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State T21, Restrictions on Flavored E-Cigarette Products, and Non-Medical Cannabis Sales Legalization in Relation to Young Adult Reports of Vape Shop Age Verification and Product Offerings A Multilevel Analysis.

Vape shop practices related to age verification and product offerings (e.g., other tobacco, cannabis), which may affect young-adult tobaccosubstance use, are likely impacted by state-level policies (i.e., Tobacco 21 T21, flavored e-cigarette restrictions, non-medical cannabis legalization). Using data from young adults (18-34 years) in 6 US states representing variability in whetherwhen they implemented the aforementioned policies, this study focused on past 6-month e-cigarette users who visited vape shops (Wave 1 W1 September-December 2018,

Evaluating the attitudes of mental health professionals towards trials of MDMA a randomised vignette trial.

To compare attitudes of mental health (MH) professionals towards trials of methylenedioxymethamphetamine-assisted psychotherapy (MDMA-AP), with a neutrally labelled pharmacotherapy trial. A randomised controlled vignette study design, with experimenters blinded to group condition. Participants were recruited online via professional societies. Psychiatrists, psychologists and MH researchers from across Australia. Participants were randomly allocated to read a vignette about a trial of either MDMA-AP or a neutrally labelled pharmacotherapy. Comparison of the difference in four attitudes towards MDMA-AP and control How likely they were to (1) recommend participating, or (2) object to participating in the trial (3) their predicted efficacy and (4) concerns about the safety of the trial. There were no overall differences between professionals attitudes towards MDMA-AP (n51) and the control pharmacotherapy (n43) trial vignettes. Psychiatrists were less likely to recommend participation in the MDMA-AP than the control trial ( Psychiatrists, but not psychologists or researchers showed more hesitancy in recommending trials of MDMA-AP versus an unknown pharmacotherapy. Experienced MH professionals were more likely to have negative views about MDMA-AP trials than less experienced MH professionals. This may reflect the experience of prior unfulfilled pharmacotherapy innovation or exuberance associated with fewer years of practice. Research into, and implementation of, MDMA-AP may face barriers with certain MH professionals, which will need be addressed if MDMA-AP continues to show promise as an efficacious treatment. The study design was registered with the ANZCTR (ACTRN12620001068954).

Drug testing in the era of new psychoactive substances.

Traditional clinical toxicology involves the analysis of patient urine samples by immunoassays designed to detect opiatesopioids, amphetaminemethamphetamine, benzodiazepines, barbiturates, cocaine metabolite and tetrahydrocannabinol. Expanded drug screens may also include assays for oxycodone, buprenorphine, methadone, 6-monoacetylmorphine, phencyclidine and fentanyl. Patient samples that are positive are commonly reflexed to be run on a liquid chromatography-tandem mass spectrometry confirmatory assay, as are samples that are negative for drugs that are prescribed to the patient. These mass spectrometry assays are targeted and so only detect the drugs or drug metabolites that they were designed to detect. With the explosion of new psychoactive substances in the past decade, it has become necessary for clinical laboratories to reevaluate traditional targeted drug screening approaches. The utility of high-resolution mass spectrometry in this arena has been recognized and this review will discuss the traditional approach to, and the recent advances in clinical toxicology including data collection and interrogation strategies for new psychoactive substances using high-resolution mass spectrometry (HRMS). Various modes of data processing techniques including targeted analysis, suspect screening and non-targeted analysis will also be described using HRMS. Several published methods will be described to demonstrate the utility of various data acquisition and processing techniques using HRMS in NPS analysis specifically.

Chronic prenatal delta-9-tetrahydrocannabinol exposure adversely impacts placental function and development in a rhesus macaque model.

Cannabis use in pregnancy is associated with adverse perinatal outcomes, which are likely mediated by the placenta. However, the underlying mechanisms and specific vasoactive effects of cannabis on the placenta are unknown. Our objective was to determine the impact of chronic prenatal delta-tetrahydrocannabinol (THC, main psychoactive component of cannabis) exposure on placental function and development in a rhesus macaque model using advanced imaging. Animals were divided into two groups, control (CON, n 5) and THC-exposed (THC, n 5). THC-exposed animals received a THC edible daily pre-conception and throughout pregnancy. Animals underwent serial ultrasound and MRI at gestational days 85 (G85), G110, G135 and G155 (full term is G168). Animals underwent cesarean delivery and placental collection at G155 for histologic and RNA-Seq analysis. THC-exposed pregnancies had significantly decreased amniotic fluid volume (p < 0.001), placental perfusion (p < 0.05), and fetal oxygen availability (p < 0.05), all indicators of placental insufficiency. Placental histological analysis demonstrated evidence of ischemic injury with microinfarctions present in THC-exposed animals only. Bulk RNA-seq demonstrated that THC alters the placental transcriptome and pathway analysis suggests dysregulated vasculature development and angiogenesis pathways. The longer-term consequences of these adverse placental findings are unknown, but they suggest that use of THC during pregnancy may deleteriously impact offspring development.

Cannabinoid receptor 2 (Cb2r) mediates cannabinol (CBN) induced developmental defects in zebrafish.

Of the three primary cannabinoids in cannabis Δ

Ketamine triggers a switch in excitatory neuronal activity across neocortex.

The brain can become transiently disconnected from the environment while maintaining vivid, internally generated experiences. This so-called dissociated state can occur in pathological conditions and under the influence of psychedelics or the anesthetic ketamine (KET). The cellular and circuit mechanisms producing the dissociative state remain poorly understood. We show in mice that KET causes spontaneously active neurons to become suppressed while previously silent neurons become spontaneously activated. This switch occurs in all cortical layers and different cortical regions, is induced by both systemic and cortical application of KET and is mediated by suppression of parvalbumin and somatostatin interneuron activity and inhibition of NMDA receptors and HCN channels. Combined, our results reveal two largely non-overlapping cortical neuronal populations-one engaged in wakefulness, the other contributing to the KET-induced brain state-and may lay the foundation for understanding how the brain might become disconnected from the surrounding environment while maintaining internal subjective experiences.

Recreational Drug Misuse and Its Potential Contribution to Male Fertility Levels Decline A Narrative Review.

Recreational drug intake may be associated with a range of medical untoward consequences, including male infertility. However, as the related evidence is still limited, the main outcome of this review is to provide a better understanding of the existence of any association between recreational drug misuse and male fertility levels decline. Whilst searching the MEDLINEPubMed, a comprehensive overview of the literature regarding male infertility and substances of abuse (e.g., phytocannabinoids, opiatesopioids, stimulants, herbal highs, psychedelics, and novel psychoactive substances) was here undertaken. Due to the paucity of robust, high-quality, empirical, human studies, a narrative strategy was here preferred over a systematic approach. Relevant data are qualitatively analyzed and presented in a table. Although most available evidence is in support of a detrimental role of cannabis on human spermatogenesis, a few remaining studies failed to document any effect of this drug on seminal quality, and it is not clear to which extent this drug impacts fertility ratestime to pregnancy. The current understanding of the impact of opiate-, cocaine- and amphetaminestimulant-misuse on human reproduction is widely unknown, and most studies dealing with this matter represent only an extrapolation of data derived from specific clinical circumstances. Although the message of no smoking, no alcohol and no street drugs should always be offered as good health advice to all patients seeking medical help for fertility issues, robust scientific clinical evidence in support of a direct detrimental impact of recreational drugs on spermatogenesis is scant to date.

Antibodies against SARS-CoV-2 S and N proteins in relapsing-remitting multiple sclerosis patients treated with disease-modifying therapies.

The course of COVID-19 in people with multiple sclerosis (PwMS) has been described, while the serological status after SARS-CoV-2 infection or vaccination, especially in patients treated with disease-modifying therapies (DMT), is still under investigation. This is a significant clinical problem, as certain DMTs may predispose to a severe course of viral infections. We analyzed the presence of antibodies against spike (S) and nucleocapsid (N) proteins of SARS-CoV-2 in relapsing-remitting PwMS treated with DMT, especially dimethyl fumarate, interferon beta, and glatiramer acetate, in a single multiple sclerosis (MS) centre in north-eastern Poland (the Department of Neurology, Medical University of Bialystok). The presence of antibodies against S and N proteins in PwMS was assessed twice on visit one (between May and June 2020) (n 186) and on visit two (between May and June 2021) (n 88). Samples were taken from 68 individuals on both visits. Demographic and clinical data was collected duration of MS, Expanded Disability Status Scale Score (EDSS), type of DMT, history of COVID-19 (positive PCR or antigen test in the past), vaccination status, and the type of vaccine. It was shown that on visit one 3.7% (n 7) PwMS were positive for IgA against S protein (IgA-S), 3.2% (n 6) for IgG against S (IgG-S) protein, and none of those examined was positive for IgG against N protein (IgG-N). On visit two, the most common detected antibodies were IgG-S (71.3% n 62), then IgA-S (65.1% n 55), and the least common was IgG-N (18.2% n 16). On visit two 20.45% of PwMS had a history of a positive SARS-CoV-2 PCR or antigen test during the last year. By the time of visit two, 42.05% (n 37) of patients who participated in visit two had been full-course vaccinated against COVID-19. It was demonstrated that vaccination against SARS-CoV-2 significantly induces the production of IgG-S and IgA-S (p < 0.0001), while no difference between vaccinated and unvaccinated patients was shown in the detection of IgG-N. There was no correlation between COVID-19 infection and antibodies against proteins S and N in the study group. Moreover, the presented study did not show any relationship between the ability to produce antibodies against the S protein with any of the used DMTs. According to our study, PwMS treated with dimethyl fumarate, interferon beta, or glatiramer acetate can efficiently produce antibodies against SARS-CoV-2 both after infection and after vaccination.

A systematic review of the efficacy, effectiveness and cost-effectiveness of workplace-based interventions for the prevention and treatment of problematic substance use.

Employee alcohol and other drug use can negatively impact the workplace, resulting in absenteeism, reduced productivity, high turnover, and worksite safety issues. As the workplace can influence employee substance use through environmental and cultural factors, it also presents a key opportunity to deliver interventions, particularly to employees who may not otherwise seek help. This is a systematic review of workplace-based interventions for the prevention and treatment of problematic substance use. Five databases were searched for efficacy, effectiveness andor cost-effectiveness studies and reviews published since 2010 that measured use of psychoactive substances (i.e., alcohol, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, and stimulants) as a primary or secondary outcome, in employees aged over 18. Thirty-nine articles were identified, 28 describing primary research and 11 reviews, most of which focused solely on alcohol use. Heterogeneity between studies with respect to intervention and evaluation design limited the degree to which findings could be synthesized, however, there is some promising evidence for workplace-based universal health promotion interventions, targeted brief interventions, and universal substance use screening. The few studies that examined implementation in the workplace revealed specific barriers including lack of engagement with e-health interventions, heavy use and reluctance to seek help amongst male employees, and confidentiality concerns. Tailoring interventions to each workplace, and ease of implementation and employee engagement emerged as facilitators. Further high-quality research is needed to examine the effectiveness of workplace substance use testing, Employee Assistance Programs, and strategies targeting the use of substances other than alcohol in the workplace. httpswww.crd.york.ac.ukprosperodisplayrecord.phpRecordID227598, PROSPERO CRD42021227598.

The Altered States Database Psychometric data from a systematic literature review.

In this paper, we present the development of the Altered States Database (ASDB), an open-science project based on a systematic literature review. The ASDB contains psychometric questionnaire data on subjective experiences of altered states of consciousness (ASC) induced by pharmacological and non-pharmacological methods. The systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Scientific journal articles were identified through PubMed and Web of Science. We included studies that examined ASC using the following validated questionnaires Altered States of Consciousness Rating Scale (APZ, 5D-ASC, 11-ASC), Phenomenology of Consciousness Inventory (PCI), Hallucinogen Rating Scale (HRS), or Mystical Experience Questionnaire (MEQ30). The systematic review resulted in the inclusion of a total of 165 journal articles, whereof questionnaire data was extracted and is now available on the Open Science Framework (OSF) website ( httpsosf.io8mbru ) and on the ASDB website ( httpalteredstatesdb.org ), where questionnaire data can be easily retrieved and visualized. This data allows the calculation of comparable psychometric values of ASC experiences and of dose-response relationships of substances inducing ASC.

Cannabis use in pregnancy and maternal and infant outcomes A Canadian cross-jurisdictional population-based cohort study.

With the recent legalization of cannabis in Canada, there is an urgent need to understand the effect of cannabis use in pregnancy. Our population-based study investigated the effects of prenatal cannabis use on maternal and newborn outcomes, and modification by infant sex. The cohort included 1,280,447 singleton births from the British Columbia Perinatal Data Registry, the Better Outcomes Registry Network Ontario, and the Perinatal Program Newfoundland Labrador from April 1st, 2012 to March 31st, 2019. Logistic regression determined the associations between prenatal cannabis use and low birth weight, small-for-gestational age, large-for-gestational age, spontaneous and medically indicated preterm birth, very preterm birth, stillbirth, major congenital anomalies, caesarean section, gestational diabetes and gestational hypertension. Models were adjusted for other substance use, socio-demographic and-economic characteristics, co-morbidities. Interaction terms were included to investigate modification by infant sex. The prevalence of cannabis use in our cohort was approximately 2%. Prenatal cannabis use is associated with increased risks of spontaneous and medically indicated preterm birth (1.801.68-1.93 and 1.941.77-2.12, respectively), very preterm birth (1.731.48-2.02), low birth weight (1.901.79-2.03), small-for-gestational age (1.211.16-1.27) and large-for-gestational age (1.061.01-1.12), any major congenital anomaly (1.711.49-1.97), caesarean section (1.131.09-1.17), and gestational diabetes (1.321.23-1.42). No association was found for stillbirth or gestational hypertension. Only small-for-gestational age (p 0.03) and spontaneous preterm birth (p 0.04) showed evidence of modification by infant sex. Prenatal cannabis use increases the likelihood of preterm birth, low birth weight, small-for-gestational age and major congenital anomalies with prenatally exposed female infants showing evidence of increased susceptibility. Additional measures are needed to inform the public and providers of the inherent risks of cannabis exposure in pregnancy.

Long-Term Outcomes of Adolescent THC Exposure on Translational Cognitive Measures in Adulthood in an Animal Model and Computational Assessment of Human Data.

