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The neural basis of psychedelic action.

Psychedelics are serotonin 2A receptor agonists that can lead to profound changes in perception, cognition and mood. In this review, we focus on the basic neurobiology underlying the action of psychedelic drugs. We first discuss chemistry, highlighting the diversity of psychoactive molecules and the principles that govern their potency and pharmacokinetics. We describe the roles of serotonin receptors and their downstream molecular signaling pathways, emphasizing key elements for drug discovery. We consider the impact of psychedelics on neuronal spiking dynamics in several cortical and subcortical regions, along with transcriptional changes and sustained effects on structural plasticity. Finally, we summarize neuroimaging results that pinpoint effects on association cortices and thalamocortical functional connectivity, which inform current theories of psychedelic action. By synthesizing knowledge across the chemical, molecular, neuronal, and network levels, we hope to provide an integrative perspective on the neural mechanisms responsible for the acute and enduring effects of psychedelics on behavior.

Could psychedelic drugs have a role in the treatment of schizophrenia Rationale and strategy for safe implementation.

Schizophrenia is a widespread psychiatric disorder that affects 0.5-1.0% of the worlds population and induces significant, long-term disability that exacts high personal and societal cost. Negative symptoms, which respond poorly to available antipsychotic drugs, are the primary cause of this disability. Association of negative symptoms with cortical atrophy and cell loss is widely reported. Psychedelic drugs are undergoing a significant renaissance in psychiatric disorders with efficacy reported in several conditions including depression, in individuals facing terminal cancer, posttraumatic stress disorder, and addiction. There is considerable evidence from preclinical studies and some support from human studies that psychedelics enhance neuroplasticity. In this Perspective, we consider the possibility that psychedelic drugs could have a role in treating cortical atrophy and cell loss in schizophrenia, and ameliorating the negative symptoms associated with these pathological manifestations. The foremost concern in treating schizophrenia patients with psychedelic drugs is induction or exacerbation of psychosis. We consider several strategies that could be implemented to mitigate the danger of psychotogenic effects and allow treatment of schizophrenia patients with psychedelics to be implemented. These include use of non-hallucinogenic derivatives, which are currently the focus of intense study, implementation of sub-psychedelic or microdosing, harnessing of entourage effects in extracts of psychedelic mushrooms, and blocking 5-HT2A receptor-mediated hallucinogenic effects. Preclinical studies that employ appropriate animal models are a prerequisite and clinical studies will need to be carefully designed on the basis of preclinical and translational data. Careful research in this area could significantly impact the treatment of one of the most severe and socially debilitating psychiatric disorders and open an exciting new frontier in psychopharmacology.

Acid liberalism Silicon Valleys enlightened technocrats, and the legalization of psychedelics.

The history of psychedelia within the New Left counterculture often implies a cultural alignment between psychedelics and progressive values or the promise of radical communitarian social reform. In contrast to these potentials, this paper examines Silicon Valleys engagement with psychedelics, a community which has demonstrated considerable financial and personal interests in these drugs despite promoting and advancing consistently neoliberal ends. This article studies Silicon Valleys culture of psychedelic drug use through extensive analysis of published interviews by tech industrialists, news reports, and recent studies on the tech industrys proliferation of mystical and utopian rhetoric. This work finds that psychedelics and their associated practices are given unconventional mystical meanings by some high-profile tech entrepreneurs, and that these meanings are integrated into belief systems and philosophies which are explicitly anti-democratic, individualist, and essentialist. It is argued that these mystical ideas are supported by a venture capital community which profits from the expression of disruptive utopian beliefs. These beliefs, when held by the extremely wealthy, have effects on legalization policy and the ways which psychedelics are commercialized within a legal marketplace. As Silicon Valley has put considerable resources into funding research and advocacy for psychedelics, I argue that the legalization of psychedelics will likely be operationalized to generate a near-monopoly on the market and promote further inequality in the United States that is reflective of both neoliberalism, and the essentialist beliefs of Silicon Valley functionaries.

A new UHPLC-MSMS method for cannabinoids determination in human plasma A clinical tool for therapeutic drug monitoring.

Cannabinoid derivates have been largely used for different medical purpose. In the literature, several methods capable of separating THC and its principles metabolites are described, although Δ8- and Δ9-THC separation has not been completely achieved. THC metabolism has not been fully understood and metabolites plasma distribution in healthy and pathological patients remains to further deepen. The aim of this study was the validation of UHPLC-MSMS method for the quantification of 10 cannabinoids in human plasma, as important tool for improving clinical efficacy of cannabis administration. Obtained results were in accordance with recommendations of ICH Harmonised Guideline for bioanalytical method validation, showing a good linearity, optimal accuracy as well as satisfactory results in terms of intra-day and inter-day precision and matrix effect. Furthermore, blood sampling study was performed to investigate the better collection method. Optimal separation of Δ-9-tetrahydrocannabinol (Δ9-THC), Δ8-tetrahydrocannabinol (Δ8-THC) was obtained. The present method showed optimal linearity and satisfactory results in terms of specificity and selectivity. Recovery was between 92.0% and 96.5% for all analytes. The matrix-effect showed good performance no carry over was observed. Cannabinoid metabolites present in higher plasma concentrations were 11-Hydroxy-Δ9-tetrahydrocannabinol, 11-Nor-9carboxy-Δ9-tetrahydrocannabinol and THC-COOH-glucuronide. Method performance makes it suitable for routine purposes and a potential tool for therapeutic ranges definition. The present work will be used to test several samples in a long-term clinical study, paving the way for further future works.

Lasting increases in trait mindfulness after psilocybin correlate positively with the mystical-type experience in healthy individuals.

Psilocybin-induced mystical-type experiences are associated with lasting positive psychological outcomes. Recent studies indicate that trait mindfulness is increased 3 months after psilocybin intake, preceded by decreases in neocortical serotonin 2A receptor (5-HT We evaluated whether psilocybin induced lasting increases in trait mindfulness in healthy volunteers, and whether the mystical-type experience was associated with this increase. We further examined the association between pre-drug trait mindfulness and 5-HT Forty-six medium-high dose psilocybin sessions were conducted in 39 healthy individuals. The mystical-type experience was measured with the Mystical Experience Questionnaire (MEQ) at the end of the session. Trait mindfulness was measured using the Mindful Attention and Awareness Scale (MAAS) at baseline and 3 months after the psilocybin session. Thirty-two of the participants completed pre-drug The MAAS score was significantly increased at 3-month follow-up ( We here show that lasting changes in trait mindfulness following psilocybin administration are positively associated with intensity of the mystical-type experience, suggesting that the acute phenomenology of psilocybin facilitates a shift in awareness conducive for mindful living. We furthermore show that higher pre-drug trait mindfulness is associated with reduced 5-HT

Elective surgery for acute pain in patients with substance use disorder lessons learned at a rural neurosurgical center. Patient series.

The incidence of pain-generating degenerative spinal problems in patients who are currently using or have previously used drugs has increased as substance use disorder (SUD) becomes a chronic, lifelong condition. Health system-level data in recent years indicate a significant increase in patients with coexisting SUD and degenerative disc disease, representing an emerging population. A retrospective electronic medical record review identified seven patients with SUD who underwent elective spine surgery by orthopedic or neurosurgical staff from 2012 to 2021. The authors present two of these illustrative cases and a framework that can be used in the treatment of similar patients. Substances used included opioids, benzodiazepines, barbiturates, cocaine, methamphetamines, hallucinogens, lysergic acid diethylamide, phencyclidine, and cannabis. All were abstaining from drug use preoperatively, with four patients in a formal treatment program. Five patients were discharged with an opioid prescription, and two patients deferred opioids. Three experienced a relapse of substance use within 1 year. All patients presented for follow-up, although two required additional contact for follow-up compliance. Perioperative protocols focusing on patient-led care plans, pain control, communication with medication for opioid use disorder providers, family and social support, and specific indicators of possible poor results can contribute to better outcomes for care challenges associated with these diagnoses.

Effects of 2,5-Dimethoxy-4-Methylamphetamine (DOM) and 2-Piperazin-1-yl-Quinoline (Quipazine) on Fentanyl Versus Food Choice in Rhesus Monkeys.

There has been increasing interest in the potential therapeutic effects of drugs with agonist properties at serotonin 2A subtype (5-HT

Default Mode Network Modulation by Psychedelics A Systematic Review.

Psychedelics are a unique class of drug which commonly produce vivid hallucinations as well as profound psychological and mystical experiences. A grouping of interconnected brain regions characterised by increased temporal coherence at rest have been termed the Default Mode Network (DMN). The DMN has been the focus of numerous studies assessing its role in self-referencing, mind wandering and autobiographical memories. Altered connectivity in the DMN has been associated with a range of neuropsychiatric conditions such as depression, anxiety, post-traumatic stress disorder (PTSD), attention deficit hyperactive disorder (ADHD), schizophrenia and obsessive-compulsive disorder (OCD). To date, a number of studies have investigated how psychedelics modulate this network, but no comprehensive review has critically evaluated how major classical psychedelic agents - Lysergic Acid Diethylamide (LSD), psilocybin, and ayahuasca - modulate the DMN. Here we present a systematic review of the knowledge base. Across psychedelics there is consistent acute disruption in resting state connectivity within the DMN and increased functional connectivity between canonical resting-state networks. Various models have been proposed to explain the cognitive mechanisms of psychedelics and in one model DMN modulation is a central axiom. Although the DMN is consistently implicated in psychedelic studies, it is unclear how central the DMN is to the therapeutic potential of classical psychedelic agents. This article aims to provide the field with a comprehensive overview that can propel future research forward in such a way that the neurocognitive mechanisms of psychedelics can be further elucidated.

Molecular determinants of tetrahydrocannabinol binding to the glycine receptor.

The recognition of Cannabis as a source of new compounds suitable for medical use has attracted strong interest from the scientific community in its research, and substantial progress has accumulated regarding cannabinoids activity however, a thorough description of their molecular mechanisms of action remains a task to complete. Highlighting their complex pharmacology, the list of cannabinoids interactors has vastly expanded beyond the canonical cannabinoid receptors. Among those, we have focused our study on the glycine receptor (GlyR), an ion channel involved in the modulation of nervous system responses, including, to our interest, sensitivity to peripheral pain. Here, we report the use of computational methods to investigate possible binding modes between the GlyR and Δ

Effective Connectivity of Functionally Anticorrelated Networks Under Lysergic Acid Diethylamide.

Classic psychedelic-induced ego dissolution involves a shift in the sense of self and a blurring of the boundary between the self and the world. A similar phenomenon is identified in psychopathology and is associated with the balance of anticorrelated activity between the default mode network, which directs attention inward, and the salience network, which recruits the dorsal attention network to direct attention outward. To test whether changes in anticorrelated networks underlie the peak effects of lysergic acid diethylamide (LSD), we applied dynamic causal modeling to infer effective connectivity of resting-state functional magnetic resonance imaging scans from a study of 25 healthy adults who were administered 100 μg of LSD or placebo. We found that inhibitory effective connectivity from the salience network to the default mode network became excitatory, and inhibitory effective connectivity from the default mode network to the dorsal attention network decreased under the peak effect of LSD. The effective connectivity changes we identified may reflect diminution of the functional anticorrelation between resting-state networks that may be a key neural mechanism of LSD and underlie ego dissolution. Our findings suggest that changes to the sense of self and subject-object boundaries across different states of consciousness may depend upon the organized balance of effective connectivity of resting-state networks.

Perceptions about THC and CBD effects among adults with and without prior cannabis experience.

Cannabis is associated with a range of therapeutic and non-therapeutic, positive and negative effects. While some benefits and harms may be specific to individual cannabinoid constituents (THC, CBD), individual expectancies may also play a role. Evaluate the extent to which individuals hold expectancies about the effects of CBD, THC, and THC CBD combined, and whether this differs with prior cannabis experience. Canadian adults (N 345 n 58 no prior cannabis use, n 287 prior cannabis use) completed a Qualtrics survey. Participants provided information regarding their expectancies about the effects of cannabinoids (THC, CBD, THC CBD combined) via a 15-item questionnaire, which included various therapeutic (e.g., helps with pain) and non-therapeutic positive (e.g., enhances positive feelings) and negative (e.g., risk for addiction) effects. They recorded their perceptions about the effects of each cannabinoid on a scale (0definitely not true, 10definitely true). Data was analyzed using linear mixed models. For most therapeutic effects, CBD-containing products (CBD, THC CBD) were rated higher than THC. For most positive and negative non-therapeutic effects, THC-containing products (THC, THC CBD) were rated higher than CBD. Those with prior cannabis use (vs no prior use) rated all cannabinoids higher regarding their association with many therapeutic and positive effects, while endorsing weaker expectancies about their role in some negative effects. Adults endorsed stronger expectancies that CBD-containing products are responsible for producing a rage of therapeutic effects. Those with prior cannabis use experience tended to emphasize the benefits and minimize potential harmful effects of cannabinoids.

Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression.

Post-traumatic stress disorder (PTSD) can develop following severe trauma, but the extent to which genetic and environmental risk factors contribute to individual clinical outcomes is unknown. Here, we compared transcriptional responses to hydrocortisone exposure in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and peripheral blood mononuclear cells (PBMCs) from combat veterans with PTSD (n 19 hiPSC and n 20 PBMC donors) and controls (n 20 hiPSC and n 20 PBMC donors). In neurons only, we observed diagnosis-specific glucocorticoid-induced changes in gene expression corresponding with PTSD-specific transcriptomic patterns found in human postmortem brains. We observed glucocorticoid hypersensitivity in PTSD neurons, and identified genes that contribute to this PTSD-dependent glucocorticoid response. We find evidence of a coregulated network of transcription factors that mediates glucocorticoid hyper-responsivity in PTSD. These findings suggest that induced neurons represent a platform for examining the molecular mechanisms underlying PTSD, identifying biomarkers of stress response, and conducting drug screening to identify new therapeutics.

Lysergic Acid Diethylamide-Assisted Therapy in Patients With Anxiety With and Without a Life-Threatening Illness A Randomized, Double-Blind, Placebo-Controlled Phase II Study.

