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Emerging drugs for the treatment of major depressive disorder.

Major depressive disorder (MDD) continues to be one of the highest contributors to disease burden and years lived with disability in the world. Current existing treatments have been associated with intolerable side effects, long onset of action and suboptimal remission rates. Newer agents are being developed that will be reviewed here, such as glutamate and gamma-aminobutyric acid (GABA) and the reinvigorated testing of psychedelic drugs. This review will summarize the target mechanisms of the newer ADTs currently in development and available on the market. It briefly covers the existing agents for MDD and treatment-resistant depression (TRD) and the need for new agents with higher efficacy. Therapeutic agents currently in Phase II or later clinical trials are listed and discussed, based on a thorough review of the US National Institutes of Health clinicaltrials.gov index and a search of the Informa Pharmaprojects database. Compounds of interest are grouped into scientific rationale and include atypical antipsychotics, GABA positive allosteric modulators, glutamatergic agents, opioids, orexin 2 receptor antagonists, and psychedelics. New therapeutic agents currently in development are promising, with a more rapid onset of action and the ability to augment and treat TRD.

Intrauterine cannabis exposure and fetal and maternal blood flow a case-control study.

Cannabis consumption during pregnancy increases the risk of pregnancy and neonatal complications. Since the underlying mechanism is unknown, the purpose of this study is to evaluate the changes in maternal and fetal blood flow in pregnancies exposed to cannabis, Δ9-tetrahydrocannabinol (THC). A case-control study between 2013 and 2020, included women with continued cannabis exposure during the pregnancies, defined by qualitative detection of THC in urine (Cannabis Group), and low-risk pregnancy women divided into tobacco smokers (Tobacco Group), and non-tobacco smokers (Control Group). We evaluated the association between cannabis consumption and maternal and fetal blood flow parameters measured by Doppler ultrasound uterine artery at 11-14, 20-22 and 33-35 weeks, umbilical artery and middle cerebral artery at 33-35 weeks. Cerebral-placental ratio was calculated. Overall, 275 participants were included, 60 in the Cannabis Group, 17 in the Tobacco Group and 198 in the Control Group. At 33-35 weeks, differences were found in the umbilical artery pulsatility index (PI) (1.05 ± 0.23, 1.06 ± 0.19, 0.93 ± 0.15, P < 0.01), middle cerebral artery PI (1.75 ± 0.35, 1.90 ± 0.45, 1.88 ± 0.34, P < 0.05), cerebral-placental ratio (1.69 ± 0.40, 1.85 ± 0.53, 2.07 ± 0.47, P < 0.05) and mean uterine artery PI (0.89 ± 0.26, 0.73 ± 0.19, 0.74 ± 0.20, P < 0.01), respectively. On logistic regression analysis, adjusted for maternal age, maternal body mass index, maternal weight and white ethnicity, both cannabis and tobacco were predictors for increased umbilical artery PI, but only cannabis was a predictor for a decreased cerebral-placental ratio and an increased uterine artery PI at 33-35 weeks. Data from a large cohort of continuous cannabis exposure pregnancies show that cannabis is associated with maternal and fetal blood flow changes. However, it is not possible to disentangle the association of the tobacco and cannabis.

Sexual Orientation, Mental Illness, and Substance Use Disorders Among Criminal Legal System-Involved Individuals.

The purpose of this study was to examine the prevalence of mental illness, substance use disorders, and access to treatment among individuals from sexual minority groups who have been involved with the criminal legal system. This study used data from 195,239 heterosexual adults and 14,995 sexual minority adults ages ≥18 years surveyed in the 2015-2019 National Survey on Drug Use and Health. The authors compared mental illness, substance use disorders, and access to treatment between sexual minority and heterosexual adults by using multivariable logistic regression models and controlling for sociodemographic characteristics. Approximately 9% of legal system-involved adults identified as belonging to a sexual minority group. Among legally involved individuals, sexual minority individuals were more likely than heterosexual individuals to have a serious mental illness, suicidal ideation, or depressive thoughts and to use inhalants, hallucinogens, alcohol, marijuana, or cocaine. Legally involved sexual minority individuals were also more likely than their heterosexual counterparts to receive treatment for mental illness or substance use disorders. The increased probability of receiving treatment for mental illness and substance use among sexual minority individuals was also observed when comparing sexual minority and heterosexual adults not involved with the criminal legal system. This study adds new population-based research to a limited body of evidence on the health disparities and mental health needs of legally involved sexual minority populations. More research and programmatic and policy interventions are needed to better support legally involved sexual minority groups in order to achieve mental health equity for this vulnerable population.

Long-Term Impact of Medical Marijuana Laws on the Burden of Cannabis Use Disorders in US Male and Female Adolescents and Young Adults.

Deregulation of cannabis use has raised concerns regarding its potential effects on health, particularly in adolescents and young adults. Here, we extracted data from the Global Burden of Disease database to estimate the long-term effect (> 5 years) of medical marijuana laws (MML) on 2019 cannabis use disorders Disability Adjusted Life Years (2019 CUD DALYs) in US male and female adolescents (15-19 years old) and young adults (20-24 years old). Socio-cultural, demographic and economic characteristics were used as baseline covariates. To improve the robustness of estimation, we took advantage of machine learning techniques. We found no significant effect of MML on 2019 CUD DALYS in each of our four agesex groups. Estimates from a marginal structural model taking into account age and sex strata in the same model were also non-significant. Our findings suggest that MML may have a negligible effect (if any) on cannabis use disorders in this population group.

Macrodosing to microdosing with psychedelics Clinical, social, and cultural perspectives.

To date, the clinical and scientific literature has best documented the effects of classical psychedelics, such as lysergic acid diethylamide (LSD), psilocybin, and dimethyltryptamine (DMT), in typical quantities most often associated with macrodosing. More recently, however, microdosing with psychedelics has emerged as a social trend and nascent therapeutic intervention. This variation in psychedelic practice refers to repeat, intermittent ingestion of less-than-macrodose amounts that do not cause the effects associated with full-blown trips. Microdosing paves the road to incorporating psychedelic drugs into a daily routine while maintaining, or even improving, cognitive and mental function. Unlike macrodosing with psychedelics, the influence of microdosing remains mostly unexplored. And yet, despite the paucity of formal studies, many informal accounts propose that microdosing plays an important role as both a therapeutic intervention (e.g., in mental disorders) and enhancement tool (e.g., recreationally-to boost creativity, improve cognition, and drive personal growth). In response to this relatively new practice, we provide an integrative synthesis of the clinical, social, and cultural dimensions of microdosing. We describe some of the overarching context that explains why this practice is increasingly in vogue, unpack potential benefits and risks, and comment on sociocultural implications. In addition, this article considers the effects that macro- and microdoses have on behavior and psychopathology in light of their dosage characteristics and contexts of use.

Voacamine is a novel inhibitor of EGFR exerting oncogenic activity against colorectal cancer through the mitochondrial pathway.

Colorectal cancer (CRC), among the most aggressive and prevailing neoplasms, is primarily treated with chemotherapy. Voacamine (VOA), a novel bisindole natural product, possesses a variety of conspicuous pharmacological activities. Within the current research, we evaluated in vitro and in vivo the anticancer efficacy of VOA against CRC and its potential mechanisms. Our results illustrated that VOA concentrationdependently suppressed the proliferation and migration of CT26 and HCT116 cells as correspondingly indicated by IC

Amphetamine, methamphetamine, and MDMA in hair samples from a rehabilitation facility Validation and applicability of HF-LPME-GC-MS.

It is known that drug abuse jeopardizes economic and social development. Toxicological analyses can guide prevention and treatment strategies in rehabilitation facilities. The current greatest challenge is finding easily adaptable and less costly sensitive methods that meet the principles of green chemistry. Hair, as a biological matrix, has several advantages, and its ability to detect consumption for longer periods keeping the matrix stable and unaltered stands out. This manuscript addresses the use of a miniaturized technique in an alternative matrix, by making use of a reduced amount of solvents to quantify amphetamines, aiming to guide prevention and treatment strategies in rehabilitation facilities. A Hollow Fiber Liquid-phase Microextraction (HF-LPME) technique for extracting amphetamines from hair samples with Gas Chromatography-Mass Spectrometry (CG-MS) was validated, adapted, and applied to ten samples from patients of a rehabilitation facility. The technique proved to be sensitive, accurate, precise, and not affected by interference from the biological matrix and the linear range for the analytes was 0.2 to 20 ng mg The HF-LPME-GC-MS technique complied with the principles of green chemistry, and proved to be a sensitive technique, adaptable to the routine of common laboratories. Validation in the analysis phase with authentic samples, thus, showed that it can be an important tool for preventing and controlling drug addiction.

Effects of Selective Serotonin Reuptake Inhibitor Use on 3,4-Methylenedioxymethamphetamine-Assisted Therapy for Posttraumatic Stress Disorder A Review of the Evidence, Neurobiological Plausibility, and Clinical Significance.

Among the renewed applications of psychedelic medicines in psychiatry, 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for posttraumatic stress disorder (PTSD) has demonstrated the most promise in early small-scale studies. Recent exploratory analyses from prior clinical trials of MDMA-assisted therapy for PTSD have suggested that recent use of selective serotonin reuptake inhibitors (SSRIs)-the only medication class with United States Food and Drug Administration (FDA) approval to treat PTSD-can significantly dampen the efficacy of this novel therapy. Although psychedelic medicines are not yet FDA approved, MDMA is very likely to be the first to achieve FDA approval-perhaps within the next 2 years. Given this timeline, the field would benefit from more knowledge about potential interactions between this novel therapy and our current treatments. This brief report reviews selected literature in the basic and clinical neurosciences relevant to the interaction of SSRIs and MDMA. The possibility that SSRI use could dampen future responses to MDMA-assisted therapy for PTSD raises many important questions about the biological mechanisms as well as ethical implications around the most appropriate way to counsel patients. In this brief report, we compare the evidence for SSRIs and MDMA-assisted therapy in the treatment of PTSD and discuss what is known about the neurobiological interactions between these 2 medicines. There is strong neurobiological plausibility for the hypothesis that chronic SSRI use dampens response to MDMA-assisted therapy, although current knowledge in the field is limited and primarily relates to acute pharmacodynamic interactions. Our commentary highlights the urgent need for future work dedicated to addressing this important clinical topic.

Adverse events in clinical treatments with serotonergic psychedelics and MDMA A mixed-methods systematic review.

Small-scale clinical studies with psychedelic drugs have shown promising results for the treatment of several mental disorders. Before psychedelics become registered medicines, it is important to know the full range of adverse events (AEs) for making balanced treatment decisions. To systematically review the presence of AEs during and after administration of serotonergic psychedelics and 3,4-methyenedioxymethamphetamine (MDMA) in clinical studies. We systematically searched PubMed, PsycINFO, Embase, and ClinicalTrials.gov for clinical trials with psychedelics since 2000 describing the results of quantitative and qualitative studies. We included 44 articles (34 quantitative 10 qualitative), describing treatments with MDMA and serotonergic psychedelics (psilocybin, lysergic acid diethylamide, and ayahuasca) in 598 unique patients. In many studies, AEs were not systematically assessed. Despite this limitation, treatments seemed to be overall well tolerated. Nausea, headaches, and anxiety were commonly reported acute AEs across diagnoses and compounds. Late AEs included headaches (psilocybin, MDMA), fatigue, low mood, and anxiety (MDMA). One serious AE occurred during MDMA administration (increase in premature ventricular contractions requiring brief hospitalization) no other AEs required medical intervention. Qualitative studies suggested that psychologically challenging experiences may also be therapeutically beneficial. Except for ayahuasca, a large proportion of patients had prior experience with psychedelic drugs before entering studies. AEs are poorly defined in the context of psychedelic treatments and are probably underreported in the literature due to study design (lack of systematic assessment of AEs) and sample selection. Acute challenging experiences may be therapeutically meaningful, but a better understanding of AEs in the context of psychedelic treatments requires systematic and detailed reporting.

An Ultra-Low Dose of ∆9-Tetrahydrocannabinol Alleviates Alzheimers Disease-Related Cognitive Impairments and Modulates TrkB Receptor Expression in a 5XFAD Mouse Model.

Alzheimers disease (AD) is the most common form of dementia, but there is still no available treatment. Δ9-tetrahydrocannabinol (THC) is emerging as a promising therapeutic agent. Using THC in conventional high doses may have deleterious effects. Therefore, we propose to use an ultra-low dose of THC (ULD-THC). We previously published that a single injection of ULD-THC ameliorated cognitive functioning in several models of brain injuries as well as in naturally aging mice. Here, 5xFAD AD model mice received a single treatment of ULD-THC (0.002 mgkg) after disease onset and were examined in two separate experiments for cognitive functions, neurotropic, and inflammatory factors in the hippocampus. We show that a single injection of ULD-THC alleviated cognitive impairments in 6- and 12-month-old 5xFAD mice. On the biochemical level, our results indicate an imbalance between the truncated TrkB receptor isoform and the full receptor, with AD mice showing a greater tendency to express the truncated receptor, and ULD-THC improved this imbalance. We also investigated the expression of three AD-related inflammatory markers and found an ameliorating effect of ULD-THC. The current research demonstrates for the first time the beneficial effects of a single ultra-low dose of THC in a mouse model of AD after disease onset.

Harmicens, Novel Harmine and Ferrocene Hybrids Design, Synthesis and Biological Activity.

Cancer and malaria are both global health threats. Due to the increase in the resistance to the known drugs, research on new active substances is a priority. Here, we present the design, synthesis, and evaluation of the biological activity of harmicens, hybrids composed of covalently bound harmineβ-carboline and ferrocene scaffolds. Structural diversity was achieved by varying the type and length of the linker between the β-carboline ring and ferrocene, as well as its position on the β-carboline ring. Triazole-type harmicens were prepared using Cu(I)-catalyzed azide-alkyne cycloaddition, while the synthesis of amide-type harmicens was carried out by applying a standard coupling reaction. The results of in vitro biological assays showed that the harmicens exerted moderate antiplasmodial activity against the erythrocytic stage of P. falciparum (IC50 in submicromolar and low micromolar range) and significant and selective antiproliferative activity against the MCF-7 and HCT116 cell lines (IC50 in the single-digit micromolar range, SI > 5.9). Cell localization experiments showed different localizations of nonselective harmicene 36 and HCT116-selective compound 28, which clearly entered the nucleus. A cell cycle analysis revealed that selective harmicene 28 had already induced G1 cell cycle arrest after 24 h, followed by G2M arrest with a concomitant drastic reduction in the percentage of cells in the S phase, whereas the effect of nonselective compound 36 on the cell cycle was much less pronounced, which agreed with their different localizations within the cell.