Although perceived as relatively harmless and nonaddictive, adolescent cannabis use significantly increases the likelihood of developing cannabis use disorder in adulthood, especially for high-potency cannabis. Risky decision-making is associated with chronic cannabis use, but given confounds of human studies, it remains unclear whether adolescent cannabis exposure and Δ9-tetrahydrocannabinol (THC) potency specifically predicts risky decision-making or influences cognitive response to the drug later in life. To leverage a human data set of cannabis users and a rat model to evaluate the long-term outcomes of adolescent THC exposure on adult decision-making and impulse control. This translational rat study tested the link between adolescent THC exposure and adulthood decision-making. A reanalysis of a previously published dataset of human chronic cannabis users was conducted to evaluate decision-making phenotypes. Computational modeling assessed the human and animal results in a single framework. Data were collected from 2017 to 2020 and analyzed from 2020 to 2022. Decision-making was measured by the Iowa Gambling Task (IGT) and Rat Gambling Task (rGT). Impulse control was assessed in the rat model. Computational modeling was used to determine reward and punishment learning rates and learning strategy used by cannabis users and THC-exposed rats. Cell-specific molecular measures were conducted in the prefrontal cortex and amygdala. Of 37 participants, 24 (65%) were male, and the mean (SD) age was 33.0 (8.3) years. Chronic cannabis users (n 22 mean SE IGT score, -5.182 1.262) showed disadvantageous decision-making compared with controls (n 15 mean SE IGT score, 7.133 2.687 Cohen d 1.436). Risky choice was associated with increased reward learning (mean SE IGT score cannabis user, 0.170 0.018 control, 0.046 0.008 Cohen d 1.895) and a strategy favoring exploration vs long-term gains (mean SE IGT score cannabis user, 0.088 0.012 control, 0.020 0.002 Cohen d 2.218). Rats exposed to high-dose THC but not low-dose THC during adolescence also showed increased risky decision-making (mean SE rGT score vehicle, 46.17 7.02 low-dose THC, 69.45 6.01 high-dose THC, 21.97 11.98 Cohen d 0.433) and elevated reward learning rates (mean SE rGT score vehicle, 0.17 0.01 low-dose THC, 0.10 0.01 high-dose THC, 0.24 0.06 Cohen d 1.541) during task acquisition. These animals were also uniquely susceptible to increased cognitive impairments after reexposure to THC in adulthood, which was correlated with even greater reward learning (r -0.525 P < .001) and a shift in strategy (r 0.502 P < .001), similar to results seen in human cannabis users. Molecular studies revealed that adolescent THC dose differentially affected cannabinoid-1 receptor messenger RNA expression in the prelimbic cortex and basolateral amygdala in a layer- and cell-specific manner. Further, astrocyte glial fibrillary acidic protein messenger RNA expression associated with cognitive deficits apparent with adult THC reexposure. In this translational study, high-dose adolescent THC exposure was associated with cognitive vulnerability in adulthood, especially with THC re-exposure. These data also suggest a link between astrocytes and cognition that altogether provides important insights regarding the neurobiological genesis of risky cannabis use that may help promote prevention and treatment efforts.

Exploratory investigation of a patient-informed low-dose psilocybin pulse regimen in the suppression of cluster headache Results from a randomized, double-blind, placebo-controlled trial.

Using a patient-informed regimen, we conducted an exploratory randomized, double-blind, placebo-controlled study to systematically investigate the effects of psilocybin in cluster headache. Sustained reductions in cluster headache burden after limited quantities of psilocybin-containing mushrooms are anecdotally reported, although to date there are no controlled studies investigating these effects. Participants were randomized to receive psilocybin (0.143 mgkg) or placebo (microcrystalline cellulose) in a pulse of three doses, each 5 days apart. Participants maintained headache diaries starting 2 weeks before and continuing through 8 weeks after the first drug session. A total of 16 participants were randomized to receive experimental drug and 14 were included in the final analysis. In the 3 weeks after the start of the pulse regimen, the change in cluster attack frequency was 0.03 (95% confidence interval CI -2.6 to 2.6) attacksweek with placebo (baseline 8.9 95% CI 3.8 to 14.0) and -3.2 (95% CI -8.3 to 1.9) attacksweek with psilocybin (baseline 9.6 95% CI 5.6 to 13.6 p 0.251). Group difference in change from baseline had a moderate effect size (d 0.69). The effect size was small in episodic participants (d 0.35) but large in chronic participants (d 1.25), which remained over the entire 8-week period measured (d 0.81). Changes in cluster attack frequency were not correlated with the intensity of acute psychotropic effects during psilocybin administration. Psilocybin was well-tolerated without any unexpected or serious adverse events. Findings from this initial, exploratory study provide valuable information for the development of larger, more definitive studies. Efficacy outcomes were negative, owing in part to the small number of participants. The separation of acute psychotropic effects and lasting therapeutic effects underscores the need for further investigation into the mechanism(s) of action of psilocybin in headache disorders.

Regular cannabis use modulates the impact of HIV on the neural dynamics serving cognitive control.

Cannabis use and HIV are independently associated with decrements in cognitive control. However, the combined effects of HIV and regular cannabis use on the brain circuitry serving higher-order cognition are unclear. Investigate the interaction between cannabis and HIV on neural interference effects during the flanker task and spontaneous activity in regions underlying higher-order cognition. The sample consisted of 100 participants, including people with HIV (PWH) who use cannabis, PWH who do not use cannabis, uninfected cannabis users, and uninfected nonusers. Participants underwent an interview regarding their substance use history and completed the Eriksen flanker task during magnetoencephalography (MEG). MEG data were imaged in the time-frequency domain and oscillatory maps depicting the neural flanker interference effect were probed for group differences. Voxel time series were then assessed for group-level differences in spontaneous activity. Group differences in behavioral performance were identified along with group differences in theta and alpha neural interference responses in higher-order regions across the cortex, with nonusers with HIV generally exhibiting the most aberrant responses. Likewise, time series analyses indicated that nonusers with HIV also had significantly elevated spontaneous alpha activity in the left inferior frontal and dorsolateral prefrontal cortices (dlPFC). Finally, we found that spontaneous and oscillatory alpha activity were significantly coupled in the inferior frontal cortex and dlPFC among cannabis users, but not nonusers. Regular cannabis use appears to suppress the impact of HIV on spontaneous and oscillatory alpha deficits in the left inferior frontal cortex and dlPFC.

Effect of lysergic acid diethylamide (LSD) on reinforcement learning in humans.

The non-selective serotonin 2A (5-HT Healthy volunteers received intravenous LSD (75 Raw data measures assessing sensitivity to immediate feedback (win-stay and lose-shift probabilities) were unaffected, whereas LSD increased the impact of the strength of initial learning on perseveration. Computational modelling revealed that the most pronounced effect of LSD was the enhancement of the reward learning rate. The punishment learning rate was also elevated. Stimulus stickiness was decreased by LSD, reflecting heightened exploration. Reinforcement sensitivity differed by phase. Increased RL rates suggest LSD induced a state of heightened plasticity. These results indicate a potential mechanism through which revision of maladaptive associations could occur in the clinical application of LSD.

Effects of 3,4-methylenedioxymethamphetamine and methamphetamine on motor vehicle driving performance A systematic review of experimental and observational studies.

Methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) are common drugs of abuse and driving under their influence may occur in 1 million people yearly in the United States. This systematic review fills the currently unmet need in understanding the effects of METH and MDMA on motor vehicle driving performance (MVP) and provides insight into the forensic community. A PubMed search on September 24, 2020, for experimental and observational studies, which evaluated the impact of METH and MDMA on MVP was performed. After a review of 208 abstracts, 103 were considered potentially interesting and full texts were obtained. After the exclusion of non-English articles, review articles, single case reports, and articles which did not evaluate METH or MDMA on MVP, a total of nine experimental studies, 10 traditional observational studies, and 35 case series were included. The clinical rigor of experimental studies was evaluated using the Jadad scale. Experimental studies often demonstrated no significant MVP safety signals for METH or MDMA use, which was contrary to the overwhelming MVP safety risks found in observational studies. Common driving behaviors while using METH or MDMA include errors in judgment, traveling at high speeds, failure to stop, merging inappropriately, lane weaving, and crashes. Limitations of experimental studies that led to dissimilar MVP outcomes from observational studies include the common use of driving simulators, as opposed to actual driving examinations, and doses of METH or MDMA administered may not be representative of blood concentrations seen in observational studies. This systematic review has no funding source and was not registered.

A Systematic Review of Medical Cannabinoids Dosing in Human.

This systematic review assesses currently available clinical information on which cannabinoids and what range of doses have been used to achieve positive effects in a diversity of medical context. The data were collected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol guidelines. Inclusion criteria were articles that assessed administration of any cannabinoid to any clinical population, reported in the ClinicalTrials.gov or PubMed databases, that involved a comparison with other treatment or placebo and a result measurement to assess the effectiveness or ineffectiveness of the cannabinoid. Exclusion criteria were review or letter articles not in the English language not full-text articles not a clinical trial, case report, case series, open-label trial, or pilot study administration in animals, in vitro, or in healthy participants cannabinoids administered in combination with other cannabinoids (except for cannabidiol CBD or tetrahydrocannabinol THC) or as whole cannabis extracts no stated concentration inhalation or smoke as a route of administration and no results described. The articles were assessed by the risk of bias. In total, 1668 articles were recovered, of which 55 studies met the inclusion criteria for 21 diseases. Positive effects were reported in clinical studies 52% with THC (range, 0.01-0.5 mgkgd 0.62-31 mgd), 74% with CBD (range, 1-50 mgkgd 62-3100 mgd), 64% with THC-CBD (mean, 11.3 mgkgd ratio, 11), and 100% with tetrahydrocannabivarin (THCV) (0.2 mgkgd). THC, CBD, and THCV can regulate activity in several pathologies. New studies of cannabinoids are highly encouraged because each patient is unique and requires a unique cannabinoid medication.

Substance Use Screening, Brief Intervention, and Referral to Treatment in Pediatric Primary Care, School-Based Health Clinics, and Mental Health Clinics.

Adolescent cannabis use is a modifiable health behavior with potential adverse developmental, cognitive, psychological, and health effects. Over the last 2 decades, work to promote implementation of screening, brief intervention, and referral to treatment has improved screening, use of validated screening tools, and preventive messaging. Current intervention strategies for cannabis use are associated with modest, short-term effects, and referral to treatment is limited by availability of resources for adolescent substance use. This article provides an update on the evidence base for screening, brief intervention, referral to treatment, and the current state of implementation focused on management of cannabis use disorder.

Prophylactic action of ayahuasca in a non-human primate model of depressive-like behavior.

Observational studies of long-term users of ayahuasca, an Amazonian psychedelic brew, suggest an increase in resilience

Structure-Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice.

4-Phosphoryloxy-

Therapeutic setting as an essential component of psychedelic research methodology Reporting recommendations emerging from clinical trials of 3,4-methylenedioxymethamphetamine for post-traumatic stress disorder.

Research of psychedelic assisted therapies is at an all-time high, though few studies highlight extra-pharmacological factors that may affect treatment efficacy. One critical set of attributes includes the therapeutic setting itself, which describe the physical and socio-cultural environments in which the drug-assisted session occurs. Despite enduring consensus of the influence of setting, recommendations for establishing and reporting key setting variables remain sparse across clinical trial protocols and published research methodologies. The purpose of this paper is to (1) present what is known of the influence and implications of setting to psychedelic-assisted therapies, with a particular focus on 3,4-methylenedioxymethamphetamine (MDMA) and (2) propose a set of reporting guidelines for operationalizing and reporting key setting variables in clinical trials of psychedelic-assisted therapies, based on recommendations emerging from clinical trials of MDMA for PTSD. In fact, recommendations should be expanded to set - the subjects mood, expectations, and broader psychological condition - once this is more fully developed in the field. The proposed reporting guidelines offer a means of increasing the volume and variability of data necessary for future empirical examination of key setting attributes influencing treatment efficacy, while preserving practitioner and patient autonomy to co-construct adaptive therapy settings according to their respective needs and expertise.

MDMA-assisted therapy is associated with a reduction in chronic pain among people with post-traumatic stress disorder.

Increasing evidence demonstrates 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy (MDMA-AT) may be a safe and effective treatment for post-traumatic stress disorder (PTSD). There is growing interest in MDMA-AT to address a range of other health challenges. Chronic pain and PTSD are frequently comorbid, reciprocally interdependent conditions, though the possible role of MDMA-AT in treating chronic pain remains under-investigated. The present analysis examined the impact of manualized MDMA-AT on chronic pain severity among participants with PTSD who were enrolled in a Phase 2 clinical trial investigating MDMA-AT for PTSD (NCT03282123). Exploratory data from a subset of participants who completed chronic pain measures ( Among the 32 participants included in this analysis, 59% ( Findings demonstrate a high prevalence of chronic pain in this sample of people with severe PTSD and that chronic pain scores among medium and high pain subgroups were significantly lower following MDMA-AT. While these data are preliminary, when considered alongside the frequency of comorbid chronic pain and PTSD and promising efficacy of MDMA-AT for treating PTSD, these findings encourage further research exploring the role of MDMA-AT for chronic pain.

Targeting the phosphoserine phosphatase MtSerB2 for tuberculosis drug discovery, an hybrid knowledge based fragment based approach.

Tuberculosis is currently still one of the leading causes of death from a treatable pathogen. The proportion of cases of resistance to common antibiotics is frequently increasing and the development of new drugs with new therapeutic targets is becoming necessary. The Mycobacterium tuberculosis phosphoserine phosphatase MtSerB2 is an interesting enzyme to target in drug design because of its ability to allow immune evasion of the bacteria. Research has already been carried out on this protein both from a mechanistic point of view and from the point of view of its inhibition by trisubstituted harmine derivatives. Based on this work, a new approach based on virtual screening is presented in the selection of fragment-sized harmine-derived compounds as well as chelators to target the catalytic magnesium of MtSerB2. The selection of a minimum list of fragments is explained as well as the screening cascade (DSF, Ligand-based NMR, High concentration enzymatic assay) to characterise their affinity for MtSerB2. Crystallogenesis assays have provided structural information on some promising fragments and the development of a pharmacophore model with the structural elements necessary for the development of more complex inhibitors. Ultimately, this work on fragment growth would allow the development of antimycobacterial molecules inhibiting MtSerB2 as well as the growth of the pathogen.

Adolescent Δ-9-tetrahydrocannabinol exposure induces differential acute and long-term neuronal and molecular disturbances in dorsal vs. ventral hippocampal subregions.

Chronic exposure to Δ-9-tetrahydrocannabinol (THC) during adolescence is associated with long-lasting cognitive impairments and enhanced susceptibility to anxiety and mood disorders. Previous evidence has revealed functional and anatomical dissociations between the posterior vs. anterior portions of the hippocampal formation, which are classified as the dorsal and ventral regions in rodents, respectively. Notably, the dorsal hippocampus is critical for cognitive and contextual processing, whereas the ventral region is critical for affective and emotional processing. While adolescent THC exposure can induce significant morphological disturbances and glutamatergic signaling abnormalities in the hippocampus, it is not currently understood how the dorsal vs. ventral hippocampal regions are affected by THC during neurodevelopment. In the present study, we used an integrative combination of behavioral, molecular, and neural assays in a neurodevelopmental rodent model of adolescent THC exposure. We report that adolescent THC exposure induces long-lasting memory deficits and anxiety like-behaviors concomitant with a wide range of differential molecular and neuronal abnormalities in dorsal vs. ventral hippocampal regions. In addition, using matrix-assisted laser desorptionionization imaging mass spectrometry (MALDI-IMS), we show for the first time that adolescent THC exposure induces significant and enduring dysregulation of GABA and glutamate levels in dorsal vs. ventral hippocampus. Finally, adolescent THC exposure induced dissociable dysregulations of hippocampal glutamatergic signaling, characterized by differential glutamatergic receptor expression markers, profound alterations in pyramidal neuronal activity and associated oscillatory patterns in dorsal vs. ventral hippocampal subregions.