This study aimed to investigate the efficacy and safety of lysergic acid diethylamide (LSD)-assisted therapy in patients who experienced anxiety with or without association with a life-threatening illness. The study is an investigator-initiated 2-center trial that used a double-blind, placebo-controlled, 2-period, random-order, crossover design with 2 sessions with either oral LSD (200 μg) or placebo per period. The primary end point was anxiety symptoms 16 weeks after the last treatment session, assessed by the Spielberger State-Trait Anxiety Inventory-Global score in 42 patients. Further outcome measures included ratings for depression symptoms (Beck Depression Inventory and Hamilton Depression Rating Scale, 21-item version) and ratings for acute subjective drug effects. The outcomes for the first period (between-subjects analysis) are primarily shown due to carryover effects. LSD treatment resulted in significant reductions of State-Trait Anxiety Inventory-Global scores up to 16 weeks after treatment (least-square mean standard error change from baseline difference -16.2 5.8, 95% CI, -27.8 to -4.5, d -1.18, p .007). Similar effects were observed for ratings of comorbid depression on the Hamilton Depression Rating Scale, 21-item version (-7.0 1.9, 95% CI, -10.8 to -3.2, d -1.1, p .0004) and the Beck Depression Inventory (-6.1 2.6, 95% CI, -11.4 to -0.9, d -0.72, p .02). Positive acute subjective drug effects and mystical-type experiences correlated with the long-term reductions in anxiety symptoms. Transient, mild, acute untoward effects of LSD treatment were reported by 8 patients (19%). One treatment-related serious adverse event (acute transient anxiety) occurred (2%). LSD produced long-lasting and notable reductions in anxiety and comorbid depression symptoms up to 16 weeks.

Therapeutic (Sub)stance Current practice and therapeutic conduct in preparatory sessions in substance-assisted psychotherapy-A systematized review.

Clinical trials are currently investigating the potential of substance-assisted psychotherapy (SAPT) as treatment for several psychiatric conditions. The potential therapeutic effects of SAPT may be influenced by contextual factors including preparation prior to and integration after the substance-assisted therapy sessions. This systematized review outlines recommendations for current practice in preparatory sessions in SAPT including safety measures and screening procedures, preparation of set and setting, session contents, methods, and roles, prerequisites, and appropriate conduct of therapists. A systematized review of the literature was conducted based on PRISMA guidelines. MEDLINE (OVID), PsycINFO (OVID), and Cochrane Library were searched and clinical trials, treatment manuals, study protocols, case studies, qualitative studies, descriptive studies, theoretical papers, reviews, book chapters, and conference proceedings published until February 1, 2022 were retrieved. The final synthesis included It is concluded that there is a consensus in the literature about the importance of adequate preparation before the administration of psychoactive substances in SAPT. However, the extent and approaches for these sessions vary across different models and there is a need for timelier and more rigorous qualitative and quantitative investigations assessing different approaches and techniques for the optimal preparation of clients in SAPT.

Psychedelic medicine at a crossroads Advancing an integrative approach to research and practice.

Psychedelics have been already used by human societies for more than 3000 years, mostly in religious and healing context. The renewed interest in the potential application of psychedelic compounds as novel therapeutics has led to promising preliminary evidence of clinical benefit in some psychiatric disorders. Despite these promising results, the potential for large-scale clinical application of these profoundly consciousness-altering substances, in isolation from the sociocultural contexts in which they were traditionally used, raises important concerns. These concerns stem from the recognition that the mechanisms of therapeutic action of psychedelics are not entirely dependent on neurobiology, but also on the psychological, social and spiritual processes for their efficacy. For these reasons, physicians or psychotherapists involved in psychedelic-assisted psychotherapy need training in ways to accompany patients through this experience to promote positive outcomes and address potential side effects. Psychedelic therapies may foster the emergence of a novel paradigm in psychiatry that integrates psychopharmacological, psychotherapeutic, and cultural interventions for patients with mental health issues.

Culture, context, and ethics in the therapeutic use of hallucinogens Psychedelics as active super-placebos

Following decades of prohibition and widespread concern about their mind-altering properties, there is increasing public, scholarly, and clinical interest in the therapeutic potential of psychedelic substances. Serotonergic substances in particular (DMT, psilocybin, and LSD) are now being tested as treatments for such ailments as depression, anxiety, and substance use disorder. This thematic issue of

IbogaineNoribogaine in the Treatment of Substance Use Disorders a Systematic Review of the Current Literature.

Ibogaine and noribogaine are psychedelic substances with dissociative properties naturally occurring in plants of the Apocynaceae family. Research has shown their efficacy in treating substance use disorders (SUD), particularly in opiate detoxification, but their efficacy and toxicity are still unclear. This review aims to assess the anti-addictive role of ibogaine and evaluate its side effects. Abstract Methods A systematic literature review was conducted on the 29th of November 2021 using PubMed, Scopus and Web of Science databases through the following search strategy (Ibogaine OR Noribogaine) AND (SUD OR substance use disorder OR craving OR abstinence OR withdrawal OR addiction OR detoxification) NOT animal NOT review NOT vitro. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was followed for data gathering purposes. Research methods were registered on PROSPERO (CRD42021287034). Thirty-one articles were selected for the systematic revision, and two were considered for analysis. The results were organised according to the type of study case reports case series, randomised-controlled trials (RCTs), open-label, survey and observational studies. The main outcomes were related to the anti-addictive effect of ibogaine and its cardiac toxicity. A meta-analysis of side effects was conducted using RevMan 5.4 software, showing a significant risk of developing headaches after ibogainenoribogaine treatment. The results show some efficacy of ibogaine in the treatment of SUDs, but its cardiotoxicity and mortality are worrying. Further studies are needed to assess its therapeutic efficacy and actual safety.

3,4-Methylenedioxy methamphetamine, synthetic cathinones and psychedelics From recreational to novel psychotherapeutic drugs.

The utility of classical drugs used to treat psychiatric disorders (e.g., antidepressants, anxiolytics) is often limited by issues of lack of efficacy, delayed onset of action or side effects. Psychoactive substances have a long history of being used as tools to alter consciousness and as a gateway to approach the unknown and the divinities. These substances were initially obtained from plants and animals and more recently by chemical synthesis, and its consumption evolved toward a more recreational use, leading to drug abuse-related disorders, trafficking, and subsequent banning by the authorities. However, these substances, by modulation of certain neurochemical pathways, have been proven to have a beneficial effect on some psychiatric disorders. This evidence obtained under medically controlled conditions and often associated with psychotherapy, makes these substances an alternative to conventional medicines, to which in many cases the patient does not respond properly. Such disorders include post-traumatic stress disease and treatment-resistant depression, for which classical drugs such as MDMA, ketamine, psilocybin and LSD, among others, have already been clinically tested, reporting successful outcomes. The irruption of new psychoactive substances (NPS), especially during the last decade and despite their recreational and illicit uses, has enlarged the library of substances with potential utility on these disorders. In fact, many of them were synthetized with therapeutic purposes and were withdrawn for concrete reasons (e.g., adverse effects, improper pharmacological profile). In this review we focus on the basis, existing evidence and possible use of synthetic cathinones and psychedelics (specially tryptamines) for the treatment of mental illnesses and the properties that should be found in NPS to obtain new therapeutic compounds.

The safety and efficacy of low oral doses of cannabidiol An evaluation of the evidence.

Global interest in the non-intoxicating cannabis constituent, cannabidiol (CBD), is increasing with claims of therapeutic effects across a diversity of health conditions. At present, there is sufficient clinical trial evidence to support the use of high oral doses of CBD (e.g., 10-50 mgkg) in treating intractable childhood epilepsies. However, a question remains as to whether low-dose CBD products confer any therapeutic benefits. This is an important question to answer, as low-dose CBD products are widely available in many countries, often as nutraceutical formulations. The present review therefore evaluated the efficacy and safety of low oral doses of CBD. The review includes interventional studies that measured the clinical efficacy in any health condition andor safety and tolerability of oral CBD dosed at less than or equal to 400 mg per day in adult populations (i.e., ≥18 years of age). Studies were excluded if the product administered had a Δ

The Use of Psychedelics in the Treatment of Medical Conditions An Analysis of Currently Registered Psychedelics Studies in the American Drug Trial Registry.

Although early therapeutic research on psychedelics dates back to the 1940s, this field of investigation was met with many cultural and legal challenges in the 1970s. Over the past two decades, clinical trials using psychedelics have resumed. Therefore, the goal of this study was to (1) better characterize the recent uptrend in psychedelics in clinical trials and (2) identify areas where potentially new clinical trials could be initiated to help in the treatment of widely prevalent medical disorders. A systematic search was conducted on the clinicaltrials.gov database for all registered clinical trials examining the use of psychedelic drugs and was both qualitatively and quantitatively assessed. Analysis of recent studies registered in clinicaltrials.gov was performed using Pearsons correlation coefficient testing. Statistical analysis and visualization were performed using R software. In totality, 105 clinical trials met this studys inclusion criteria. The recent uptrend in registered clinical trials studying psychedelics (p 0.002) was similar to the uptrend in total registered clinical trials in the registry (p < 0.001). All trials took place from 2007 to 2020, with 77.1% of studies starting in 2017 or later. A majority of clinical trials were in phase 1 (53.3%) or phase 2 (25.7%). Common disorders treated include substance addiction, post-traumatic stress disorder, and major depressive disorder. Potential research gaps include studying psychedelics as a potential option for symptomatic treatment during opioid tapering. There appears to be a recent uptrend in registered clinical trials studying psychedelics, which is similar to the recent increase in overall trials registered. Potentially, more studies could be performed to evaluate the potential of psychedelics for symptomatic treatment during opioid tapering and depression refractory to selective serotonin reuptake inhibitors.

Supercritical fluids in analysis of cannabinoids in various Cannabis products.

We developed a fast, selective, and sensitive method for the determination of various neutral and acidic phytocannabinoids with an emphasis on the separation of structurally related compounds. Optimized ultra-high performance supercritical fluid chromatography (UHPSFC) allowed the separation of 2 groups of structural isomers, including isomers of mz 357 cannabidiolic and Δ

A rapid Dilute-and-Shoot LC-MSMS method for quantifying THC-COOH and THC-COO(Gluc) in urine.

Cannabis remains one of the most commonly used psychotropes. Cannabis use is frequently evaluated via the testing of suspected patient samples. Thus, there is a high demand for simple, accurate and fast assays to support the increasing needs for testing. This report highlights a reliable, simple and fast liquid chromatography - tandem mass spectrometry assay that quantifies the cannabis metabolites THC-COOH and THC-COO(Gluc) in human urine. The assay employs a direct dilute-and-shoot approach, whereby urine samples are diluted 10X before being directly injected on the liquid chromatography and mass spectrometer. The assay quantification is based on an internal calibration approach that used deuterated analogues for THC-COOH and THC-COO(Gluc) as internal standards. The assays analysis time was 5 min. The quantification was valid over a wide linear range (25 - 8,000 ngmL) for both analytes and was free of matrix interferences. The within-day and between-day precision was determined to be ≤ 15 % CV for both analytes. The assay was validated based on the College of American Pathologists (CAP) and Clinical Laboratory Standards Institute (CLSI) guidelines.

Adolescent nicotine potentiates the inhibitory effect of raclopride, a D

The association between schizophrenia and nicotine addiction becomes evident during adolescence. Here, to investigate interactive events that might underlie the early establishment of this comorbidity, we used phencyclidine-evoked locomotor sensitization, a proxy model of psychotic behavior, and nicotine minipump infusions in adolescent mice. Considering the involvement of dopamine D

Mescaline The forgotten psychedelic.

Mescaline (3,4,5-trimethoxyphenethylamine) is one of the oldest hallucinogens, with evidence of use dating back 5700 years. Mescaline is a naturally occurring alkaloid found in cacti, mainly in the peyote cactus (Lophophora williamsii) and in the cacti of the Echinopsis genus. Since the prohibition of psychoactive substances in the early 70s, research on mescaline and other classical psychedelics has been limited. This article aims to review the pharmacology and behavioural effects of mescaline, focusing on preclinical and clinical research. Mescaline is a serotonin 5HT2A2C receptor agonist, with its main hallucinogenic effects being mediated via its 5HT2A receptor agonist action. It also exerts effects via agonist binding at α1A2A noradrenaline and D123 dopamine receptors. Overall, mescaline has anxiolytic-like effects in animals and increases prosocial behaviour, locomotion, and response reactivity. In humans, mescaline can induce euphoria, hallucinations, improvements in well-being and mental health conditions, and psychotomimetic effects in a naturalistic or religious setting. The pharmacological mechanisms of mescaline are similar to those of other classical psychedelics, like psilocybin and lysergic acid diethylamide (LSD). Mescaline appears to be safe to consume, with most intoxications being mild and easily treatable. Improvement in mental well-being and its ability to overcome alcoholism render mescaline potentially beneficial in clinical settings. This article is part of the Special Issue on Psilocybin Research.

The inverse association of state cannabis vaping prevalence with the e-cigarette or vaping product-use associated lung injury.

The e-cigarette or vaping product-use-associated lung injury (EVALI) epidemic was primarily associated with the use of e-cigarettes containing tetrahydrocannabinol (THC)- the principal psychoactive substance in cannabis, and vitamin-E-acetate- an additive sometimes used in informally sourced THC-containing e-liquids. EVALI case burden varied across states, but it is unclear whether this was associated with state-level cannabis vaping prevalence. We, therefore, used linear regression models to assess the cross-sectional association between state-level cannabis vaping prevalence (obtained from the 2019 behavioral Risk Factor Surveillance System) and EVALI case burden (obtained from the Centers for Disease Control and Prevention) adjusted for state cannabis policies. Cannabis vaping prevalence ranged from 1.14%(95%CI, 0.61%-2.12%) in Wyoming to 3.11%(95%CI, 2.16%-4.44%) in New Hampshire. EVALI cases per million population ranged from 1.90(0.38-3.42) in Oklahoma to 59.10(19.70-96.53) in North Dakota. There was no significant positive association but an inverse association between state cannabis vaping prevalence and EVALI case burden (Coefficient, -18.6 95%CI, -37.5-0.4 p-value, 0.05). Thus, state-level cannabis vaping prevalence was not positively associated with EVALI prevalence, suggesting that there may not be a simple direct link between state cannabis vaping prevalence and EVALI cases, but rather the relationship is likely more nuanced and possibly reflective of access to informal sources of THC-containing e-cigarettes.