A Comparison of Vaping Behavior, Perceptions, and Dependence among Individuals Who Vape Nicotine, Cannabis, or Both.

Background Electronic delivery systems (e.g., vapes, e-cigarettes) are now popular modes of cannabis and nicotine administration that are often used by the same individuals however, we still know little about dual nicotine and cannabis vaping. Materials Methods An online convenience sample of adult nicotine andor cannabis vape users residing in the United States completed a 60 min survey on sociodemographic characteristics, cannabis andor nicotine vape use behaviors and dependence, reasons for vape use, and perceptions of benefits and harms. After data cleaning, we compared dual vs. nicotine-only and cannabis-only vape users with univariate statistics and step-wise hierarchical linear regression analyses. Additionally, we assessed the factor structure, internal consistency, and criterion and convergent validity of the Penn State Cannabis Vaping Dependence Index (PSCVDI). Results The final sample included 357 dual, 40 cannabis, and 106 nicotine vape users. Compared to nicotine- and cannabis-only vapers, dual vapers started using their nicotine and cannabis vapes at a younger age (p < 0.001), used them for more years (p < 0.001), and were less likely to use their nicotine vape to replace combustible cigarettes (p 0.047). Dual users vs. single-substance users did not have significantly higher nicotine or cannabis vape dependence scores after controlling for sociodemographic and use behaviors. The PSCVDI showed adequate validity for measuring cannabis vape dependence. Conclusions This survey is the first to highlight important differences in vape use behaviors and reasons for use between dual vs. cannabis- and nicotine-only vape users.

The Rise and Rise of Medicinal Cannabis, What Now Medicinal Cannabis Prescribing in Australia 2017-2022.

Medicinal cannabis was legalised in Australia in November 2016. By August 2022, there were 5284 specialist physician and general practitioner (GP) prescribers who submitted Special Access Scheme (SAS) applications to the Therapeutic Goods Administration (TGA) for the provision of medicinal cannabis prescriptions their patients. In this article we examine the impact of the delivery of publicly available clinical guidance documents, provision of education to prescribers, establishment of the TGA online portal, and launching of cannabis clinics on the number of applications approved by the TGA over time. We considered these findings in the context of the need to align the interventions facilitating the prescribing of medicinal cannabis with the establishment of processes to enable the systematic monitoring of patient outcomes. The cumulative number of medicinal cannabis Special Access Scheme-B (SAS-B) prescription approvals from January 2017 to June 2022 was 258,926. SAS-B approvals increased at an average rate of 208.55% p < 0.000, (95% CI 187.25−229.85) per month. Conclusion There has been a rapid growth in prescribing since the legalisation of medicinal cannabis in Australia and this expansion has not been accompanied by parallel processes for the monitoring of medicinal cannabis. The capture of more highly granulated data, as found in the electronic medical record (EMR), patient smartphone applications, and social media provide an opportunity to monitor medicinal cannabis effectiveness and safety across multiple prescribing indications.

The Cannabis-Induced Epigenetic Regulation of Genes Associated with Major Depressive Disorder.

The prevalence of depression is increasing worldwide, as is the number of people suffering from treatment-resistant depression these patients constitute 30% of those treated. Unfortunately, there have not been significant advances in the treatment of this disorder in the past few decades. Exposure to cannabis and cannabis-derived compounds impacts depression symptomatology in different ways, with evidence indicating that cannabidiol has antidepressant effects there have been mixed results with medical cannabis. Even though the exact molecular mechanisms of the action underlying changes in depression symptomatology upon exposure to cannabis and cannabis-derived compounds are still unknown, there is strong evidence that these agents have a widespread impact on epigenetic regulation. We hypothesized that exposure to cannabis or cannabis-derived compounds changes the DNA methylation levels of genes associated with depression. To test this hypothesis, we first performed a literature search to identify genes that are differentially methylated upon exposure to cannabis and cannabis-derived compounds, as reported in methylome-wide association studies. We next checked whether genes residing in loci associated with depression, as identified in the largest currently available genome-wide association study of depression, were reported to be epigenetically regulated by cannabis or cannabis-related compounds. Multiple genes residing in loci associated with depression were found to be epigenetically regulated by exposure to cannabis or cannabis-derived compounds. This epigenomic regulation of depression-associated genes by cannabis or cannabis-derived compounds was reported across diverse organisms, tissues, and developmental stages and occurred in genes crucial for neuronal development, functioning, survival, and synapse functioning, as well as in genes previously implicated in other mental disorders.

Diminished Structural Brain Integrity in Long-term Cannabis Users Reflects a History of Polysubstance Use.

Cannabis legalization and use are outpacing our understanding of its long-term effects on brain and behavior, which is fundamental for effective policy and health practices. Existing studies are limited by small samples, cross-sectional measures, failure to separate long-term from recreational use, and inadequate control for other substance use. Here, we address these limitations by determining the structural brain integrity of long-term cannabis users in the Dunedin Study, a longitudinal investigation of a population-representative birth cohort followed to midlife. We leveraged prospective measures of cannabis, alcohol, tobacco, and other illicit drug use in addition to structural neuroimaging in 875 study members at age 45 to test for differences in both global and regional gray and white matter integrity between long-term cannabis users and lifelong nonusers. We additionally tested for dose-response associations between continuous measures of cannabis use and brain structure, including careful adjustments for use of other substances. Long-term cannabis users had a thinner cortex, smaller subcortical gray matter volumes, and higher machine learning-predicted brain age than nonusers. However, these differences in structural brain integrity were explained by the propensity of long-term cannabis users to engage in polysubstance use, especially with alcohol and tobacco. These findings suggest that diminished midlife structural brain integrity in long-term cannabis users reflects a broader pattern of polysubstance use, underlining the importance of understanding comorbid substance use in efforts to curb the negative effects of cannabis on brain and behavior as well as establish more effective policy and health practices.

Meta-analysis of cognitive behaviour therapy and selective serotonin reuptake inhibitors for the treatment of hypochondriasis Implications for trial design.

Classification of hypochondriasis as an obsessive-compulsive and related disorder in the International Classification of Diseases 11th Revision (ICD-11) has generated new heuristics for treatment of this common, chronic and disabling disorder. Standard treatment involves cognitive behaviour therapy (CBT) or selective serotonin reuptake inhibitors (SSRIs), but no meta-analysis has so far considered hypochondriasis as a structured diagnosis or assessed the role of medication. A clearer understanding of the relative effectiveness of these interventions and identification of clinically relevant factors moderating the treatment response is needed for clinical guideline development. The current systematic review and meta-analysis of interventions for hypochondriasis was preregistered on PROSPERO (CRD42020185768) and follows PRISMA guidelines. We searched MEDLINE, PsycINFO, and Cochrane Library databases until July 2021 for randomized controlled trials (RCTs) of interventions for patients diagnosed with hypochondriasis (or historical diagnostic equivalents). We assessed aspects of study quality using the CONSORT Checklist for evaluation of RCTs, the Cochrane Risk of Bias 2 tool, researcher allegiance and treatment fidelity. The primary outcome was improvement in hypochondriasis symptoms, comparing intervention and control groups at trial endpoint. Moderator variables were assessed using subgroup and meta-regression analyses. Searches identified 13 randomised controlled trials (RCTs) (N 1405) 12 included CBT (N 1212) and three included SSRI (N 193) arms as the experimental intervention. Random effects meta-analysis yielded a moderate-to-large effect size for CBT versus all controls (g -0.70 95% CI -0.99 to -0.41, k 18, I CBT and SSRIs are effective in the acute treatment of hypochondriasis, with some indication that intervention at a younger age produces better outcomes for CBT. In the case of CBT, effect sizes appear to have been significantly inflated by the use of wait list controls, and researcher allegiance bias. We recommend that a definitive, adequately controlled trial, designed with respect to the methodological issues raised in this meta-analysis, is needed to determine the magnitude effects for CBT and SSRIs with confidence and the long-term effect of treatments, to inform mental health service provision for this overlooked patient group.

Increasing prevalence of illicit drug use among employees at Swedish workplaces over a 25-year period.

Reports indicate that the proportion of adults using drugs of abuse has been increasing in recent years in Europe. Although there are various indicators of increased drug use in Sweden over time, few studies could demonstrate an increase in the proportion of adults using drugs. To investigate changes in drug use prevalence over time, drug testing at the workplace has been used for a 25-year period. The urine samples of employees sent by occupational health services from all over Sweden during a 25-year period were analyzed. The analyzing capacity increased over time (from 3411 in 1994 to 60 315 samples analyzed in 2019), and the majority of the samples was analyzed for the following drugs cannabis (tetrahydrocannabinol), amphetamine, opiates, cocaine, and benzodiazepines. There was an overall increase in the proportion of samples that tested positive for illicit drugs over a 25-year period. This increase seemed to take place step-wise, with phases of linear increases and plateaus that over time became shorter. About 1.3% of samples tested positive for drugs in 1994, whereas 5.6% tested positive in 2019. Since 2007, the rate of positive samples has increased for cannabis and decreased for benzodiazepines. Although the rate of samples tested positive for opiates had remained relatively stable over the last 20 years, this rate had increased for amphetamine and cocaine between 2013 and 2019. The results indicate that the use of illicit drugs among employees at Swedish workplaces has increased during a 25-year period.

Affinity Assays for Cannabinoids Detection Are They Amenable to On-Site Screening

Roadside testing of illicit drugs such as tetrahydrocannabinol (THC) requires simple, rapid, and cost-effective methods. The need for non-invasive detection tools has led to the development of selective and sensitive platforms, able to detect phyto- and synthetic cannabinoids by means of their main metabolites in breath, saliva, and urine samples. One may estimate the time passed from drug exposure and the frequency of use by corroborating the detection results with pharmacokinetic data. In this review, we report on the current detection methods of cannabinoids in biofluids. Fluorescent, electrochemical, colorimetric, and magnetoresistive biosensors will be briefly overviewed, putting emphasis on the affinity formats amenable to on-site screening, with possible applications in roadside testing and anti-doping control.

Skepticism about Recent Evidence That Psilocybin Liberates Depressed Minds.

A recent paper in

Comparison of psychedelic and near-death or other non-ordinary experiences in changing attitudes about death and dying.

Both psychedelic drug experiences and near-death experiences can occasion changes in perspectives on death and dying, but there have been few direct comparisons of these phenomena. This study directly compared psychedelic occasioned and non-drug experiences which altered individuals beliefs about death. Individuals who reported an experience that altered their beliefs about death occasioned by either a psychedelic drug or a near-death or other non-ordinary experience completed an online survey. Circumstances of the experience, mystical and near-death subjective features, changes in attitudes about death, and other persisting effects were evaluated. The study sample (n 3192) included five groups non-drug near-death or other non-ordinary experiences (n 933), and drug experiences occasioned by lysergic acid diethylamide (LSD) (n 904), psilocybin (n 766), ayahuasca (n 282), or N,N-dimethyltryptamine (DMT) (n 307). Analyses of differences in experiences were adjusted statistically for demographic differences between groups. Compared to the psychedelic groups, the non-drug group was more likely to report being unconscious, clinically dead, and that their life was in imminent danger. The groups were remarkably similar in the reported changes in death attitudes attributed to the experience, including a reduced fear of death and high ratings of positive persisting effects and personal meaning, spiritual significance, and psychological insight. Although both psychedelic and non-drug participants showed robust increases on standardized measures of mystical and near-death experiences, these measures were significantly greater in the psychedelic participants. Non-drug participants were more likely to rate their experiences as the single most meaningful of their lives. Comparing across psychedelic substances, ayahuasca and DMT groups tended report stronger and more positive enduring consequences of the experience than the psilocybin and LSD groups, which were largely indistinguishable. These data provide a detailed characterization and comparison of psychedelic occasioned and non-drug experiences that changed attitudes about death and suggest the importance of future prospective psychedelic administration studies.

Pharmacokinetics, systemic toxicity, thermoregulation and acute behavioural effects of 25CN-NBOMe.

N-(2-methoxybenzyl)phenethylamines (NBOMes) are a family of potent 5-HT

Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder A Randomized Clinical Trial.

Although classic psychedelic medications have shown promise in the treatment of alcohol use disorder (AUD), the efficacy of psilocybin remains unknown. To evaluate whether 2 administrations of high-dose psilocybin improve the percentage of heavy drinking days in patients with AUD undergoing psychotherapy relative to outcomes observed with active placebo medication and psychotherapy. In this double-blind randomized clinical trial, participants were offered 12 weeks of manualized psychotherapy and were randomly assigned to receive psilocybin vs diphenhydramine during 2 day-long medication sessions at weeks 4 and 8. Outcomes were assessed over the 32-week double-blind period following the first dose of study medication. The study was conducted at 2 academic centers in the US. Participants were recruited from the community between March 12, 2014, and March 19, 2020. Adults aged 25 to 65 years with a DSM-IV diagnosis of alcohol dependence and at least 4 heavy drinking days during the 30 days prior to screening were included. Exclusion criteria included major psychiatric and drug use disorders, hallucinogen use, medical conditions that contraindicated the study medications, use of exclusionary medications, and current treatment for AUD. Study medications were psilocybin, 25 mg70 kg, vs diphenhydramine, 50 mg (first session), and psilocybin, 25-40 mg70 kg, vs diphenhydramine, 50-100 mg (second session). Psychotherapy included motivational enhancement therapy and cognitive behavioral therapy. The primary outcome was percentage of heavy drinking days, assessed using a timeline followback interview, contrasted between groups over the 32-week period following the first administration of study medication using multivariate repeated-measures analysis of variance. A total of 95 participants (mean SD age, 46 12 years 42 44.2% female) were randomized (49 to psilocybin and 46 to diphenhydramine). One participant (1.1%) was American IndianAlaska Native, 3 (3.2%) were Asian, 4 (4.2%) were Black, 14 (14.7%) were Hispanic, and 75 (78.9%) were non-Hispanic White. Of the 95 randomized participants, 93 received at least 1 dose of study medication and were included in the primary outcome analysis. Percentage of heavy drinking days during the 32-week double-blind period was 9.7% for the psilocybin group and 23.6% for the diphenhydramine group, a mean difference of 13.9% (95% CI, 3.0-24.7 F1,86 6.43 P .01). Mean daily alcohol consumption (number of standard drinks per day) was also lower in the psilocybin group. There were no serious adverse events among participants who received psilocybin. Psilocybin administered in combination with psychotherapy produced robust decreases in percentage of heavy drinking days over and above those produced by active placebo and psychotherapy. These results provide support for further study of psilocybin-assisted treatment for AUD. ClinicalTrials.gov Identifier NCT02061293.