Examining the role of cannabinoids on osteoporosis a review.

Prior research studies have shown that the endocannabinoid system, influenced by CBD and THC, plays a role in bone remodeling. As both the research on cannabis and use of cannabis continue to grow, novel medicinal uses of both its constituents as well as the whole plant are being discovered. This review examines the role of cannabinoids on osteoporosis, more specifically, the endocannabinoid system and its role in bone remodeling and the involvement of the cannabinoid receptors 1 and 2 in bone health, as well as the effects of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and synthetic cannabinoids on bone. A comprehensive literature search of online databases including PUBMED was utilized. A total of 29 studies investigating the effects of cannabis andor its constituents as well as the activation or inactivation of cannabinoid receptors 1 and 2 were included and discussed. While many of the mechanisms are still not yet fully understood, both preclinical and clinical studies show that the effects of cannabis mediated through the endocannabinoid system may prove to be an effective treatment option for individuals with osteoporosis.

Molecular study of endo and phytocannabinoids on lipid membranes of different composition.

The discovery of the endocannabinoid system (ECS) dates back only 30 years. Although many research groups have been elucidating its components, location, functions and metabolism, the peculiarities of the compounds considered neurotransmitters of ECS generate questions that have not yet been answered or controversies in the literature. In this context, we studied the molecular behaviour of the main endocannabinoid compounds and the main phytocannabinoids in eukaryotic outer and inner model membranes. The high lipophilicity of these compounds gives place to the hypothesis that cannabinoids may reach the molecular targets through the lipid bilayer. This consideration is not only for the cannabinoid receptors but also for other (many) targets that these bioactive molecules modulate (Watkins, 2019 Nelson et al., 2020 Jakowiecki and Filipek, 2016). Given the reported multitarget action of these compounds and the differential behaviour towards the different receptors, studying the properties and dynamics of these cannabinoids in POPC and POPE model membranes become relevant. In this regard, we have studied the differential modulation of the endocannabinoids anandamide and 2-arachidonoyl-glycerol and the phytocannabinoids cannabidiol and trans-Δ

Ethical Issues Regarding Nonsubjective Psychedelics as Standard of Care.

Evidence suggests that psychedelics bring about their therapeutic outcomes in part through the subjective or qualitative effects they engender and how the individual interprets the resulting experiences. However, psychedelics are contraindicated for individuals who have been diagnosed with certain mental illnesses, on the grounds that these subjective effects may be disturbing or otherwise counter-therapeutic. Substantial resources are therefore currently being devoted to creating psychedelic substances that produce many of the same biological changes as psychedelics, but without their characteristic subjective effects. In this article, we consider ethical issues arising from the prospect of such potential nonsubjective psychedelics. We are broadly supportive of efforts to produce such substances for both scientific and clinical reasons. However, we argue that such nonsubjective psychedelics should be reserved for those special cases in which the subjective effects of psychedelics are specifically contraindicated, whereas classic psychedelics that affect subjective experience should be considered the default and standard of care. After reviewing evidence regarding the subjective effects of psychedelics, we raise a number of ethical concerns around the prospect of withholding such typically positive, meaningful, and therapeutic experiences from most patients.

New mescaline-related N-acylhydrazone and its unsubstituted benzoyl derivative Promising metallophores for copper-associated deleterious effects relief in Alzheimers disease.

Alzheimers disease (AD) is related to the presence of extracellular aggregated amyloid-β peptide (Aβ), which binds copper(II) with high affinity in its N-terminal region. In this sense, two new 1-methylimidazole-containing N-acylhydrazonic metallophores, namely, X1TMP and X1Benz, were synthesized as hydrochlorides and characterized. The compound X1TMP contains the 3,4,5-trimethoxybenzoyl moiety present in the structure of mescaline, a natural hallucinogenic protoalkaloid that occurs in some species of cacti. Single crystals of X1Benz, the unsubstituted derivative of X1TMP, were obtained. The experimental partition coefficients of both compounds were determined, as well as their apparent affinity for Cu

Divergent effects of oral cannabis oil extracts marketed as C. indica or C. sativa on exertion of cognitive effort in rats.

The main psychoactive compound within the cannabis plant, Δ9-tetrahydrocannabinol (THC), is thought to drive both the sensation of high and the cognitive impairments associated with cannabis consumption. Researchers keen to understand how cannabis impairs cognition have, therefore, studied the behavioral effects of systemic injections of THC in animal models. However, cannabis contains multiple other cannabinoids which may critically modulate the resulting cognitive effects. Users also typically eat or smoke cannabis, leading to concern over the translational validity of pure THC injections. We, therefore, tested whether acute oral administration of two different commercially available cannabis extracts, marketed as

Neuroinflammation and neuroprogression in depression Effects of alternative drug treatments.

Given that available antidepressant pharmacotherapies are not optimally effective, there is a need for alternative treatment options that are rooted in a comprehensive understanding of the illnesss pathophysiology. Major depressive disorder (MDD) has been historically attributed to monoamine, i.e., serotonin (5-hydroxytryptamine, 5-HT) imbalance and some brain morphological pathologies that have directed treatment towards particular medications that are only minimally effective. MDD pathophysiologies have now been regarded as linked to chronic inflammation and MDD can be treated with compounds that have anti-inflammatory properties. Individuals vulnerable to MDD have increased baseline neuroinflammatory response that is exacerbated by psychogenic stress. When pro-inflammatory mechanisms are chronically hyperactive, dysfunction of brain-related processes occur. We propose that inflammation is one of the primary mechanisms that trigger biological changes leading to MDD. Inflammatory resolution occurs when homeostasis is achieved after an inflammatory response. However, cascading biological events are likely to prevent resolution from occurring and worsen both inflammation and MDD. Novel and alternative pharmacotherapies-e.g., ketamine, cannabinoids, and psychedelics-provide a richer mechanistic perspective on the role of neuroinflammation and neuroprogression by means of rapid, short-term, and long-term symptom relief potentially based on their anti-inflammatory properties. These drugs ultimately decrease proinflammatory cytokine levels that correspond with improved symptoms. However, it is unclear what differentiates these compounds from others in their mechanistic efficacy. Thus, a closer investigation into their anti-inflammatory effects is imperative in order to better elucidate the link between MDD and inflammation, as well as uncover the mechanisms involved in long-term symptom reduction of MDD.

Preliminary evidence of links between ayahuasca use and the corpus callosum.

Recent research suggests that ayahuasca and its alkaloid-containing ingredients may be helpful in the treatment and prevention of certain movement and neurodegenerative disorders. However, such research is still in its infancy and more studies in normative samples seem necessary to explore effects of ayahuasca on clinically relevant brain structures, such as the corpus callosum. The purpose of the present study was to investigate links between ayahuasca use and callosal structure in a normative sample. Using structural imaging data from 22 ayahuasca users and 22 matched controls we compared the thickness of the corpus callosum between both groups at 100 equidistant points across the entire midsagittal surface. In addition, we investigated point-wise correlations between callosal thickness and the number of past ayahuasca sessions. The corpus callosum was significantly thicker within the isthmus in the ayahuasca group than in the control group. There was also a significant positive correlation between callosal thickness and the number of past ayahuasca sessions within the rostral body, albeit none of these effects survived corrections for multiple comparisons. No region was significantly thicker in the control than in the ayahuasca group, and no callosal region was negatively linked to ayahuasca use, even at uncorrected significance thresholds. This study provides preliminary evidence of links between ayahuasca use and the corpus callosum. However, future studies need to replicate these findings, preferably using larger sample sizes and ideally also utilizing longitudinal research designs, to draw any practical conclusion and offer implications for follow-up clinical research.

Changes in mental health, wellbeing and personality following ayahuasca consumption Results of a naturalistic longitudinal study.

Suicidal ideation among Canadian adults during the COVID-19 pandemic the role of psychosocial factors and substance use behaviours.

Suicide is one of the most important and increasing public health agenda around the world. Since the COVID-19 pandemic, concerns have been raised about the potential adverse impacts of the pandemic on suicide-related outcomes. The main objective of this study was to examine the association of psychosocial risk factors (mental health illnesses and social isolation) and substance use behaviors (cannabis and alcohol consumption) with suicidal ideation during the COVID-19 pandemic among Canadian adults. The study was conducted based on a total of 4005 persons 18 years of age or older, living in Canadas ten provinces. The data used in this study were collected during April 20-28, 2021, by Mental Health Research Canada. Multivariable logistic regression was used to determine the association of mental health conditions (anxiety, depression, and other mood disorder) before and since COVID-19 outbreaks, social isolation and living arrangement, as well as cannabis and alcohol consumption with suicidal ideation during COVID-19. The results of adjusted logistic regression showed that the odds of suicidal ideation were 1.526 times higher (95% CI1.082-2.152) among those who reported continued negative impacts of social isolation. The odds of suicidal ideation were also higher for those who were diagnosed as having depression before (OR 3.136, 95% CI 2.376-4.138) and since the COVID-19 pandemic (OR 3.019, 95% CI1.929-4.726) and 1.627 times higher (95% CI 1.225-2.163) for those who were diagnosed as having anxiety before the COVID-19 pandemic. Those who reported having increased and those who were consuming cannabis during the pandemic were 1.970 (95% CI 1.463-2.653) and 1.509 times (95% CI 1.158-1.966) more likely to have thought of suicide than non-takers, respectively. Given the significant associations of psychosocial factors (mental health illnesses and social isolation) and cannabis use with suicidal ideation, more attention and support need to be given to adults who had mental health conditions before and since COVID-19, those who were negatively impacted by social isolation, and those are exposed to substance use (cannabis).

Cannabinoids and drug metabolizing enzymes potential for drug-drug interactions and implications for drug safety and efficacy.

Cannabis is an increasingly popular recreational and medicinal drug in the USA. While cannabis is still a Schedule 1 drug federally, many states have lifted the ban on its use. With its increased usage, there is an increased possibility for potential drug-drug interactions (DDI) that may occur with concomitant use of cannabis and pharmaceuticals. This review focuses on the current knowledge of cannabis induced DDI, with a focus on pharmacokinetic DDI arising from enzyme inhibition or induction. Phase I and phase II drug metabolizing enzymes, specifically cytochrome P450s, carboxylesterases, and uridine-5-diphosphoglucuronosyltransferases, have historically been the focus of research in this field, with much of the current knowledge of the potential for cannabis to induce DDI within these families of enzymes coming from Based upon the current literature, there is a strong potential for cannabis-induced DDI among major drug-metabolizing enzymes.

Understanding subjective experience in psychedelic-assisted psychotherapy The need for phenomenology.

Psychedelic-assisted psychotherapy is being investigated as a treatment for a range of psychiatric illnesses. Current research suggests that the kinds of subjective experiences induced by psychedelic compounds play key roles in producing therapeutic outcomes. To date, most knowledge of therapeutic psychedelic experiences are derived from psychometric assessments with scales such as the Mystical Experience Questionnaire. While these approaches are insightful, more nuanced and detailed descriptions of psychedelic-induced changes to subjective experience are required. Drawing on recent advancements in qualitative methods arising from the interdisciplinary field of phenomenological psychopathology, we propose a systematic and comprehensive investigation into how psychedelic-assisted psychotherapy alters subjective experience. This research programme aims to characterise the nature of therapeutic psychedelic experiences by drawing on concepts from philosophical phenomenology. Such characterisations should, moreover, contribute to our understanding of the mechanisms of psychedelic therapy, the role of integration therapy, and related philosophical debates.

Potential Therapeutic Effects of Psilocybin A Systematic Review.

Psilocybin is a plant alkaloid that is derived from precursors of tryptamine and is present in many different types of mushrooms. It has been utilized by indigenous peoples of Central and South America for centuries in a ceremonial setting to promote spiritual experiences. Indigenous societies have long employed psilocybin and other 5-HT 2A agonist classic psychedelics in their rites. They were a focus in psychiatry in the middle of the 20th century as both experimental medicines and tools for studying brain function. Due to the fact that traditional psychedelics were being used for purposes other than medical research and in connection with the burgeoning counterculture by the late 1960s and early 1970s, these scientific investigations fell out of favor. However, thanks to a number of encouraging studies that validated the earlier research, interest in traditional psychedelics has surged among scientists in the 21st century. In this review, we examine therapeutic studies on psilocybin, the traditional psychedelic that has received the lions share of recent attention. According to three controlled studies, psilocybin may reduce symptoms of depression and anxiety in the context of cancer-related psychological discomfort for at least six months after a single acute treatment for mood and anxiety disorders. Three months after two acute doses, individuals in a small, open-label study with treatment-resistant depression reported fewer depressive and anxiety symptoms. Small, open-label pilot studies on addiction have demonstrated encouraging success rates for alcohol and cigarette addiction. The review also briefly discusses the synthesis, mechanism of action, effects, molecular pharmacology, adverse effects, and contraindications of psilocybin.

Should we be leery of being Leary Concerns about psychedelic use by psychedelic researchers.

Psychedelic research is proceeding rapidly, despite ongoing legal and regulatory barriers and lingering questions about study design, such as the difficulty of ensuring adequate blinding, the relative overrepresentation in studies of participants who have previously used psychedelics, and the importance of personal experience with psychedelics for those who provide psychedelic-assisted therapy. Here we wish to explore a distinct concern whether personal use of psychedelics by researchers could threaten the objectivity and ethical conduct of psychedelic research itself. In 2020, Anderson et al. suggested that psychedelic use could lead even conservative individuals to become wildly enthusiastic about the potentials of psychedelics to heal and transform. Recent popular press criticisms of psychedelic science, in particular critiques of the MAPS Phase II and Phase III MDMA-Assisted Therapy trials for PTSD, have also raised questions about whether personal use of psychedelic drugs by psychedelic therapists could compromise scientific objectivity, lead to the exploitation of research subjects, or promote biased reporting of results. Here, we elaborate on and attempt to delimit these concerns, with the goal of informing policy related to psychedelic research and the eventual clinical use of psychedelics. In particular, we explore whether the possibility that psychedelic use can directly and positively affect investigators enthusiasm about psychedelics themselves raises concerns about bias and scientific integrity. We then discuss several practical strategies to reduce perceived conflict of interest.

Genuine high-order interactions in brain networks and neurodegeneration.