Generalized Simultaneous Localization and Mapping (G-SLAM) as unification framework for natural and artificial intelligences towards reverse engineering the hippocampalentorhinal system and principles of high-level cognition.

Simultaneous localization and mapping (SLAM) represents a fundamental problem for autonomous embodied systems, for which the hippocampalentorhinal system (HE-S) has been optimized over the course of evolution. We have developed a biologically-inspired SLAM architecture based on latent variable generative modeling within the Free Energy Principle and Active Inference (FEP-AI) framework, which affords flexible navigation and planning in mobile robots. We have primarily focused on attempting to reverse engineer HE-S design properties, but here we consider ways in which SLAM principles from robotics may help us better understand nervous systems and emergent minds. After reviewing LatentSLAM and notable features of this control architecture, we consider how the HE-S may realize these functional properties not only for physical navigation, but also with respect to high-level cognition understood as generalized simultaneous localization and mapping (G-SLAM). We focus on loop-closure, graph-relaxation, and node duplication as particularly impactful architectural features, suggesting these computational phenomena may contribute to understanding cognitive insight (as proto-causal-inference), accommodation (as integration into existing schemas), and assimilation (as category formation). All these operations can similarly be describable in terms of structurecategory learning on multiple levels of abstraction. However, here we adopt an ecological rationality perspective, framing HE-S functions as orchestrating SLAM processes within both concrete and abstract hypothesis spaces. In this navigationsearch process, adaptive cognitive equilibration between assimilation and accommodation involves balancing tradeoffs between exploration and exploitation this dynamic equilibrium may be near optimally realized in FEP-AI, wherein control systems governed by expected free energy objective functions naturally balance model simplicity and accuracy. With respect to structure learning, such a balance would involve constructing models and categories that are neither too inclusive nor exclusive. We propose these (generalized) SLAM phenomena may represent some of the most impactful sources of variation in cognition both within and between individuals, suggesting that modulators of HE-S functioning may potentially illuminate their adaptive significances as fundamental cybernetic control parameters. Finally, we discuss how understanding HE-S contributions to G-SLAM may provide a unifying framework for high-level cognition and its potential realization in artificial intelligences.

N,N-Diformylmescaline A novel analogue of mescaline detected in Queensland.

N,N-Diformylmescaline, a novel analogue of mescaline, has recently been detected in Australia in two unrelated seizures. To confirm the identification, a three-step synthesis from 3,4,5-trimethoxyphenylacetic acid was devised. However, purification of the final product proved problematic with the compound prone to degradation in solution. Analysis of the compound by LC-MS indicated that the compound was unstable under acidic and basic conditions, breaking down to N-formylmescaline. Further degradation to mescaline was observed when the compound was dissolved in hydrochloric acid for an extended period of time suggesting that N,N-diformylmescaline may be a prodrug for mescaline. The GC-MS, NMR and FTIR data for the seized compound are presented along with details of the synthesis and studies of the compounds stability in solution.

Changes in alcohol beliefs mediate the effects of a school-based prevention program on alcohol use among Brazilian adolescents.

To investigate the mechanisms of the Tamojunto2.0 program that mediated the prevention of lifetime alcohol and drug use, including drug knowledge, behavioral beliefs, attitudes, decision-making skills, and refusal skills. A cluster-randomized controlled trial was conducted in 73 public middle schools in three Brazilian cities. The sample included 5208 students (49.4 % girls M Outcomes in the whole sample and among non-users showed that Tamojunto2.0 indirectly prevented lifetime alcohol use and binge drinking by increasing negative and non-positive alcohol beliefs. Only the direct effect on decreasing lifetime alcohol consumption was statistically significant. However, an indirect increase in binge drinking was observed through knowledge about alcohol, but the direct effect was not statistically significant. No effects were reported for marijuana, tobacco, or inhalants. Among users, no statistically significant effects were found for alcohol or drug use. The results suggest that the Tamojunto2.0 program was only effective in delaying alcohol consumption via increasing negative and non-positive alcohol beliefs. It seems that mediating mechanisms vary depending on contextual characteristics, differences in socializing among adolescents, features of the educational systems, psychosocial conditions, or, fidelity issues of program implementation.

Effects of super-class cannabis terpenes beta-caryophyllene and alpha-pinene on zebrafish behavioural biomarkers.

Terpenes possess a wide range of medicinal properties and are potential therapeutics for a variety of pathological conditions. This study investigated the acute effects of two cannabis terpenes, β-caryophyllene and α-pinene, on zebrafish locomotion, anxiety-like, and boldness behaviour using the open field exploration and novel object approach tests. β-caryophyllene was administered in 0.02%, 0.2%, 2.0%, and 4% doses. α-pinene was administered in 0.01%, 0.02%, and 0.1% doses. As α-pinene is a racemic compound, we also tested its () and (-) enantiomers to observe any differential effects. β-caryophyllene had only a sedative effect at the highest dose tested. α-pinene had differing dose-dependent effects on anxiety-like and motor variables. Specifically, ()-α-pinene and (-)-α-pinene had significant effects on anxiety measures, time spent in the thigmotaxis (outer) or center zone, in the open field test, as well as locomotor variables, swimming velocity and immobility. ( -)-α-pinene showed only a small effect on the open field test on immobility at the 0.1% dose. This study demonstrates that α-pinene can have a sedative or anxiolytic effect in zebrafish and may have different medicinal properties when isolated into its () or (-) enantiomers.

Psilocybin-assisted therapy for reducing alcohol intake in patients with alcohol use disorder protocol for a randomised, double-blinded, placebo-controlled 12-week clinical trial (The QUANTUM Trip Trial).

Alcohol use disorder is a difficult-to-treat psychiatric disorder and a major burden on public health. Existing treatment efficacy is moderate, and relapse rates are high. Preliminary findings suggest that psilocybin, a psychedelic compound, can safely and reliably occasion highly meaningful experiences that may spur a positive change in drinking behaviour when administered in a therapeutic context. However, the efficacy of a single psilocybin administration and its potential neurobiological underpinnings still remain unknown. To establish efficacy, we will investigate the effects of psilocybin-assisted therapy versus placebo in a randomised, double-blinded, placebo-controlled 12-week clinical trial. Ninety treatment-seeking patients, aged 20-70 years, diagnosed with alcohol use disorder will be recruited from the community via advertisement and referrals from general practitioners or specialised treatment units. The psilocybin or placebo will be administered in accordance with a protocol for psychological support before, during and after the dosing. Outcome assessments will be carried out 1, 4, 8 and 12 weeks postdosing. The primary outcome is reduction in the percentage of heavy drinking days from baseline to follow-up at 12 weeks. Key secondary outcomes are as follows (1) total alcohol consumption, (2) phosphatidyl-ethanol, an objective biomarker for alcohol, (3) plasma psilocin, the active metabolite, to establish a possible therapeutic range, (4) the acute subjective drug experience as a possible predictor of treatment outcome and (5) neuronal response to alcohol cues and cognitive flexibility within corticostriatal pathways by use of functional MR brain imaging 1-week postdosing. Ethical approval has been obtained from the Committee on Health Research Ethics of the Capital Region of Denmark (H-20043832). All patients will be provided oral and written information about the trial before screening. The study results will be disseminated by peer-review publications and conference presentations. EudraCT 2020-000829-55 and NCT05416229.

Cannabidiol inhibits microglia activation and mitigates neuronal damage induced by kainate in an in-vitro seizure model.

Epilepsy is one of the most common brain disorder and, despite the possible use of several therapeutic options, many patients continue to have seizures for their entire lifespan and they need new therapeutic approaches. In the last years the interest on the non-psychoactive compounds present in Cannabis sativa has massively increased, and cannabidiol (CBD) has been shown to be effective in the treatment of different types of neurological disorders and neurodegenerative diseases such as epilepsy, ischemia, multiple sclerosis and Alzheimers Disease. We investigated the effects of the selected cannabinoids, Δ9-tetrahydrocannabinol (THC), CBD and cannabigerol (CBG) in rat organotypic hippocampal slices exposed to kainate, an in vitro seizure model. Cell death in the cornu Ammonis 3 (CA3) hippocampal subregion was quantified by propidium iodide fluorescence. Morphological analysis and tissue organization were examined by immunohistochemistry and confocal microscopy and microglia activation and polarization was evaluated using flow cytometry and morphology analysis. When present in the incubation medium, cannabidiol reduced dose-dependent CA3 injury induced by kainate. Conversely, incubation with THC exacerbated hippocampal damage. The neuroprotective effects of cannabidiol were blocked by TRPV1, TRPV2, 5-HT1A, and PPARγ antagonists. Confocal microscopy confirmed that CBD but not THC had a significant protective effect against neuronal damage and tissue disorganization caused by kainate. Cannabidiol incubation significantly block the microglia activation from the M0 to M1 phenotype observed in the kainate in-vitro seizure model, pushing toward a transition from M0 to M2. Our results suggest that CBD mitigated neuronal damage induced by kainate and blocked the transition from the M0 to the M1 phenotype.

Pilot clinical and pharmacokinetic study of Δ9-Tetrahydrocannabinol (THC)Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain.

This pilot study aimed to assess the safety, tolerability, pharmacokinetics and exploratory analgesic effect of a novel water-soluble oro-buccal nanoparticle spray of a cannabis-based medicine (MDCNS-01) in patients with advanced incurable malignancy with unrelieved pain from opioid analgesic. The study was a non-blinded single arm 2 stage study. Stage I was a single escalating dose (n 5) 2.5 mg Δ9-THC and 2.5 mg CBD) versus a 3-fold escalated dose. Stage II was an up-titrated dose in patients with advanced cancers and intractable pain (n 25). During Stage I with an increased cannabis-based medicine dose, maximum observed plasma concentrations of cannabinoids were dose dependant. The water-soluble formulation in the current study resulted in a higher median (min, max) systemic exposure of Δ9-THC than CBD (AUC from 2.5 mg each of Δ9-THC and CBD, was 1.71 ng mL.h-1 (1.1, 6.6) and 0.65 ng mL.h-1 (0.49, 4.1), respectively). During stage II a subgroup of patients diagnosed with breast and prostate cancers with bone metastases, had the highest mean pain score improvement from baseline of 40% (unadjusted) and 33% (adjusted for rescue medication use). For all patients the most reported adverse events were mild or moderate drowsiness affecting 11 (44%) and 4 (6%) patients, respectively, and nausea and vomiting that affected 18 (72%) patients. The water-soluble cannabis-based medicine provided acceptable bioavailability for Δ9-THCCBD, appeared safe and tolerable in advanced incurable cancers with uncontrolled pain with preliminary evidence of analgesic efficacy.

Anti-inflammatory potential of delta-9-tetrahydrocannabinol in hyperinsulinemia an experimental study.

Hyperinsulinemia (HI) means that the amount of insulin in the blood is higher than normal and is often associated with type 2 diabetes. It is known that delta-9-tetrahydrocannabinol (THC) obtained from a medicinal plant, Cannabis sativa, has therapeutic effects on many diseases. This study aimed to investigate the effects of THC on inflammatory and oxidant status in rat pancreas with HI. Rats were divided into groups Control, HI, THC and HI THC. Each group consists of 8 animals. HI and HI THC groups were given 10% fructose in the drinking water for 12 weeks. In the last four weeks of the experiment, 1.5 mg kg Levels of IL-6, NF-κβ, and TNF-α mRNA expression were higher in the pancreas with HI than in the control (p < 0.001 for all). THC treatment reduced the expression of IL-6, NF-κβ, and TNF-α mRNAs in the HI THC group compared to the HI group (p < 0.001 for all). TOC increased in the HI group compared to the control group (p < 0.001). However, THC treatment reduced TOC levels in the HI THC group compared to the HI group (p < 0.001). According to the results, the THC treatment may regulate inflammation and TOC in rats with hyperinsulinemia. Thus, we can say that THC may have anti-inflammatory and antioxidant potential in metabolic disorders.

Use of psychedelics in the Czech Republic results of recent population surveys.

Different psychoactive substances are widely used in todays society. So far limited data are available on the use of psychedelics in the general population. The main aim of this study is to estimate the numbers of users of substances with psychedelic properties (classical psychedelics, cannabis, ecstasy, and ketamine) in the Czech Republic. Data from two samples enrolled in representative cross-sectional questionnaire surveys in the Czech adult population in 2016 (n 2,785) and 2018 (n 1,665) were analysed. Prevalence rates were extrapolated to estimate numbers of current, i.e., last-year, users of psychedelics, and their socio-demographic profiles were compared with non-users and users of cannabis. An estimated 5-6% of the Czech adult population (350-430 thousand people) used classical psychedelics (LSD, psilocybin mushrooms, ayahuasca) in their lifetime, increasing up to 28-30% when cannabis is included (1.9-2.1 million users). Current use of classical psychedelics reached 0.7-1.9% (50-130 thousand people), and 9-11% (590-750 thousand users) when cannabis was included. Users of psychedelics were more often males, of younger age and single. No significant socio-demographic differences were found between users of classical psychedelics and recreational cannabis users, however, differences were significant when compared to non-users and users of other illicit drugs. Findings should further serve to inform drug policy and social and healthcare systems in respect to the use of psychedelics.

Facing death, returning to life A qualitative analysis of MDMA-assisted therapy for anxiety associated with life-threatening illness.

Anxiety associated with life-threatening illness (LTI) is a pervasive mental health issue with a wide impact. A spectrum of traditional pharmacotherapies and psychotherapies are available, but offer varying success in reducing symptoms and improving quality of life. We explore a novel therapy for this condition by assessing prominent thematic elements from participant narrative accounts of a pilot phase 2 clinical trial of 3,4 Methylenedioxymethamphetamine-Assisted Therapy (MDMA-AT) for treating anxiety associated with LTI. Semi-structured qualitative interviews were conducted with a subset of adult participants 3 months following completion of this trial. This qualitative analysis sought to complement, clarify, and expand upon the quantitative findings obtained from the clinical trial to further understand the process and outcomes of the treatment. Interviews were coded and analyzed using an Interpretative Phenomenological Analysis (IPA) methodological framework. Participants described in detail their experiences from before, during and after the trial, which were analyzed and categorized into thematic clusters. Specifically, participants explored what they felt were important elements of the therapeutic process including processing trauma and grief, exploring mystical and existential experiences, engaging with the present moment with reduced physiological activation, and facing illness and existential fears. Outcomes of the treatment included increased ability to cope with LTI, reduced psychological symptoms, improved vitality and quality of life, and feeling more resourced. Participant narratives also showed a reconnection to life and greater emotional resilience in response to trauma and medical relapse. These findings are compared to similar treatments for the same indication. Limitations and challenges encountered in conducting this study are discussed along with implications for theory and clinical treatment.