Treating Alcohol Use Disorder With Hallucinogens-Renewed Interest After a 50-Year Hiatus.

This Viewpoint discusses the use of hallucinogens to treat alcohol use disorder.

Assessing the quality of publicly available videos on MDMA-assisted psychotherapy for PTSD.

Patients increasingly rely on the Internet for healthcare information. This study aimed to evaluate the quality of videos on 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder (PTSD) on YouTube™. YouTube™ was searched for the terms MDMA and PTSD. The 100 most viewed videos were analyzed using three standard quality measures Global Quality Scores (GQS), JAMA benchmark, and DISCERN. Viewer engagement features and source of upload, video duration, inclusion of patient narrative andor MDDOPhD, the mention of lack of Food and Drug Administration (FDA) approval, side effects, potential for abuse, and use in conjunction with psychotherapy were recorded. The videos were of poor quality (mean GQS 2.26 ± 0.945, JAMA 1.96 ± 0.454, and DISCERN 29.5 ± 8.280). A significant positive association was found between video quality and duration (GQS r .5857, p < .0001, JAMA r .279, p .0409, DISCERN r .5783, p < .0001). Videos including an MDDOPhD had the highest scores (GQS 2.875 1.22, p .006, DISCERN 38.3580 13.32, p < .0003). A minority of videos were uploaded by academic institutions (1%) most were from professional organizations (29%). No correlation was found between quality and viewer engagement features-number of views, subscribers, likesdislikes, or comments. A majority mentioned that MDMA must be used in conjunction with psychotherapy (85%) and is not FDA-approved (82%) for PTSD. Only 32% of videos mentioned risks or potential for abuse. These findings highlight the need for better quality of online health material and an opportunity for involvement of healthcare professionals in the dissemination of accurate health information via content creation. This is the first study to examine publicly available information on the use of MDMA for PTSD.

Anhedonia, Apathy, Pleasure, and Effort-Based Decision-Making in Adult and Adolescent Cannabis Users and Controls.

Cannabis use may be linked with anhedonia and apathy. However, previous studies have shown mixed results, and few have examined the association between cannabis use and specific reward sub-processes. Adolescents may be more vulnerable than adults to harmful effects of cannabis. This study investigated (1) the association between non-acute cannabis use and apathy, anhedonia, pleasure, and effort-based decision-making for reward and (2) whether these relationships were moderated by age group. We used data from the CannTeen study. Participants were 274 adult (26-29 years) and adolescent (16-17 years) cannabis users (1-7 dwk use in the past 3 months) and gender- and age-matched controls. Anhedonia was measured with the Snaith-Hamilton Pleasure Scale (n 274), and apathy was measured with the Apathy Evaluation Scale (n 215). Effort-based decision-making for reward was measured with the Physical Effort task (n 139), and subjective wanting and liking of rewards was measured with the novel Real Reward Pleasure task (n 137). Controls had higher levels of anhedonia than cannabis users (F1,258 5.35, P .02, η p2 .02). There were no other significant effects of user-group and no significant user-groupage-group interactions. Null findings were supported by post hoc Bayesian analyses. Our results suggest that cannabis use at a frequency of 3 to 4 dwk is not associated with apathy, effort-based decision-making for reward, reward wanting, or reward liking in adults or adolescents. Cannabis users had lower anhedonia than controls, albeit at a small effect size. These findings are not consistent with the hypothesis that non-acute cannabis use is associated with amotivation.

Chronic adolescent exposure to cannabis in mice leads to sex-biased changes in gene expression networks across brain regions.

During adolescence, frequent and heavy cannabis use can lead to serious adverse health effects and cannabis use disorder (CUD). Rodent models of adolescent exposure to the main psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), mimic the behavioral alterations observed in adolescent users. However, the underlying molecular mechanisms remain largely unknown. Here, we treated female and male C57BL6N mice with high doses of THC during early adolescence and assessed their memory and social behaviors in late adolescence. We then profiled the transcriptome of five brain regions involved in cognitive and addiction-related processes. We applied gene coexpression network analysis and identified gene coexpression modules, termed cognitive modules, that simultaneously correlated with THC treatment and memory traits reduced by THC. The cognitive modules were related to endocannabinoid signaling in the female dorsal medial striatum, inflammation in the female ventral tegmental area, and synaptic transmission in the male nucleus accumbens. Moreover, cross-brain region module-module interaction networks uncovered intra- and inter-region molecular circuitries influenced by THC. Lastly, we identified key driver genes of gene networks associated with THC in mice and genetic susceptibility to CUD in humans. This analysis revealed a common regulatory mechanism linked to CUD vulnerability in the nucleus accumbens of females and males, which shared four key drivers (Hapln4, Kcnc1, Elavl2, Zcchc12). These genes regulate transcriptional subnetworks implicated in addiction processes, synaptic transmission, brain development, and lipid metabolism. Our study provides novel insights into disease mechanisms regulated by adolescent exposure to THC in a sex- and brain region-specific manner.

Effects of psychotropic drugs on ocular parameters relevant to traffic safety A systematic review.

Driving is a complex neurobehavioural task necessitating the rapid selection, uptake, and processing of visual information. Eye movements that are critical for the execution of visually guided behaviour such as driving are also sensitive to the effects of psychotropic substances. The Embase (via Ovid), EBSCOHost, Psynet, Pubmed, Scopus and Web of Science databases were examined from January 01st, 2000 to December 31st, 2021. Study selection, data extraction and Cochrane Risk of Bias (RoB2) assessments were conducted according to PRISMA guidelines. The review was prospectively registered (CRD42021267554). In total, 36 full-text articles examined the effects of six principal psychotropic drug classes on measures of oculomotor parameters relevant to driving. Centrally depressing substances affect oculomotor responses in a dose-dependent manner. Psychostimulants improve maximal speed, but not accuracy, of visual search behaviours. Inhaled Δ-9-tetrahydrocannabinol (THC) increases inattention (saccadic inaccuracy) but does not consistently affect other oculomotor parameters. Alterations to composite ocular parameters due to psychoactive substance usage likely differently compromises performance precision during driving through impaired ability to select and process dynamic visual information.

Mesoporous carbon decorated with MIL-100(Fe) as an electrochemical platform for ultrasensitive determination of trace cadmium and lead ions in surface water.

In this work, MIL-100(Fe)-decorated mesoporous carbon powders (MCMIL-100(Fe)) were prepared by in situ growth of MIL-100(Fe) on the surface of ZIF-8 framework-based mesoporous carbons (MC). The hybrid material was characterized using SEM equipped with EDS mapping for morphology investigation, X-ray photoelectron spectroscopy for chemical valence analysis, and X-ray diffraction for crystal structure determination. The developed sensor separated from the traditional bismuth film decoration, and simultaneously, MCMIL-100(Fe) was applied for the first time to electrochemically detect trace amounts of Pb(II) and Cd(II). The fabricated MCMIL-100(Fe)-based electrochemical sensor showed excellent response to the target analytes at -0.55 and - 0.75 V for lead and cadmium ions, respectively. By adjusting some measurement parameters, that is, the loading concentration of MCMIL-100(Fe), acidity of the HAc-NaAc buffer (ABS), deposition potential, and deposition time, the analytical performance of the proposed electrochemical sensor was examined by exploring the calibration curve, repeatability, reproducibility, stability, and anti-interference under optimized conditions. The response current of the proposed MCMIL-100(Fe) electrochemical sensor showed a well-defined linear relationship in the concentration ranges of 2-250 and 2-270 μg·L

Awe as a Pathway to Mental and Physical Health.

How do experiences in nature or in spiritual contemplation or in being moved by music or with psychedelics promote mental and physical health Our proposal in this article is awe. To make this argument, we first review recent advances in the scientific study of awe, an emotion often considered ineffable and beyond measurement. Awe engages five processes-shifts in neurophysiology, a diminished focus on the self, increased prosocial relationality, greater social integration, and a heightened sense of meaning-that benefit well-being. We then apply this model to illuminate how experiences of awe that arise in nature, spirituality, music, collective movement, and psychedelics strengthen the mind and body.

Psychedelic integration An analysis of the concept and its practice.

The concept of integration has garnered increased attention in the past few years, despite a long history of only brief mention. Integration services are offered by therapists, coaches, and other practitioners, or may be self-guided. There are many definitions of psychedelic integration, and the term encompasses a range of practices and techniques. This seems to have led to confusion about what integration is and how it is best practiced. The primary focus of this manuscript is the presentation of the first extensive review and concept analysis of definitions, practices, and models of psychedelic integration. We provide a synthesized definition of integration, synthesized model of integration, and comprehensive summary of integration practices to bring clarity to the subject.

Helpful or Harmful The Therapeutic Potential of Medications with Varying Degrees of Abuse Liability in the Treatment of Substance Use Disorders.

This review summarizes recent clinical trial research on pharmacological treatments for substance use disorders, with a specific focus on agents with potential abuse liability. Pharmacological treatments for substance use disorders may include gabapentinoids, baclofen, modafinil, ketamine, cannabinoids, gamma-hydroxybutyrate, and psychedelics. Gabapentinoids may decrease negative subjective effects of withdrawal in alcohol and cannabis use disorders. Cannabinoids similarly appear to decrease use and withdrawal symptoms in cannabis use disorder, while research shows stimulant medications may reduce cravings and increase abstinence in cocaine use disorder. Ketamine and psychedelics may help treat multiple substance use disorders. Ketamine may reduce withdrawal symptoms, promote abstinence, and diminish cravings in alcohol and cocaine use disorders and psychedelics may promote remission, decrease use, and reduce cravings in alcohol and opioid use disorders. Regardless of current regulatory approval statuses and potentials for abuse, multiple agents should not be dismissed prematurely as possible treatments for substance use disorders. However, further clinical research is needed before effective implementation can begin in practice. The online version contains supplementary material available at 10.1007s40429-022-00432-9.

Exceptionally high selectivity in the separation of light hydrocarbons by adsorption on MIL-127(Fe) and on a (9,9) carbon nanotube.

Porous solids with channel sizes that are not much above the size of small hydrocarbons can yield extremely large adsorption selectivity. Our Grand Canonical Monte-Carlo simulations indicate exceptionally high selectivity for the separation of methane, ethane and propane from natural gas. At 250 K the C

Broad-spectrum cannabis oil ameliorates reserpine-induced fibromyalgia model in mice.

Fibromyalgia (FM) is an idiopathic disorder characterized by generalized pain and associated symptoms such as depression and anxiety. Cannabis sativa shows different pharmacological activities, such as analgesic, anti-inflammatory, neuroprotective, and immunomodulatory. Associated with this, the use of an oil with low concentrations of THC can reduce the psychomimetic adverse effects of the plant. Therefore, the present study aimed to evaluate the analgesic effect of broad-spectrum cannabis oil with low THC concentration in an experimental model of FM. Mechanical hyperalgesia, thermal allodynia, depressive- and anxious-related behavior, and locomotor activity were evaluated after reserpine (0.25 mgkg injected subcutaneously (s.c.) once daily for three consecutive days) administration. Our results showed that oral administration of broad-spectrum cannabis oil (0.1, 1, and 3 mgkg, p.o.) in a single dose on the 4th day inhibited mechanical hyperalgesia and thermal allodynia induced by reserpine. Relevantly, treatment during four days with broad-spectrum cannabis oil (0.1 mgkg, p.o.) reduced mechanical hyperalgesia 1 h after reserpine administration. Intraplantar treatment with cannabis oil significantly reversed mechanical and heat thermal nociception induced by reserpine injection. Interestingly, spinal and supraspinal administration of broad-spectrum cannabis oil completely inhibited mechanical hyperalgesia and thermal sensitivity induced by reserpine. The repeated cannabis oil administration, given daily for 14 days, markedly mitigated the mechanical and thermal sensitivity during the FM model, and its reduced depressive-like behavior induced by reserpine. In summary, broad-spectrum cannabis oil is an effective alternative to reverse the reserpine-induced fibromyalgia model.

Psychedelic drug abuse potential assessment research for new drug applications and Controlled Substances Act scheduling.

New medicines containing classic hallucinogenic and entactogenic psychedelic substance are under development for various psychiatric and neurological disorders. Many of these, including psilocybin, lysergic acid diethylamide (LSD), and 3,4-methylenedioxymethamphetamine (MDMA) are Schedule I controlled substances of the United States Controlled Substances Act (US CSA), and similarly controlled globally. The implications of the CSA for research and medicines development, the path to approval of medicines, and their subsequent removal from Schedule I in the US are discussed. This entire process occurs within the framework of the CSA in the US and its counterparts internationally in accordance with international drug control treaties. Abuse potential related research in the US informs the eight factors of the CSA which provide the basis for rescheduling actions that must occur upon approval of a drug that contains a Schedule I substance. Abuse-related research also informs drug product labeling and the risk evaluation and mitigation strategies (REMS) will likely be required for approved medicines. Human abuse potential studies typically employed in CNS drug development may be problematic for substances with strong hallucinogenic effects such as psilocybin, and alternative strategies are discussed. Implications for research, medicinal development, and controlled substance scheduling are presented in the context of the US CSA and FDA requirements with implications for global regulation. We also discuss how abuse-related research can contribute to understanding mechanisms of action and therapeutic effects as well as the totality of the effects of the drugs on the brain, behavior, mood, and the constructs of spirituality and consciousness.

Consumption of common illicit drugs in twenty-one cities in southwest China through wastewater analysis.

Wastewater-based epidemiology (WBE) was applied to estimate illicit drugs consumption at a provincial scale in southwest China. A large-scale wastewater sampling campaign was carried out from October to November in 2021 in 156 different wastewater treatment plants (WWTPs). Two 24-h composite influent wastewater samples were collected in each WWTP. Concentrations of 11 illicit drugs or their metabolites were determined using liquid chromatography coupled with tandem mass spectrometry (LC-MSMS). Benzoylecgonine, cocaine, 6-monoacetylmorphine, norketamine, 3,4-methylenedioxymethamphetamine (MDMA), and MDA were not detected in any of the wastewater samples. Methamphetamine and morphine were detected in >84% of samples, while ketamine was found in about 6% of the samples. The city-specific population-weighted consumption of methamphetamine and ketamine were in the range of 0.6-49.7 and N.D.-7.0 mg 1000 inh

Cannabinoid CB1 receptors regulate salivation.