Brain functional networks have been traditionally studied considering only interactions between pairs of regions, neglecting the richer information encoded in higher orders of interactions. In consequence, most of the connectivity studies in neurodegeneration and dementia use standard pairwise metrics. Here, we developed a genuine high-order functional connectivity (HOFC) approach that captures interactions between 3 or more regions across spatiotemporal scales, delivering a more biologically plausible characterization of the pathophysiology of neurodegeneration. We applied HOFC to multimodal (electroencephalography EEG, and functional magnetic resonance imaging fMRI) data from patients diagnosed with behavioral variant of frontotemporal dementia (bvFTD), Alzheimers disease (AD), and healthy controls. HOFC revealed large effect sizes, which, in comparison to standard pairwise metrics, provided a more accurate and parsimonious characterization of neurodegeneration. The multimodal characterization of neurodegeneration revealed hypo and hyperconnectivity on medium to large-scale brain networks, with a larger contribution of the former. Regions as the amygdala, the insula, and frontal gyrus were associated with both effects, suggesting potential compensatory processes in hub regions. fMRI revealed hypoconnectivity in AD between regions of the default mode, salience, visual, and auditory networks, while in bvFTD between regions of the default mode, salience, and somatomotor networks. EEG revealed hypoconnectivity in the γ band between frontal, limbic, and sensory regions in AD, and in the δ band between frontal, temporal, parietal and posterior areas in bvFTD, suggesting additional pathophysiological processes that fMRI alone can not capture. Classification accuracy was comparable with standard biomarkers and robust against confounders such as sample size, age, education, and motor artifacts (from fMRI and EEG). We conclude that high-order interactions provide a detailed, EEG- and fMRI compatible, biologically plausible, and psychopathological-specific characterization of different neurodegenerative conditions.

Psychedelic-Assisted Therapy for People with Eating Disorders.

A growing body of research suggests psychedelic-assisted therapy (PAT) may be safe and effective for a variety of mental health conditions. Among these, eating disorders have been a recent target of interest. This review provides an up-to-date summary of the potential mechanisms and use of PAT in people diagnosed with eating disorders, with a focus on anorexia nervosa. Classic psychedelics may have transdiagnostic efficacy through several mechanisms relevant to eating disorder pathology. Interest in, and efforts to increase access to PAT are both high. Early clinical trials are focused on establishing the safety and utility of this treatment in eating disorders, and efficacy remains unclear. High-quality published data to support the use of PAT for people with eating disorders remains lacking. Recent studies however suggest PAT has the potential to augment the efficacy of current interventions for these difficult-to-treat conditions.

Body mass index (BMI) does not predict responses to psilocybin.

Psilocybin is a serotonin type 2A (5-HT Data were pooled across three studies using a fixed 25 mg dose of psilocybin delivered in a therapeutic context to assess whether BMI predicts characteristics of the acute experience and changes in well-being 2 weeks later. Supplementing frequentist analysis with Bayes Factors has enabled for conclusions to be drawn regarding the null hypothesis. Results support the null hypothesis that BMI does not predict overall intensity of the altered state, mystical experiences, perceptual changes or emotional breakthroughs during the acute experience. There was weak evidence for greater dread of ego dissolution in participants with lower BMI, however, further analysis suggested BMI did not meaningfully add to the combination of the other covariates (age, sex and study). While mystical-type experiences and emotional breakthroughs were strong predictors of improvements in well-being, BMI was not. These findings have important implications for our understanding of pharmacological and extra-pharmacological contributors to psychedelic-assisted therapy and for the standardization of a fixed therapeutic dose in psychedelic-assisted therapy.

Deceptively Simple Can Urine Samples from CLIA-Waived Urine Drug Screen Devices Be Reused for Confirmatory Testing

Many low-complexity urine drug screen (UDS) devices are approved by the Food and Drug Administration as waived under Clinical Laboratory Improvement Amendments (CLIA) criteria. Labeling instructs patients to urinate directly into the device and also states that positive results should be confirmed. However, the device itself may pose a risk of drug adsorption andor specimen contamination that could affect results in confirmatory assays if specimens are reused. Collecting urine in a separate container before performing the UDS would reclassify the test as nonwaived, negating the conveniences of a CLIA-waived test. Also, patients may be unable or unwilling to urinate in an additional container for confirmatory testing. This study examined reusing urine from a UDS device (NexScreen) for confirmatory testing. 25 patient specimens were pooled and verified to be drug-free. To evaluate drug leaching from the UDS device, 30 mL of this pool was incubated in NexScreen cups, followed by confirmatory testing. To evaluate drug adsorption, 14 representative analytes were spiked slightly over the NexScreen positivity cutoffs, followed by incubation in NexScreen cups and confirmation testing. All negative samples incubated in NexScreen cups remained negative upon confirmation testing, indicating that NexScreen test strips do not contaminate the specimen. For the drug adsorption experiment, 11 of 14 analytes had recoveries of at least 95%, whereas buprenorphine and 11-nor-9-carboxy-tetrahydrocannabinol recovered at 94% and 87%, respectively, suggesting minor adsorption. All analytes recovered above their respective confirmation cutoffs. Urine aliquots from NexScreen cups may be used for confirmatory testing.

Cannabinoid treatments for anxiety A systematic review and consideration of the impact of sleep disturbance.

Cannabidiols (CBD) safety profile and broad action has made it a popular treatment option for anxiety and co-occurring sleep disturbance. However, its efficacy in healthy and clinical populations, treatment duration, formulation and doses for optimal therapeutic benefits remains unclear. Selected databases were examined from inception to October 2022. Study selection, data extraction and Cochrane Risk of Bias assessments were conducted according to PRISMA guidelines and registered on the PROSPERO database (CRD42021247476) with 58 full-text studies meeting the eligibility criteria and administered CBD only or with Δ-9-tetrahydrocannabinol (THC) across healthy and clinical populations. In healthy populations and certain non-cannabis using clinical populations, CBD had greater anxiolytic effects without prominent effects on sleep. An inverted U-shaped dose relationship, and CBD ratio to THC in combined treatments likely moderated these effects. Mechanistically, observed CBD effects occurred via primary modulation of the endocannabinoid system and secondary regulation of neuroendocrine function. Additional research is needed to understand CBD mechanisms of action across diverse groups.

Systematic review of the efficacy, effectiveness, and cost-effectiveness of stepped-care interventions for the prevention and treatment of problematic substance use.

Stepped-care is a commonly recommended and implemented care model across health care domains, including substance use. Despite their presumed efficient allocation of treatment resources, a current and robust evidence synthesis is needed on the efficacy, effectiveness and cost-effectiveness of stepped-care for substance use. This systematic review analyzed articles describing evaluations of stepped-care models that measured the use of acutely psychoactive substances (i.e., alcohol, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, and stimulants) as a primary or secondary outcome, in participants over 18 years old. The analysis investigated model and participant characteristics associated with treatment outcomes. The study team conducted a search of five databases of literature (PsychINFO, MEDLINE, Embase, Cochrane Library and Scopus) published between January 1, 2010, and November 1, 2020. The search yielded 1051 unique articles, 19 of which were included in the analysis. The studies had considerable variability in sample sizes (n 18-2310), time to follow-up (4.5 months to 3 years), and retention rates (35.1-100 %). Studies examined outcomes for either alcohol alone (n 9), alcohol and other drug use (n 9), or drug use alone (n 1). Most studies (n 13) were rated as good quality. Three (15.8 %) were rated as fair and three (15.8 %) were rated as poor quality. The evidence regarding the efficacy, effectiveness and cost-effectiveness of stepped-care approaches is limited, but four of seven studies found that adaptive-care interventions delivered in the context of other systemic interventions produced greater benefit than control conditions in relation to at least one alcohol-related outcome. We have insufficient evidence to determine whether the modes or intensity of interventions included in the models, or decision rules used to step people up or down to differing levels of care, have an impact on outcome. Heterogeneity between studies with regard to model and evaluation design limited the degree to which the analysis could draw robust conclusions. Sample recruitment and statistical power are particular challenges, and the field needs more innovative evaluation designs to assess the efficacy, effectiveness, and cost-effectiveness of stepped-care models.

First few seconds for flow A comprehensive proposal of the neurobiology and neurodynamics of state onset.

Flow is a cognitive state that manifests when there is complete attentional absorption while performing a task. Flow occurs when certain internal as well as external conditions are present, including intense concentration, a sense of control, feedback, and a balance between the challenge of the task and the relevant skillset. Phenomenologically, flow is accompanied by a loss of self-consciousness, seamless integration of action and awareness, and acute changes in time perception. Research has begun to uncover some of the neurophysiological correlates of flow, as well as some of the states neuromodulatory processes. We comprehensively review this work and consider the neurodynamics of the onset of the state, considering large-scale brain networks, as well as dopaminergic, noradrenergic, and endocannabinoid systems. To accomplish this, we outline an evidence-based hypothetical situation, and consider the flow state in a broader context including other profound alterations in consciousness, such as the psychedelic state and the state of traumatic stress that can induce PTSD. We present a broad theoretical framework which may motivate future testable hypotheses.

Ayahuascas therapeutic potential What we know - and what not.

The therapeutic potential of the psychedelic brew ayahuasca has been investigated in preclinical and clinical studies. Currently, the most consistent evidence refers to depression. However, various studies suggest that ayahuasca may comprise therapeutic benefits in other health conditions. This narrative review provides a comprehensive, up-to-date overview of ayahuascas therapeutic effects in diverse clinical conditions in human (clinical, cross-sectional, observational, and qualitative) and preclinical (animal and in vitro) studies. In addition to summarizing and discussing the most commonly studied conditions, such as depression, anxiety, and substance use disorders (SUD), we also examine less frequently studied psychiatric, neurological, and physical conditions. Moreover, we discuss evidence from epidemiological studies on the impact of regular, long-term ayahuasca use on health and psychosocial outcomes. Overall, evidence for depression and SUD is more consistent, with numerous and diverse studies. However, a growing body of evidence suggests that other conditions equally relevant to public health might be promising targets for ayahuascas therapeutic effects. This includes preliminary studies indicating potential for grief, eating disorders, posttraumatic stress disorder, personality disorders, Parkinsons and Alzheimers disease, and severe physical illnesses (e.g., cancer, chronic conditions). Moreover, preliminary evidence in long-term ayahuasca users does not suggest detrimental effects but possible benefits for individual and collective health. In light of the emerging evidence of psychedelic drugs as therapeutic agents, it is essential to further investigate in rigorous designs the therapeutic potential of ayahuasca in conditions other than depression.

The socialization of hallucinations Cultural priors, social interactions, and contextual factors in the use of psychedelics.

The effects of so-called psychedelic or hallucinogenic substances are known for their strong conditionality on context. While the so-called culturalist approach to the study of hallucinations has won the favor of anthropologists, the vectors by which the features of visual and auditory imagery are structured by social context have been so far little explored. Using ethnographic data collected in a shamanic center of the Peruvian Amazon and an anthropological approach dialoguing with phenomenology and recent models of social cognition of Bayesian inspiration, I aim to shed light on the nature of these dynamics through an approach I call the socialization of hallucinations. Distinguishing two levels of socialization of hallucinations, I argue that cultural background and social interactions organize the relationship not only to the hallucinogenic experience, but also to its very phenomenological content. I account for the underpinnings of the socialization of hallucinations proposing such candidate factors as the education of attention, the categorization of perceptions, and the shaping of emotions and expectations. Considering psychedelic experiences in the light of their noetic properties and cognitive penetrability debates, I show that they are powerful vectors of cultural transmission. I question the ethical stakes of this claim, at a time when the use of psychedelics is becoming increasingly popular in the global North. I finally emphasize the importance of better understanding the extrapharmacological factors of the psychedelic experience and its subjective implications, and sketch out the basis for an interdisciplinary methodology in order to do so.

Within-person associations of escalated electronic nicotine delivery systems use with cigarette, alcohol, marijuana and drug use behaviors among US young adults.

Most extant evidence has addressed between-person differences, short-term or cross-sectional associations of electronic nicotine delivery systems (ENDS) use with other substance use, the majority focusing on current rather than escalated use. The present study aimed to examine within-person changes in escalated ENDS use and their associations with individual and combined substance use over a 6-year period. This study used a longitudinal cohort design with US young adults. A generalized linear mixed-model approach was employed to fit a series of weighted logistic regression models. Data were drawn from waves 1-5 of the Population Assessment of Tobacco and Health (PATH) study in the United States. Of the 9110 young adults at baseline, aged 18-24 years, a total of 5042 individuals had matched data across all five waves of assessments. Escalated ENDS use was computed by subtracting the number of days of ENDS use within the past 30 days at wave Escalated ENDS use gradually decreased over time, with the lowest prevalence at wave 4 (4.0%) but sharply increasing at wave 5 (8.4%). Escalated ENDS use was associated with increased odds of using each substance (binge drinking, marijuana use, marijuana vaping, prescription and illicit drugs) and different combinations of polysubstance use between cigarette smoking, binge drinking and marijuana use (Ps < 0.05). In addition, sweetfruit flavor use (versus mentholmint) was associated with increased likelihood of reporting co-use of cigarettes and marijuana. In the United States, the prevalence of young adults using electronic nicotine delivery systems appears to have increased steadily between 2013 and 2019, although the rate of increase may have started to accelerate in recent years. Escalated electronic nicotine delivery systems use and time-lagged established electronic nicotine delivery systems use appear to be prospectively associated with individual and combined substance use, particularly between cigarettes, alcohol and marijuana. Among established electronic nicotine delivery systems users, sweetfruit flavor appears to be associated with increased risk of co-using cigarettes and marijuana.

Comparative Metabolomic Profiling of the Metabolic Differences of Δ9-Tetrahydrocannabinol and Cannabidiol.

More than one hundred cannabinoids have been found in cannabis. Δ9-Tetrahydrocannabinol (THC) is the recognized addictive constituent in cannabis however, the mechanisms underlying THC-induced toxicity remain elusive. To better understand cannabis-induced toxicity, the present study compared the metabolic pathways of THC and its isomer cannabidiol (CBD) in human and mouse liver microsomes using the metabolomic approach. Thirty-two metabolites of THC were identified, including nine undescribed metabolites. Of note, two glutathione (GSH) and two cysteine (Cys) adducts were found in THCs metabolism. Molecular docking revealed that THC conjugates have a higher affinity with GSH and Cys than with the parent compound, THC. Human recombinant cytochrome P450 enzymes, and their corresponding chemical inhibitors, demonstrated that CYP3A4 and CYP1B1 were the primary enzymes responsible for the formation of THC-GSH and THC-Cys, thus enabling conjugation to occur. Collectively, this study systematically compared the metabolism of THC with the metabolism of CBD using the metabolomic approach, which thus highlights the critical role of metabolomics in identifying novel drug metabolites. Moreover, this study also facilitates mechanistic speculation in order to expand the knowledge of drug metabolism and safety.

Phytocannabinoid Compositions from Cannabis Act Synergistically with PARP1 Inhibitor against Ovarian Cancer Cells In Vitro and Affect the Wnt Signaling Pathway.

Ovarian cancer (OC) is the single most lethal gynecologic malignancy.

Trauma and Remembering From Neuronal Circuits to Molecules.