Synthesis, Molecular Docking Study, and Cytotoxicity Evaluation of Some Novel 1,3,4-Thiadiazole as Well as 1,3-Thiazole Derivatives Bearing a Pyridine Moiety.

Pyridine, 1,3,4-thiadiazole, and 1,3-thiazole derivatives have various biological activities, such as antimicrobial, analgesic, anticonvulsant, and antitubercular, as well as other anticipated biological properties, including anticancer activity. The starting 1-(3-cyano-4,6-dimethyl-2-oxopyridin-1(2

Esketamine and Psilocybin-The Comparison of Two Mind-Altering Agents in Depression Treatment Systematic Review.

This publication discusses two compounds belonging to the psychoactive substances group which are studied in the context of depression treatment-psilocybin and esketamine. The former is a naturally occurring psychedelic. The latter was invented in the laboratory exactly 60 years ago. Although the substances were controversial in the past, recent studies indicate the potential of those substances as novel antidepressant agents. The PubMedMEDLINE database was used to identify articles for systematic review, using the following search terms (depression) AND (psilocybin) OR (ketamine). From 617 items, only 12 articles were obtained in the final analyses. Three articles were devoted to psilocybin in depression treatment and nine to esketamine. In most studies, esketamine showed a significant reduction in both depressive symptoms and suicidal ideation shortly after intake and after a month of treatment compared to baseline and to standard-of-care antidepressant agents. Psilocybins antidepressive effects occurred one day after intake and after 6-7 weeks of treatment and were maintained for up to 6 or 8 months of follow-up. One study indicated that psilocybins effects are comparable with and may be superior to escitalopram treatment. Both esketamine and psilocybin demonstrated rapid and long-term effects in reducing depression symptoms and, after overcoming some limitations, may be considered as novel antidepressant agents in future.

The Cytotoxic Effect of Isolated Cannabinoid Extracts on Polypoid Colorectal Tissue.

Purified cannabinoids have been shown to prevent proliferation and induce apoptosis in colorectal carcinoma cell lines. To assess the cytotoxic effect of cannabinoid extracts and purified cannabinoids on both colorectal polyps and normal colonic cells, as well as their synergistic interaction. Various blends were tested to identify the optimal synergistic effect. Methods Biopsies from polyps and healthy colonic tissue were obtained from 22 patients undergoing colonic polypectomies. The toxicity of a variety of cannabinoid extracts and purified cannabinoids at different concentrations was evaluated. The synergistic effect of cannabinoids was calculated based on the cells survival. Isolated cannabinoids illustrated different toxic effects on the viability of cells derived from colorectal polyps. THC-d8 and THC-d9 were the most toxic and exhibited persistent toxicity in all the polyps tested. CBD was more toxic to polypoid cells in comparison to normal colonic cells at a concentration of 15 µM. The combinations of the cannabinoids CBDV, THCV, CBDVA, CBCA, and CBGA exhibited a synergistic inhibitory effect on the viability of cells derived from colon polyps of patients. Isolated cannabinoid compounds interacted synergistically against colonic polyps, and some also possessed a differential toxic effect on polyp and adjacent colonic tissue, suggesting possible future therapeutic value.

Substance Use and Mental Health during the First COVID-19 Lockdown in Germany Results of a Cross-Sectional Survey.

The measures taken to contain the COVID-19 pandemic have led to significant changes in peoples daily lives. This paper examines changes in substance use during the first lockdown (March-July 2020) and investigates mental health burdens in substance users with increased consumption of alcohol, nicotine or tetrahydrocannabinol (THC) in Germany compared to users with unchanged or reduced consumption. In a cross-sectional online survey, 2369 people were asked about their mental health and their substance use during the first lockdown in Germany. Of the participants, 28.5% increased their alcohol use, 28.8% their use of tobacco products, and 20.6% their use of THC-containing products during the pandemic. The groups with increased alcohol, nicotine, and THC use during the first lockdown reported more depressive symptoms and anxiety. Individuals who reported increased consumption of alcohol or nicotine were also more likely to experience loneliness and have suicidal thoughts and were more often stressed due to social distancing. Alcohol, nicotine and THC increased in a subgroup of consumers who reported to have more mental health problems compared to individuals who did not increase their consumption. This increased substance use could, therefore, be understood as a dysfunctional strategy to cope with negative emotions during the lockdown.

Healthcare Cost and Utilization Project (HCUP) Statistical Briefs

This Healthcare Cost and Utilization Project (HCUP) Statistical Brief presents statistics on SUD-related ED visits by patient race and ethnicity using weighted estimates from the 2019 Nationwide Emergency Department Sample (NEDS). SUDs include disorders involving alcohol, cannabis, stimulants, opioids, sedatives, hallucinogens, and inhalants, as well as other substances. The number and percentage of SUD-related ED visits are presented for select patient characteristics and primary expected payer. The population rate of SUD-related ED visits is presented by race and ethnicity for select demographic characteristics, including sex, age group, ruralurban location, and the social vulnerability of the county in which the individual resides (i.e., community’s ability to prevent human suffering and financial loss during a disaster). Because of the large sample size of the NEDS data, small differences can be statistically significant. Thus, only differences greater than or equal to 10 percent are discussed in the text.

State Trends of Cannabis Liberalization as a Causal Driver of Increasing Testicular Cancer Rates across the USA.

The cause of the worldwide doubling-tripling of testicular cancer rates (TCRs) in recent decades is unknown. Previous cohort studies associated cannabis use with TCR including dose-response relationships but the contribution of cannabis to TCRs at the population level is unknown. This relationship was tested by analyzing annual trends across US states and formally assessed causality. Four US datasets were linked at state level age-adjusted TCRs from Centers for Disease Control Surveillance Epidemiology and End Results database drug use data from annual National Survey of Drug Use and Health including 74.1% response rate ethnicity and median household income data from the US Census Bureau and cannabinoid concentration data from Drug Enforcement Agency reports. Data was processed in R in spatiotemporal and causal inference protocols. Cannabis-use quintile scatterplot-time and boxplots closely paralleled those for TCRs. The highest cannabis-use quintile had a higher TCR than others (3.44 ± 0.05 vs. 2.91 ± 0.2, mean ± S.E.M., t 10.68, Cannabis use is closely and causally associated with TCRs across both time and space and higher in States with liberal cannabis legislation. Strong dose-response effects were demonstrated for THC, cannabigerol, cannabinol, cannabichromene and cannabidiol. Cannabinoid genotoxicity replicates all major steps to testicular carcinogenesis including whole-genome doubling, chromosomal arm excision, generalized DNA demethylation and chromosomal translocations thereby accelerating the pathway to testicular carcinogenesis by several decades.

Evaluation of the anti-inflammatory effects of selected cannabinoids and terpenes from Cannabis Sativa employing human primary leukocytes.

Cannabis is well established as possessing immune modulating activity. The objective of this study was to evaluate the anti-inflammatory properties of selected cannabis-derived terpenes and cannabinoids. Based on their activity in cannabis-chemovar studies, α-pinene, trans-nerolidol, D-limonene, linalool and phytol were the selected terpenes evaluated. The cannabinoid compounds evaluated included cannabidivarin, cannabidiol, cannabinol, cannabichromene, cannabigerol and delta-9-tetrahydrocannabinol. Human PBMC were pretreated with each compound, individually, at concentrations extending from 0.001 to 10 μM and then stimulated with CpG (plasmacytoid dendritic cell), LPS (monocytes), or anti-CD3CD28 (T cells). Proliferation, activation marker expression, cytokine production and phagocytosis, were quantified. Of the 21 responses assayed for each compound, cannabinoids showed the greatest immune modulating activity compared to their vehicle control. Delta-9-tetrahydrocannabinol possessed the greatest activity affecting 11 immune parameters followed by cannabidivarin, cannabigerol, cannabichromene, cannabinol and cannabidiol. α-Pinene showed the greatest immune modulating activity from the selected group of terpenes, followed by linalool, phytol, trans-nerolidol. Limonene had no effect on any of the parameters tested. Overall, these studies suggest that selected cannabis-derived terpenes displayed minimal immunological activity, while cannabinoids exhibited a broader range of activity. Compounds possessing anti-inflammatory effects may be useful in decreasing inflammation associated with a range of disorders, including neurodegenerative disorders.

Cannabis containing equivalent concentrations of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) induces less state anxiety than THC-dominant cannabis.

Delta-9-tetrahydrocannabinol (THC), an active component of cannabis, can cause anxiety in some users during intoxication. Cannabidiol (CBD), another constituent of cannabis, has anxiolytic properties suggesting that cannabis products containing CBD in addition to THC may produce less anxiety than THC-only products. Findings to date around this issue have been inconclusive and could conceivably depend on moderating factors such as baseline anxiety levels in users. The present study examined whether anxiety following single doses of vaporised THC, CBD and THCCBD might be explained by state and trait anxiety levels at baseline. A placebo-controlled, randomised, within-subjects study including 26 healthy recreational cannabis users tested the effects of vaporised THC-dominant cannabis (13.75 mg THC), CBD-dominant cannabis (13.75 mg CBD), THCCBD-equivalent cannabis (13.75 mg THC13.75 mg CBD) and placebo cannabis on anxiety. Self-rated trait anxiety was assessed with the State-Trait Anxiety Inventory (STAI). State levels of anxiety were objectively assessed with a computer-based emotional Stroop task (EST) and subjectively rated with the STAI-state questionnaire and a visual analogue scale. Both THC and THCCBD significantly increased self-rated state anxiety compared to placebo. State anxiety after THCCBD was significantly lower than after THC alone. THC-induced anxiety was independent of anxiety at baseline. When baseline anxiety was low, CBD completely counteracted THC-induced anxiety however, when baseline anxiety was high, CBD did not counteract THC-induced anxiety. There were no effects of any treatment condition on the EST. Overall, the study demonstrated that the THCCBD-equivalent cannabis induces less state anxiety than THC-dominant cannabis.

Polysubstance use profiles among US adults using Kratom (Mitragyna speciosa) A latent class analysis using The National Survey on Drug Use and Health (NSDUH).

Kratom (Mitragyna speciosa) use is associated with polysubstance use (PSU) and use disorders. However, additional research on PSU heterogeneity in populations using this novel psychoactive substance is necessary. The authors investigated patterns of past 12-month PSU among US adults reporting past 12-month use of kratom and at least one additional substance. Latent class models were fit using 2019 National Survey on Drug Use and Health (NSDUH) data which was collected from 412 US adults reporting past 12-month use of kratom and at least one of 11 additional substances. Three distinct profiles were identified marijuanaalcoholtobacco (63.3%), marijuanaalcoholtobacco psychedelics (19.3%), and marijuanaalcoholtobacco psychedelicsheroinprescriptions (17.4%). This is the first epidemiological study in which a latent class analysis was used to identify unique PSU profiles among US adults using kratom and other substances. Understanding the profiles of people using kratom in relation to the use of other drugs might help guide screening interventions, treatment needs, and policy.

Evaluation of suspected drug-facilitated sexual assault cases in the city of Houston from 2014 to 2020.

Drug-facilitated sexual assault is a form of sexual violence against an individual incapacitated by alcohol andor drugs consumed voluntarily or covertly administered. The purpose of this study was to evaluate toxicological results and the associated demographics of sexual assault-related cases submitted to Houston Forensic Science Center from 2014 to 2020. In total, 1240 samples (1230 cases) were tested during the six-year period that consisted of blood, urine, or both specimens. Blood was analyzed for ethanol by dual-column headspace gas chromatography with flame ionization detection. Drug screen analysis was performed preferably on urine specimens using enzyme-linked immunosorbent assay. Positive screening results were confirmed upon request only due to laboratory policy. A total of 22% (n 176) of requested samples were confirmed positive. Ethanol was the most prevalent substance detected, present in 17% of the samples (n 212), followed by 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THC-COOH) (n 118). The combination of ethanol and THC-COOH was the most frequent one found (n 17) in cases positive for two or more drugs (n 101). Demographic data showed the majority of DFSA victims were white (25%) females (72%) with an average age of 27 years old (n 348). Almost 90% of cases where the presence of drugs was confirmed resulted in no charges being made, either due to lack of suspect information or unknown reasons by the laboratory.

Cannabidiol pharmacotherapy for delta-9-tetrahidrocannabinol dependence.

Addictions are one of the most important health problems worldwide. Within these disorders, cannabis is one of the psychoactive substances with more burden of morbidity and mortality worldwide. The actual knowledge about the effectiveness of treatments for cannabis use disorders is unsatisfactory. This review aims to explore the evidence on cannabidiol for the treatment of cannabis use disorder. There are several clinical pharmacotherapy trials researching cannabis use disorders with limited evidence. A smaller number of trials in animal models and humans on the use of cannabinoids, especially Cannabidiol and Tetrahydrocannabinol to treat cannabis dependence show evidence of reduction in days of use, withdrawal symptoms and craving. New trials are under development, and there is an urgent need for trials with larger numbers of patients and longer treatment periods to support possible indications in the near future. Las adicciones son uno de los problemas de salud más importantes a nivel mundial. Dentro de estos trastornos, el cannabis es una de las sustancias psicoactivas que provoca mayor morbimortalidad a nivel mundial. La efectividad documentada de los tratamientos para los trastornos por uso de cannabis no es satisfactoria. Esta revisión tiene por objetivo explorar las evidencias sobre la implementación de tratamientos con cannabinoides para el abordaje de estos trastornos. La bibliografía actual cuenta con muchos ensayos sobre el uso de neuropsicofármacos en los trastornos por uso de cannabis con limitada evidencia a favor mientras que un número más reducido de ensayos en modelos animales y en pacientes sobre el uso de cannabinoides, en especial Cannabidiol y Tetrahidrocannabinol para tratar dicha dependencia muestran evidencias de reducción en días de consumo, síntomas de abstinencia y craving. Se encuentran en desarrollo nuevos ensayos clínicos, estos son una necesidad imperiosa para proveer mayor número de pacientes y con períodos de tratamiento más prolongados y así poder explorar más a fondo su posible indicación en un futuro cercano.

