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Treatment-Resistant Bipolar Depression Therapeutic Trends, Challenges and Future Directions.

Bipolar disorder (BD) is a chronic mental illness impacting 1-2% of the population worldwide and causing high rates of functional impairment. Patients with BD spend most of their time in depressive episodes and up to one-third of patients do not respond to adequate doses of medications. Although no consensus exists for definition of treatment-resistant bipolar depression (TRBD), failure of symptoms improvement despite an adequate trial of two therapeutic agents is a common theme of TRBD. In this paper, we review the evidence base of therapeutic interventions, challenges, and potential future directions for TRBD. We conducted a literature search for randomized controlled trials on PubMed for the treatment of TRBD and ongoing trials for the treatment of TRBDbipolar depression on clinicaltrials.gov. Several therapeutic agents have been investigated for TRBD. Adjunctive pramipexole and modafinil have data supporting short-term efficacy in TRBD, along with limited data for racemic intravenous ketamine. Celecoxib augmentation of escitalopram and treatment with metformin in patients with insulin resistance showed promising results. Right unilateral electroconvulsive therapy displayed statistically significant response rate and improvement, but not remission compared to pharmacotherapy. Trials for transcranial magnetic stimulation (TMS) have failed to show a significant difference from sham treatment in TRBD. Pharmacological treatments with novel mechanisms of actions like brexpiprazole and vortioxetine are being investigated following successes in unipolar depression. Modified TMS protocols such as accelerated TMS are under investigation. Innovative approaches like psychedelic-assisted psychotherapy, interleukin-2, fecal microbiota transplantation and multipotent stromal cells are being studied. Evidence on current treatment modalities for TRBD is limited with low efficacy. More research is needed for successful treatment of TRBD. Effective therapies and innovative approaches to treatment are being investigated and could show promise.

Microwave- and Ultrasound-Assisted Extraction of Cannabinoids and Terpenes from Cannabis Using Response Surface Methodology.

Limited studies have explored different extraction techniques that improve cannabis extraction with scale-up potential. Ultrasound-assisted and microwave-assisted extraction were evaluated to maximize the yield and concentration of cannabinoids and terpenes. A central composite rotatable design was used to optimize independent factors (sample-to-solvent ratio, extraction time, extraction temperature, and duty cycle). The optimal conditions for ultrasound- and microwave-assisted extraction were the sample-to-solvent ratios of 115 and 114.4, respectively, for 30 min at 60 °C. Ultrasound-assisted extraction yielded 14.4% and 14.2% more oil and terpenes, respectively, compared with microwave-assisted extracts. Ultrasound-assisted extraction increased cannabinoid concentration from 13.2−39.2%. Considering reference ground samples, tetrahydrocannabinolic acid increased from 17.9 (g 100 g dry matter−1) to 28.5 and 20 with extraction efficiencies of 159.2% and 111.4% for ultrasound-assisted and microwave-assisted extraction, respectively. Principal component analyses indicate that the first two principal components accounted for 96.6% of the total variance (PC1 93.2% and PC2 3.4%) for ultrasound-assisted extraction and 92.4% of the total variance (PC1 85.4% and PC2 7%) for microwave-assisted extraction. Sample-to-solvent ratios significantly (p < 0.05) influenced the secondary metabolite profiles and yields for ultrasound-assisted extracts, but not microwave-assisted extracts.

Cold Ethanol Extraction of Cannabinoids and Terpenes from Cannabis Using Response Surface Methodology Optimization and Comparative Study.