Individuals with posttraumatic stress disorder (PTSD) experience intrusions of vivid traumatic memories, heightened arousal, and display avoidance behavior. Disorders in identity, emotion regulation, and interpersonal relationships are also common. The cornerstone of PTSD is altered learning, memory, and remembering, regulated by a complex neuronal and molecular network. We propose that the essential feature of successful treatment is the modification of engrams in their unstable state during retrieval. During psychedelic psychotherapy, engrams may show a pronounced instability, which enhances modification. In this narrative review, we outline the clinical characteristics of PTSD, its multifaceted neuroanatomy, and the molecular pathways that regulate memory destabilization and reconsolidation. We propose that psychedelics, acting by serotonin-glutamate interactions, destabilize trauma-related engrams and open the door to change them during psychotherapy.

Role of Cannabidiol for Improvement of the Quality of Life in Cancer Patients Potential and Challenges.

There is currently a growing interest in the use of cannabidiol (CBD) to alleviate the symptoms caused by cancer, including pain, sleep disruption, and anxiety. CBD is often self-administered as an over-the-counter supplement, and patients have reported benefits from its use. However, despite the progress made, the mechanisms underlying CBDs anti-cancer activity remain divergent and unclear. Herein, we provide a comprehensive review of molecular mechanisms to determine convergent anti-cancer actions of CBD from pre-clinical and clinical studies. In vitro studies have begun to elucidate the molecular targets of CBD and provide evidence of CBDs anti-tumor properties in cell and mouse models of cancer. Furthermore, several clinical trials have been completed testing CBDs efficacy in treating cancer-related pain. However, most use a mixture of CBD and the psychoactive, tetrahydrocannabinol (THC), andor use variable dosing that is not consistent between individual patients. Despite these limitations, significant reductions in pain and opioid use have been reported in cancer patients using CBD or CBDTHC. Additionally, significant improvements in quality-of-life measures and patients overall satisfaction with their treatment have been reported. Thus, there is growing evidence suggesting that CBD might be useful to improve the overall quality of life of cancer patients by both alleviating cancer symptoms and by synergizing with cancer therapies to improve their efficacy. However, many questions remain unanswered regarding the use of CBD in cancer treatment, including the optimal dose, effective combinations with other drugs, and which biomarkersclinical presentation of symptoms may guide its use.

Epidemiological Patterns of Cannabis- and Substance- Related Congenital Uronephrological Anomalies in Europe Geospatiotemporal and Causal Inferential Study.

Recent reports linking prenatal and community cannabis exposure to elevated uronephrological congenital anomaly (UCA) rates (UCARs) raise the question of its European epidemiology given recent increases in community cannabinoid penetration there. UCAR data from Eurocat. Drug use data from European Monitoring Centre for Drugs and Drug Addiction. Income from World bank. UCAR increased across Spain, Netherlands, Poland and France. UCARs and cannabis resin THC increased simultaneously in France, Spain, Netherlands and Bulgaria. At bivariate analysis all UCAs were related to cannabis herb and resin THC concentrations. All UCARs were bivariately related to cannabis metrics ordered by median minimum E-value (mEV) as hypospadias > multicystic renal disease > bilateral renal agenesis > UCAs > hydronephrosis > posterior urethral valve > bladder exstrophyepispadias. At inverse probability weighted multivariable analysis terms including cannabis were significant for the following series of anomalies UCAs, multicystic renal disease, bilateral renal agenesis, hydronephrosis, congenital posterior urethral valves from P 1.91 × 10 Analysis confirms a close relationship between cannabis metrics and all seven UCAs and fulfill formal criteria for quantitative causal inference. Given the exponential cannabinoid genotoxicity dose-response relationship results provide a powerful stimulus to constrain community cannabinoid exposure including protection of the food chain to preserve the genome and epigenome of coming generations.

Molecular Pathways of the Therapeutic Effects of Ayahuasca, a Botanical Psychedelic and Potential Rapid-Acting Antidepressant.

Ayahuasca is a psychoactive brew traditionally used in indigenous and religious rituals and ceremonies in South America for its therapeutic, psychedelic, and entheogenic effects. It is usually prepared by lengthy boiling of the leaves of the bush

Functional consequences of short-term exposure to opioids versus cannabinoids in nonhuman primates.

Opioids provide pain relief but are associated with several adverse effects. Researchers are exploring cannabis-based medicine as an alternative. However, little is known about the tendency for physical dependence on cannabinoids in comparison with that on opioids in primates. The aim of this study was to compare the potency of heroin and delta-9-tetrahydrocannabinol (THC) in eliciting analgesic effects and the development of physical dependence between opioids and cannabinoids in both male and female rhesus monkeys. Systemic administration of either heroin (0.03-0.18 mgkg) or THC (0.3-1.8 mgkg) in a dose-dependent manner produced antinociceptive effects against an acute thermal nociceptive stimulus. The μ-opioid receptor antagonist naltrexone (0.01 mgkg) and the cannabinoid receptor antagonist SR141716A (0.3 mgkg) produced the same degree of rightward shift in the dose-response curves for heroin- and THC-induced antinociception, respectively. Monkeys implanted with telemetry devices were subjected to short-term repeated administrations (two injections per day for 1-3 days) of either heroin (0.18 mgkg), morphine (1.8 mgkg), THC (1.8 mgkg), or CP 55,940 (0.032 mgkg). Administration of naltrexone (0.01 mgkg) increased respiration, heart rate, and blood pressure in heroin- or morphine-treated monkeys. In contrast, administration of SR141716A (0.3 mgkg) did not cause a significant change in these physiological parameters in THC- or CP 55,940-treated monkeys. Additionally, morphine, but not CP 55,940, enhanced the monkeys hypersensitivity to the algogen capsaicin. Collectively, these results demonstrate that in nonhuman primates, both opioids and cannabinoids exert comparable antinociception however, physical dependence on opioids, but not cannabinoids, at their antinociceptive doses, occurs following short-term exposures.

Targeted delivery of harmine to xenografted human pancreatic islets promotes robust cell proliferation.

Type 1 diabetes (T1D) occurs as a consequence of the autoimmune destruction of insulin-producing pancreatic beta (β) cells and commonly presents with insulin deficiency and unregulated glycemic control. Despite improvements in the medical management of T1D, life-threatening complications are still common. Beta-cell replication to replace lost cells may be achieved by using small-molecule mitogenic drugs, like harmine. However, the safe and effective delivery of such drugs to beta cells remains a challenge. This work aims to deploy an antibody conjugated nanocarrier platform to achieve cell-specific delivery of candidate therapeutic and imaging agents to pancreatic endocrine cells. We approached this goal by generating core-shell type micellar nanocarriers composed of the tri-block copolymer, Pluronic®F127 (PEO

Psychedelics and Neural Plasticity Therapeutic Implications.

Psychedelic drugs have reemerged as tools to treat several brain disorders. Cultural attitudes toward them are changing, and scientists are once again investigating the neural mechanisms through which these drugs impact brain function. The significance of this research direction is reflected by recent work, including work presented by these authors at the 2022 meeting of the Society for Neuroscience. As of 2022, there were hundreds of clinical trials recruiting participants for testing the therapeutic effects of psychedelics. Emerging evidence suggests that psychedelic drugs may exert some of their long-lasting therapeutic effects by inducing structural and functional neural plasticity. Herein, basic and clinical research attempting to elucidate the mechanisms of these compounds is showcased. Topics covered include psychedelic receptor binding sites, effects of psychedelics on gene expression, and on dendrites, and psychedelic effects on microcircuitry and brain-wide circuits. We describe unmet clinical needs and the current state of translation to the clinic for psychedelics, as well as other unanswered basic neuroscience questions addressable with future studies.

Alcohol use disorder with comorbid anxiety disorder a case report and focused literature review.

Alcohol use disorder (AUD) and anxiety disorders (AnxD) are prevalent health concerns in clinical practice which frequently co-occur (AUD-AnxD) and compound one another. Concurrent AUD-AnxD poses a challenge for clinical management as approaches to treatment of one disorder may be ineffective or potentially counterproductive for the other disorder. We present the case of a middle-aged man with anxiety disorder, AUD, chronic pain, and gamma-hydroxybutyrate use in context of tapering prescribed benzodiazepines who experienced severe alcohol withdrawal episodes during a complicated course of repeated inpatient withdrawal management. After medical stabilization, the patient found significant improvement in symptoms and no return to alcohol use with a regimen of naltrexone targeting his AUD, gabapentin targeting both his AUD and AnxD, and engagement with integrated psychotherapy, Alcoholics Anonymous, and addictions medicine follow-up. Proper recognition and interventions for AUD and AnxD, ideally with overlapping efficacy, can benefit individuals with comorbid AUD-AnxD. Gabapentin, tobacco cessation, and integrated psychotherapy have preliminary evidence of synergistic effects in AUD-AnxD. Meta-analysis evidence does not support serotoninergic medications (e.g. selective serotonin reuptake inhibitors) which are commonly prescribed in AnxD and mood disorders as their use has not been associated with improved outcomes for AUD-AnxD. Additionally, several double-blind placebo-controlled randomized trials have suggested that serotonergic medications may worsen alcohol-related outcomes in some individuals with AUD. Areas for future investigation are highlighted.

(De)criminalisation of psychedelics in the Czech Republic-Where are we heading in drug policy and legislation

The article deals with the issue of decriminalization of drugs, in all relevant contexts, both in terms of criminal policy and legislation, as well as law enforcement, with focus on the Czech Republic. The article proceeds deductively from the general to the specific. First, it discusses the role of law in society and its legitimacy, with focus on legitimate criminal sanctions, which are discussed in the context of the principle of subsidiarity of criminal repression and the principle of opportunity (discretionary prosecution). After these general considerations, the article turns to the issue of drugs and discusses both drug policy and legislation, arguing that the general considerations are in favor of decriminalization tendencies in this area. In the final part, the article focuses on psychedelics, emphasizing a fundamental discrepancy between their factual and legal status and then considering ways of changing the perspective. At this point, the article outlines the importance of decriminalization of psychedelics for therapeutic use, which basically consist of rescheduling of these drugs. The aim of such decriminalization is to make psychedelic-assisted therapy legally available. The article concludes that this is the direction that criminal policy and law in the Czech Republic should take.

Evaluation of Cannabis Use Among US Adults During the COVID-19 Pandemic Within Different Legal Frameworks.

This cross-sectional study analyzes the prevalence of cannabis use by US adults during the COVID-19 pandemic within different legal frameworks and evaluates differences in associated behaviors.

Ketanserin Reverses the Acute Response to LSD in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Participants.

Lysergic acid diethylamide (LSD) is currently being investigated in psychedelic-assisted therapy. LSD has a long duration of acute action of 8-11 hours. It produces its acute psychedelic effects via stimulation of the serotonin 5-hydroxytryptamine-2A (HT2A) receptor. Administration of the 5-HT2A antagonist ketanserin before LSD almost fully blocks the acute subjective response to LSD. However, unclear is whether ketanserin can also reverse the effects of LSD when administered after LSD. We used a double-blind, randomized, placebo-controlled, crossover design in 24 healthy participants who underwent two 14-hour sessions and received ketanserin (40 mg p.o.) or placebo 1 hour after LSD (100 µg p.o.). Outcome measures included subjective effects, autonomic effects, acute adverse effects, plasma brain-derived neurotrophic factor levels, and pharmacokinetics up to 12 hours. Ketanserin reversed the acute response to LSD, thereby significantly reducing the duration of subjective effects from 8.5 hours with placebo to 3.5 hours. Ketanserin also reversed LSD-induced alterations of mind, including visual and acoustic alterations and ego dissolution. Ketanserin reduced adverse cardiovascular effects and mydriasis that were associated with LSD but had no effects on elevations of brain-derived neurotrophic factor levels. Ketanserin did not alter the pharmacokinetics of LSD. These findings are consistent with an interaction between ketanserin and LSD and the view that LSD produces its psychedelic effects only when occupying 5-HT2A receptors. Ketanserin can effectively be used as a planned or rescue option to shorten and attenuate the LSD experience in humans in research and LSD-assisted therapy. ClinicalTrials.gov (NCT04558294).

Psilocybin modulation of time-varying functional connectivity is associated with plasma psilocin and subjective effects.

Psilocin, the neuroactive metabolite of psilocybin, is a serotonergic psychedelic that induces an acute altered state of consciousness, evokes lasting changes in mood and personality in healthy individuals, and has potential as an antidepressant treatment. Examining the acute effects of psilocin on resting-state time-varying functional connectivity implicates network-level connectivity motifs that may underlie acute and lasting behavioral and clinical effects. Evaluate the association between resting-state time-varying functional connectivity (tvFC) characteristics and plasma psilocin level (PPL) and subjective drug intensity (SDI) before and right after intake of a psychedelic dose of psilocybin in healthy humans. Fifteen healthy individuals completed the study. Before and at multiple time points after psilocybin intake, we acquired 10-minute resting-state blood-oxygen-level-dependent functional magnetic resonance imaging scans. Leading Eigenvector Dynamics Analysis (LEiDA) and diametrical clustering were applied to estimate discrete, sequentially active brain states. We evaluated associations between the fractional occurrence of brain states during a scan session and PPL and SDI using linear mixed-effects models. We examined associations between brain state dwell time and PPL and SDI using frailty Cox proportional hazards survival analysis. Fractional occurrences for two brain states characterized by lateral frontoparietal and medial fronto-parietal-cingulate coherence were statistically significantly negatively associated with PPL and SDI. Dwell time for these brain states was negatively associated with SDI and, to a lesser extent, PPL. Conversely, fractional occurrence and dwell time of a fully connected brain state partly associated with motion was positively associated with PPL and SDI. Our findings suggest that the acute perceptual psychedelic effects induced by psilocybin may stem from drug-level associated decreases in the occurrence and duration of lateral and medial frontoparietal connectivity motifs. We apply and argue for a modified approach to modeling eigenvectors produced by LEiDA that more fully acknowledges their underlying structure. Together these findings contribute to a more comprehensive neurobiological framework underlying acute effects of serotonergic psychedelics.

A 11 ratio of cannabidiol tetrahydrocannabinol attenuates methamphetamine conditioned place preference in mice A prospective study of antidopaminergic mechanism.

A 11 ratio of cannabidiol to tetrahydrocannabinol (CT) was suggested to be safer for therapeutic purposes in many illnesses. However, CT effects on methamphetamine (METH) conditioned place preference (CPP) remained largely unexplored. This study aimed to examine the effects of CT on METH CPP mice evaluated by animal behaviors accompanied by local field potential (LFP) signals analysis. Male ICR mice were implanted with the LFP electrode in the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Animals were next subjected to induce METH CPP by peritoneal injection with 1 mgkg METH and 0.9 % NaCl on an alternate day for ten sessions and confined to the corresponding compartment for 30 min meanwhile control mice were given normal saline all day for both compartments. On testing day, either 10 mgkg CT or 20 mgkg bupropion (BP), a dopamine reuptake inhibitor, and VTA GABAergic suppressor were orally administered before CPP testing. The results revealed that CPP scores elevation was observed in the METHvehicle and METHBP mice, but this was reversed by CT treatment. Although both METHvehicle and METHBP enhanced the VTA delta power, NAc gamma I power, NAc delta-gamma coupling, and VTA-NAc gamma I coherence, changes in opposite trends of all mentioned parameters were seen by CT application. These improvements were postulated to involve the antidopaminergic effects of CT via modulations of neural signaling in the VTA and NAc. Altogether, the evidence-based study may suggest the use of CT as alternative drug for METH-seeking and craving therapy.