Bibliometric Analysis of Academic Journal Articles Reporting Results of Psychedelic Clinical Studies.

Following a decades long period of investigational dormancy, there is renewed interest in employing psychedelics as psychiatric treatments. The academic journals, institutions, and countries that have helped sustain clinical psychedelic research and the evolution of the literature on clinical studies of psychedelics have only recently begun to be investigated. To expand upon this work, we conducted a bibliometric analysis of clinical studies of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT), ayahuasca, dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), ibogaine, mescaline, 3,4-methylenedioxymethamphetamine (MDMA), and psilocybin published from 1965-2021. Our search revealed 394 relevant articles. After a lull from the 1970s-1990s, publications in this area have resurged. Studies most frequently focused on MDMA (49%), LSD (19%), psilocybin (18%), and ayahuasca (7%). A subanalysis of studies from 1965 to 2009 (Older cohort) compared to 2010-2021 (Recent cohort) revealed that the Recent cohort had a higher proportion of studies investigating psychedelics therapeutic applications and a lower proportion of studies investigating the effects of psychedelics on people using them in non-research settings. Compared to the Older cohort, psilocybin studies increased proportionally in the Recent cohort, while DMT and mescaline studies decreased. Network analyses of inter-country collaborations suggested that psychedelic researchers in the United Kingdom have the most diverse international collaborations.

Race and ethnicity moderate the associations between lifetime psychedelic use (MDMA and psilocybin) and psychological distress and suicidality.

Psychedelic compounds have been linked to salutary mental health outcomes in both naturalistic and clinical settings however, current research on psychedelics suffers from a lack of inclusion and focus on racial and ethnic minorities. Thus, the goal of our study was to assess whether race and ethnicity moderate the associations that naturalistic lifetime MDMA (3,4-Methylenedioxymethamphetamine) use and psilocybin use share with past month psychological distress and past year suicidality (ideation and planning). Using data from the National Survey on Drug Use and Health (NSDUH) (2008-2019) (N 484,732), we conducted survey-weighted multivariable logistic regression to conduct interaction tests and to assess the associations that MDMA use and psilocybin use share with the aforementioned outcomes for each racial and ethnic group. Race and ethnicity significantly moderated the associations between MDMA and psilocybin use and psychological distress and suicidality. For White participants, MDMA and psilocybin use conferred lowered odds of all distress and suicidality outcomes. For racial and ethnic minority participants, the associations between psychedelic use and suicidality were far fewer. These findings invite further research into the impact of race, ethnicity, and other identity factors (e.g., socioeconomic status, sexualgender minority status) on the effects of psychedelic substances.

UHPLC-MS-MS Determination of THC, CBD and Their Metabolites in Whole Blood of Light Cannabis Smokers.

Light cannabis is a product legally sold in Europe with Δ9-tetrahydrocannabinol (THC) concentration <0.2% and variable cannabidiol (CBD) content. In this study, we aimed to assess the time courses of THC and metabolites (11-nor-9-carboxy-THC and 11-hydroxy-THC) and CBD and metabolites (CBD-7-oic acid, 7-hydroxy-CBD, 6α-hydroxy-CBD and 6β-hydroxy-CBD) in whole blood of 10 healthy participants after smoking one or four light cannabis cigarettes (0.16% THC and 5.8% CBD). Blood samples were collected 0.5-4 h after administration. Blood analysis was performed by reversed-phase ultra-performance liquid chromatography-tandem mass spectrometry in multiple reaction monitoring mode after glucuronide hydrolysis and liquid-liquid extraction in basic and acidic conditions. The method was validated following the most recent guidelines in toxicology the method was linear, accurate, precise and sensitive (lower limits of quantification ranged from 0.005 to 0.01 ngmL) carryover, matrix effect, recovery, process efficiency and dilution integrity were also assessed. As previously reported, the main metabolites of THC were THC-COOH and then 11-OH-THC, and the main metabolites of CBD were 7-OH-CBD and then 7-COOH-CBD. The time of the first collection, which likely occurred after the maximal concentration of most of the analytes, and the short monitoring time, up to 4 h after smoking, limited the evaluation of the pharmacokinetic parameters.

Synthesis, biological evaluation and preliminary mechanisms of 6-amino substituted harmine derivatives as potential antitumor agents.

To explore the effect of the introduction of the amino and substituted amino groups on the antitumor activity of harmine, twenty-five novel 6-amino substituted harmine derivatives (3a-3j and 5a-5o) were synthesized and evaluated for anti-proliferative activity on a panel of cancer cell lines. Compounds 3i and 5n exhibited the most potent antiproliferative activity with IC

Psychedelic therapy for depressive symptoms A systematic review and meta-analysis.

Psychedelic therapy shows promise for Major Depressive Disorder, especially when treatment-resistant, as well as life-threatening illness distress. The objective of this systematic review, inclusive of meta-analysis, is to examine recent clinical research on the therapeutic effects of classic psychedelics on depressive symptoms. Fourteen psychedelic therapy studies, utilising psilocybin, ayahuasca, or LSD, were systematically reviewed. For the meta-analysis, standardised mean differences were calculated for seven randomised controlled trials. The systematic review indicated significant short- and long-term reduction of depressive symptoms in all conditions studied after administration of psilocybin, ayahuasca, or LSD, with psychological support. In the meta-analysis, symptom reduction was significantly indicated in three timepoints out of four, including 1-day, 1-week, and 3-5 weeks, supporting the results of the systematic review, with the exception of the 6-8 weeks follow-up point which was less conclusive. The absence of required data for 2 studies necessitated the less precise use of graphical extraction and imputation. The small sample size in all but one study negatively affected the statistical power. None of the studies had long-term follow-up without also utilising the cross-over method, which did not allow for long-term results to be included in the meta-review. This review indicates an association between psychedelic therapy and significant reduction of depressive symptoms at several time points. However, the small number of studies, and low sample sizes, calls for careful interpretation of results. This suggests the need for more randomised clinical trials of psychedelic therapy, with larger and more diverse samples.

Correlates of treatment engagement and client outcomes results of a randomised controlled trial of nabiximols for the treatment of cannabis use disorder.

There is increasing interest and evidence for the use of cannabinoid medications in the treatment of cannabis use disorder, but little examination of the correlates of successful treatment. This paper is a secondary analysis of a randomised placebo-controlled trial of nabiximols for the treatment of cannabis use disorder (CUD), aiming to identify which client and treatment characteristics impact treatment engagement and outcomes. Bayesian multiple regression models were used to examine the impact of age, gender, duration of regular cannabis use, daily quantity of cannabis, cannabis use problems, self-efficacy for quitting, sleep, mental health, pain measures, and treatment group upon treatment engagement (retention, medication dose, and counselling participation) and treatment outcomes (achieving end-of-study abstinence, and a 50% or greater reduction in cannabis use days) among the 128 clients participating in the 12-week trial. Among the treatment factors, greater counselling attendance was associated with greater odds of abstinence and ≥ 50% reduction in cannabis use nabiximols with greater odds of ≥ 50% reduction and attending counselling, and reduced hazard of treatment dropout and higher dose with lower odds of ≥ 50% reduction. Among the client factors, longer duration of regular use was associated with higher odds of abstinence and 50% reduction, and lower hazard of treatment dropout greater quantity of cannabis use with reduced hazard of dropout, greater odds of attending counselling, and higher average dose greater pain at baseline with greater odds of ≥ 50% reduction and higher average dose and more severe sleep issues with lower odds of ≥ 50% reduction. Males had lower odds of attending counselling. These findings suggest that counselling combined with agonist pharmacotherapy may provide the optimal treatment for cannabis use disorder. Younger clients, male clients, and clients with sleep issues could benefit from extra support from treatment services to improve engagement and outcomes. Australian New Zealand Clinical Trials Registry (ACTRN12616000103460) httpswww.anzctr.org.au.

Potential effects of nicotine content in cigarettes on use of other substances.

A national nicotine reduction policy has the potential to reduce cigarette smoking and associated adverse health impacts among vulnerable populations. However, possible unanticipated adverse effects of reducing nicotine content in cigarettes, such as increasing the use of alcohol or other abused substances, must be examined. The purpose of this study was to evaluate the effects of exposure to varying doses of nicotine in cigarettes on use of other substances. This was a secondary analysis (n 753) of three simultaneous, multisite, double-blind, randomized-controlled trials examining 12 weeks of exposure to study cigarettes varying in nicotine content (0.4, 2.4, 15.8 mg nicotineg tobacco) among daily smokers from three vulnerable populations individuals with affective disorders (n 251), individuals with opioid use disorder (n 256), and socioeconomically-disadvantaged women of reproductive age (n 246). Effect of study cigarette assignment on urine toxicology screens (performed weekly) and responses to drug and alcohol use questionnaires (completed at study weeks 6 and 12) were examined using negative binomial regression, logistic regression, or repeated measures analysis of variance, controlling for sex, age, and menthol status. The most common substances identified using urine toxicology included tetrahydrocannabinol (THC 44.8%), cocaine (9.2%), benzodiazepine (8.6%), and amphetamines (8.0%), with 57.2% of participants testing positive at least once for substance use (27.3% if excluding THC). No significant main effects of nicotine dose were found on any of the examined outcomes. These results suggest that reducing nicotine content does not systematically increase use of other substances, even among individuals at increased risk of substance use. ClinicalTrials.gov Identifiers NCT02232737, NCT2250664, NCT2250534.

The neuroprotective and neuroplastic potential of glutamatergic therapeutic drugs in bipolar disorder.

The monoamine hypothesis has dominated research on the pathophysiology of mood disorders as well as the development of therapeutic drugs by over half a century. Nowadays a change of perspective is taking place. The glutamate system is increasingly implicated in the pathophysiology of mood disorders. The evidence spans from animal, post-mortem, imaging, pharmacological and genome-wide association studies. Bipolar disorder has been recently re-conceptualized as a synaptic plasticity-related disorder rather than simply as a result of deficits or excesses in individual neurotransmitters. A paradigm shift from a monoamine hypothesis to a neuroplasticity hypothesis focused on glutamate may represent a substantial advancement in the research for new drugs and therapies. In this review we summarize data from clinical and pre-clinical studies that have addressed glutamatergic alterations in bipolar disorder. Along with an in-depth discussion of glutamatergic alterations in bipolar disorder, we also report available data on the neuroprotective and neuroplastic potential of the classic mood stabilizers, ketamine, and psychedelics. The glutamatergic mechanisms underlying the efficacy of these drugs are described and discussed.

Methylone pre-exposure differentially impacts the aversive effects of MDPV and MDMA in male and female Sprague-Dawley rats Implications for abuse vulnerability.

Polydrug use is well documented in synthetic cathinone users, although the consequences of such use are not well characterized. In pre-clinical research, a pre-exposure to a drug has been reported to attenuate the aversive effects of other drugs which has implications for their abuse potential. The goal of the present study was to investigate the impact of pre-exposure to the synthetic cathinone methylone on the aversive effects of MDPV and MDMA. Male and female Sprague-Dawley rats were exposed to 10 mgkg of methylone every 4th day (for a total of five injections) prior to taste avoidance training with 1.8 mgkg of MDPV or 1 mgkg of MDMA. MDPV and MDMA induced taste avoidance in males and females (all ps < 0.05). In males, methylone pre-exposure attenuated the avoidance induced by MDPV and MDMA (all ps < 0.05) with the attenuation greater with MDPV. In females, methylone pre-exposure attenuated avoidance induced by MDPV (all ps < 0.05), but it had no effect on those induced by MDMA (all ps > 0.05). The effects of exposure to methylone on taste avoidance induced by MDPV and MDMA were drug- (MDPV > MDMA) and sex- (MDMA only in males) dependent. The attenuating effects of methylone pre-exposure on MDPV and MDMA were discussed in terms of their shared neurochemical action. These findings suggest that a history of methylone use may reduce the aversive effects of MDPV and MDMA which may have implications for polydrug use involving the synthetic cathinones.

Self-administration of Psilocybin in the Setting of Treatment-resistant Depression.

Patients diagnosed with major depressive disorder (MDD) who fail to respond to two or more antidepressants are often considered to have treatment-resistant depression (TRD). Many of the current options for TRD have significant side effect profiles, are expensive, and are difficult to access. There has been a revival of psychedelic research in recent years that shows promising results in the treatment of TRD. Here, the case of a 43-year-old man with TRD is presented. TRD symptoms were greatly interfering with his life. He underwent psychological testing, lab work, adequate trials of numerous medications, transcranial magnetic stimulation (TMS), and electroconvulsive therapy, all without adequate relief of his symptoms. The patient began self-administering a microdosing regimen of psilocybin and experienced significant improvement of MDD symptoms, as characterized by Hamilton Depression Rating Scale (HDRS). In recent years, multiple randomized, controlled trials (RCTs) have shown the benefit of psilocybin in the treatment of varying types of depression. One trial evaluated psilocybin and escitalopram as treatments for depression, and psilocybin was found to be superior. This case suggests the possible benefit of psilocybin in the setting of TRD, as outlined in recent research. Additional research is needed to confirm these observations.

A Cannabinoid Hypothesis of Schizophrenia Pathways to Psychosis.

Observations regarding psychostimulant and psychedelic drug-induced psychotic states led to the dopamine, serotonin, and glutamate hypotheses of schizophrenia. Expanding knowledge about the endocannabinoid system and the impact of exogenous cannabinoids on the brain and behavior have elucidated several putative pathways to cannabis-induced psychosis. The purpose of the present article was to describe these pathways and propose a cannabinoid hypothesis of schizophrenia. The endocannabinoid system was reviewed. Evidence regarding the effect of delta 9-tetrahydrocannabinol (THC) on the brain was described. A connection between cannabis use and first-episode psychosis was elucidated. Understanding the putative pathways to cannabis-induced psychosis might lead to targeted therapeutic interventions and prevention of schizophrenia in susceptible individuals.

Knowing and being known Psychedelic-assisted psychotherapy and the sense of authenticity.