Saliva serves multiple important functions within the body that we typically take for granted, such as helping prepare food for swallowing and defense against oral pathogens. Dry mouth is a primary symptom of Sjӧgrens syndrome and is a side effect of many drug treatments. Cannabis users frequently report dry mouth, but the basis for this is still unknown. If the effects occur via the endogenous cannabinoid signaling system, then this may represent a novel mechanism for the regulation of salivation. We examined expression of cannabinoid CB1 receptors in submandibular salivary gland using immunohistochemistry and tested regulation of salivation by THC and cannabinoid-related ligands. We now report that CB1 receptors are expressed in the axons of cholinergic neurons innervating the submandibular gland. No staining is seen in submandibular gland epithelial cells (acinar and ductal), or myoepithelial cells (MECs). Treatment with THC (4 mgkg, IP) or the cannabinoid receptor agonist CP55940 (0.5 mgkg) reduced salivation in both male and female mice 1 h after treatment. CBD had no effect on its own but reversed the effect of THC in a concentration-dependent manner. Neither the CB1 receptor antagonist SR141716 (4 mgkg) nor the CB2-selective agonist JWH133 (4 mgkg) had an effect on salivation. We also found that fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide and related lipids, regulates salivation. Salivation was reduced in FAAH knockout mice as well as mice treated with the FAAH blocker URB597 (4 mgkg). URB597 had no effect in CB1 knockout mice. FAAH protein is detected intracellularly in acinar but not ductal epithelial cells. In lipidomics experiments, we found that FAAH knockout mice chiefly had elevated levels of acylethanolamines, including anandamide, and reduced levels of acyglycines. Our results are consistent with a model wherein endocannabinoids activate CB1 receptors on cholinergic axons innervating the submandibular gland. THC likely acts by plugging into this system, activating CB1 receptors to reduce salivation, thus offering a mechanism underlying the dry mouth reported by cannabis users.

Sex-dependent Effect of In-utero Exposure to Δ

Administration of Δ Pregnant Wistar rat dams were injected with Δ At PND21, control and Δ Collectively, the reduced GS ratio in both islet and serum in association with an increased serum IG ratio has direct correlations with early glucose intolerance and insulin resistance observed exclusively in females offspring in this prenatal cannabinoid model.

Recent challenges and trends in forensic analysis Δ9-THC isomers pharmacology, toxicology and analysis.

Δ9-tetrahydrocannabinol (Δ9-THC) isomers, especially Δ8-tetrahydrocannabinol (Δ8-THC), are increasing in foods, beverages, and e-cigarettes liquids. A major factor is passage of the Agriculture Improvement Act (AIA) that removed hemp containing less than 0.3 % Δ9-THC from the definition of marijuana or cannabis. CBD-rich hemp flooded the market resulting in excess product that could be subjected to CBD cyclization to produce Δ8-THC. This process utilizes strong acid and yields toxic byproducts that frequently are not removed prior to sale and are currently inadequately studied. Pharmacological activity is qualitatively similar for Δ8-THC and Δ9-THC, but most preclinical studies in mice, rats, and monkeys documented greater ∆9-THC potency. Both isomers caused graded dose-response effects on euphoria, blurred vision, mental confusion and lethargy, although Δ8-THC was at least 25 % less potent. The most common analytical methodologies providing baseline resolution of ∆8-THC and ∆9-THC in non-biological matrices are liquid-chromatography coupled to diode-array detection (LC-DAD or LC-PDA), while liquid chromatography coupled to mass spectrometry is preferred for biological matrices. Other available analytical methods are gas-chromatography-mass spectrometry (GC-MS) and quantitative nuclear magnetic resonance (QNMR). Current knowledge on the pharmacology of ∆8-THC and other ∆9-THC isomers are reviewed to raise awareness of the activity of these isomers in cannabis products, as well as analytical methods to discriminate ∆9-THC qualitatively, and quantitatively and ∆8-THC in biological and non-biological matrices.

Effects of Δ

Δ

Characterization of Cannabis Products Purchased for Medical Use in New York State.

This cross-sectional study examines the purchase of medical cannabis products made in New York State from dispensaries operated by a single integrated manufacturer and licensed retail company within the state.

The Association of Classic Serotonergic Psychedelic Use and Intention of Future Use with Nature Relatedness.

This study sought to investigate the effects of different substances on nature relatedness (NR) in the general population. An online cross-sectional survey done in Brazil investigated use of ayahuascaDMT,

Facilitated extinction of conditioned fear responses by delta 9-tetrahyrdrocannabidol in humans a pilot study.

We sought to determine whether acute delta 9-tetrahyrdrocannabidol (THC) administration would facilitate fear extinction in young occasional cannabis users, given that animal models indicate THC facilitates extinction learning, and recent studies indicate THC administration may also enhance threat memory extinction in humans. On each of the 2 days, 24 hour THC-deprived participants were conditioned to fear visual stimuli in a delay conditioning and extinction paradigm. Both CS and CS- were faces of negative emotional valence, with the CS paired with mild electric shock. Throughout both conditioning and extinction paradigms, EEG was measured to quantify event-related potentials for these learning processes. Following conditioning, individuals, in a randomized and counter-balanced order, smoked either an active THC cigarette (26.25 mg2.7% THC) or a placebo marijuana cigarette (0.002% THC) on 1 day and the opposite cigarette on the second day. After smoking, CS and CS- were presented without shock, resulting in extinction of conditioned fear. Relative to placebo, THC facilitated extinction of the conditioned response to the CS, as reflected by reductions in late positive potential amplitude during extinction learning. The results indicate that acute THC administration may facilitate extinction of the conditioned fear response in humans.

Medical cannabinoids a pharmacology-based systematic review and meta-analysis for all relevant medical indications.

Medical cannabinoids differ in their pharmacology and may have different treatment effects. We aimed to conduct a pharmacology-based systematic review (SR) and meta-analyses of medical cannabinoids for efficacy, retention and adverse events. We systematically reviewed (registered at PROSPERO CRD42021229932) eight databases for randomized controlled trials (RCTs) of dronabinol, nabilone, cannabidiol and nabiximols for chronic pain, spasticity, nausea vomiting, appetite, ALS, irritable bowel syndrome, MS, Chorea Huntington, epilepsy, dystonia, Parkinsonism, glaucoma, ADHD, anorexia nervosa, anxiety, dementia, depression, schizophrenia, PTSD, sleeping disorders, SUD and Tourette. Main outcomes and measures included patient-relevantdisease-specific outcomes, retention and adverse events. Data were calculated as standardized mean difference (SMD) and ORs with confidence intervals (CI) via random effects. Evidence quality was assessed by the Cochrane Risk of Bias and GRADE tools. In total, 152 RCTs (12,123 participants) were analysed according to the type of the cannabinoid, outcome and comparator used, resulting in 84 comparisons. Significant therapeutic effects of medical cannabinoids show a large variability in the grade of evidence that depends on the type of cannabinoid. CBD has a significant therapeutic effect for epilepsy (SMD - 0.5CI - 0.62, - 0.38 high grade) and Parkinsonism (- 0.41CI - 0.75, - 0.08 moderate grade). There is moderate evidence for dronabinol for chronic pain (- 0.31CI - 0.46, - 0.15), appetite (- 0.51CI - 0.87, - 0.15) and Tourette (- 1.01CI - 1.58, - 0.44) and moderate evidence for nabiximols on chronic pain (- 0.25- 0.37, - 0.14), spasticity (- 0.36CI - 0.54, - 0.19), sleep (- 0.24CI - 0.35, - 0.14) and SUDs (- 0.48CI - 0.92, - 0.04). All other significant therapeutic effects have either low, very low, or even no grade of evidence. Cannabinoids produce different adverse events, and there is low to moderate grade of evidence for this conclusion depending on the type of cannabinoid. Cannabinoids are effective therapeutics for several medical indications if their specific pharmacological properties are considered. We suggest that future systematic studies in the cannabinoid field should be based upon their specific pharmacology.

Structural basis for cannabinoid-induced potentiation of alpha1-glycine receptors in lipid nanodiscs.

Nociception and motor coordination are critically governed by glycine receptor (GlyR) function at inhibitory synapses. Consequentially, GlyRs are attractive targets in the management of chronic pain and in the treatment of several neurological disorders. High-resolution mechanistic details of GlyR function and its modulation are just emerging. While it has been known that cannabinoids such as Δ

Cannabinoid modulation of brain activation during volitional regulation of negative affect in trauma-exposed adults.

Emotion dysregulation is considered a core component of posttraumatic stress disorder (PTSD). Cognitive reappraisal is one therapeutic emotion regulation strategy that has been widely studied among individuals with mood and anxiety disorders, and numerous differences in brain activation patterns have been shown between individuals with and without PTSD during tasks of cognitive reappraisal. Prior research among healthy subjects suggests that an acute, low dose of Δ9-tetrahydrocannabinol (THC) could attenuate the neurophysiological discrepancies that exist between individuals with and without PTSD during tasks of emotional processing however, the effect of an acute, low dose of THC on corticolimbic activity during emotion regulation among individuals with PTSD has not yet been studied. The present study aimed to investigate the effect of THC on negative affect and brain activation in a priori regions of interest during cognitive reappraisal among trauma-exposed individuals with and without PTSD. Using a double-blind design, 51 individuals were randomized to receive THC or placebo (PBO) before participating in a well-established emotion regulation task during functional magnetic resonance imaging (fMRI). THC but not PBO reduced negative affect during reappraisal, and THC increased dorsomedial prefrontal cortex (dmPFC) activation in response to neutral images. Individuals with PTSD displayed less activation in the angular gyrus, overall, compared to the trauma-exposed control (TEC) group, however THC increased angular gyrus activation in the PTSD group so that there was no significant difference in angular gyrus activation between the TEC and PTSD groups that received THC. Compared to PBO, THC also increased cerebellar activation during exposure to neutral images in individuals with PTSD. Lastly, in participants that received THC, greater posterior cingulate cortex (PCC)precuneus activation during reappraisal was associated with less self-reported negative affect following reappraisal blocks. Together these findings suggest that THC may prove to be a beneficial pharmacological adjunct to cognitive reappraisal therapy in the treatment of PTSD.

Prevalence and associations of classic psychedelic-related seizures in a population-based sample.

Previous studies have reported links between classic psychedelic use and seizures, but little remains known about prevalence and potential risk factors of classic psychedelic-related seizures. Using a sample representative of the US adult population with regard to sex, age, and ethnicity (N 2822), this study examined the prevalence and potential risk factors of classic psychedelic-related seizures, in a subsample of respondents who reported lifetime classic psychedelic use (n 613). Among those who reported lifetime classic psychedelic use, 1.5 % reported classic psychedelic-related seizures, a statistic that comports with the prevalence of epilepsy in the US population. Among those who reported seizures while using a classic psychedelic, almost half reported co-use of antidepressants, mood stabilizers, or opioid replacement therapies at the time of the seizures. Notably, classic psychedelic-related seizures were more commonly reported in certain respondents, especially those with a personal or family history of epilepsy. These results suggest that classic psychedelic use could increase the risk of seizures in certain populations, particularly those with a personal or family history of epilepsy.

Evidence Brief Psychedelic Medications for Mental Health and Substance Use Disorders

The ESP Coordinating Center (ESP CC) is responding to a request from the VA Office of Research and Development (ORD) and VHA Office of Mental Health and Suicide Prevention (OMHSP) for an Evidence Brief on the use of psychedelic substances for treating mental health and substance use disorders. Findings from this Evidence Brief will be used to inform VA research activities and clinical care in the areas of mental health and substance use disorder treatment.

Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders Proceedings of a Workshop

Psychiatric illnesses — such as major depressive disorder, anxiety disorder, substance use disorder, and posttraumatic stress disorder (PTSD) — are widely prevalent and represent a substantial health burden worldwide. Yet, conventional medications for mental illnesses often fail to provide relief to patients disruptive and disabling symptoms. Existing and emerging evidence that psychedelics (e.g., LSD and psilocybin) and entactogens (e.g., MDMA) may be useful as tools to alleviate mental illness has sparked a renaissance of interest by investigators, clinicians, drug developers, and patient advocates in recent years. While promising data on therapeutic efficacy has energized research and development, resolving the mechanisms of action will be important for optimizing the efficacy and safety of these medicines. Further, evaluating the effect of psychedelics and entactogens on mood and behavior comes with unique challenges still in need of resolution. These include unresolved questions relating to blinding, placebo and nocebo effects, and the impact of psychosocial contexts. In response to this renewed interest, the National Academies of Sciences, Engineering, and Medicines Forum on Neuroscience and Nervous System Disorders convened a workshop on March 29-30, 2022. The workshop brought together a diverse group of stakeholders to explore the use of psychedelics and entactogens as treatments for psychiatric disorders. This Proceedings of a Workshop summarizes the presentations and discussions of the workshop.

A Smoking Cessation Mobile App for Persons Living With HIV Preliminary Efficacy and Feasibility Study.

The prevalence of smoking in the United States general population has gradually declined to the lowest rate ever recorded however, this has not been true for persons with HIV. We conducted a pilot test to assess the feasibility and efficacy of the Lumme Quit Smoking mobile app and smartwatch combination with sensing capabilities to improve smoking cessation in persons with HIV. A total of 40 participants were enrolled in the study and randomly assigned 11 to the control arm, which received an 8-week supply of nicotine replacement therapy, a 30-minute smoking cessation counseling session, and weekly check-in calls with study staff, or to the intervention arm, which additionally received the Lumme Quit Smoking app and smartwatch. Of the 40 participants enrolled, 37 completed the follow-up study assessments and 16 used the app every day during the 56-day period. During the 6-month recruitment and enrollment period, 122 people were screened for eligibility, with 67.2% (82122) deemed ineligible. Smoking criteria and incompatible tech were the major reasons for ineligibility. There was no difference in the proportion of 7-day point prevalence abstinence by study arm and no significant decrease in exhaled carbon monoxide for the intervention and control arms separately. However, the average exhaled carbon monoxide decreased over time when analyzing both arms together (P.02). Results suggest excellent feasibility and acceptability of using a smoking sensor app among this smoking population. The knowledge gained from this research will enable the scientific community, clinicians, and community stakeholders to improve tobacco cessation outcomes for persons with HIV. ClinicalTrials.gov NCT04808609 httpsclinicaltrials.govct2showNCT04808609.

Adolescent and adult time trends in US hallucinogen use, 2002-19 any use, and use of ecstasy, LSD and PCP.