More than meets the eye The role of sensory dimensions in psychedelic brain dynamics, experience, and therapeutics.

Psychedelics are undergoing a major resurgence of scientific and clinical interest. While multiple theories and frameworks have been proposed, there is yet no universal agreement on the mechanisms underlying the complex effects of psychedelics on subjective experience and brain dynamics, nor their therapeutic benefits. Despite being prominent in psychedelic phenomenology and distinct from those elicited by other classes of hallucinogens, the effects of psychedelics on low-level sensory - particularly visual - dimensions of experience, and corresponding brain dynamics, have often been disregarded by contemporary research as epiphenomenal byproducts. Here, we review available evidence from neuroimaging, pharmacology, questionnaires, and clinical studies we propose extensions to existing models, provide testable hypotheses for the potential therapeutic roles of psychedelic-induced visual hallucinations, and simulations of visual phenomena relying on low-level cortical dynamics. In sum, we show that psychedelic-induced alterations in low-level sensory dimensions 1) are unlikely to be entirely causally reconducible to high-level alterations, but rather co-occur with them in a dialogical interplay, and 2) are likely to play a causally relevant role in determining high-level alterations and therapeutic outcomes. We conclude that reevaluating the currently underappreciated role of sensory dimensions in psychedelic states will be highly valuable for neuroscience and clinical practice, and that integrating low-level and domain-specific aspects of psychedelic effects into existing nonspecific models is a necessary step to further understand how these substances effect both acute and long-term change in the human brain.

Whos at greatest risk Latent profiles of alcohol and cannabis use and related consequences among college students.

There is significant heterogeneity in alcohol and cannabis use patterns among college students, with some engaging in use patterns that heighten their risk for adverse consequences. Person-centered approaches can help identify those subgroups of students with riskier use patterns. Latent Profile Analyses (LPA) were conducted to identify subgroups based on alcohol and cannabis use frequency and quantity, to explore demographic covariates and to examine mean differences across subgroups on alcohol- and cannabis-related consequences, simultaneous use, and other substance use. Participants were 2,423 college students (M A four-profile solution was the best fitting model. Profile 1 represented light, infrequent alcohol and cannabis use (73.8 %), Profile 2 represented heavy, infrequent alcohol and moderate, frequent cannabis use (15.9 %), Profile 3 represented moderate, frequent alcohol and cannabis use (5.6 %) and Profile 4 represented very heavy, frequent alcohol and heavy, frequent cannabis use (4.7 %). Students who identify as male, White non-Hispanic, andor Greek-affiliated were more likely to be in the heavy alcohol use profiles. Profiles 3 and 4 represent high-risk profiles, with both having a higher likelihood of simultaneous use, Profile 3 endorsing more cannabis consequences, and Profile 4 endorsing more alcohol consequences. Results suggest that heavy alcohol or heavy co-use heightens risk for serious adverse consequences.

Psilocin - The real deal or an extraction byproduct.

Most illicit drug casework samples at the Israel Police National Drug Laboratory are found to be mixtures of substances. Some are a mixture of an illicit drug with fillers, and others may contain more than one illicit drug. This study was triggered by a routine gas chromatography-mass spectrometry (GC-MS) analysis of an unusual casework sample. The sample chromatogram showed a mixture of two illicit drugs, 4-acetoxy-DMT and psilocin. Considering the two substances similar skeletal structure, the authors wondered whether the sample was indeed a mixture of the two substances, or whether perhaps 4-acetoxy-DMT was hydrolyzed to psilocin during the analysis. This study hypothesized that indeed the base used in the pre-injection sample preparation hydrolyzed the ester group on the 4-acetoxy-DMT yielding a hydroxide group. This was tested using several concentrations of ammonium hydroxide and two additional bases - pyridine (a weak base) and sodium hydroxide (a strong base). Results showed that media with a higher pH (induced by the stronger base) yielded a higher psilocin to 4-acetoxy-DMT ratio which is compatible with degradation of 4-acetoxy-DMT. This study also explored the possibility that psilocin was a byproduct of thermal decomposition of 4-acetoxy-DMT and found it thermally stable in the temperature of the GC injection port (200°C). The 4-acetoxy-DMT case demonstrates how pre-injection laboratory procedures can inadvertently modify casework samples. Caution is clearly advisable in selecting reagents and processes in general, and specifically in the case of GC-MS pre-injection procedures conducted to analyze substances like the ones in the present study.

Psilocybin for alcohol use disorder Rationale and design considerations for a randomized controlled trial.

Several lines of evidence suggest that classic psychedelics (5-HT

Closing the Loophole on Hemp-Derived Cannabis Products A Public Health Priority.

This Viewpoint discusses a federal policy loophole that allows psychotropic cannabis products to be commercially marketed and sold across the US, even in states where recreational cannabis is not legal.

Nature Biotechnologys academic spinouts 2021.

An Assessment of Psychedelic Knowledge Among People Using Psychedelics Naturalistically.

Identifying gaps and strengths in psychedelic-related knowledge is key to developing effective, evidence-based education to inform appropriate use of and harm reduction practices for psychedelics in the naturalistic use landscape. The current study piloted an assessment instrument with questions on legal status, therapeutic potential, and side effects of psychedelics among people reporting current psychedelic use. We recruited participants (

Protocol for a mobile laboratory study of co-administration of cannabis concentrates with a standard alcohol dose in humans.

Cannabis is commonly used among people who drink alcohol, yet evidence on acute effects of co-use is conflicting. Two important variables that may influence the effects of cannabis and alcohol are cannabinoid content (i.e., the ratio of cannabidiol CBD and 9-tetrahydrocannabinol THC) as well as the order of use (i.e., cannabis before alcohol vs. alcohol before cannabis). Research is mixed regarding the acute imapct of cannabis on alcohol consumption and intoxication, with some studies suggesting additive effects of alcohol and cannabis, and others demonstrating negligible effects of combining these substances. Further complicating this, high-THC-content cannabis concentrates are increasingly popular on the legal-market, but to our knowledge, no studies have explored concentrate and alcohol co-use. In addition to cannabinoid content, order of use may influence intoxication and other acute effects, but is also understudied. Co-use studies typically administer a fixed dose of alcohol before cannabis, and there is a lack of data on the acute effects of cannabis before alcohol. Thus, there is a need for experimental co-use studies exploring the impact of cannabinoid content (particularly of highly potent cannabis concentrates) and order effects on intoxication. This study uses a federally-compliant mobile laboratory procedure to explore the effects of co-administration of legal-market cannabis concentrates with a moderate alcohol dose (.8gkg) in a sample of community participants who regularly use alcohol and cannabis. The study will also explore alcohol and cannabis order effects (cannabis before alcohol vs. alcohol before cannabis). Outcomes are objective intoxication (measured using blood cannabinoid level, heart rate, psychomotor performance and breath alcohol level BrAC) and subjective intoxication (assessed via self-report measures). Overall, this study may influence harm-reduction recommendations for individuals who drink alcohol and use cannabis.

Characterization of the Gateway Decarboxylase for Psilocybin Biosynthesis.

The l-tryptophan decarboxylase PsiD catalyzes the initial step of the metabolic cascade to psilocybin, the major indoleethylamine natural product of the magic mushrooms and a candidate drug against major depressive disorder. Unlike numerous pyridoxal phosphate (PLP)-dependent decarboxylases for natural product biosyntheses, PsiD is PLP-independent and resembles type II phosphatidylserine decarboxylases. Here, we report on the in vitro biochemical characterization of Psilocybe cubensis PsiD along with in silico modeling of the PsiD structure. A non-canonical serine protease triad for autocatalytic cleavage of the pro-protein was predicted and experimentally verified by site-directed mutagenesis.

The Missing Piece A Case for Microglias Prominent Role in the Therapeutic Action of Anesthetics, Ketamine, and Psychedelics.

There is much excitement surrounding recent research of promising, mechanistically novel psychotherapeutics - psychedelic, anesthetic, and dissociative agents - as they have demonstrated surprising efficacy in treating central nervous system (CNS) disorders, such as mood disorders and addiction. However, the mechanisms by which these drugs provide such profound psychological benefits are still to be fully elucidated. Microglia, the CNSs resident innate immune cells, are emerging as a cellular target for psychiatric disorders because of their critical role in regulating neuroplasticity and the inflammatory environment of the brain. The following paper is a review of recent literature surrounding these neuropharmacological therapies and their demonstrated or hypothesized interactions with microglia. Through investigating the mechanism of action of psychedelics, such as psilocybin and lysergic acid diethylamide, ketamine, and propofol, we demonstrate a largely under-investigated role for microglia in much of the emerging research surrounding these pharmacological agents. Among others, we detail sigma-1 receptors, serotonergic and γ-aminobutyric acid signalling, and tryptophan metabolism as pathways through which these agents modulate microglial phagocytic activity and inflammatory mediator release, inducing their therapeutic effects. The current review includes a discussion on future directions in the field of microglial pharmacology and covers bidirectional implications of microglia and these novel pharmacological agents in aging and age-related disease, glial cell heterogeneity, and state-of-the-art methodologies in microglial research.

The perceptions of cancer health-care practitioners in New Zealand and the USA toward psychedelic-assisted therapy with cancer patients A cross-sectional survey.

A resurgence of research investigating the administration of psychedelic compounds alongside psychotherapy suggests that this treatment is a promising intervention for anxiety, depression, and existential distress in people with cancer. However, psychedelic treatment that induces a mind-altering experience potentially poses barriers to vulnerable cancer patients, and health-care practitioners may have concerns about referring their patients to trials investigating this approach. The aim of the current study was to investigate the perceptions of cancer health-care practitioners based in New Zealand and the USA related to psychedelic-assisted therapy. This study utilized a cross-sectional survey of cancer health-care practitioners in New Zealand and the USA via convenience sampling to identify their perceptions about the concept of conducting psychedelic-assisted therapy with cancer patients. Participants perceived that (1) psychedelic-assisted therapy has the potential to provide benefit for cancer patients, (2) research in this area across a variety of domains is important, (3) work should consider spiritual and indigenous perspectives of health, and (4) there was willingness to refer patients to trials in this area, especially patients with advanced disease who were no longer going through curative treatment. Participants in the USA had greater awareness of psychedelics than the New Zealand sample however, New Zealand participants more strongly believed that spiritualindigenous factors should be considered in psychedelic-assisted therapy. Cancer health-care practitioners in our sample considered research investigating the potential for psychedelic-assisted therapies to be important and may be more open to studies that start in palliative and end-of-life contexts.

Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.

Psilocybin is being studied for use in treatment-resistant depression. In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits). A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval CI, -10.2 to -2.9 P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2 P 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups. In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder EudraCT number, 2017-003288-36 ClinicalTrials.gov number, NCT03775200.).

Analytical profile of the lysergamide 1cP-AL-LAD and detection of impurities.

The development of novel lysergamides continues to occur, based on both the needs of psychedelic medicine and commercial interest in new recreational substances. The present study continues the authors research on novel lysergamides and describes the analytical profile of 1-cyclopropanoyl-AL-LAD (IUPAC name 1-(cyclopropanecarbonyl)-N,N-diethyl-6-(prop-2-en-1-yl)-9,10-didehydroergoline-8β-carboxamide 1cP-AL-LAD), using various chromatographic, mass spectrometric, and spectroscopic methods. Analysis of a powdered sample of 1cP-AL-LAD, obtained from an online vendor, by high performance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry in full scanAutoMSMS mode revealed the detection of 17 impurities based on high-resolution tandem mass spectral data tentative determination of their identity was based on mass spectral grounds alone, though detection of AL-LAD and 1P-AL-LAD was confirmed using available reference standards. Other tentative compound identifications included 1-acetyl-AL-LAD and several other substances potentially reflecting oxidation of the N

Cardiac effects of ephedrine, norephedrine, mescaline, and 3,4-methylenedioxymethamphetamine (MDMA) in mouse and human atrial preparations.

The use of recreational drugs like ephedrine, norephedrine, 3,4-methylenedioxymethamphetamine (MDMA), and mescaline can lead to intoxication and, at worst, to death. One reason for a fatal course of intoxication with these drugs might lie in cardiac arrhythmias. To the best of our knowledge, their inotropic effects have not yet been studied in isolated human cardiac preparations. Therefore, we measured inotropic effects of the hallucinogenic drugs ephedrine, norephedrine, mescaline, and MDMA in isolated mouse left atrial (mLA) and right atrial (mRA) preparations as well as in human right atrial (hRA) preparations obtained during cardiac surgery. Under these experimental conditions, ephedrine, norephedrine, and MDMA increased force of contraction (mLA, hRA) and beating rate (mRA) in a time- and concentration-dependent way, starting at 1-3 µM but these drugs were less effective than isoprenaline. Mescaline alone or in the presence of phosphodiesterase inhibitors did not increase force in mLA or hRA. The positive inotropic effects of ephedrine, norephedrine, or MDMA were accompanied by increases in the rate of tension and relaxation and by shortening of time of relaxation and, moreover, by an augmented phosphorylation state of the inhibitory subunit of troponin in hRA. All effects were greatly attenuated by cocaine (10 µM) or propranolol (10 µM) treatment. In summary, the hallucinogenic drugs ephedrine, norephedrine, and MDMA, but not mescaline, increased force of contraction and increased protein phosphorylation presumably, in part, by a release of noradrenaline in isolated human atrial preparations and thus can be regarded as indirect sympathomimetic drugs in the human atrium.

The Relationship Between Cannabis, Cognition, and Schizophrenia Its Complicated.

The consequences of cannabis use, especially in the context of schizophrenia, have gained increased importance with the legalization of cannabis in North America and across the globe. Cannabis use has multifaceted impacts on cognition in schizophrenia patients and healthy subjects. Healthy subjects, particularly those who initiated cannabis use at earlier ages and used high-potency cannabis for longer durations, exhibited poorer cognition mainly in working memory and attention. Cannabis use in schizophrenia has been associated with symptom exacerbation, longer and more frequent psychotic episodes, and poorer treatment outcomes. However, cannabis-using patients have better overall cognitive performance compared to patients who were not cannabis users. Interestingly, these effects were only apparent in lifetime cannabis users, but not in current (or within last 6 months) users. Moreover, higher frequency and earlier age of cannabis use initiation (i.e., before 17 years of age) were associated with better cognitive performance, although they had an earlier illness onset. Three possible hypotheses seem to come forward to explain this paradox. First, some components of cannabis may have antipsychotic or cognitive-enhancing properties. Secondly, chronic cannabis use may alter endocannabinoid signaling in the brain which could be a protective factor for developing psychosis or cognitive impairments. A third explanation could be their representation of a phenotypically distinct patient group with more intact cognitive functioning and less neurodevelopmental pathology. Multiple factors need to be considered to understand the complex relationship between cannabis, cognitive function, and schizophrenia. In short, age at initiation, duration and rate of cannabis use, abstinence duration, co-use of substances and alcohol, prescribed medications, relative cannabinoid composition and potency of cannabis, presence of genetic and environmental vulnerability factors are prominent contributors to the variability in outcomes. Animal studies support the disruptive effects of Δ9-tetrahydrocannabinol (THC) administration during adolescence on attention and memory performance. They provide insights about interaction of cannabinoid receptors with other neurotransmitter systems, such as GABA and glutamate, and other regulatory molecules, such as PSD95 and synaptophysin. Cannabidiol (CBD), on the other hand, can improve cognitive deficits seen in neurodevelopmental and chemically-induced animal models of schizophrenia. Future studies focusing on bridging the translational gaps between human and animal studies, through the use of translationally relevant methods of exposure (e.g., vaping), consistent behavioral assessments, and congruent circuit interrogations (e.g., imaging) will help to further clarify this complex picture.