Participants in MDMA- and psychedelic-assisted psychotherapy often emerge from these treatments with new beliefs about themselves and the world. Studies have linked changed beliefs with mystical experiences reported by some participants during drug sessions. While there has been some debate about the epistemic value of drug-induced mystical experiences, and about the need for consent to treatments that may alter metaphysical beliefs, less attention has been given to the sense of authenticity that attends these experiences. In this paper, I consider the intersubjective context in which these changed beliefs arise. I suggest that the sense of authenticity people experience with MDMA- and psychedelic-assisted psychotherapy derives from a simultaneous feeling of knowing and being known. The medications used in these treatments reduce the defensive barriers which ordinarily prevent powerful feelings from being intersubjectively shared, allowing the subject to experience knowing and being known with the therapist andor internalized or imagined others. In explaining this thesis, I discuss Ratcliffes existential feeling ipseity in incipient psychosis and psychedelic states Winnicotts notions of the True Self, omnipotence, creativity, and transitional phenomena implicit relational knowing and moments of meeting infant-mother dyad research predictive processing and the relaxed beliefs model of psychedelic action the role of the partner in thought in knowing and feeling known. I propose that a transitional space model of MDMA- and psychedelic-assisted psychotherapy is well-suited for working through not-me or dissociated experience.

Preparedness for healthy ageing and polysubstance use in long-term cannabis users a population-representative longitudinal study.

Cannabis is often characterised as a young persons drug. However, people who began consuming cannabis in the 1970s and 1980s are no longer young and some have consumed it for many years. This study tested the preregistered hypothesis that long-term cannabis users show accelerated biological ageing in midlife and poorer health preparedness, financial preparedness, and social preparedness for old age. In this longitudinal study, participants comprised a population-representative cohort of 1037 individuals born in Dunedin, New Zealand, between April, 1972, and March, 1973, and followed to age 45 years. Cannabis, tobacco, and alcohol use and dependence were assessed at ages 18 years, 21 years, 26 years, 32 years, 38 years, and 45 years. Biological ageing and health, financial, and social preparedness for old age were assessed at age 45 years. Long-term cannabis users were compared using independent samples t tests with five groups lifelong cannabis non-users, long-term tobacco users, long-term alcohol users, midlife recreational cannabis users, and cannabis quitters. In addition, regression analyses tested dose-response associations for continuously measured persistence of cannabis dependence from age 18 years to 45 years, with associations adjusted for sex, childhood socioeconomic status, childhood IQ, low childhood self-control, family substance dependence history, and persistence of alcohol, tobacco, and other illicit drug dependence. Of 997 cohort members still alive at age 45 years, 938 (94%) were assessed at age 45 years. Long-term cannabis users showed statistically significant accelerated biological ageing and were less equipped to manage a range of later-life health, financial, and social demands than non-users. Standardised mean differences between long-term cannabis users and non-users were large 0·70 (95% CI 0·46 to 0·94 p<0·0001) for biological ageing, -0·72 (-0·96 to -0·49, p<0·0001) for health preparedness, -1·08 (-1·31 to -0·85 p<0·0001) for financial preparedness, and -0·59 (-0·84 to -0·34, p<0·0001) for social preparedness. Long-term cannabis users did not fare better than long-term tobacco or alcohol users. Tests of dose-response associations suggested that cannabis associations could not be explained by the socioeconomic origins, childhood IQ, childhood self-control, and family substance-dependence history of long-term cannabis users. Statistical adjustment for long-term tobacco, alcohol, and other illicit drug dependence suggested that long-term cannabis users tendency toward polysubstance dependence accounted for their accelerated biological ageing and poor financial and health preparedness, although not for their poor social preparedness (β -0·10, 95% CI -0·18 to -0·02 p0·017). Long-term cannabis users are underprepared for the demands of old age. Although long-term cannabis use appears detrimental, the greatest challenge to healthy ageing is not use of any specific substance, but rather the long-term polysubstance use that characterises many long-term cannabis users. Substance-use interventions should include practical strategies for improving health and building financial and social capital for healthy longevity. The National Institute on Aging and the UK Medical Research Council. The Dunedin Research Unit is supported by the New Zealand Health Research Council and the New Zealand Ministry of Business, Innovation and Employment.

Analysis of state portrayals of the risks of e-cigarette use and the cause of the EVALI outbreak.

In August 2019, an outbreak of e-cigarette or vaping product use-associated lung injury (EVALI) prompted many states and health organizations to warn against the use of electronic cigarettes, or e-cigarettes, due to the presumed link between e-cigarette use and the illness. However, it was later shown that vitamin E acetate, a component of some illicit vaporizable THC products, was the causative agent in this outbreak. We conducted a series of cross-sectional surveys of the websites of all state departments of health to determine how they communicated the risk of e-cigarette use during and after the EVALI outbreak. We then paired this analysis with data from the 2016 through 2020 Behavioral Risk Factor Surveillance System to measure changes in cigarette and e-cigarette use. Website data from 24 states was available for analysis at all three time points of interest, and BRFSS data was only available for 8 of these states. We found that by January 2020, a majority of the states surveyed did not list vaporizable THC use as a cause of EVALI however, differences in state messaging did not appear to be associated with changes in e-cigarette and cigarette use. Given the number of states that did not appear to update their messaging regarding the cause of EVALI, we believe that states should re-evaluate this messaging to accurately communicate the risks of e-cigarette use.

Predictors of Psychedelic Experience A Thematic Analysis.

Research on the therapeutic potential of psychedelic substances is expanding. A limitation within this field is the unpredictability of individual responses to psychedelics. Better understanding of factors predicting psychedelic experience is essential to clinical progress and wider harm reduction frameworks. Ketamine, MDMA, LSD and psilocybin were selected for comparison due to their promising therapeutic effects and different mechanisms of action. This study aimed to (a) identify factors that produce positive and adverse psychedelic experience, and (b) compare these potential predictors across four psychedelic substances. A thematic analysis was conducted on twenty-two first-person reports of psychedelic use (six per substance), sourced from the Erowid database. This revealed three external predictors (nature, music, and preparation) and three internal predictors (understanding, mind-set, and motivation). Each factor identified contained two sub-themes that further elucidated meaning and impact. Nature and music emerged as potential tools for de-escalating adverse reactions to psychedelics. Substance-specific perceptual and sensorial effects were also examined. Finally, the importance of, and interrelationship between, preparation, mind-set, understanding, and motivation was examined as common themes that emerged. The broader clinical and sociological implications are discussed, with reference to developing harm reduction frameworks. These findings constitute an early step in developing a more nuanced understanding of factors shaping psychedelic experience.

Low-dose THC in geriatric and palliative patients.

Cannabis-containing medicines have been successfully used in our practice for more than 20 years in pain and especially in geriatric and palliative patients. While it was initially a very indication-specific use (pain, loss of appetite, etc.) and also with higher THC doses, this changed over time to low THC doses and a therapy focus on suffering-perpetuating symptoms and especially on stress (Matrix of Symptoms). As part of the legally prescribed companion survey, we evaluated our data in parallel and discussed it publicly in a series of publications. Based on these published results, the article is intended to show an overview of our experiences. Low-dose THC has a positive effect on morbidity, side effects, quality of life and mortality in geriatric and palliative patients. Early therapy is particularly appropriate in geriatric and palliative patients due to the clear benefit-risk ratio of low-dose THC.

Anxiety sensitivity and cigarette use on cannabis use problems, perceived barriers for cannabis cessation, and self-efficacy for quitting among adults with cannabis use disorder.

Many individuals diagnosed with cannabis use disorder (CUD) report a desire to quit using cannabis due to problems associated with use. Yet, successful abstinence is difficult for a large subset of this population. Thus, the present study sought to elucidate potential risk factors for cannabis use problems, perceived barriers for quitting, and diminished self-efficacy for remaining abstinent. Specifically, this investigation examined cigarette user status, anxiety sensitivity, and the interplay between these individual difference factors in terms of cannabis-related problems, perceived barriers for cannabis cessation, and self-efficacy for quitting cannabis use. The sample consisted of 132 adult cannabis users who met criteria for CUD and were interested in quitting (38 % female 63.6 % Black M

A Critical Appraisal of Evidence on the Efficacy and Safety of Serotonergic Psychedelic Drugs as Emerging Antidepressants Mind the Evidence Gap.

There has been resurgence of interest in the therapeutic use of serotonergic (classic) psychedelics in major depressive disorder (MDD) and end-of-life distress. This commentary offers a critical appraisal of current evidence for antidepressant effects of classic psychedelics from contemporary clinical trials and highlights pitfalls that should be addressed before clinical translation. A narrative review was conducted to identify clinical trials of serotonergic psychedelics for the treatment of MDD and end-of-life distress. Trials published between January 1990 and May 2022 were identified on PubMed using combinations of search terms. Psilocybin, lysergic acid diethylamide, and ayahuasca have clinical trials to evaluate antidepressant effects. Two studies showed preliminary positive effects of single-dose ayahuasca for treatment-resistant depression. Similar results were seen in lysergic acid diethylamide for end-of-life distress. Small randomized clinical trials (RCTs) of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy and safety to an active comparator in MDD, with additional RCTs showing efficacy in end-of-life distress. Adverse events associated with psychedelics were reported as mild and transient. Small homogenous samples, expectancy bias, functional unblinding, and lack of consensus and standardization of psychotherapy are major limitations of all studies. Given the methodological limitations of published RCTs, the evidence supporting the efficacy and safety of serotonergic psychedelics for depression is currently of low level. Future research should assess the role of expectancy and psychedelic effects in moderating and mediating treatment response. Innovative trial designs are needed to overcome functional unblinding. For now, psychedelics should remain experimental interventions used within clinical trials.

Ketamine-assisted meaning-centered psychotherapy for a patient with severe suicidal behavior.

There is a current debate in society as to whether depression can be a terminal illness. Meaning-centered psychotherapy (MCP) and psychedelic medicines have both been shown to treat existential distress in palliative care settings. We are reporting the case of a patient for whom MCP combined with ketamine was an effective treatment for his recurrent and severe depressive disorder with suicidal ideation. His complex assessment and management of suicide (CAMS) scores improved significantly with this treatment modality. Ketamine is generally well tolerated and can enhance treatment outcomes in patients undergoing MCP.

Cannabis use for pain relief in the context of health service barriers Accounts of street-involved Nigerian women suffering chronic pain.

This study explored cannabis use for pain relief among socially marginalised Nigerian women in the context of barriers to pain management. The study was designed as a qualitative exploratory study of pain experience and management. Sixteen in-depth, individual interviews were conducted with street-involved women who use drugs and had chronic pain. Transcripts were coded and analysed thematically. Pain was experienced as a pervasive feature of everyday life that disrupted daily routines, affected economic activities, strained social relationships and had adverse effects on health and wellbeing. Participants sought treatment in health facilities, but faced social and health system barriers to service utilisation including financial cost of services, dismissal of symptoms by providers, stigma due to physical appearance, substance use and lack of social support. These barriers encouraged disengagement from services and reliance on cannabis (along with heroin and diverted prescription opioids) for pain management. Cannabis use relieved pain and improved daily functioning, enabling participants to undertake economic activities. However, using cannabis to enhance the effects of opioids and heavy and long-term use owing to pain chronicity and disability generated concerns about harms. Findings show the therapeutic benefits of cannabis in the face of barriers to pain management. This support calls to explore the potentials of cannabis for pain management for socially marginalised populations and to develop medical guidelines to reduce the risk of adverse health consequences. Therapeutic cannabis, provided based on medical guidance, could improve pain management for socially marginalised populations.

Hemp microgreens as an innovative functional food Variation in the organic acids, amino acids, polyphenols, and cannabinoids composition of six hemp cultivars.

Hemp (Cannabis sativa L.) is a multi-functional crop cultivated for fiber, seeds, or phytochemical extraction. Once a major industrial crop in several agro-environments, its cultivation strongly declined in developed countries since World War II. Exploiting hemp vegetative tissue as innovative food has remained largely unexplored. The current work examined the potential production of hemp microgreens. Six cultivars were assessed for yield and composition of organic acids, amino acids, polyphenols and phytocannabinoids, through IC, FLD-HPLC and UHPLC-HRMS, respectively. Bioactive composition was strongly related to the hemp variety. Silvana demonstrated the highest total content of amino acids and essential amino acids, high concentrations of cannflavin A and B, and moderate levels of cannabidiol and cannabigerol. Finola distinguished by the highest concentration of cannflavins and total polyphenols, and the lowest levels of Δ

The effect of medical cannabis on cognitive functions a systematic review.

Cannabis-based medicines are widely used in the treatment of a number of medical conditions. Unfortunately, cognitive disturbances are often reported as adverse events, although conversely, cognitive improvements have been reported. Hence, the objective of the present study was to identify, critically appraise and synthesise research findings on the potential impact of cannabis-based medicines on cognitive functioning. Four databases (EMBASE, PsycINFO, PubMed and Scopus) were systematically searched. Studies were included if they provided findings on the impact of cannabis-based medicines in controlled settings on cognitive functioning measured by recognised cognitive tests in human adults. Study participants were required to be their own case-control, and neither studies on abuse, abstinences, patients with severe neurodegenerative diseases nor cancer-related pain conditions were included. Screening, risk of bias assessment and data extraction were conducted independently by two researchers. Findings were tabulated and synthesised by outcome. Twenty-three studies were included, comprising a total of N 917. Eight studies used Sativex as the cannabis-based medicine two used Epidiolex, two other studies used sprays, three studies used gelatine capsules, five smoked cannabis, two other and finally one studied cannabis withdrawal. Fifteen studies reported non-significant findings six reported cognitive impairments one study found cognitive improvement and a single study found improvement following withdrawal. Thirteen studies had cognitive or neuropsychological functioning as the primary outcome. Due to a large heterogeneity and methodological limitations across studies, it is not possible to make any definite conclusions about the impact of cannabis-based medicines on cognitive functioning. However, the majority of high-quality evidence points in the direction that the negative impact of cannabis-based medicines on cognitive functioning is minor, provided that the doses of THC are low to moderate. On the other hand, long-term use of cannabis based medicines may still adversely affect cognitive functioning. In the studies that found impaired cognitive functioning to be significant, all of the test scores were either within the normal range or below what would be characterised as a neuropsychologically cognitive impairment.

Adverse events of recreational cannabis use during pregnancy reported to the French Addictovigilance Network between 2011 and 2020.