Efficient cannabis biomass extraction can increase yield while reducing costs and minimizing waste. Cold ethanol extraction was evaluated to maximize yield and concentrations of cannabinoids and terpenes at different temperatures. Central composite rotatable design was used to optimize two independent factors sample-to-solvent ratio (12.9 to 117.1) and extraction time (5.7 min-34.1 min). With response surface methodology, predicted optimal conditions at different extraction temperatures were a cannabis-to-ethanol ratio of 115 and a 10 min extraction time. With these conditions, yields (g 100 g dry matter

Dysmenorrhoea Can Medicinal Cannabis Bring New Hope for a Collective Group of Women Suffering in Pain, Globally

Dysmenorrhoea effects up to 90% of women of reproductive age, with medical management options including over-the-counter analgesia or hormonal contraception. There has been a recent surge in medicinal cannabis research and its analgesic properties. This paper aims to critically investigate the current research of medicinal cannabis for pain relief and to discuss its potential application to treat dysmenorrhoea. Relevant keywords, including medicinal cannabis, pain, cannabinoids, tetrahydrocannabinol, dysmenorrhoea, and clinical trial, have been searched in the PubMed, EMBASE, MEDLINE, Google Scholar, Cochrane Library (Wiley) databases and a clinical trial website (clinicaltrials.gov). To identify the relevant studies for this paper, 84 papers were reviewed and 20 were discarded as irrelevant. This review critically evaluated cannabis-based medicines and their mechanism and properties in relation to pain relief. It also tabulated all clinical trials carried out investigating medicinal cannabis for pain relief and highlighted the side effects. In addition, the safety and toxicology of medicinal cannabis and barriers to use are highlighted. Two-thirds of the clinical trials summarised confirmed positive analgesic outcomes, with major side effects reported as nausea, drowsiness, and dry mouth. In conclusion, medicinal cannabis has promising applications in the management of dysmenorrhoea. The global medical cannabis market size was valued at USD 11.0 billion in 2021 and is expected to expand at a compound annual growth rate (CAGR) of 21.06% from 2022 to 2030. This will encourage academic as well as the pharmaceutical and medical device industries to study the application of medical cannabis in unmet clinical disorders.

Arylcyclohexylamine Derivatives Pharmacokinetic, Pharmacodynamic, Clinical and Forensic Aspects.

Since the 2000s, an increasing number of new psychoactive substances (NPS) have appeared on the drug market. Arylcyclohexylamine (ACH) compounds such as ketamine, phencyclidine and eticyclidine derivatives are of particular concern, given their rapidly increasing use and the absence of detailed toxicity data. First used mainly for their pharmacological properties in anesthesia, their recreational use is increasing. ACH derivatives have an antagonistic activity against the N-methyl-D-aspartate receptor, which leads to dissociative effects (dissociation of body and mind). Synthetic ketamine derivatives produced in Asia are now arriving in Europe, where most are not listed as narcotics and are, thus, legal. These structural derivatives have pharmacokinetic and pharmacodynamic properties that are sometimes very different from ketamine. Here, we describe the pharmacology, epidemiology, chemistry and metabolism of ACH derivatives, and we review the case reports on intoxication.

Cannabidiol and Beta-Caryophyllene in Combination A Therapeutic Functional Interaction.

Cannabis contains over 500 distinct compounds, which include cannabinoids, terpenoids, and flavonoids. However, very few of these compounds have been studied for their beneficial effects. There is an emerging concept that the constituents of the cannabis plant may work in concert to achieve better therapeutic benefits. This study is aimed at determining if the combination of a minor cannabinoid (cannabidiol, CBD) and a terpene (beta-caryophyllene, BCP) works in concert and if this has any therapeutic value. We used an inflammatory pain model (formalin) in mice to test for any functionality of CBD and BCP in combination. First, we determined the analgesic effect of CBD and BCP individually by establishing dose-response studies. Second, we tested the analgesic effect of fixed-ratio combinations and monitored any adverse effects. Finally, we determined the effect of this combination on inflammation. The combination of CBD and BCP produces a synergistic analgesic effect. This effect was without the cannabinoid receptor-1 side effects. The analgesic effect of CBD and BCP in combination involves an inflammatory mechanism. The combination of these two constituents of the cannabis plant, CBD and BCP, works in concert to produce a therapeutic effect with safety profiles through an inflammatory mechanism.

Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis.

Twelve separate streams of empirical data make a strong case for cannabis-induced accelerated aging including hormonal, mitochondriopathic, cardiovascular, hepatotoxic, immunological, genotoxic, epigenotoxic, disruption of chromosomal physiology, congenital anomalies, cancers including inheritable tumorigenesis, telomerase inhibition and elevated mortality. Results from a recently published longitudinal epigenomic screen were analyzed with regard to the results of recent large epidemiological studies of the causal impacts of cannabis. We also integrate theoretical syntheses with prior studies into these combined epigenomic and epidemiological results. Cannabis dependence not only recapitulates many of the key features of aging, but is characterized by both age-defining and age-generating illnesses including immunomodulation, hepatic inflammation, many psychiatric syndromes with a neuroinflammatory basis, genotoxicity and epigenotoxicity. DNA breaks, chromosomal breakage-fusion-bridge morphologies and likely cycles, and altered intergenerational DNA methylation and disruption of both the histone and tubulin codes in the context of increased clinical congenital anomalies, cancers and heritable tumors imply widespread disruption of the genome and epigenome. Modern epigenomic clocks indicate that, in cannabis-dependent patients, cannabis advances cellular DNA methylation age by 25-30% at age 30 years. Data have implications not only for somatic but also stem cell and germ line tissues including post-fertilization zygotes. This effect is likely increases with the square of chronological age. Recent epigenomic studies of cannabis exposure provide many explanations for the broad spectrum of cannabis-related teratogenicity and carcinogenicity and appear to account for many epidemiologically observed findings. Further research is indicated on the role of cannabinoids in the aging process both developmentally and longitudinally, from stem cell to germ cell to blastocystoids to embryoid bodies and beyond.

Hopelessness, Suicidality, and Co-Occurring Substance Use among Adolescent Hallucinogen Users-A National Survey Study.

(1) Objectives Hallucinogens are being explored as a potential treatment of psychiatric disorders. Micro dosing of illicitly purchased hallucinogen drugs is on the rise despite conclusive benefits. We aimed to evaluate the prevalence and odds of hopelessness, suicidality, and co-occurring substance use among adolescent hallucinogen users. (2) Methods We performed a retrospective analysis of the Centers for Disease Control and Prevention’s Youth Risk Behavior Surveillance System (YRBSS) 2001−2019 data that nationally represents school-going US adolescents. We identified hallucinogen use based on the survey questions, exploring the use of hallucinogens (LSD, PCP, mescaline, and mushrooms). (3) Results Out of a total of 125,550 respondents, 8.4% reported using hallucinogens. Overall, the trend of hallucinogen use decreased from 13.3% (2001) to 7.0% (2019) (pTrend < 0.0001). Hallucinogen users were at high odds of feeling sad and hopeless (aOR 1.40 95%CI 1.21−1.61 p < 0.0001), considering suicide (aOR 1.36 95%CI 1.08−1.70 p 0.009), and planning suicide (aOR 1.49 95%CI 1.19−1.86 p 0.001). Additionally, adolescent hallucinogen users had a higher prevalence of alcohol, cigarette, e-cigarette, marijuana, synthetic marijuana, inhalants, heroin, cocaine, methamphetamine, and ecstasy use. (4) Conclusions The overall trend of hallucinogen use decreased among school-going American adolescents. We found a high prevalence of co-occurring substance use among hallucinogen users. We found that hallucinogen users were at high odds of feeling sad, hopeless, and considering and planning suicide. Further research is needed to explore the effects of recreational hallucinogen use among the adolescent population.

Efficient Synthesis for Altering Side Chain Length on Cannabinoid Molecules and Their Effects in Chemotherapy and Chemotherapeutic Induced Neuropathic Pain.