Belief changes associated with psychedelic use.

Psychedelic use is anecdotally associated with belief changes, although few studies have tested these claims. Characterize a broad range of psychedelic occasioned belief changes. A survey was conducted in 2374 respondents who endorsed having had a belief changing psychedelic experience. Participants rated their agreement with belief statements Before and After the psychedelic experience as well as at the time of survey administration. Factor analysis of 45 belief statements revealed five factors Dualism, ParanormalSpirituality, Non-mammal consciousness, Mammal consciousness, and Superstition. Medium to large effect sizes from Before to After the experience were observed for increases in beliefs in Dualism (β 0.72), ParanormalSpirituality (β 0.90), Non-mammal consciousness (β 0.72), and Mammal consciousness (β 0.74). In contrast, negligible changes were observed for Superstition (β -0.18).). At the individual item level, increases in non-physicalist beliefs included belief in reincarnation, communication with the dead, existence of consciousness after death, telepathy, and consciousness of inanimate natural objects (e.g., rocks). The percentage of participants who identified as a Believer (e.g., in Ultimate Reality, Higher Power, andor God, etc.) increased from 29% Before to 59% After. At both the factor and individual item level, higher ratings of mystical experience were associated with greater changes in beliefs. Belief changes assessed after the experience (an average 8.4 years) remained largely unchanged at the time of survey. A single psychedelic experience increased a range of non-physicalist beliefs as well as beliefs about consciousness, meaning, and purpose. Further, the magnitude of belief change is associated with qualitative features of the experience.

Microdosing with classical psychedelics Research trajectories and practical considerations.

Microdosing-the intermittent ingestion of minute, sub-hallucinogenic amounts of psychedelic substances, repeatedly and over time-has become a widespread, albeit largely understudied, phenomenon. Regulations around using psychedelics at any dose-micro, mini, macro, or mega-pose all sorts of difficulties for those who wish to systematically study the effects of Schedule I drugs, especially in the United States. Microdosers commonly claim that taking a sub-hallucinogenic (pre-hallucinogenic or sub-perceptual) dose improves higher brain functions, including creativity, productivity, and mood. If true, these results would provide an important experimental edge in distinguishing psychosocial effects (e.g. caused by expectation) from those related to the active psychedelic ingredient. In this critical integrative synthesis, we explore the psychobiological science of dose amounts and how it informs microdosing with classical psychedelics (e.g. lysergic acid diethylamide LSD and psilocybin) to highlight and fuel research into questions (e.g. in cognitive neuroscience, consciousness studies, and metacognition). We sketch the hurdle-laden regulatory landscape and the procedures that shroud research with Schedule I drugs. Finally, we offer some future directions relevant to both scholars and clinicians in the social and behavioral sciences as well as in mental health and neurological science.

Effects of repeated lysergic acid diethylamide (LSD) on the mouse brain endocannabinoidome and gut microbiome.

Psychedelics elicit prosocial, antidepressant and anxiolytic effects via neuroplasticity, neurotransmission and neuro-immunomodulatory mechanisms. Whether psychedelics affect the brain endocannabinoid system and its extended version, the endocannabinoidome (eCBome) or the gut microbiome, remains unknown. Adult C57BL6N male mice were administered lysergic acid diethylamide (LSD) or saline for 7 days. Sociability was assessed in the direct social interaction and three chambers tests. Prefrontal cortex and hippocampal endocannabinoids, endocannabinoid-like mediators and metabolites were quantified via high-pressure liquid chromatography with tandem mass spectrometry (HPLC-MSMS). Neurotransmitter levels were assessed via HPLC-UVfluorescence. Gut microbiome changes were investigated by 16S ribosomal DNA sequencing. LSD increased social preference and novelty and decreased hippocampal levels of the N-acylethanolamines N-linoleoylethanolamine (LEA), anandamide (N-arachidonoylethanolamine) and N-docosahexaenoylethanolamine (DHEA) the monoacylglycerol 12-docosahexaenoylglycerol (12-DHG) the prostaglandins D The prosocial effects elicited by repeated LSD administration are accompanied by alterations of hippocampal eCBome and kynurenine levels, and the composition of the gut microbiota. Modulation of the hippocampal eCBome and kynurenine pathway might represent a mechanism by which psychedelic compounds elicit prosocial effects and affect the gut microbiome.

Race and ethnicity moderate the associations between lifetime psychedelic use (MDMAecstasy and psilocybin) and major depressive episodes.

Psychedelics are receiving renewed attention within Western medicine as they represent potential treatments for many difficult-to-treat mental health disorders. However, psychedelic science is limited in its focus and inclusion of racial and ethnic minorities. Hence, this study examines whether race and ethnicity moderate the associations that naturalistic 3,4-methylenedioxymethamphetamine (MDMA)ecstasy use and psilocybin use share with major depressive episodes (MDEs). Data for this project are from The National Survey on Drug Use and Health (2005-2019). Participants were adults aged 18 years and older (unweighted Race and ethnicity significantly moderated the associations between MDMAecstasy use and psilocybin use and MDEs. For White participants, MDMAecstasy use and psilocybin use each were associated with lowered odds of all three MDE outcomes (adjusted odds ratio (aOR) range 0.82-0.92). For Hispanic participants, MDMAecstasy use and psilocybin use each conferred lowered odds of only a past year MDE (MDMAecstasy aOR 0.82 psilocybin aOR 0.79). For Non-Hispanic Racial Minority participants, MDMAecstasy and psilocybin use did not confer lowered odds of any MDE outcomes. Race and ethnicity have an impact on the associations that psychedelics share with mental health outcomes. Future research should explore the impact of identity and discrimination on the effects of psychedelics and should explore whether these substances can serve as effective treatments for minorities when used in culturally informed contexts.

A proposed mechanism for the MDMA-mediated extinction of traumatic memories in PTSD patients treated with MDMA-assisted therapy.

Post-traumatic stress disorder (PTSD) is a devastating psychiatric disorder afflicting millions of people around the world. Characterized by severe anxiety, intrusive thoughts, pervasive nightmares, an assortment of somatic symptoms, associations with severe long-term health problems, and an elevated risk of suicide, as much as 40-70% of patients suffer from refractory disease. 3,4-Methylenedioxy-methamphetamine (MDMA), like classic psychedelics such as psilocybin, have been used to enhance the efficacy of psychotherapy almost since their discovery, but due to their perceived potential for abuse and inclusion on USFDA (United States Food and Drug Administration) schedule 1, research into the mechanism by which they produce improvements in PTSD symptomology has been limited. Nevertheless, several compelling rationales have been explored, with the pro-social effects of MDMA thought to enhance therapeutic alliance and thus facilitate therapist-assisted trauma processing. This may be insufficient to fully explain the efficacy of MDMA in the treatment of psychiatric illness. Molecular mechanisms such as the MDMA mediated increase of brain-derived neurotrophic factor (BDNF) availability in the fear memory learning pathways combined with MDMAs pro-social effects may provide a more nuanced explanation for the therapeutic actions of MDMA.

Validation of a new instrument for assessing attitudes on psychedelics in the general population.

Although there is research interest to assess attitudes on psychedelics, no validated instrument exists for this purpose. We aimed to develop and examine the psychometric properties of the Attitudes on Psychedelics Questionnaire (APQ) in a sample of the Croatian general population. A cross-sectional, web-based survey among the general population was conducted on 1153 participants (62.1% female, 77.7% with a graduate or high school degree, 15.1% health care workers). We assessed participants ability to recognize psychedelic substances using a short knowledge test. The APQ consists of 20 items with four sub-scales Legal Use of Psychedelics, Effects of Psychedelics, Risk Assessment of Psychedelics, and Openness to Psychedelics. This model demonstrated best fit in a confirmatory factor analysis. Total scale reliability was excellent (McDonalds ω 0.949, 95% CI 0.944-0.953). A strong correlation with a similar unvalidated measure (r 0.885, P < 0.001) demonstrated convergent validity. We observed an association between attitudes and knowledge on psychedelics (r 0.494, P < 0.001). Younger age, male gender, and lower educational status were associated with higher APQ scores. The APQ is valid, reliable, and could be applied in assessing educational interventions, patients treatment outcomes, and the attitudes of different groups of experts. We encourage further validation of the APQ in English.

Examining the Systemic Bioavailability of Cannabidiol and Tetrahydrocannabinol from a Novel Transdermal Delivery System in Healthy Adults A Single-Arm, Open-Label, Exploratory Study.

Transdermal cannabinoids may provide better safety and bioavailability profiles compared with other routes of administration. This single-arm, open-label study investigated a novel topical transdermal delivery system on the pharmacokinetics of cannabidiol (CBD) and tetrahydrocannabinol (THC). Participants were 39.5 ± 7.37 years old and healthy, based on a review by the Medical Director. Blood was collected pre-dose and 10, 20, 30, and 45 min, and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 h after topical application of 100 mg CBD100 mg THC. Psychoactive effects were assessed prior to each timepoint. Area-under-the-curve (AUC AUC To our knowledge, this is the first pharmacokinetic study in humans that demonstrated CBD and THC entering systemic circulation via transdermal administration . This study represents an important contribution to understanding the pharmacokinetics of transdermal cannabinoids. ClinicalTrials.gov Identifier-NCT05121506 (November 16, 2021).

Cannabis in Adolescence Lasting Cognitive Alterations and Underlying Mechanisms.

Cannabis consumption during adolescence is an area of particular concern, owing to changes in the social and political perception of the drug, and presents a scientific, medical, and economic challenge. Major social and economic interests continue to push toward cannabis legalization as well as pharmaceutical development. As a result, shifting perceptions of both legal and illicit cannabis use across the population have changed the collective evaluation of the potential dangers of the product. The wave of cannabis legalization therefore comes with new responsibility to educate the public on potential risks and known dangers associated with both recreational and medical cannabis. Among these is the risk of long-term cognitive and psychological consequences, particularly following early-life initiation of use, compounded by high-potency andor synthetic cannabis, and heavyfrequent use of the drug. Underlying these cognitive and psychiatric consequences are lasting aberrations in the development of synaptic function, often secondary to epigenetic changes. Additional factors such as genetic risk and environmental influences or nondrug toxic insults during development are also profound contributors to these long-term functional alterations following adolescent cannabis use. Preclinical studies indicate that exposure to cannabinoids during specific windows of vulnerability (e.g., adolescence) impacts neurodevelopmental processes and behavior by durably changing dendritic structure and synaptic functions, including those normally mediated by endogenous cannabinoids and neuronal circuits.

Classic psychedelics and alcohol use disorders A systematic review of human and animal studies.

Classic psychedelics refer to substances such as lysergic acid diethylamide (LSD), psilocybin, ayahuasca, and mescaline, which induce altered states of consciousness by acting mainly on 5-HT

Psychosis and psychedelics Historical entanglements and contemporary contrasts.

Experiences of psychedelics and psychosis were deeply entangled in scientific practices in the mid-20th century, from uses of psychedelic drugs that could model psychosis, to detailed phenomenological comparisons of endogenous and drug-induced madness. After the moral panic of the 1960s shut down psychedelic research, however, these two phenomena became disentangled. In the decades following, the science of psychosis transformed, shedding the language of psychoanalysis, and adopting the new scientific veneer of psychiatry. Today, as psychedelic science re-emerges, the research programs surrounding psychosis and psychedelics now stand in stark contrast. Here, I look closely at how these research programs respond to questions related to what is worth measuring, what is worth investigating, and how we ought to respond to these experiences. This comparison reveals radically different assumptions and values that guide each research paradigm and shape clinical practice. While psychedelic research often includes scales that seek to capture experiences of mysticism, meaningfulness, and ego dissolution, research related to psychosis focuses on the measurement of pathological symptoms and functioning. Research into psychosis primarily seeks universal and reductionist causal explanations and interventions, while psychedelic research embraces the importance of set and setting in shaping unique experiences. Responses to psychedelic crisis involve warmth, compassion, and support, while responses to psychotic experiences often involve restraint, seclusion, and weapons. I argue that these differences contain important lessons for psychiatry. However, as psychedelic research struggles to meet regulatory requirements and fit within the paradigm of evidence-based medicine, these differences may quickly dissolve.

MDMA-assisted psychotherapy Inclusion of transgender and gender diverse people in the frontiers of PTSD treatment trials.

Transgender and gender diverse (TGD) people experience stigma, discrimination, trauma, and post-traumatic stress disorder (PTSD) at higher rates compared to the general population however, TGD people have been underrepresented in PTSD research. Clinical trials of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy demonstrate promising safety and efficacy for the treatment of PTSD. Issues related to equitable access, power imbalances in the therapeutic relationship, and vulnerable states of consciousness occasioned by MDMA are magnified when working with people affected by structural vulnerabilities and health disparities, and community engagement in research planning and implementation is essential. To inform the inclusion and safety of TGD people in future MDMA-assisted psychotherapy research, the aims of the current study were to characterize TGD experiences with trauma-related mental health care, assess openness of TGD people to participate in experimental PTSD research, and to gather specific feedback on protocol design for conducting MDMA-assisted psychotherapy with TGD people. We conducted three virtual focus group discussions (FGDs) with 5-6 participants each ( We have identified several key issues TGD people face when seeking and engaging in trauma-related mental health care, including barriers to receiving adequate gender-affirming and trauma-informed mental health care and frustration with providers lacking cultural humility. Suggested amendments to MDMA-assisted psychotherapy protocols include routine collection of trans-inclusive gender identity data, implementing an explicit gender-affirming treatment approach, ensuring a culturally safe setting, and diversifying co-therapy dyads. The inclusion of TGD voices in early conversations about emerging experimental PTSD interventions promotes equitable access, in the context of health and healthcare disparities, and helps researchers understand the needs of the community and tailor research to meet those needs. Through an ongoing conversation with the TGD community, we aim to incorporate a gender-affirming approach into existing research protocols and inform future applications of MDMA-assisted psychotherapy in addressing the effects of minority stress and boosting resilience.

Delta-8 Tetrahydrocannabinol Product Impurities.