Hallucinogen use is potentially harmful. Information on whether such use has increased in recent decades is lacking. This study assessed overall and age-specific time trends in the prevalence of 12-month hallucinogen use in the US general population. Cross-sectional. Data from the US National Survey on Drug Use and Health, 2002-19. Respondents aged ≥ 12 years (n 1 006 051). Predictors were continuous years. Outcome variables included any hallucinogen use and use of lysergic acid diethylamide (LSD), ecstasy and phencyclidine (PCP) in the past year. Socio-demographic variables (gender, age, raceethnicity, educational level and family income) were covariates. Overall, hallucinogen use increased between 2015 and 2019 prevalence difference (PD) 0.44, P < 0.05. Since 2002, hallucinogen use has increased in adults aged ≥ 26 years (PD, 2002-14 0.24, P < 0.05 PD, 2015-19 0.45, P < 0.001) and decreased in adolescents aged 12-17 years (PD, 2002-14 -1.60, P < 0.0001 PD, 2015-19 -0.73, P < 0.001). Ecstasy use has decreased in adolescents (PD, 2002-14 -0.56, P < 0.001), adults aged 18-25 years (PD, 2015-19 -0.96, P < 0.01) and ≥ 26 years (PD, 2015-19 -0.13, P < 0.05). LSD use between 2002 and 2019 increased overall (PD 0.71, P < 0.0001) and in all age groups (12-17 PD 0.67, P < 0.001 18-25 PD 3.12, P < 0.0001 ≥ 26 PD 0.36, P < 0.0001). Conversely, PCP use between 2002 and 2019 decreased overall (PD -0.06, P < 0.001), in adolescents (PD -0.24, P < 0.001) and young adults (PD -0.32, P < 0.0001). Since 2002, hallucinogen use in the United States has decreased among adolescents but increased in adults and is now estimated to affect more than 3 million adults aged 26 years and more than 5.5 million adults aged 18 years.

Molecular insights into the regulation of constitutive activity by RNA editing of 5HT

RNA editing is a process by which post-transcriptional changes of mRNA nucleotides alter protein function through modification of the amino acid content. The 5HT

Effect of Delta-9-tetrahydrocannabinol and cannabidiol on milk proteins and lipid levels in HC11 cells.

Pregnant and lactating women have been discouraged from using cannabis by Health Canada. However, the increasing rate of cannabis use among pregnant women has presented an urgent need to investigate its physiological effects during the perinatal period. During pregnancy, the mammary gland (MG) undergoes remodeling, which involves alveolar differentiation of mammary epithelial cells (MECs), which is essential for breast milk production and secretion. Limited evidence has been reported on the impact of cannabis or its components, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), on MG development or MEC differentiation. In this study, we investigated the effects of THC and CBD on the differentiation of MECs by assessing changes in cellular viability, lipid accumulation, and gene and protein expression of major milk protein and lipid synthesizing markers. using the HC11 cells as a model. We hypothesized that THC and CBD will negatively impact the synthesis of milk proteins and lipids, as well as lipid markers in HC11 cells. Our results demonstrated that THC and CBD reduced cellular viability at concentrations above 30μM and 20μM, respectively. Relative to control, 10μM THC and 10μM CBD reduced mRNA levels of milk proteins (CSN2 and WAP), lipid synthesizing and glucose transport markers (GLUT 1, HK2, FASN, FABP4, PLIN2 and LPL), as well as whey acidic protein and lipid levels. In addition, co-treatment of a CB2 antagonist with THC, and a CB2 agonist with CBD, reversed the impact of THC and CBD on the mRNA levels of key markers, respectively. In conclusion, 10μM THC and CBD altered the differentiation of HC11 cells, in part via the CB2 receptor.

New investigational agents for the treatment of major depressive disorder.

Pharmacotherapy of depression is characterized by the delayed onset of action, chronic treatment requirements, and insufficient effectiveness. Ketamine, with its rapid action and long-lasting effects, represents a breakthrough in the modern pharmacotherapy of depression. The current review summarizes the latest findings on the mechanism of the antidepressant action of ketamine and its enantiomers and metabolites. Furthermore, the antidepressant potential of psychedelics, non-hallucinogenic serotonergic modulators, and metabotropic glutamate receptor ligands was discussed. Recent data indicated that to achieve fast and long-acting antidepressant-like effects, compounds must induce durable effects on the architecture and density of dendritic spines in brain regions engaged in mood regulation. Such mechanisms underlie the actions of ketamine and psychedelics. These compounds trigger hallucinations however, it is thought that these effects might be essential for their antidepressant action. Behavioral studies with serotonergic modulators affecting 5-HT1A (biased agonists), 5-HT4 (agonists), and 5-HT-7 (antagonists) receptors exert rapid antidepressant-like activity, but they seem to be devoid of these effects. Another way to avoid psychomimetic effects and achieve the desired rapid antidepressant-like effects is combined therapy. In this respect, ligands of metabotropic receptors show some potential.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Report Serotonergic Psychedelic Treatments for Major Depressive Disorder.

Serotonergic psychedelics are re-emerging as potential novel treatments for several psychiatric disorders including major depressive disorder. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence and provide a consensus recommendation for the clinical use of psychedelic treatments for major depressive disorder. A systematic review was conducted to identify contemporary clinical trials of serotonergic psychedelics for the treatment of major depressive disorder and cancer-related depression. Studies published between January 1990 and July 2021 were identified using combinations of search terms, inspection of bibliographies and review of other psychedelic reviews and consensus statements. The levels of evidence for efficacy were graded according to the Canadian Network for Mood and Anxiety Treatments criteria. Only psilocybin and ayahuasca have contemporary clinical trials evaluating antidepressant effects. Two pilot studies showed preliminary positive effects of single-dose ayahuasca for treatment-resistant depression (Level 3 evidence). Small randomized controlled trials of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy and safety to an active comparator (escitalopram with supportive psychotherapy) in major depressive disorder, with additional randomized controlled trials showing efficacy specifically in cancer-related depression (Level 3 evidence). There was only one open-label trial of psilocybin in treatment-resistant unipolar depression (Level 4 evidence). Small sample sizes and functional unblinding were major limitations in all studies. Adverse events associated with psychedelics, including psychological (e.g., psychotomimetic effects) and physical (e.g., nausea, emesis and headaches) effects, were generally transient. There is currently only low-level evidence to support the efficacy and safety of psychedelics for major depressive disorder. In Canada, as of 2022, psilocybin remains an experimental option that is only available through clinical trials or the special access program. As such, Canadian Network for Mood and Anxiety Treatments considers psilocybin an experimental treatment and recommends its use primarily within clinical trials, or, less commonly, through the special access program in rare, special circumstances.

Policy considerations that support equitable access to responsible, accountable, safe, and ethical uses of psychedelic medicines.

There is mounting evidence suggesting psychedelic and entactogen medicines (namely psilocybin and 3,4-methylenedioxymethamphetamine MDMA), in conjunction with proper psychosocial support, hold the potential to provide safe, rapid acting, and robust clinical improvements with durable effects. In the US, both psilocybin and MDMA have been granted Breakthrough Therapy designations by the US Food and Drug Administration and may potentially receive full FDA approval with similar regulatory considerations occurring in multiple countries. At the same time, regulatory changes are poised to increase access to legal or decriminalized psychedelic use in various non-medical settings. This review provides a brief discussion on the historical use of psychedelic medicines, the status of the empirical evidence, and numerous significant policy considerations that must be thoughtfully addressed regarding standards-of-practice, consumer protection, engagement of communities, safeguarding access for all, and developing data standards, which supports the responsible, accountable, safe, and ethical uses of these medicines in clinical, faith-based, and other contexts. We provide suggestions for how public health and harm reduction can be supported through a public-private partnership that engages a community of stakeholders from various disciplines in the co-creation and dissemination of best practices and public policies.

Separation of organic contaminant (dye) using the modified porous metal-organic framework (MIL).

Herein, the porous metal-organic framework (MIL-88B Materials Institute Lavoisier) was synthesized and identified by FT-IR (Fourier transform infrared), SEM (Scanning Electron Microscopy), EDS (Energy Dispersive X-Ray Spectroscopy), and XRD (X-ray powder diffraction) analyses. Then MIL-88B was modified using 3-aminopropyl trimethoxy silane and presented as NH

Is psychedelic use associated with cancer Interrogating a half-century-old claim using contemporary population-level data.

In 1967, concerns about the carcinogenic potential of psychedelics arose after a study reported chromosomal damage in human leukocytes following in vitro lysergic acid (LSD) exposure. Worries were further heightened by subsequent reports of leukemia and other cancers in LSD users. Additional investigations of psychedelics effects on chromosomes were published over the next decade, with the majority suggesting these concerns were unfounded. However, the relationship between psychedelics and cancer has been explored only minimally from an epidemiological perspective. To determine whether associations exist between psychedelic use and either lifetime cancer or hematologic cancer diagnoses. We analyzed data from adult participants in the 2015-2019 administrations of the National Survey on Drug Use and Health for associations between lifetime use of psychedelics and lifetime diagnosis of either any cancer or hematologic cancer. We identified no associations between lifetime psychedelic use and either lifetime cancer diagnosis or hematologic cancer diagnosis. Sub-analyses of lifetime lysergamide, phenethylamine, and tryptamine use also revealed no associations with lifetime cancer or hematologic cancer diagnosis. While laboratory studies and case reports from the 1960s and 1970s generated concerns about psychedelics carcinogenic potential, this analysis of recent epidemiological data does not support an association between psychedelic use and development of cancer in general or hematologic cancer. Important study limitations to consider include a lack of information about psychedelic dosage, number of lifetime psychedelic exposures, and the temporal relationship between psychedelic use and cancer diagnosis.

Prenatal exposure to Cannabis smoke induces early and lasting damage to the brain.

Cannabis is the most widely used illegal drug during pregnancy, however, the effects of gestational exposure to Cannabis smoke (CS) on the central nervous system development remain uncharacterised. This study investigates the effects of maternal CS inhalation on brain function in the offspring. Pregnant mice were exposed daily to 5 min of CS during gestational days (GD) 5.5-17.5. On GD 18.5 half of the dams were euthanized for foetus removal. The offspring from the remaining dams were euthanized on postnatal days (PND) 20 and 60 for evaluation. Brain volume, cortex cell number, SOX2, histone-H3, parvalbumin, NeuN, and BDNF immunoreactivity were assessed in all groups. In addition, levels of NeuN, CB1 receptor, and BDNF expression were assessed and cortical primary neurons from rats were treated with Cannabis smoke extract (CSE) for assessment of cell viability. We found that male foetuses from the CS exposed group had decreased brain volume, whereas mice at PND 60 from the exposed group presented with increased brain volume. Olfactory bulb and diencephalon volume were found lower in foetuses exposed to CS. Mice at PND 60 from the exposed group had a smaller volume in the thalamus and hypothalamus while the cerebellum presented with a greater volume. Also, there was an increase in cortical BDNF immunoreactivity in CS exposed mice at PND 60. Protein expression analysis showed an increase in pro-BDNF in foetus brains exposed to CS. Mice at PND 60 presented an increase in mature BDNF in the prefrontal cortex (PFC) in the exposed group and a higher CB1 receptor expression in the PFC. Moreover, hippocampal NeuN expression was higher in adult animals from the exposed group. Lastly, treatment of cortical primary neurons with doses of CSE resulted in decreased cell viability. These findings highlight the potential negative neurodevelopmental outcomes induced by gestational CS exposure.

High-efficient peroxymonosulfate activation for rapid atrazine degradation by FeS

FeS

On-site forensic analysis of colored seized materials Detection of brown heroin and MDMA-tablets by a portable NIR spectrometer.

The increasing workload for forensic laboratories and the expanding complexity of the drug market necessitates efficient approaches to detect drugs of abuse. Identification directly at the scene of crime enables investigative forces to make rapid decisions. Additionally, on-site identification of the material also leads to considerable efficiency and cost benefits. As such, paperwork, transportation, and time-consuming analysis in a laboratory may be avoided. Near-infrared (NIR) spectroscopy is an analysis technique suitable for rapid drug testing using portable equipment. A possible limitation of spectroscopic analysis concerns the complexity of seized materials. NIR measurements represent composite spectra for mixtures and diagnostic spectral features can be obscured by excipients such as colorants. Herein, a NIR-based (1300-2600 nm) detection of heroin and MDMA in colored casework (i.e., brown powders and ecstasy tablets) using a portable analyzer is presented. The application includes a multistage data analysis model based on the net analyte signal (NAS) approach. This identification model was specifically designed for mixture analysis and requires a limited set of pure reference spectra only. Consequently, model calibration efforts are reduced to a minimum. A total of 549 forensic samples was tested comprising brown heroine samples and a variety of colored tablets with different active ingredients. This investigation led to a >99% true negative and >93% true positive rate for heroin and MDMA. These results show that accurate on-site detection in colored casework is possible using NIR spectroscopy combined with an efficient data analysis model. These findings may eventually help in the transition of routine forensic laboratories from laboratory-based techniques to portable equipment operated on scene.

Inconsistencies between national drug policy and professional beliefs about psychoactive drugs among psychiatrists in the United States.

Evidence points to an incongruence between international drug policy and expert opinion about safety, abuse potential, and therapeutic potential of specific drugs. However, no prior studies have directly explored psychiatrists attitudes about the current drug schedule. Therefore, we examined whether American psychiatrists perceptions of four psychoactive drugs differed from those indicated by their schedules. A quasi-experimental online survey of a convenience sample of psychiatrists in the United States (N181 Mean age48.7 Female35%). Participants were randomized to receive 1-of-4 vignettes, each depicting a depressed patient reporting relief from symptoms after non-prescribed psychoactive drug use (i.e., psilocybin Schedule I, methamphetamine SchedII, ketamine SchedIII, or alprazolam SchedIV). Participants responded to questions related to this clinical scenario and then rated the safety, therapeutic, and abuse potentials of these four drugs and alcohol. There were significant differences by vignette condition in mean likelihood ratings of warning against engaging in drug use again (p<.01), being concerned about developing a new psychiatric problem (p<.001), being concerned about increased suicide risk (p<.01) and being supportive of further use of this drug as part of the treatment plan (p<.001). Overall, non-prescribed use of methamphetamine and alprazolam was rated more concerning and less acceptable than non-prescribed use of psilocybin and ketamine. Compared to psilocybin and ketamine, participants rated methamphetamine and alprazolam as less safe (p<.001), having less therapeutic potential (p<.001), and having more abuse potential (p<.001). Mean ratings of safety and abusetherapeutic potential of alprazolam and methamphetamine were equivalent to that of alcohol, and all three were rated more harmful than psilocybin and ketamine. American psychiatrists perceptions about safety and abusetherapeutic potentials associated with certain psychoactive drugs were inconsistent with those indicated by their placement in drug schedules. These findings add to a growing consensus amongst experts that the current drug policy is not scientifically coherent.