Cannabis is the main illicit psychoactive substance used by pregnant women in France. The aim of the present national survey was to describe adverse events (AEs) of recreational cannabis use during pregnancy reported to the French Addictovigilance Network (FAN). Spontaneous reports (SRs) of AEs related to recreational cannabis use during pregnancy were collected by the FAN between 01012011 and 31012021 (excluding cannabidiol and synthetic cannabinoids). Over the study period, 160 SRs involved cannabis use alone or in association with tobacco (59% of all SRs) which increased. Among the 175 maternal AEs, the most commons were psychiatric AEs experienced by 96 (64.9%) women, in particular cannabis use disorders (n 89, 60.1%), dependence (n 54, 36.5%) and abuse (n 21, 14.2%). Among the 57 fetal AEs, the most common were heart rhythm disorders that affected 25 (16.9%) fetuses and intrauterine growth restriction (IUGR) (n 20, 13.5%). Among the 140 neonatal AEs, the most common were IUGR experienced by 39 (26.3%) newborns and prematurity (n 32, 21.6%). Twelve cases of congenital malformations were observed and 4 intrauterineneonatal deaths. Furthermore, some of these AEs (n 13) were unexpected. Cannabis use during pregnancy has problematic consequences for both mothers and infants who need close monitoring.

Receptor-informed network control theory links LSD and psilocybin to a flattening of the brains control energy landscape.

Psychedelics including lysergic acid diethylamide (LSD) and psilocybin temporarily alter subjective experience through their neurochemical effects. Serotonin 2a (5-HT2a) receptor agonism by these compounds is associated with more diverse (entropic) brain activity. We postulate that this increase in entropy may arise in part from a flattening of the brains control energy landscape, which can be observed using network control theory to quantify the energy required to transition between recurrent brain states. Using brain states derived from existing functional magnetic resonance imaging (fMRI) datasets, we show that LSD and psilocybin reduce control energy required for brain state transitions compared to placebo. Furthermore, across individuals, reduction in control energy correlates with more frequent state transitions and increased entropy of brain state dynamics. Through network control analysis that incorporates the spatial distribution of 5-HT2a receptors (obtained from publicly available positron emission tomography (PET) data under non-drug conditions), we demonstrate an association between the 5-HT2a receptor and reduced control energy. Our findings provide evidence that 5-HT2a receptor agonist compounds allow for more facile state transitions and more temporally diverse brain activity. More broadly, we demonstrate that receptor-informed network control theory can model the impact of neuropharmacological manipulation on brain activity dynamics.

A century of research on psychedelics A scientometric analysis on trends and knowledge maps of hallucinogens, entactogens, entheogens and dissociative drugs.

A scientometric analysis was realized to outline clinical research on psychedelics over the last century. Web of Science Core Collection was searched up to March 18, 2022, for publications on psychedelics. Network analyses and bibliometrics were combined, to identify research themes and trends with Bibliometrix and CiteSpace. The primary aim was to measure research trends evolution over time, and the secondary aims were to identify bibliometric performance and influence networks of publications, authors, institutions, and countries. Sensitivity analyses were conducted for 2016-2022, and 2021 time periods. We included 31,687 documents (591,329 references), which aggregated into a well-structured network with credible clustering. Research productivity was split into an early less productive period mainly focusing on safety issues, and a psychedelic renaissance after the 1990s. Major trends were identified for hallucinogensentheogens, entactogens, novel psychoactive substances (NPS), and on dissociative substances. There was a translational evolution from the bench to the bedside, with phase 2 and 3 trials andor evidence synthesis in particular. The most recent trends concerned NPS, ketamine-associated brain changes, and ayahuasca-assisted psychotherapy. The USA and Canada were the most productive settings for the research overall, and more recently this geographical distribution became more prominent, reflecting legislative contextpolicy making. A translational evolution of psychedelics has been occurring, that has brought approval of esketamine for depression and will likely lead to approval of additional psychedelics across mental and physical conditions. Toxicology screening tools for NPS are urgently needed, which in turn might follow the same translational evolution of psychedelics in the future.

Will tetrahydrocannabinol be formed from cannabidiol in gastric fluid An in vivo experiment.

Cannabidiol (CBD) products have ascribed an uprising trend for their health-promoting effects worldwide. In contrast to Δ

Associations between MDMAecstasy use and physical health in a U.S. population-based survey sample.

3,4-Methylenedioxymethamphetamine (MDMAecstasy) is an empathogen that can give rise to increased pleasure and empathy and may effectively treat post-traumatic stress disorder. Although prior research has demonstrated associations between ecstasy use and favorable mental health outcomes, the associations between ecstasy and physical health have largely been unexplored. Thus, the goal of this study was to examine the associations between ecstasy use and physical health in a population-based survey sample. This study utilized data from the National Survey on Drug Use and Health (2005-2018), a yearly survey that collects information on substance use and health outcomes in a nationally representative sample of U.S. adults. We used multinomial, ordered, and logistic regression models to test the associations between lifetime ecstasy use and various markers of physical health (self-reported body mass index, overall health, past year heart condition andor cancer, past year heart disease, past year hypertension, and past year diabetes), controlling for a range of potential confounders. Lifetime ecstasy use was associated with significantly lower risk of self-reported overweightness and obesity (adjusted relative risk ratio range 0.55-0.88) and lower odds of self-reported past year heart condition andor cancer (adjusted odds ratio (aOR) 0.67), hypertension (aOR 0.85), and diabetes (aOR 0.58). Ecstasy use was also associated with significantly higher odds of better self-reported overall health (aOR 1.18). Ecstasy shares protective associations with various physical health markers. Future longitudinal studies and clinical trials are needed to more rigorously test these associations.

The Safety and Efficacy of Psychedelic-Assisted Therapies for Older Adults Knowns and Unknowns.

Psychedelics and related compounds have shown efficacy for the treatment of a variety of conditions that are prevalent among older adults, including mood disorders, the psychological distress associated with a serious medical illness, post-traumatic stress disorder (PTSD), and prolonged grief disorder. Psychedelics also have properties that could help provide therapeutic benefits for patients with dementing disorders, as well as promoting personal growth among healthy older adults. This article focuses on psilocybin, a classic psychedelic, and MDMA, a substituted amphetamine with properties similar to classic psychedelics. Both act on the 5HT

Illegal drugs and periodontal conditions.

In recent years, the practice of dentistry and periodontology has become complicated by several risk factors, including the treatment of an increasing number of patients with substance use disorder. This review presents an update in the current literature of the impact of illegal drug use on periodontal conditions and their possible effect as risk factors or indicators. The main illegal drugs that may have an impact on periodontal health and conditions are described, including their effect, medical manifestations, risks, and the overall effect on oral health and on the periodontium. Where available, data from epidemiologic studies are analyzed and summarized. The clinical management of periodontal patients using illegal drugs is reported in a comprehensive approach inclusive of the detection of illicit drug users, screening, interviewing and counseling, the referral to treatment, and the dental and periodontal management. With regard to the impact of illegal substance use on periodontal conditions, there is moderate evidence that regular long-term use of cannabis is a risk factor for periodontal disease, manifesting as a loss of periodontal attachment, deep pockets, recessions, and gingival enlargements. Limited evidence also shows that the use of cocaine can cause a series of gingival conditions that mostly presents as chemical induced-traumatic lesions (application of cocaine on the gingiva) or necrotizing ulcerative lesions. There is a scarcity of data regarding the impact of other drug use on periodontal health. There is evidence to suggest that regular long-term use of cannabis is a risk factor for periodontal disease and that the use of cocaine can cause a series of periodontal conditions. The dental treatment of subjects that use illegal substances is becoming more common in the daily clinical practice of periodontists and other dental clinicians. When the clinicians encounter such patients, it is essential to manage their addiction properly taking into consideration the impact of it on comprehensive dental treatment. Further studies and clinical observations are required to obtain sound and definitive information.

Construct validity of DSM-5 cannabis use disorder diagnosis and severity levels in adults with problematic substance use.

The DSM-5 definition of cannabis use disorder (CUD) differs from DSM-IV by combining abuse and dependence criteria (without the legal criterion) and including withdrawal and craving criteria. Information on construct validity of the DSM-5 CUD diagnosis and severity levels is lacking. This study examines the associations between DSM-5 CUD and severity classification and a set of concurrent validators. Adults with problematic substance use were recruited from two settings a research setting in an urban medical center and a suburban inpatient addiction treatment program. Participants who reported past-year cannabis use (n 392) were included in this study and completed a semi-structured, clinician-administered diagnostic interview. Regression models estimated the associations between binary DSM-5 CUD and severity levels with a set of validators, including cannabis use variables, psychopathology, and functional impairment. DSM-5 CUD and all severity levels were associated with cannabis use validators, including number of days used, self-reporting that cannabis use was a major problem, and greater cannabis craving. DSM-5 CUD and severe CUD were associated with other psychiatric disorders and social impairment. Findings add information about the validity of DSM-5 CUD diagnosis and severity levels, with severe CUD receiving the strongest support from its association with validators across all domains, as distinct from the mild and moderate CUD measures that were associated with cannabis-specific validators alone. Severe CUD is likely to require more intensive treatment to bolster physical, psychiatric, and social functioning, whereas the mild and moderate severity thresholds provide useful information for identifying less severe disorders for prevention and brief intervention.

Hypothalamic-pituitary-adrenal and sympathetic nervous system responses to social evaluative stress in chronic cannabis users and non-users.

To advance our understanding of the health-related consequences of chronic cannabis use, this study examined hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) reactivity and regulation in response to a well-characterized, acute, social evaluative stress task among cannabis users and non-users. We also explored differences in HPA-SNS coordination across the stress task in cannabis users and non-users. Participants were 75 adults (53% female) who reported no use of tobacconicotine products. Cannabis use was measured using self-report and salivaryurinary THC levels. Participants were classified as cannabis users (n 33) if they reported using cannabis at least twice per week in the prior year and had a positive salivaryurinary THC test or as non-users (n 42) if they reported no use in the prior year and had a negative THC test. During a laboratory visit, participants completed the standard Trier Social Stress Test (TSST) and provided saliva samples before, and 5, 20, and 40 min after the task. Samples were assayed for salivary cortisol and alpha-amylase (sAA) as indices of HPA axis and SNS activity, respectively. Multilevel piecewise growth models revealed that, relative to non-users, cannabis users showed (a) blunted cortisol reactivity and recovery to the TSST, and (b) greater reductions in sAA concentrations following the TSST. Chronic cannabis users may exhibit blunted HPA axis responses and greater SNS recovery to acute psychosocial stress. Implications of individual differences in stress reactivity and regulation for the biobehavioral health of chronic cannabis users are discussed.

Animal Behavior in Psychedelic Research.

Psychedelic-assisted psychotherapy holds great promise in the treatment of mental health disorders. Research into 5-hydroxytryptamine 2A receptor (5-HT

Psychedelics therapeutics What we know, what we think, and what we need to research.

Psychedelic therapy is perhaps the most exciting new development in psychiatry. Not only does it offer a radical new approach to treatment where mainstream approaches have proven ineffective, but the growing evidence for transdiagnostic efficacy is eliciting a re-think of current diagnostic and symptom-specific approaches to psychiatry. This excitement has led to a massive investment in this field with many tens of new pharmaceutical companies being set up to research the effects of known psychedelics and develop new patentable molecules. Whilst this enthusiasm is to be welcomed, it is important that new research is properly grounded in established facts and reflects current knowledge. In this commentary we lay out the knowledge framework that should be taken into account by all innovative researchers in this field.

The influence of parent and peer disapproval on youth marijuana use mediated by youth risk perception Focusing on the state comparison.

The prevention of youth marijuana use has become a national priority in the United States. This study examined the influence of parent and peer disapproval on youth marijuana use, mediated by youth risk perception. Because the legal status of marijuana use can influence individual perceptions of the drug, this study investigated differences in the mediating mechanism between youth living in states with medical marijuana legalization (MML) and those living in non-MML states. The 2019 National Survey of Drug Use and Health was used with a youth population aged 12-17 years (N 2293). Structural equation modeling and bias-corrected bootstrapping were used to examine hypothesized path models and to evaluate the mediating effect of youth risk perception. Findings demonstrated that parent and peer disapproval significantly increased youth risk perception of marijuana and reduced youth marijuana use. Second, youth risk perception significantly mediated the association between parent and peer disapproval and youth marijuana use. Third, parent disapproval had a more significant direct effect on youth marijuana use, while peer disapproval had a more significant indirect effect on youth marijuana use via youth risk perception. Finally, the results showed a similar pattern in the mechanism between youths living in MML states compared with those in non-MML states in terms of significance and direction. The findings suggested a need for improvements in marijuana related policies for both MML and non-MML states. Moreover, parent and peer focused strategies for education and prevention concerning marijuana use among youth are emphasized.

Assessment of dependence potential and abuse liability of Δ

Delta-8-tetrahydrocannabinol (Δ

Graphene oxideMIL 101(Cr) (GOMOF) nano-composite for adsorptive removal of 2,4-dichlorophenoxyacetic acid (2,4 D) from aqueous media synthesis, characterization, kinetic and isotherm studies.

Contamination of water resources with various pollutants and therefore lack of clean water resources are major problems that threaten many human societies. The need to develop efficient methods and materials to decontaminate water resource is an undeniable fact. Metal-organic frameworks (MOFs), as new class of highly crystalline porous solids, have attracted a great deal of attention in different research fields, especially in adsorptive removal and purification. In this study, MIL 101(Cr) MOF decorated with graphene oxide nano-layers (GOMOF) was synthesized by a simple one-pot hydrothermal method. Scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and electron dispersion energy (EDS) were utilized to approve the growing of Cr-MOF on graphene oxide nano-layer. The synthesized nano-composite was used as a potential adsorbent for the removal of a pesticide, 2, 4-dichlorophenoxyacetic acid (2,4 D). The adsorption performance, kinetic and mechanism of 2,4 D adsorption onto GOMOF were studied. The highest adsorption capacities of 476.9 mg g

Semiquantitative Screening of THC Analogues by Silica Gel TLC with an Ag(I) Retention Zone and Chromogenic Smartphone Detection.