Due to increased concerns regarding unidentified impurities in delta-8 tetrahydrocannabinol (Δ-8 THC) consumer products, a study using Nuclear Magnetic Resonance (NMR), high performance liquid chromatography (HPLC), and mass spectrometry (MS) was conducted to further investigate these products. Ten Δ-8 THC products, including distillates and ready to use vaporizer cartridges, were analyzed. The results yield findings that the tested products contain several impurities in concentrations far beyond what is declared on certificates of analysis for these products. As Δ-8 THC is a synthetic product synthesized from cannabidiol (CBD), there are valid concerns regarding the presence of impurities in these products with unknown effects on the human body. Compounding this problem is apparent inadequate testing of these products by producers and independent laboratories.

Optimal Treatment with Cannabis Extracts Formulations Is Gained via Knowledge of Their Terpene Content and via Enrichment with Specifically Selected Monoterpenes and Monoterpenoids.

Differences between therapeutic effects of medical cannabis inflorescences and those of their extracts are generally attributed to the differences in administration form and in the resultant pharmacokinetics. We hypothesized that difference may further extend to the composition of the actually consumed drug. Cannabinoid and terpene contents were compared between commercial cannabis inflorescences (

Socioeconomic, Ethnocultural, Substance- and Cannabinoid-Related Epidemiology of Down Syndrome USA 1986-2016 Combined Geotemporospatial and Causal Inference Investigation.

Down syndrome (DS) is the commonest of the congenital genetic defects whose incidence has been rising in recent years for unknown reasons. This study aims to assess the impact of substance and cannabinoid use on the DS Rate (DSR) and assess their possible causal involvement. An observational population-based epidemiological study 1986-2016 was performed utilizing geotemporospatial and causal inferential analysis. Participants included all patients diagnosed with DS and reported to state based registries with data obtained from National Birth Defects Prevention Network of Centers for Disease Control. Drug exposure data was from the National Survey of Drug Use and Health (NSDUH) a nationally representative sample interviewing 67,000 participants annually. Drug exposures assessed were cigarette consumption, alcohol abuse, analgesicopioid abuse, cocaine use and last month cannabis use. Covariates included ethnicity and median household income from US Census Bureau maternal age of childbearing from CDC births registries and cannabinoid concentrations from Drug Enforcement Agency. NSDUH reports 74.1% response rate. Other data was population-wide. DSR was noted to rise over time and with cannabis use and cannabis-use quintile. In the optimal geospatial model lagged to four years terms including Δ9-tetrahydrocannabinol and cannabigerol were significant (from β-est. 4189.96 (95%C.I. 1924.74, 6455.17), Data show that the association between DSR and substance- and cannabinoid- exposure is robust to multivariable geotemporospatial adjustment, implicate particularly cannabigerol and Δ9-tetrahydrocannabinol, and fulfil quantitative epidemiological criteria for causality. Nevertheless, detailed experimental studies would be required to formally demonstrate causality. Cannabis legalization was associated with elevated DSRs at both bivariate and multivariable analysis. Findings are consistent with those from Hawaii, Colorado, Canada, Australia and Europe and concordant with several cellular mechanisms. Given that the cannabis industry is presently in a rapid growth-commercialization phase the present findings linking cannabis use with megabase scale genotoxicity suggest unrecognized DS risk factors, are of public health importance and suggest that re-focussing the cannabis debate on multigenerational health concerns is prudent.

The Protective Effect of CBD in a Model of In Vitro Ischemia May Be Mediated by Agonism on TRPV2 Channel and Microglia Activation.

Cannabinoids, used for centuries for recreational and medical purposes, have potential therapeutic value in stroke treatment. Cannabidiol (CBD), a non-psychoactive compound and partial agonist of TRPV2 channels, is efficacious in many neurological disorders. We investigated the effects of CBD or Δ9-tetrahydrocannabinol (THC) in rat organotypic hippocampal slices exposed to oxygen-glucose deprivation (OGD), an in vitro model of ischemia. Neuronal TRPV2 expression decreased after OGD, but it increased in activated, phagocytic microglia. CBD increased TRPV2 expression, decreased microglia phagocytosis, and increased rod microglia after OGD. THC had effects contrary to those of CBD. Our results show that cannabinoids have different effects in ischemia. CBD showed neuroprotective effects, mediated, at least in part, by TRPV2 channels, since the TRPV2 antagonist tranilast blocked them, while THC worsened the neurodegeneration caused by ischemia. In conclusion, our results suggest that different cannabinoid molecules play different roles in the mechanisms of post-ischemic neuronal death. These different effects of cannabinoid observed in our experiments caution against the indiscriminate use of cannabis or cannabinoid preparations for recreational or therapeutic use. It was observed that the positive effects of CBD may be counteracted by the negative effects caused by high levels of THC.

The Pharmacogenetics of Cannabis in the Treatment of Chronic Pain.

The increase in the medical use of cannabis has revealed a number of beneficial effects, a variety of adverse side effects and great inter-individual variability. Association studies connecting consumption, addiction and side effects related to recreational cannabis use have led to the identification of several polymorphic genes that may play a role in the pharmacodynamics and pharmacokinetics of cannabis. In total, 600 patients treated with cannabis were genotyped for several candidate polymorphic genes (single-nucleotide polymorphism SNP), encoding receptors CNR1 and TRPV1 for the ABCB1 transporter for biotransformation, bioactivation and biosynthesis and CYP3A4, COMT and UGT2B7 conjugation. Three polymorphic genes (ABCB1, TRPV1 and UGT2B7) were identified as being significantly associated with decline in pain after treatment with cannabis. Patients simultaneously carrying the most favourable allele combinations showed a greater reduction (polygenic effect) in pain compared to those with a less favourable combination. Considering genotype combinations, we could group patients into good responders, intermediate responders and poor or non-responders. Results suggest that genetic makeup is, at the moment, a significant predictive factor of the variability in response to cannabis. This study proves, for the first time, that certain polymorphic candidate genes may be associated with cannabis effects, both in terms of pain management and side effects, including therapy dropout. Our attention to pharmacogenetics began in 2008, with the publication of a first study on the association between genetic polymorphisms and morphine action in pain relief. The study we are presenting is the first observational study conducted on a large number of patients involving several polymorphic candidate genes. The data obtained suggest that genetic makeup can be a predictive factor in the response to cannabis therapy and that more extensive and planned studies are needed for the opening of new scenarios for the personalization of cannabis therapy.

Sex Differences in the Neuropsychiatric Effects and Pharmacokinetics of Cannabidiol A Scoping Review.

Cannabidiol (CBD) is a non-intoxicating cannabinoid compound with diverse molecular targets and potential therapeutic effects, including effects relevant to the treatment of psychiatric disorders. In this scoping review, we sought to determine the extent to which sex and gender have been considered as potential moderators of the neuropsychiatric effects and pharmacokinetics of CBD. In this case, 300 articles were screened, retrieved from searches in PubMedMedline, Scopus, Google Scholar, PsycInfo and CINAHL, though only 12 met our eligibility criteria eight studies in preclinical models and four studies in humans. Among the preclinical studies, three suggested that sex may influence long-term effects of gestational or adolescent exposure to CBD two found no impact of sex on CBD modulation of addiction-relevant effects of Δ⁹-tetrahydrocannabinol (THC) two found antidepressant-like effects of CBD in males only and one found greater plasma and liver CBD concentrations in females compared to males. Among the human studies, two found no sex difference in CBD pharmacokinetics in patient samples, one found greater plasma CBD concentrations in healthy females compared to males, and one found no evidence of sex differences in the effects of CBD on responses to trauma recall in patients with post-traumatic stress disorder (PTSD). No studies were identified that considered the role of gender in CBD treatment effects. We discuss potential implications and current limitations of the existing literature.

Set and setting in microdosing an oft-overlooked principle.

The use of psychedelics for medical and recreational purposes is rising. Contextual factors such as expectancy, intention, and sensory and social environment (set and setting) are widely recognized as moderating the effects of these substances. Nevertheless, clinical trials of microdosing - the ingestion of small, sub-hallucinogenic doses of psychedelics - rarely report their set and setting. This fact suggests that such factors are not considered important in the context of microdosing. This paper challenges this assumption and makes the case for the crucial relevance of set and setting in microdosing practice. Building on set and setting theory and placebo theory, we explain why set and setting are of crucial importance in the case of microdosing. This reasoning helps elucidate the role of set and setting in determining the outcomes of microdosing and helps explain some of the contradictory results that have emerged in microdosing research in recent years. Set and setting are important constructs to be considered especially in the context of microdosing psychedelics. By reporting set and setting, the results of microdosing research can be made more reliable and consistent.

Low doses of lysergic acid diethylamide (LSD) increase reward-related brain activity.

Renewed interest in classic psychedelics as treatments for psychiatric disorders warrants a deeper understanding of their neural mechanisms. Single, high doses of psychedelic drugs have shown promise in treating depressive disorders, perhaps by reversing deficits in reward processing in the brain. In addition, there are anecdotal reports that repeated ingestion of low doses of LSD, or microdosing, improve mood, cognition, and feelings of wellbeing. However, the effects of low doses of classic psychedelics on reward processing have not been studied. The current study examined the effects of two single, low doses of LSD compared to placebo on measures of reward processing. Eighteen healthy adults completed three sessions in which they received placebo (LSD-0), 13 μg LSD (LSD-13) and 26 μg LSD (LSD-26) in a within-subject, double-blind design. Neural activity was recorded while participants completed the electrophysiological monetary incentive delay task. Event-related potentials were measured during feedback processing (Reward-Positivity RewP, Feedback-P3 FB-P3, and Late-Positive Potential LPP). Compared to placebo, LSD-13 increased RewP and LPP amplitudes for reward (vs. neutral) feedback, and LSD-13 and LSD-26 increased FB-P3 amplitudes for positive (vs. negative) feedback. These effects were unassociated with most subjective measures of drug effects. Thus, single, low doses of LSD (vs. placebo) increased three reward-related ERP components reflecting increased hedonic (RewP), motivational (FB-P3), and affective processing of feedback (LPP). These results constitute the first evidence that low doses of LSD increase reward-related brain activity in humans. These findings may have important implications for the treatment of depressive disorders.

Neonatal outcomes of preterm infants with in-utero exposure to drugs of substance use US national data.

Infants exposed prenatally to drugs of substance use are at increased risk for seizures, strabismus, feeding difficulty, and neurodevelopmental delays. Exposed preterm infants may have additional morbidities related to prematurity. There is limited literature on national outcomes of preterm infants exposed to drugs of substance use. We aimed to evaluate the trends and neonatal outcomes of preterm infants born in the USA who were exposed in-utero to drugs of substance use. Retrospective cohort study of preterm live born (<37 weeks gestation) exposed in-utero to opioids, hallucinogens, or cocaine in the Healthcare Cost and Utilization Project database from 2002 to 2017. Neonatal outcomes were identified using international classification of diseases 910 codes. Of the 54,469,720 live-born infants, 7.7% (4,194,816) were preterm, and 58 679 (1.4%) were exposed in-utero to maternal opioidshallucinogens (n 39,335) or cocaine (n 19,344). There was a trend for increased exposure to opioidshallucinogens (Z score 76.14, p < 0.001) during the study period. Exposed preterm infants had significantly more neurological anomalies, intra-ventricular hemorrhage and periventricular leukomalacia (p < 0.001). There was a trend for increased in-utero exposure to opioids and hallucinogens in the preterm infants in the USA. Exposed preterm infants had more neurological morbidities.

Involvement of esterases in the pulmonary metabolism of beclomethasone dipropionate and the potential influence of cannabis use.

Beclomethasone dipropionate (BDP) is an inhaled glucocorticoid used for maintenance treatment of asthma in adults and children. BDP is a prodrug activated in lung when hydrolyzed to its major active metabolite beclomethasone-17-monopropionate (17-BMP), which can be further deactivated to beclomethasone (BOH). The specific hydrolases contributing to these processes have not been identified which warrants an investigation to enable a better assessment of the drug-drug interaction (DDI) liability and a better management of drug efficacy and systemic toxicity. In the present study, the pulmonary metabolism of BDP was investigated using both human lung S9 (HLuS9) and recombinant carboxylesterase 1 (CES1) S9. By employing the relative activity approach, we tested the hypothesis of CES1 being the major enzyme involved. Assessment of other hydrolases were conducted in an assay with selective esterase inhibitors. In addition, the DDI potentials between BDP and Δ

Lucy is back in Brazil with a new dress.

Lucy in the Sky with Diamonds, a John Lennon song that was a hit in the 1960s, was born amidst a social context enlightened by lysergic acid diethylamide (LSD). In Brazil, both the drug and the song were very popular at the time, although it gradually mitigated. Nevertheless, while the song remains out of the spotlight, LSD derivatives are currently gaining attention with the rising of the new psychoactive substances (NPS). With this new presentation, the drug is returning to Brazil after a few decades and herein we report and discuss the first cases of an LSD prodrug seized in our country. Nine suspected blotter paper samples were seized by the Sao Paulo State Police in different cities of the State. Gas chromatography-mass spectrometry (GC-MS), attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) and liquid chromatography coupled with electrospray ionization-mass spectrometry (LC-ESI-MS) analyses were utilized to confirm the identity of the LSD derivative. The compound was identified as 4-acetyl-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo4,3-fgquinoline-9-carboxamide (ALD-52 or 1A-LSD) and no other active substance was detected in all samples. The identity of the unknown compound found in seized blotter papers has been successfully confirmed as an LSD prodrug, ALD-52, which was not controlled by Brazilian legislation. The arrival of a new type of designer drug in Brazil is in support by other reports, although those are still scarce and should not be overlooked. Altogether, these findings indicate the rising of a new NPS strategy that merits proper discussion.

Adaptation and latent structure of the Brazilian version of the Ego Dissolution Inventory (EDI-BR) An exploratory study.

Existing scales that seek to measure alterations in self-experience were based on studies conducted in developed countries. Therefore, the aim of this study was to evaluate the psychometric properties of the Ego-Dissolution Inventory (EDI), translate and adapt it to the Brazilian context. Translation of the measure was made by two translators fluent in both English and Portuguese, with back-translation into English to ensure there was no loss of meaning. The scale was included in an online survey exploring substance use. A total of 528 participants answered the full scale. We calculated the Kaiser-Meyer-Olkin (KMO) measure to evaluate sampling adequacy, then ran Exploratory Analysis Factor (EFAs) to investigate the factor structure of the EDI. The scale showed acceptable psychometric properties, with excellent internal consistency and sampling adequacy for a factor analysis. Kaiser-Gutmans criteria and Hulls method pointed to a three-factor solution, while Parallel Analysis suggested a two-factor solution. All items showed salient loadings, with two items exhibiting cross-loading. Positive but weak correlations were found between EDI factors 1 and 2 and nature-relatedness. The validated scale showed solid psychometric properties, with potential differences in factor structure in relation to the English version. Considering validation as ongoing process, it is recommended to conduct studies comparing the scores of ego dissolution across distinct substances and different regions of the country.