Differences across sexes on head-twitch behavior and 5-HT

Psychedelics, also known as classical hallucinogens, affect processes related to perception, cognition and sensory processing mostly via the serotonin 5-HT

Development and validation of an LC-MSMS method for the quantification of mescaline and major metabolites in human plasma.

Mescaline is a psychedelic phenethylamine found in different species of cacti. Currently, mescalines acute subjective effects and pharmacokinetics are investigated in several modern clinical studies. Therefore, we developed a bioanalytical method for the rapid quantification of mescaline and its metabolites in human plasma. Mescaline and its metabolites 3,4,5-trimethoxyphenylacetic acid (TMPAA), N-acetyl mescaline (NAM), and 3,5-dimethoxy-4-hydroxyphenethylamine (4-desmethyl mescaline) were simultaneously analyzed by ultra-high performance liquid chromatography tandem mass spectrometry (LC-MSMS). Optimal chromatographic separation was achieved with an Acquity Premier HSS T3 C

Tobacconicotine use among individuals using cannabis for therapeutic purposes.

While the relationship between recreational cannabis and nicotine use is well established, little is known about nicotine use among users of cannabis for therapeutic purposes (CTP). Patients attending a medical marijuana dispensary (N 697 75.3% White 60.0% male) completed a survey examining nicotine use, motivation to quit cigarette smoking, routes of administration of nicotine and cannabis, and CTP qualifying conditions. More than one-third (39.3%) of participants reported current nicotine use. Compared to exclusive cigarette smokers, e-cigarette users and non-users of nicotine were approximately four times more likely to vape, rather than to smoke, cannabis. Furthermore, 46.8% of cigarette smokers reported plans to quit smoking in the next 6 months (but not in the next month) and an additional 31.6% planned to quit in the next month. Having a psychiatric condition was associated with nicotine use and higher motivation to quit smoking. Users of CTP are more likely to use nicotine products than the general population and the route of administration of nicotine products is related to the route of administration of CTP. If aerosolized CTP is a less harmful route of administration than smoked CTP, dispensary staff should be aware of this relationship and take this into account when recommending a noncombustible route. This study further characterizes nicotine use behaviors and motivation to quit smoking among users of CTP and may be among the first to examine nicotine use among patients of a medical marijuana dispensary.

Highly selective detection of adenine and guanine by NH

Adenine (A) and guanine (G) are mainly found in deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) and play a crucial role in genetic information transfer and protein synthesis. In this study, NH

Effect of Lipid Vehicles on Solubility, Stability, and Topical Permeation of Delta-9-Tetrahydrocannabinol.

Delta-9-tetrahydrocannabinol (THC) is one of the most effective antinociceptive agents used in the treatment of peripheral neuropathy. THC is highly lipophilic and susceptible to thermal and oxidative degradation. Identifying appropriate solvents in which THC is stable as well as adequately solubilized is crucial in developing topical dosage forms. Lipid solvent systems are of utmost utility and relevance for formulating highly lipophilic drugs. Hence, the objective of this project was to screen the solubility of THC in lipidic excipients, monitor THC content in the selected vehicles during stability, and study the influence of these excipients on permeation of THC across skin. The solubility of THC in liquid lipid excipients was in the range of 421 to 500 mgg. The solubility of THC in solid lipid excipients was in the range of 250 to 750 mgg. THC in its neat form was poorly stable, but when dissolved in lipid-based excipients, its stability improved significantly. THC in lipid excipients was more stable at 4 ± 3°C compared to samples stored at 25 ± 2°C. The antioxidants (butylated hydroxytoluene and ascorbyl palmitate) used in the excipients further improved the stability of THC. The results demonstrated that the liquid and solid lipid excipients used in the study could solubilize THC freely and mitigate the degradation of THC significantly. The binary combination of lipid excipients enhanced THC skin permeation and retention, demonstrating the potential for topical formulation development of THC.

Case report of a phencyclidine false positive due to lamotrigine use with confirmatory testing.

Urine toxicology screens are useful in diagnosing patients who present with acute psychosis with a history of substance abuse. Being aware of potential false positive reactants is paramount in diagnostic accuracy. Currently, lamotrigine is not listed among common cross-reactants with phencyclidine (PCP). A 49 year old male (98 kg) was brought to the ED by a family member for worsening confusion and agitation. He had a history of Bipolar I, PTSD, schizoaffective disorder, hypertension, and cannabisopioid abuse. His home medications included paliperidone, duloxetine, lamotrigine, tizanidine, hydroxyzine, and lisinopril. Upon examination, he denied intentional overdose or illicit substances, but largely mumbled incoherently. Blood pressure was 14090 mmHg, pulse 113. A urine toxicology screen was positive for PCP and cannabinoids. Other labs were unremarkable, co-ingestants negative. By day three, his mental status vacillated but he largely gave unintelligible responses. Given the short half-life of PCP, false positives were investigated. A confirmatory blood test (collected upon admission) for PCP was found to be negative, and a serum lamotrigine level was confirmed to be positive (1.5μgml). Once more lucid, the patient admitted to taking large quantities of mirtazapine and tizanidine, making serotonin syndrome the more likely diagnosis. There is little in the medical literature describing cross-reactivity of lamotrigine and PCP on urine drug screens. This can be especially difficult to deduce in a known drug abuser who presents psychotic and non-contributory in their work up.

De novo synthesis of a MIL-125(Ti) carrier for thermal- and pH-responsive drug release.

Microporous round cake-like (diameter 900 ± 100 nm) MIL-125(Ti) carrier with a central metal (Ti) exhibiting bio-affinity and possessing a great potential to be used as drug release platform, has been synthesized in the present study. The thermal and pH responsiveness of drug delivery systems (DDS) are the most important parameters for drug release and can be provided through polymer coating techniques. The Pluronic F127 (F127) and chitosan (CH) monomers were inserted into the crystal lattice of MIL-125(Ti) carrier during the de novo synthesis process, which were subsequently loaded with doxorubicin (DOX). The results reveal particle size changes (ranged between 30 and 50 %) from the original size of the MIL-125(Ti) carrier in response to temperature and pH when the carrier reaches acid environment. The drug release profiles have been completed through self-design device, which provides for the real-time release in the DOX amounts via UV-Vis spectra. The kinetics analysis was used to evaluate the R

Buddhist-like opposite diminishing and non-judging during ketamine infusion are associated with antidepressant response an open-label personalized-dosing study.

Intrathecal Actions of the Cannabis Constituents Δ(9)-Tetrahydrocannabinol and Cannabidiol in a Mouse Neuropathic Pain Model.

(1) Background The psychoactive and non-psychoactive constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), synergistically reduce allodynia in various animal models of neuropathic pain. Unfortunately, THC-containing drugs also produce substantial side-effects when administered systemically. We examined the effectiveness of targeted spinal delivery of these cannabis constituents, alone and in combination. (2) Methods The effect of acute intrathecal drug delivery on allodynia and common cannabinoid-like side-effects was examined in a mouse chronic constriction injury (CCI) model of neuropathic pain. (3) Results intrathecal THC and CBD produced dose-dependent reductions in mechanical and cold allodynia. In a 11 combination, they synergistically reduced mechanical and cold allodynia, with a two-fold increase in potency compared to their predicted additive effect. Neither THC, CBD nor combination THCCBD produced any cannabis-like side-effects at equivalent doses. The anti-allodynic effects of THC were abolished and partly reduced by cannabinoid CB1 and CB2 receptor antagonists AM281 and AM630, respectively. The anti-allodynic effects of CBD were partly reduced by AM630. (4) Conclusions these findings indicate that intrathecal THC and CBD, individually and in combination, could provide a safe and effective treatment for nerve injury induced neuropathic pain.

Comparative Transcriptome Analysis Reveals Coordinated Transcriptional Regulation of Central and Secondary Metabolism in the Trichomes of Cannabis Cultivars.

Cannabis is one of the few plant genera capable of producing cannabinoids, the effects of which are synergized by terpene interactions. As the biosynthesis of both metabolite classes requires the same intracellular feedstocks, this work describes the coordinated regulation of global metabolic pathways that allows for their joint copious production in vivo. To this end, a transcriptomics-based approach to characterize the glandular trichomes of five Cannabis cultivars was pursued. Besides revealing metabolic traits that enhanced and proportionated the supply of critical carbon precursors, in-depth analysis showed significantly increased gene expression of two particular enzymes to meet the huge nicotinamide adenine dinucleotide phosphate (NADPH) demand of secondary metabolite production. Furthermore, it led to a hypothesis that the methyl-d-erythritol 4-phosphate pathway might be utilized more than the mevalonic acid pathway in Cannabis trichomes. While both pathways were found to be activated in a modular and calibrated way that reflected their broad participation in physiological processes, the genes for hexanoate, cannabinoid, and terpene biosynthesis were, in contrast, up-regulated in an en bloc and multi-loci manner due to their specific roles in secondary metabolite production. In addition, three new terpene synthases were characterized based on both in silico and experimental assays. Altogether, the study enhances the current understanding of secondary metabolite production in Cannabis cultivars, which may assist in their characterization and development.

Psilocybin Efficacy and Mechanisms of Action in Major Depressive Disorder a Review.

We aim to provide an overview of the current state of knowledge about the efficacy of psilocybin in the treatment of depression, as well as its mechanisms of action. Psilocybin has a large, rapid, and persistent clinical effect in the treatment of resistant or end-of-life depression. Tolerance is good, with mild side effects limited to a few hours after dosing. The studies conducted to date have had small sample sizes. One clinical trial has been conducted against a reference treatment (escitalopram) without showing a significant superiority of psilocybin in the main outcome. The neurobiological mechanisms, mostly unknown, differ from those of SSRI antidepressants. Psilocybin represents a promising alternative in the treatment of depression. Further research with larger sample sizes, particularly against reference treatments, is needed to better understand the neurobiological factors of its effects and to investigate its potential for use in everyday practice.

Acute and long-term effects of psilocybin on energy balance and feeding behavior in mice.

Psilocybin and other serotonergic psychedelics have re-emerged as therapeutics for neuropsychiatric disorders, including addiction. Psilocybin induces long-lasting effects on behavior, likely due to its profound ability to alter consciousness and augment neural connectivity and plasticity. Impaired synaptic plasticity in obesity contributes to addictive-like behaviors, including heightened motivation for palatable food, and excessive food seeking and consumption. Here, we evaluate the effects of psilocybin on feeding behavior, energy metabolism, and as a weight-lowering agent in mice. We demonstrate that a single dose of psilocybin substantially alters the prefrontal cortex transcriptome but has no acute or long-lasting effects on food intake or body weight in diet-induced obese mice or in genetic mouse models of obesity. Similarly, sub-chronic microdosing of psilocybin has no metabolic effects in obese mice and psilocybin does not augment glucagon-like peptide-1 (GLP-1) induced weight loss or enhance diet-induced weight loss. A single high dose of psilocybin reduces sucrose preference but fails to counter binge-like eating behavior. Although these preclinical data discourage clinical investigation, there may be nuances in the mode of action of psychedelic drugs that are difficult to capture in rodent models, and thus require human evaluation to uncover.

Naturalistic Psychedelic Use A World Apart from Clinical Care.

Interest in and availability of psychedelics for therapeutic purposes has increased in recent decades. In a large, anonymous, online survey, we investigated patterns of communication with healthcare providers and awareness and utilization of substance testing kits or services among people using psychedelics naturalistically. The sample population included attendees of a psychedelic activism event and users of psychedelic social media forums. Among 1,435 participants, 72.5% never discussed psychedelic use with their primary care provider (PCP). Only 4.4% reported using psychedelics with a therapist and 3% in clinical settings, although 77.8% were very or extremely likely to take psychedelics with a therapist if one were legally available. While 62.6% of participants were aware of substance testing services, 42.6% of these indicated never using them. Regression analyses identified several variables associated with disclosure to PCP and utilization of substance testing services including age, gender, frequency and number of psychedelics used, and likelihood of consuming psychedelics under the guidance of a therapist if one were legally available. Further research is necessary to investigate these findings among other groups. Our findings suggest that relevant training and education for healthcare providers is needed, along with more visible options for substance identity testing.

Can cannabis kill Characteristics of deaths following cannabis use in England (1998-2020).

Cannabis is the most widely used illegal drug but is rarely considered a causal factor in death. This study aimed to understand trends in deaths in England where cannabinoids were detected at post-mortem, and to evaluate the clinical utility of post-mortem cannabinoid concentrations in coronial investigations. Deaths with cannabinoid detections reported to the National Programme on Substance Abuse Deaths (NPSAD) were extracted and analysed. From 1998 to 2011, on average 7% of all cases reported to NPSAD had a cannabinoid detected ( Risk of death due to cannabis toxicity is negligible. However, cannabis can prove fatal in circumstances with risk of traumatic physical injury, or in individuals with cardiac pathophysiologies. These indirect harms need careful consideration and further study to better elucidate the role cannabis plays in drug-related mortality. Furthermore, the relevance of cannabinoid quantifications in determining cause of death in coronial investigations is limited.

Discrepancies between validated GC-FID and UHPLC-DAD methods for the analysis of Δ-9-THC and CBD in dried hemp flowers.

Herbal products for smoking containing cannabidiol (CBD) are available as low-tetrahydrocannabinol cannabis products in most EU countries. In Belgium, Δ9-tetrahydrocannabinol (THC) content of these products must be less than 0.2% ww, which is also the limit for agricultural hemp. For agricultural hemp, the official and only valid method for European regulators is gas-chromatography coupled to flame ionization detector (GC-FID). There is no such method, for smoking products. Many of these herbal for smoking products are analyzed as part of their quality control and have certificate of analysis. During surveillance by official labs, discrepancies were seen between the official results and the certificate of analysis. In this study, a GC-FID method based on the European method and an ultra-high-performance liquid chromatography coupled to diode array detection (UHPLC-DAD) method were validated and applied for samples analysis in order to investigate these discrepancies. The GC-FID method shows better results for the validation parameters notably, it has β-expectation tolerance limits within 10% with a β value of 95% while the validated UHPLC-DAD method has β-expectation tolerance limits within 15% with a β value of 90%. Furthermore, the other parameters evaluated are generally better with the GC-FID method. The statistic t test shows that the difference between both methods was significantly different for total-THC, but not significantly different for the total-CBD. The authors state that, as for agricultural hemp, the GC-FID method is to be preferred for the analysis of THC and CBD in products for smoking.