With the ever-evolving cannabis industry, low-cost and high-throughput analytical methods for cannabinoids are urgently needed. Normally, (potentially) psychoactive cannabinoids, typically represented by Δ9-tetrahydrocannabinol (Δ9-THC), and nonpsychoactive cannabinoids with therapeutic benefits, typically represented by cannabidiol (CBD), are the target analytes. Structurally, the former (tetrahydrocannabinolic acid (THCA), cannabinol (CBN), and THC) have one olefinic double bond and the latter (cannabidiolic acid (CBDA), cannabigerol (CBG), and CBD) have two, which results in different affinities toward Ag(I) ions. Thus, a silica gel thin-layer chromatography (TLC) plate with the lower third impregnated with Ag(I) ions enabled within minutes a digital chromatographic separation of strongly retained CBD analogues and poorly retained THC analogues. The resolution (

Animal evidence considered in determination of cannabis smoke and Δ

On December 11, 2019, Californias Developmental and Reproductive Toxicant Identification Committee (DARTIC) met to consider the addition of cannabis smoke and Δ While the HID included both human and animal data, this set of three reviews will highlight the animal-derived data pertaining to somatic development (Part I), neurodevelopmental effects (Part II), and proposed neurodevelopmental mechanisms of action (Part III). Endogenous cannabinoids (eCBs) and their receptors serve many critical functions in normal development. Δ In reaching its decision to list cannabis and Δ

Harmine, an inhibitor of the type III secretion system of

New therapeutic strategies for clinical

Neurovascular Uncoupling Multimodal Imaging Delineates the Acute Effects of 3,4-Methylenedioxymethamphetamine.

Psychedelic compounds such as 3,4-methylenedioxymethamphetamine (MDMA) have attracted increasing interest in recent years because of their therapeutic potential in psychiatric disorders. To understand the acute effects of psychedelic drugs in vivo, blood-oxygenation-level-dependent (BOLD) functional MRI (fMRI) has been widely used. In particular, fMRI studies have suggested that MDMA leads to inhibition of brain activity, challenging previous hypotheses indicating mainly excitatory effects based, among others, on increased metabolism shown by

In vivo investigation of the inhibitory effect of Peganum harmala L. and its major alkaloids on ethylene glycol-induced urolithiasis in rats.

Peganum harmala L. is a traditional medicinal plant used for centuries in folk medicine. It has a wide array of therapeutic attributes, which include hypoglycemic, sedative, anti-inflammatory, and antioxidant properties. The fruit decoction of this plant was claimed by Avicenna as traditional therapy for urolithiasis. Also, P. harmala seed showed a clinical reduction in kidney stone number and size in patients with urolithiasis. In light of the above-mentioned data, the anti-urolithiatic activities of the seed extracts and the major β-carboline alkaloids of P. harmala were investigated. Extraction, isolation, and characterization of the major alkaloids were performed using different chromatographic and spectral techniques. The in vivo anti-urolithiatic action was evaluated using ethylene glycol (EG)-induced urolithiasis in rats by studying their mitigating effects on the antioxidant machinery, serum toxicity markers (i.e. nitrogenous waste, such as blood urea nitrogen, uric acid, urea, and creatinine), minerals (such as Ca, Mg, P, and oxalate), kidney injury marker 1 (KIM-1), and urinary markers (i.e. urine pH and urine output). Two major alkaloids, harmine (P1) and harmalacidine HCl (P2), were isolated and in vivo evaluated alongside the different extracts. The results showed that P. harmala and its constituentsfractions significantly reduced oxidative stress at 50 mgkg body weight, p.o., as demonstrated by increased levels of glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx), and catalase (CAT) in kidney homogenate as compared to the EG-treated group. Likewise, the total extract, pet. ether fraction, n-butanol fraction, and P1, P2 alleviated malondialdehyde (MDA) as compared to the EG-treated group. Serum toxicity markers like blood urea nitrogen (BUN), creatinine, uric acid, urea, kidney injury molecule-1 (Kim-1), calcium, magnesium, phosphate, and oxalate levels were decreased by total extract, pet. ether fraction, n-butanol fraction, P1, and P2 as compared to the EG-treated group. Inflammatory markers like NFκ-B and TNF-α were also downregulated in the kidney homogenate of treatment groups as compared to the EG-treated group. Moreover, urine output and urine pH were significantly increased in treatment groups as compared to the EG-treated group deciphering anti-urolithiatic property of P. harmala. Histopathological assessment by different staining patterns also supported the previous findings and indicated that treatment with P. harmala caused a gradual recovery in damaged glomeruli, medulla, interstitial spaces and tubules, and brown calculi materials as compared to the EG-treated group. The current research represents scientific evidence on the use of P. harmala and its major alkaloids as an effective therapy in the prevention and management of urolithiasis.

Effects of Sativex

Cognitive impairment is a common manifestation of multiple sclerosis (MS). To assess by systematic review and meta-analysis available evidence regarding the impact of nabiximols oromucosal spray on cognition in patients with MS. A systematic literature search of clinical studies (all types, any comparator) that measured cognitive function in patients with MS spasticity treated with nabiximols. Meta-analysis for cognitive endpoints was not possible due to heterogenous measurement instruments and outcomes. Meta-analysis was performed for adverse events (AEs) of special interest (cognition disorders) reported in randomized controlled trials (RCTs) of nabiximols versus placebo in patients with MS (with or without spasticity). Certainty of evidence and risk of bias were assessed. Seven clinical studies (three RCTs) directly assessing cognitive function were included in the qualitative analysis. There was no consistent evidence to suggest that nabiximols causes cognitive impairment as assessed by a range of specific psychometric instruments across cognitive domains. Thirteen double-blind, placebo-controlled RCTs (nabiximols, n 964 placebo, n 904) were included in the meta-analysis of cognitive AEs. Most cognitive AEs (30 of 32 events, 93.8%) reported with nabiximols in MS patients occurred with not in-label use, i.e., dosage >12 sprays per day andor not administered primarily for treatment of spasticity. Within the limitations of the review, we can conclude that no detrimental effects of nabiximols on cognitive function were observed in patients with MS spasticity during up to 12 months follow-up and that cognitive AEs were rare and occurred only when nabiximols was not used according to its approved label.

The use of classic psychedelics among adults a Danish online survey study.

Clinical studies report preliminary therapeutic effects of classic psychedelic drugs in several psychiatric conditions and international drug trends show increased use of these compounds. However, the epidemiology of classic psychedelic drug use in Scandinavian countries remains sparsely investigated. To this end, we investigated the patterns of use and the subjectively perceived acute and persisting effects of lysergic acid diethylamide (LSD), psilocybin, N,N-dimethyltryptamine (DMT), and mescaline, among Danish adults. An anonymous online survey with 152 items was conducted using the secure survey web application REDCap. Results were presented descriptively and as comparisons between psychedelic drugs. Five-hundred participants (30.0% female, mean age 34.5 years) were included. Classic psychedelics were mostly used with therapeutic (28.0%) or spiritual (27.2%) intentions. Sixty-seven per cent used classic psychedelics once a year or less. Most participants (56.4%) preferred using psilocybin. Classic psychedelic use was for some individuals, associated with hazardous use of alcohol (39.4%). Among participants with a psychiatric treatment history, 80.9% reported subjective improvements in symptoms following classic psychedelic use. Participants most memorable experiences were moderate-to-strong mystical-type experiences (MEQ30 mean ± SD 3.4 ± 1.0 range 1-5) and had positive persisting effects on well-being (mean ± SD 2.1 ± 1.0), social relationships (mean ± SD 1.7 ± 1.2), meaning of life (mean ± SD 1.9 ± 1.1), and mood (mean ± SD 1.8 ± 1.1) range -3 to 3. DMT users experienced significantly greater subjective positive effects. Classic psychedelics were mostly used therapeutically or spiritually and had self-reported positive persisting effects, but were also associated with hazardous use of alcohol, among Danish adults. DMT was associated with significantly greater positive effects compared to LSD and psilocybin.

Embracing sensorimotor history Time-synchronous and time-unrolled Markov blankets in the free-energy principle.

The free-energy principle (FEP) builds on an assumption that sensor-motor loops exhibit Markov blankets in stationary state. We argue that there is rarely reason to assume a systems internal and external states are conditionally independent given the sensorimotor states, and often reason to assume otherwise. However, under mild assumptions internal and external states are conditionally independent given the sensorimotor

Psychedelics Their Limited Understanding and Future in the Treatment of Chronic Pain.

Psychedelics are hallucinogenic drugs that alter the state of consciousness substantially. They bring about psychological, auditory, and visual changes. The psychedelics act on the brain, implying that they have a powerful psychological impact. One of the main factors contributing to disability worldwide is pain. The majority of people deal with pain on a daily basis. Living with chronic pain affects daily life and has social implications. Chronic pain can be associated with any disease that may be genetic, idiopathic, or traumatic. The standard management of pain is done with pharmacological intervention and physical therapy. However, with time, patients may become resistant to a particular class of drugs. As these drugs do not help in treating the cause of pain, they act by blocking receptors and suppressing nervous systems, as this pharmacological intervention is not a permanent solution for pain management. Long-term use of the pharmacological intervention, which acts by suppressing the nervous system, may develop other side effects on the body. These standard therapies are not as effective in managing pain. The opioid class of drugs has good pain-relieving properties but causes addiction it needs therapeutic drug monitoring to monitor that it is not abused. Since the first synthetic psychedelic was developed, until today, we have had a fair chance to understand its effects and side effects.​These drugs are very potent and effective. They have shown promising developments in the field of clinical psychology. There is upcoming research on psychedelics use in treating pain disorders. In this article, let us understand the effect of psychedelic drugs on the brain and body and how they modulate pain. Even today, the precise mechanism of chronic pain is still not understood completely. Psychedelics application and uses in future medicine and pain management are being studied. Understanding psychedelics effects on the brain and how they function allows us to link how they might be used to treat chronic pain.

Getting to the Root Ayahuasca Ceremony Leaders Perspectives on Eating Disorders.

Given the mortality, chronicity, and treatment drop-out rates observed among individuals with eating disorders (EDs), innovative approaches are needed. Ayahuasca, a psychedelic plant medicine from the Amazon, is currently being investigated. This study expands on prior exploratory research by describing the perspectives of ayahuasca ceremony leaders regarding their conceptualizations of EDs and the potential therapeutic mechanisms of action of ayahuasca for individuals with EDs. Qualitative content analysis of interviews with 15 ayahuasca ceremony leaders produced two main categories, with relevant subcategories. The first category encompassed the leaders theories of EDs from a shamanic perspective, including that EDs are symptomatic of an underlying concern, serve a function and affect health in multiple domains. The second category described leaders perspectives on the potential mechanisms of action of ayahuasca for EDs, including that ayahuasca facilitates energetic healing helps identify, process, and integrate the root of the ED promotes holistic healing and enhances andor reorganizes relationships. From the perspectives of ceremony leaders and consistent with previous exploratory research, ceremonial ayahuasca use may offer a potentially useful, novel and complementary intervention for EDs.

Bespoke library docking for 5-HT

There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally

Prenatal THC Exposure Induces Sex-Dependent Neuropsychiatric Endophenotypes in Offspring and Long-Term Disruptions in Fatty-Acid Signaling Pathways Directly in the Mesolimbic Circuitry.

Despite increased prevalence of maternal cannabis use, little is understood regarding potential long-term effects of prenatal cannabis exposure (PCE) on neurodevelopmental outcomes. While neurodevelopmental cannabis exposure increases the risk of developing affectivemood disorders in adulthood, the precise neuropathophysiological mechanisms in male and female offspring are largely unknown. Given the interconnectivity of the endocannabinoid (ECb) system and the brains fatty acid pathways, we hypothesized that prenatal exposure to Δ

Prenatal marijuana exposure and neonatal outcomes a retrospective cohort study.

Previous literature on the effects of marijuana exposure on neonatal outcomes has been limited by the reliance on maternal self-report. The objective of this study was to examine the relationship of prenatal marijuana exposure on neonatal outcomes in infants with marijuana exposure confirmed with meconium drug testing. Retrospective cohort study. Meconium drug screens obtained on infants born in a hospital system in the Pacific Northwest in the USA over a 2.5-year period. 1804 meconium drug screens were initially obtained, with 1540 drug screens included in the analysis. Neonates with meconium drug screens positive for delta-9-tetrahydrocannabinol (THC) only were compared with neonates with negative drug screens. The following neonatal outcomes were examined gestational age, preterm birth (<37 weeks), birth weight, low birth weight (defined as birth weight <2.5 kg), length, head circumference, Apgar scores and admission to the neonatal intensive care unit (NICU). Using multivariable logistical and linear regression, we controlled for confounding variables. 1540 meconium drug screens were included in the analysis, with 483 positive for delta-9-THC only. Neonates exposed to delta-9-THC had significantly lower birth weight, head circumference and length (p<0.001). Neonates with THC exposure had 1.9 times the odds (95% CI 1.3 to 2.7, p0.001) of being defined as low birth weight. Birth weight was on average 0.16 kg lower (95% CI 0.10 to 0.22, p<0.001) in those exposed to THC. Prenatal marijuana exposure was significantly associated with decreases in birth weight, length and head circumference, and an increased risk of being defined as low birth weight. These findings add to the previous literature demonstrating possible negative effects of prenatal marijuana use on neonatal outcomes.

Absence of Relevant Thermal Conversion of Cannabidiol to Tetrahydrocannabinol in E-Cigarette Vapor and Low-Tetrahydrocannabinol Cannabis Smoke.

Medical Cannabis Patients Report Improvements in Health Functioning and Reductions in Opiate Use.

Non-sedative cortical EEG signatures of allopregnanolone and functional comparators.

Neurosteroids that positively modulate GABA

Synthesis of mesoporous-structured MIL-68(Al)MCM-41-NH

Here, we report a novel amino-modified mesoporous-structured aluminum-based metal-organic framework adsorbent, MIL-68(Al)MCM-41-NH

Nitrovinylindoles as Heterotrienes Electrocyclic Cyclization En Route to β-Carbolines Total Synthesis of Alkaloids Norharmane, Harmane, and Eudistomin N.

Unusual cascade transformation was developed involving microwave assisted electrocyclic cyclization of aci (alkylideneazinic acid) forms of nitrovinylindoles acting as heterotrienes. Subsequent one-pot reduction allowed for efficient access to β-carbolines, including several natural products, alkaloids norharmane, harmane and eudistomin N.