogeneity with an I

A neurophenomenological approach to non-ordinary states of consciousness hypnosis, meditation, and psychedelics.

No contemporary unifying framework has been provided for the study of non-ordinary states of consciousness (NSCs) despite increased interest in hypnosis, meditation, and psychedelics. NSCs induce shifts in experiential contents (what appears to the experiencer) andor structure (how it appears). This can allow the investigation of the plastic and dynamic nature of experience from a multiscale perspective that includes mind, brain, body, and context. We propose a neurophenomenological (NP) approach to the study of NSCs which highlights their role as catalysts of transformation in clinical practice by refining our understanding of the relationships between experiential (subjective) and neural dynamics. We outline the ethical implications of the NP approach for standard conceptions of health and pathology as well as the crucial role of experience-based know-how in NSC-related research and application.

The varieties of psychedelic law.

After decades of prohibition, psychedelics are generating intense public and private interest. Scientists are researching the therapeutic properties of these substances, and mounting evidence supports their ability to treat a variety of mental health conditions. Meanwhile, dozens of cities and states are proposing or enacting psychedelics legislation to promote research, increase therapeutic and non-therapeutic access, and decrease criminal penalties associated with producing, possessing, or consuming psychedelics. This article is the first to produce a typology of state and local psychedelic laws, which fall into five general categories decriminalization, supported adult use, medical use, clinical research, and policy analysis. The article defines each category and explains how some jurisdictions create hybrid psychedelic laws that blend elements of multiple categories. Following enactment, government agencies can shift laws from one category to another during the rulemaking process. This article is part of the Special Issue on National Institutes of Health Psilocybin Research Speaker Series.

Gender differences in cannabis use disorder symptoms A network analysis.

While cannabis use in women is increasing worldwide, research into gender differences in cannabis use disorder (CUD) symptomology is lacking. In response to limited effectiveness of addiction treatment, research focus has been shifting from clinical diagnoses towards interactions between symptoms, as patterns of symptoms and their interactions could be crucial in understanding etiological mechanisms in addiction. The aim of this study was to evaluate the CUD symptom network and assess whether there are gender differences therein. A total of 1257 Dutch individuals reporting weekly cannabis use, including 745 men and 512 women, completed online questionnaires assessing DSM-5 CUD symptoms and additional items on plans to quit or reduce use, cigarette use, and the presence of psychological diagnoses. Gender differences were assessed for all variables and an Ising model estimation method was used to estimate CUD symptom networks in men and women using network comparison tests to assess differences. There were gender differences in the prevalence of 6 of the 11 symptoms, but symptom networks did not differ between men and women. Cigarette use appeared to only be connected to the network through withdrawal, indicating a potential role of cigarette smoking in enhancing cannabis withdrawal symptoms. Furthermore, there were gender differences in the network associations of mood and anxiety disorders with CUD symptoms. The association between smoking and withdrawal as well as gender differences in the role of comorbidities in the CUD network highlight the value of using network models to understand CUD and how symptom interactions might affect treatment.

Beliefs and Perceived Barriers Regarding Psychedelic-assisted Therapy in a Pilot Study of Service Members and Veterans With a History of Traumatic Brain Injury.

Posttraumatic stress disorder (PTSD) and depression are common in service members and veterans, and the response to currently available treatments is often modest at best. Recent studies suggest potential benefit with psychedelic-assisted therapies (PATs), particularly 3,4-methylenedioxymethamphetamine-assisted therapy for PTSD and psilocybin-assisted therapy for depression. This study examined beliefs and perceived barriers regarding PAT among service members and veterans to inform the delivery of these treatments if they are approved by the FDA. Twenty-one service members and veterans (67% male, 81% White, and 43% active duty) with a history of traumatic brain injury and co-occurring cognitive and psychological symptoms completed a measure assessing baseline knowledge and views of PAT, read a brief psychoeducation regarding PAT, and then responded to questions related to their beliefs and perceived barriers to PAT. Before psychoeducation, participants reported a neutral view of psychedelic drugs (M 2.76 range 1-5), PAT (M 3.33), and interest in PAT (M 3.10). After psychoeducation, participants reported a significantly more positive view of psychedelic drugs (M 3.24, P .014) and interest in PAT (M 3.67, P .016). Overall, participants indicated that they would support PAT availability in medical settings if proven beneficial (M 4.52 5 agree strongly) and they would support a loved one engaging in PAT (M 4.29). The most frequently reported health concerns were concern of long-term effects (43%), fear of losing their mind (33%), fear of personality changes (33%), and fear of traumatic brain injury complications (24%). The most frequently endorsed barriers were time commitment, transportation, financial concerns, work, and childcare (33%-19%), with 48% reporting no barriers. This is the first study to explore beliefs and perceived barriers regarding PAT among service members and veterans. These results indicate that military populations may be interested in PAT, particularly if psychoeducation and outreach regarding these treatments occurred. If FDA approved, it will be important to facilitate command support and address logistical barriers to ensure appropriate access within military contexts.

Probing the antidepressant potential of psilocybin integrating insight from human research and animal models towards an understanding of neural circuit mechanisms.

Interest in the therapeutic potential of serotonergic psychedelic compounds including psilocybin has surged in recent years. While human clinical research suggests psilocybin holds promise as a rapid and long-lasting antidepressant, little is known about how its acute mechanisms of action mediate enduring alterations in cognition and behavior. Human neuroimaging studies point to both acute and sustained modulation of functional connectivity in key cortically dependent brain networks. Emerging evidence in preclinical models highlights the importance of psilocybin-induced neuroplasticity and alterations in the prefrontal cortex (PFC). Overviewing research in both humans and preclinical models suggests avenues to increase crosstalk between fields. We review how acute modulation of PFC circuits may contribute to long-term structural and functional alterations to mediate antidepressant effects. We highlight the potential for preclinical circuit and behavioral neuroscience approaches to provide basic mechanistic insight into how psilocybin modulates cognitive and affective neural circuits to support further development of psilocybin as a promising new treatment for depression.

Effects of cannabinoids on resting state functional brain connectivity A systematic review.

Cannabis products are widely used for medical and non-medical reasons worldwide and vary in content of cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Resting state functional connectivity offers a powerful tool to investigate the effects of cannabinoids on the human brain. We systematically reviewed functional neuroimaging evidence of connectivity during acute cannabinoid administration. A pre-registered (PROSPERO ID CRD42020184264) systematic review of 13 studies comprising 318 participants (mean age of 25 years) was conducted and reported using the PRISMA checklist. During THC and THCv exposure vs placebo reduced connectivity with the NAcc was widely reported. Limited evidence shows that such effects are offset by co-administration of CBD. NAcc-frontal region connectivity was associated with intoxication levels. Cannabis intoxication vs placebo was associated with lower striatal-ACC connectivity. CBD and CBDv vs placebo were associated with both higher and lower connectivity between striatal-prefrontalother regions. Overall, cannabis and cannabinoids change functional connectivity in the human brain during resting state as a function of the type of cannabinoid examined.