Synthetic cannabinoid poisonings and access to the legal cannabis market findings from US national poison centre data 2016-2019.

To investigate trends in synthetic cannabinoid exposures reported to United States (US) poison control centres, and their association with status of state cannabis legalisation. A retrospective study of National Poison Data System (NPDS) data from 2016 to 2019 identified and associated synthetic poisoning reports with annual state cannabis law and market status. State status was categorised as restrictive (cannabis illegal or limited medical legalisation), medical (allowing THC-containing medical cannabis use) and permissive (allowing non-medical use of THC-containing cannabis by adults). We categorised a subset of states with permissive policies by their implementation of legal adult possessionuse and opening retail markets, on a quarterly basis. Mixed-effects Poisson regression models assessed synthetic exposures associated with legal status, first among all states using annual counts, and then among states that implemented permissive law alone using quarterly counts. A total of 7600 exposures were reported during the study period. Overall, reported synthetic exposures declined over time. Most reported exposures (64.8%) required medical attention, and 61 deaths were documented. State implementation of medical cannabis law was associated with 13% fewer reported annual exposures. Adoption of permissive state cannabis policy was independently and significantly associated with 37% lower reported annual synthetic exposures, relative to restrictive policies (IRR 0.63, 95% CI 0.50-0.79). Among states with permissive law during the period, implementation of legal adult possessionuse was associated with 22% fewer reported quarterly exposures. Opening of retail markets was associated with 36% fewer reported exposures, relative to states with medical cannabis only. Adoption of permissive cannabis law was associated with significant reductions in reported synthetic cannabinoid exposures. More permissive cannabis law may have the unintended benefit of reducing both motivation and harms associated with use of synthetic cannabis products.

Trends in cannabis or cocaine-related dependence and alcoholdrug treatment in Argentina, Chile, and Uruguay.

In the context of changing cannabis and other drug policy and regulation, concerns may arise regarding drug treatment access and use. We assessed cannabiscocaine-related dependence and treatment in Argentina, Chile, and Uruguay. Nationally representative cross-sectional household surveys of people ages 15-64 in Argentina (4 surveys, 2006-2017), Chile (7 surveys, 2006-2018), and Uruguay (4 surveys, 2006-2018) were harmonized. We estimated weighted prevalences of cannabis or cocaine-related (cocaine or cocaine paste) dependence, based on meeting 3 past-year ICD-10 dependence criteria. We estimated weighted prevalences of past-year alcoholdrug treatment use (Argentina, Chile) or useseeking (Uruguay) among people with past-year cannabiscocaine-related dependence. We tested model-based prevalence trends over time and described individual-level treatment correlates by country. Cannabiscocaine dependence prevalence increased in the region starting in 2010-2011, driven by cannabis dependence. Adjusted cannabis dependence prevalence increased from 0.7% in 2010 to 1.5% in 2017 in Argentina (aPD0.8, 95% CI 0.3, 1.2), from 0.8% in 2010 to 2.8% in 2018 in Chile (aPD2.0, 95% CI 1.4, 2.6), and from 1.4% in 2011 to 2.4% in 2018 in Uruguay (aPD0.9, 95% CI 0.2, 1.6). Cocaine-related dependence increased in Uruguay, decreased in Argentina, and remained stable in Chile. Among people with past-year cannabiscocaine dependence, average alcoholdrug treatment use prevalence was 15.3% in Argentina and 6.0% in Chile, while treatment useseeking was 14.7% in Uruguay. Alcoholdrug treatment prevalence was lower among people with cannabis dependence than cocaine-related dependence. Treatment correlates included older ages in all countries and male sex in Argentina only. Alcoholdrug treatment use among people with cannabiscocaine-related dependence remained low, signaling an ongoing treatment gap in the context of growing cannabis dependence prevalence in the region. Additional resources may be needed to increase treatment access and uptake. Future studies should assess contributors of low treatment use, including perceived need, stigma, and service availability.

Rapid quantification of cannabinoids in beef tissues and bodily fluids using direct-delivery electrospray ionization mass spectrometry.

Hempseed cake is a byproduct of hempseed oil extraction and is potentially a useful source of protein and fiber for use in ruminant diets. However, data are lacking on the appearance andor clearance of cannabinoids in tissues of animals fed hempseed cake. To this end, a rapid method for quantifying cannabinol (CBN), cannabidiol (CBD), cannabinolic acid (CBNA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), cannabichromenic acid (CBCA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), tetrahydrocannabinol (THC) and tetrahydrocannabinolic acid (THCA) in cattle tissues, plasma, and urine was developed using rapid screen electrospray ionization mass spectrometry (RS-ESI-MS). Regression coefficients of matrix-matched standard curves ranged from 0.9946 to >0.9999 and analyte recoveries averaged from 90.2 ± 15.5 to 108.7 ± 18.7% across all compounds. Limits of detection and quantification ranged from 0.05 to 2.79 ng · mL

The Watts Connectedness Scale a new scale for measuring a sense of connectedness to self, others, and world.

A general feeling of disconnection has been associated with mental and emotional suffering. Improvements to a sense of connectedness to self, others and the wider world have been reported by participants in clinical trials of psychedelic therapy. Such accounts have led us to a definition of the psychological construct of connectedness as a state of feeling connected to self, others and the wider world. Existing tools for measuring connectedness have focused on particular aspects of connectedness, such as social connectedness or nature connectedness, which we hypothesise to be different expressions of a common factor of connectedness. Here, we sought to develop a new scale to measure connectedness as a construct with these multiple domains. We hypothesised that (1) our scale would measure three separable subscale factors pertaining to a felt connection to self, others and world and (2) improvements in total and subscale WCS scores would correlate with improved mental health outcomes post psychedelic use. To validate and test the Watts Connectedness Scale (WCS). Psychometric validation of the WCS was carried out using data from three independent studies. Firstly, we pooled data from two prospective observational online survey studies. The WCS was completed before and after a planned psychedelic experience. The total sample of completers from the online surveys was N 1226. Exploratory and confirmatory factor analysis were performed, and construct and criterion validity were tested. A third dataset was derived from a double-blind randomised controlled trial (RCT) comparing psilocybin-assisted therapy (n 27) with 6 weeks of daily escitalopram (n 25) for major depressive disorder (MDD), where the WCS was completed at baseline and at a 6-week primary endpoint. As hypothesised, factor analysis of all WCS items revealed three main factors with good internal consistency. WCS showed good construct validity. Significant post-psychedelic increases were observed for total connectedness scores (η2 0.339, p < 0.0001), as well as on each of its subscales (p < 0.0001). Acute measures of mystical experience, emotional breakthrough, and communitas correlated positively with post-psychedelic changes in connectedness (r 0.42, r 0.38, r 0.42, respectively, p < 0.0001). In the RCT, psilocybin therapy was associated with greater increases in WCS scores compared with the escitalopram arm (η The WCS is a new 3-dimensional index of felt connectedness that may sensitively measure therapeutically relevant psychological changes post-psychedelic use. We believe that the operational definition of connectedness captured by the WCS may have broad relevance in mental health research.

Neuroimaging Correlates of Treatment Response with Psychedelics in Major Depressive Disorder A Systematic Review.

Preliminary evidence supports the use of psychedelics for major depressive disorder (MDD). However, less attention has been given to the neural mechanisms behind their effects. We conducted a systematic review examining the neuroimaging correlates of antidepressant response following psychedelic interventions for MDD. Through MEDLINE, Embase, and APA PsycINFO, 187 records were identified and 42 articles were screened. Six published studies and one conference abstract were included. Five ongoing trials were included from subjective outcomesTrials.gov. Our search covered several psychedelics, though included studies were specific to psilocybin, ayahuasca, and lysergic acid diethylamide. Three psilocybin studies noted amygdala activity and functional connectivity (FC) alterations that correlated with treatment response. Two psilocybin studies reported that FC changes in the medial and ventromedial prefrontal cortices correlated with treatment response. Two trials from a single study reported global decreases in brain network modularity which correlated with antidepressant response. One ayahuasca study reported increased activity in the limbic regions following treatment. Preliminary evidence suggests that the default mode and limbic networks may be a target for future research on the neural mechanisms of psychedelics. More data is required to corroborate these initial findings as the evidence summarized in this review is based on four datasets.

Where do we go next in antidepressant drug discovery A new generation of antidepressants a pivotal role of AMPA receptor potentiation and mGlu23 receptor antagonism.

Major depressive disorder remains a prevalent world-wide health problem. Currently available antidepressant medications take weeks of dosing, do not produce antidepressant response in all patients, and have undesirable ancillary effects. The present opinion piece focuses on the major inroads to the creation of new antidepressants. These include N-methyl-D-aspartate (NMDA) receptor antagonists and related compounds like ketamine, psychedelic drugs like psilocybin, and muscarinic receptor antagonists like scopolamine. The preclinical and clinical pharmacological profile of these new-age antidepressant drugs is discussed. Preclinical and clinical data have accumulated to predict a next generation of antidepressant medicines. In contrast to the current standard of care antidepressant drugs, these compounds differ in that they demonstrate rapid activity, often after a single dose, and effects that outlive their presence in brain. These compounds also can provide efficacy for treatment-resistant depressed patients. The mechanism of action of these compounds suggests a strong glutamatergic component that involves the facilitation of AMPA receptor function. Antagonism of mGlu23 receptors is also relevant to the antidepressant pharmacology of this new class of drugs. Based upon the ongoing efforts to develop these new-age antidepressants, new drug approvals are predicted in the near future.

DNA methylation changes associated with cannabis use and verbal learning performance in adolescents an exploratory whole genome methylation study.

The association between extent of chronic cannabis use (CCU-extent) and cognitive impairment among adolescents has been the subject of controversial debate. Linking DNA methylation to CCU-extent could help to understand cannabis associated changes in cognitive performance. We analyzed cognitive task performances, CpG methylation in peripheral whole-blood samples and self-reported past-year CCU-extent of n 18 adolescents (n 9 psychiatric outpatients with chronic cannabis use (CCU), n 9 without) who were matched for age, gender and psychiatric disorders. Patients with CCU were at least 24 h abstinent when cognitive tasks were performed. A Principal Component Analysis (PCA) was carried out to identify group differences in whole genome DNA methylation. Mediation analyses were performed between CCU-extent associated CpG sites and CCU-extent associated variables of cognitive tasks. PCA results indicated large differences in whole genome DNA methylation levels between the groups that did not reach statistical significance. Six CpG sites revealed reduced methylation associated with CCU-extent. Furthermore, CCU-extent was associated with lower scores in verbal learning. All six CpG sites mediated the effects between CCU-extent and verbal learning free recall. Our results indicate that CCU is associated with certain patterns in the methylome. Furthermore, CCU-extent associated impairments in memory function are mediated via differential methylation of the six CCU-associated CpG sits. Six identified CpG are located in genes previously described in the context of neurodegeneration, hippocampus-dependent learning and neurogenesis. However, these results have to be carefully interpreted due to a small sample size. Replication studies are warranted.

Distress tolerance and reactivity to negative affective cues in naturalistic environments of cannabis-using emerging adults.

Distress tolerance (DT) has been implicated as an important factor in the experience of negative affect (NA) and cannabis craving. However, previous research is limited by its use of laboratory paradigms that may not replicate in naturalistic settings. The current study examined how DT influenced reactivity to NA cues in daily life in a sample of frequent (≥3 times per week) cannabis-using emerging adults (age 18-21). Using cue-reactivity ecological momentary assessment (CREMA), 63 (54 % female 85.7 % white M NA cues consistently predicted higher-than-normal post-cue sadness and lower relaxation, but not greater-than-normal post-cue craving. Cue type interacted with sex and DT to predict post-cue sadness, but not craving. Female participants and those reporting low DT reported higher sadness following NA cues compared to males and those with high DT, respectively. Frequent cannabis-using emerging adults differed in affect, but not cannabis craving, reactivity to NA cues as a function of sex and DT. Our results were partially consistent with prior human laboratory and CREMA research finding greater reactivity to NA cues among females and individuals with low DT.

Schizophrenia and psychedelic state Dysconnection versus hyper-connection. A perspective on two different models of psychosis stemming from dysfunctional integration processes.

Psychotic symptoms are a cross-sectional dimension affecting multiple diagnostic categories, despite schizophrenia represents the prototype of psychoses. Initially, dopamine was considered the most involved molecule in the neurobiology of schizophrenia. Over the next years, several biological factors were added to the discussion helping to constitute the concept of schizophrenia as a disease marked by a deficit of functional integration, contributing to the formulation of the Dysconnection Hypothesis in 1995. Nowadays the notion of dysconnection persists in the conceptualization of schizophrenia enriched by neuroimaging findings which corroborate the hypothesis. At the same time, in recent years, psychedelics received a lot of attention by the scientific community and astonishing findings emerged about the rearrangement of brain networks under the effect of these compounds. Specifically, a global decrease in functional connectivity was found, highlighting the disintegration of preserved and functional circuits and an increase of overall connectivity in the brain. The aim of this paper is to compare the biological bases of dysconnection in schizophrenia with the alterations of neuronal cyto-architecture induced by psychedelics and the consequent state of cerebral hyper-connection. These two models of psychosis, despite diametrically opposed, imply a substantial deficit of integration of neural signaling reached through two opposite paths.

Catalytic potential of a fungal indole prenyltransferase toward β-carbolines, harmine and harman, and their prenylation effects on antibacterial activity.

The prenylation of compounds has attracted much attention, since it often adds bioactivity to non-prenylated compounds. We employed an enzyme assay with CdpNPT, an indole prenyltransferase from Aspergillus fumigatus with two naturally occurring β-carbolines, harmine (3) and harman (4) as prenyl acceptors, in the presence of dimethylallyl diphosphate (DMAPP) as the prenyl donor. The enzyme accepted these two prenyl acceptor substrates to produce 6-(3,3-dimethylallyl)harmine (5) from 3 and 9-(3,3-dimethylallyl)harman (6) and 6-(3,3-dimethylallyl)harman (7) from 4. The X-ray crystal structure analysis of the CdpNPT (38-440) truncated mutant complexed with 4, and docking simulation studies of DMAPP to the crystal structure of the CdpNPT (38-440) mutant, suggested that CdpNPT could employ the two-step prenylation mechanism to produce 7, while the enzyme produced 6 with either one- or two-step prenylation mechanisms. Furthermore, the antibacterial assays revealed that the 3,3-dimethylallylation of 3 and 4, as well as harmol (1), at C-6 enhanced the activities against Staphylococcus aureus and Bacillus subtilis.

Cis-Δ

Cannabidiolic acid (CBDA) and trans-Δ

Alcohol and Cannabis Use Milestones in Diverse Urban Adolescents Associations with Demographics, Parental Rule Setting, Sibling and Peer Deviancy, and Outcome Expectancies.

Corrigendum A cohort-based case report The impact of ketamine-assisted therapy embedded in a community of practice framework for healthcare providers with PTSD and depression.

This corrects the article DOI 10.3389fpsyt.2021.803279..

Rapid-Response Treatments for Depression and Requests for Physician-Assisted Death An Ethical Analysis.

Depression is common at the end of life, and there is longstanding concern that it may affect terminally ill patients decisions to request physician-assisted death (PAD). However, it is difficult for clinicians to determine the role of depression in a patients PAD request. A recent case series described rapid responses to intranasal ketamine in three patients with terminal illness and comorbid depression who had requested PAD. One patient withdrew her request (which, in retrospect, had been driven by her depression) while the others maintained their requests in all three, the rapid relief clarified the role of depression in the patients decision-making. In addition to ketamine, there are other emerging rapid-response treatments for depression, including psilocybin with psychological support and functional connectivity-guided transcranial magnetic stimulation. We examine three key ethical implications of such treatments their role in clarifying the decision-making capacity of depressed patients requesting PAD the potential tension between the legal definition of irremediability in some jurisdictions and the ethical obligations of clinicians and the likely obstacles to treatment access and their implications for equal respect for autonomy of patients.

Antidepressant effects of a psychedelic experience in a large prospective naturalistic sample.

Over the last two decades, a number of studies have highlighted the potential of psychedelic therapy. However, questions remain to what extend these results translate to naturalistic samples, and how contextual factors and the acute psychedelic experience relate to improvements in affective symptoms following psychedelic experiences outside labsclinics. The present study sought to address this knowledge gap. Here, we aimed to investigate changes in anxiety and depression scores before versus after psychedelic experiences in naturalistic contexts, and how various pharmacological, extrapharmacological and experience factors related to outcomes. Individuals who planned to undergo a psychedelic experience were enrolled in this online survey study. Depressive symptoms were assessed at baseline and 2 and 4 weeks post-psychedelic experience, with self-rated Quick Inventory of Depressive Symptomatology (QIDS-SR-16) as the primary outcome. To facilitate clinical translation, only participants with depressive symptoms at baseline were included. Sample sizes for the four time points were Relative to baseline, reductions in depressive symptoms were observed at 2 and 4 weeks. A medicinal motive, previous psychedelic use, drug dose and the type of acute psychedelic experience (i.e. specifically, having an emotional breakthrough) were all significantly associated with changes in self-rated QIDS-SR-16. These results lend support to therapeutic potential of psychedelics and highlight the influence of pharmacological and non-pharmacological factors in determining response. Mindful of a potential sample and attrition bias, further controlled and observational longitudinal studies are needed to test the replicability of these findings.

Psychedelics, Mystical Experience, and Therapeutic Efficacy A Systematic Review.

The mystical experience is a potential psychological mechanism to influence outcome in psychedelic therapy. It includes features such as oceanic boundlessness, ego dissolution, and universal interconnectedness, which have been closely linked to both symptom reduction and improved quality of life. In this review, 12 studies of psychedelic therapy utilizing psilocybin, ayahuasca, or ketamine were analyzed for association between mystical experience and symptom reduction, in areas as diverse as cancer-related distress, substance use disorder, and depressive disorders to include treatment-resistant. Ten of the twelve established a significant association of correlation, mediation, andor prediction. A majority of the studies are limited, however, by their small sample size and lack of diversity (gender, ethnic, racial, educational, and socioeconomic), common in this newly re-emerging field. Further, 6 out of 12 studies were open-label in design and therefore susceptible to bias. Future studies of this nature should consider a larger sample size with greater diversity and thus representation by use of randomized design. More in-depth exploration into the nature of mystical experience is needed, including predictors of intensity, in order to maximize its positive effects on treatment outcome benefits and minimize concomitant anxiety.

Microdosing with psilocybin mushrooms a double-blind placebo-controlled study.

The use of low sub-perceptual doses of psychedelics (microdosing) has gained popularity in recent years. Although anecdotal reports claim multiple benefits associated with this practice, the lack of placebo-controlled studies severely limits our knowledge of microdosing and its effects. Moreover, research conducted in standard laboratory settings could fail to capture the motivation of individuals engaged or planning to engage in microdosing protocols, thus underestimating the likelihood of positive effects on creativity and cognitive function. We recruited 34 individuals starting to microdose with psilocybin mushrooms (Psilocybe cubensis), one of the materials most frequently used for this purpose. Following a double-blind placebo-controlled experimental design, we investigated the acute and short-term effects of 0.5 g of dried mushrooms on subjective experience, behavior, creativity (divergent and convergent thinking), perception, cognition, and brain activity. The reported acute effects were significantly more intense for the active dose compared to the placebo, but only for participants who correctly identified their experimental condition. These changes were accompanied by reduced EEG power in the theta band, together with preserved levels of Lempel-Ziv broadband signal complexity. For all other measurements there was no effect of microdosing except for few small changes towards cognitive impairment. According to our findings, low doses of psilocybin mushrooms can result in noticeable subjective effects and altered EEG rhythms, but without evidence to support enhanced well-being, creativity and cognitive function. We conclude that expectation underlies at least some of the anecdotal benefits attributed to microdosing with psilocybin mushrooms.

A polarized supercell produces specialized metabolites in cannabis trichomes.

For centuries, humans have cultivated cannabis for the pharmacological properties that result from consuming its specialized metabolites, primarily cannabinoids and terpenoids. Today, cannabis is a multi-billion-dollar industry whose existence rests on the biological activity of tiny cell clusters, called glandular trichomes, found mainly on flowers. Cannabinoids are toxic to cannabis cells,

Vaping motivations Association of behavioral inhibition and behavioral activation systems with nicotine and cannabis vaping among adolescents.

Despite copious information on the hazards of nicotine and cannabis, many adolescents report vaping nicotine and cannabis. To advance knowledge on the precursors of vaping behaviors, this study examined the association of behavioral inhibition system (BIS) and behavioral activation system (BAS) sensitivities with nicotine and cannabis vaping among adolescents. Data were part of a longitudinal survey on substance use and mental health among adolescents and included 2,467 11th grade students from 10 public high schools in California. Participants completed a 20-item scale assessing BIS (one aspect) and BAS (three aspects drive, fun-seeking, reward responsiveness) sensitivities at baseline and reported their past 30-day nicotine and cannabis vaping at baseline and again at 6-month follow-up. Unadjusted and adjusted (controlled for demographic characteristics and product-specific baseline vaping) regression models estimated vaping risk at follow-up by BISBAS scores at baseline. Bivariate analyses showed participants who vaped nicotine had significantly higher drive and fun-seeking scores (p < 0.05) and cannabis vapers had lower BIS and reward responsiveness scores (p < 0.05) compared to non-users. Higher fun seeking scores was associated with increased odds (OR 1.15, 95 %CI 1.03-1.29) of nicotine vaping and higher reward responsiveness scores reduced odds (OR 0.89, 95 %CI 0.79-0.99) of nicotine vaping. Higher scores on BIS was associated with decreased the odds (OR 0.91, 95 %CI 0.84-0.99) of cannabis vaping. Different behavioral motivations should be targeted when developing interventions designed to reduce nicotine and cannabis vaping among diverse adolescents.

Repetitive transcranial magnetic stimulation (r-TMS) and selective serotonin reuptake inhibitor-resistance in obsessive-compulsive disorder A meta-analysis and clinical implications.

Despite promising results from several randomized controlled trials (RCTs) and meta-analyses, the efficacy of r-TMS as a treatment for OCD remains controversial, at least in part owing to inconsistency in the trial methodologies and heterogeneity in the trial outcomes. This meta-analysis attempts to explain some of this heterogeneity by comparing the efficacy of r-TMS in patients with or without resistance to treatment with selective serotonin reuptake inhibitors (SSRI), defined using standardized criteria. We conducted a pre-registered (PROSPERO ID 241381) systematic review and meta-analysis. English language articles reporting blinded RCTs were retrieved from searches using MEDLINE, PsycINFO, and Cochrane Library databases. Studies were subjected to subgroup analysis based on four stages of treatment resistance, defined using an adaptation of published criteria (1 not treatment resistant, 2 one SSRI trial failed, 3 two SSRI trials failed, 4 two SSRI trials failed plus one or more CBT trial failed). Meta-regression analyses investigated patient and methodological factors (age, duration of OCD, illness severity, stage of treatment-resistance, or researcher allegiance) as possible moderators of effect size. Twenty-five independent comparisons (23 studies) were included. Overall, r-TMS showed a medium-sized reduction of Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores (Hedges g -0.47 95%CI - 0.67 to -0.27) with moderate heterogeneity (I This meta-analysis shows that r-TMS is an effective treatment for OCD, but largely for those not resistant to SSRI or failing to respond to only one SSRI trial. As a consequence, r-TMS may be best implemented earlier in the care pathway. These findings would have major implications for clinical service development, but further well-powered RCTs, which eliminate bias from researcher allegiance, are needed before definitive conclusions can be drawn.

Inhibition of Dyrk1A Attenuates LPS-Induced Neuroinflammation via the TLR4NF-κB P65 Signaling Pathway.

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) is a highly conserved protein kinase, playing a key role in the regulation of physiological brain functions and pathological processes. In Alzheimers disease (AD), Dyrk1A promotes hyperphosphorylation of tau protein and abnormal aggregation of amyloid-β protein (Aβ). This study investigated the role of Dyrk1A in regulating neuroinflammation, another critical factor that contributes to AD. In the present study, we used an immortalized murine BV2 microglia cell line induced by lipopolysaccharide (LPS) to study neuroinflammation. The expression and activity of Dyrk1A kinase were both increased by inflammation. Dyrk1A inhibition using harmine or siRNA silencing significantly reduced the production of proinflammatory factors in LPS-stimulated BV2 cells. Reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), and nitric oxide (NO), as well as the expression of the inflammatory proteins, cyclooxygenase 2 (COX2), and inducible nitric synthase (iNOS), were attenuated. In vivo, in ICR mice injected with LPS into the left lateral cerebral ventricle, harmine (20 mgkg) administration decreased the expression of inflammatory proteins in the cortex and hippocampus of mice brain. In addition, immunohistochemical detection of ionized calcium-binding adapter molecule 1 (Iba1) and Nissl staining showed that harmine significantly attenuated microglia activation and neuronal damage in the CA1 region of hippocampus. Further mechanistic studies indicated that Dyrk1A suppression may be related to inhibition of the TLR4NF-κB signaling pathway in LPS-induced neuroinflammation. Taken together, our studies suggest that Dyrk1A may be a novel target for the treatment of neurodegenerative diseases with an inflammatory component.

3,4-Methylenedioxymethamphetamine (MDMA)-Assisted Therapy in Hawaii A Brief Review.

The Food and Drug Administration (FDA) granted breakthrough therapy status to 3,4-methyl​enedioxy​methamphetamine-assisted therapy (MDMA-AT) in 2017 due to preliminary evidence supporting its efficacy and safety in treating post-traumatic stress disorder (PTSD). A series of six phase-II clinical trials studying MDMA-AT for treatment-resistant PTSD found that 54% of MDMA-AT full-dose participants no longer met the diagnosis of PTSD after two MDMA sessions, compared to 23% in the control group. In the first phase-III clinical trial, 67% no longer met the criteria for PTSD after three sessions. The effects are durable, with 67% no longer diagnosable after one year and 74% at nearly four years. The MDMA-AT is being fast-tracked for potential FDA approval by 2023. In 2021, Hawaiis Senate Bill 738 unsuccessfully proposed that psilocybin be removed from the Schedule I controlled substances list due to its clinical efficacy for major depressive disorder. Methyl​enedioxy​methamphetamine is also a Schedule I controlled substance and has proven to be a treatment option that could potentially benefit the people of Hawaii.

Ortholog genes from cactophilic Drosophila provide insight into human adaptation to hallucinogenic cacti.

Cultural transformations of lifestyles and dietary practices have been key drivers of human evolution. However, while most of the evidence of genomic adaptations is related to the hunter-gatherer transition to agricultural societies, little is known on the influence of other major cultural manifestations. Shamanism is considered the oldest religion that predominated throughout most of human prehistory and still prevails in many indigenous populations. Several lines of evidence from ethno-archeological studies have demonstrated the continuity and importance of psychoactive plants in South American cultures. However, despite the well-known importance of secondary metabolites in human health, little is known about its role in the evolution of ethnic differences. Herein, we identified candidate genes of adaptation to hallucinogenic cactus in Native Andean populations with a long history of shamanic practices. We used genome-wide expression data from the cactophilic fly Drosophila buzzatii exposed to a hallucinogenic columnar cactus, also consumed by humans, to identify ortholog genes exhibiting adaptive footprints of alkaloid tolerance. Genomic analyses in human populations revealed a suite of ortholog genes evolving under recent positive selection in indigenous populations of the Central Andes. Our results provide evidence of selection in genetic variants related to alkaloids toxicity, xenobiotic metabolism, and neuronal plasticity in Aymara and Quechua populations, suggesting a possible process of gene-culture coevolution driven by religious practices.

Task-independent acute effects of delta-9-tetrahydrocannabinol on human brain function and its relationship with cannabinoid receptor gene expression A neuroimaging meta-regression analysis.

The neurobiological mechanisms underlying the effects of delta-9-tetrahydrocannabinol (THC) remain unclear. Here, we examined the spatial acute effect of THC on human regional brain activation or blood flow (hereafter called activation signal) in a core network of brain regions from 372 participants, tested using a within-subject repeated measures design under experimental conditions. We also investigated whether the neuromodulatory effects of THC are related to the local expression of the cannabinoid-type-1 (CB1R) and type-2 (CB2R) receptors. Finally, we investigated the dose-response relationship between THC and key brain substrates. These meta-analytic findings shed new light on the localisation of the effects of THC in the human brain, suggesting that THC has neuromodulatory effects in regions central to many cognitive tasks and processes, related to dose, with greater effects in regions with higher levels of CB1R expression.