(1) Background Recently, a number of side chain length variants for tetrahydrocannabinol and cannabidiol have been identified in cannabis however, the precursor to these molecules would be based upon cannabigerol (CBG). Because CBG, and its side chain variants, are rapidly converted to other cannabinoids in the plant, there are typically only small amounts in plant extracts, thus prohibiting investigations related to CBG and CBG variant therapeutic effects. (2) Methods To overcome this, we developed an efficient synthesis of corresponding resorcinol fragments using the Wittig reaction which, under acid catalyzed coupling with geraniol, produced the desired side chain variants of CBG. These compounds were then tested in an animal model of chemotherapeutic-induced neuropathic pain and to reduce colorectal cancer cell viability. (3) Results We found that all side-chain variants were similarly capable of reducing neuropathic pain in mice at a dose of 10 mgkg. However, the molecules with shorter side chains (i.e., CBGV and CBGB) were better at reducing colorectal cancer cell viability. (4) Conclusions The novel synthesis method developed here will be of utility for studying other side chain derivatives of minor cannabinoids such as cannabichromene, cannabinol, and cannabielsoin.

Effects of delta-9 tetrahydrocannabinol on fear memory labilization and reconsolidation A putative role of GluN2B-NMDA receptor within the dorsal hippocampus.

Cannabis preparations could be an effective reconsolidation-based treatment for post-traumatic stress disorder. However, the effects of Δ

An electrochemical aptasensor for Δ

We present a novel on-off, cost-effective, rapid electrochemical aptasensor combined with a microfluidics cartridge system for the detection of Δ

Subacute effects of a single dose of psilocybin on biomarkers of inflammation in healthy humans An open-label preliminary investigation.

Psilocybin is a serotonergic psychedelic that has gained prominent attention recently as a potential therapeutic for neuropsychiatric disorders including Major Depressive Disorder. Pre-clinical and initial studies in humans suggest that serotonin 2A receptor agonists, including serotonergic psychedelics, have anti-inflammatory effects. This may contribute to its therapeutic effects as previous studies indicate a link between neuropsychiatric disorders and inflammatory processes. However, the effect of psilocybin on biomarkers of inflammation has not been evaluated in humans. Investigate the effect of a single dose of psilocybin on peripheral biomarkers of inflammation in healthy humans. Blood samples were collected from 16 healthy participants before and one day after the administration of a single oral dose of psilocybin (mean dose 0.22 mgkg) and subsequently analyzed for concentrations of high-sensitivity C-reactive protein (hsCRP), tumor-necrosis-factor (TNF) and soluble urokinase plasminogen activator receptor (suPAR). Change in inflammatory markers was evaluated using a paired We did not observe statistically significant changes in any of the above biomarkers of inflammation (all Cohens d ≤ 0.31 all p ≥ 0.23). Our data do not support that a single dose of psilocybin reduces biomarkers of inflammation in healthy individuals one day after administration. Nevertheless, we suggest that future studies consider additional markers of inflammation, including markers of neuroinflammation, and evaluate potential anti-inflammatory effects of psilocybin therapy in clinical cohorts where more prominent effects may be observable.

The economics of psychedelic-assisted therapies A research agenda.

After a long hiatus, psychiatry is undergoing a resurgence of interest in psychedelic drugs as therapy for a wide range of mental health disorders Accumulating clinical evidence suggests substantial potential for psychedelics used in a therapeutic context, as treatment for, among other disorders, depression, post-traumatic stress disorder (PTSD), and addictions to tobacco, opioids and alcohol. As soon as 2024, powerful new therapeutic modalities could become available for individuals with mental health problems refractory to traditional therapies. Yet research has lagged on economic considerations, such as costs and cost-effectiveness, the economic effects of widespread implementation, pricing, and economic appraisals methodological considerations relevant to psychedelic therapies. These issues are critical if psychedelic therapies are to become widely accessible. We describe six types of economic analyses and their rationale for decisions and planning including the needs of health care payers. We also outline desirable features of this research, including scientific rigor, long horizons, equity, and a global view.

Moderators of ayahuascas biological antidepressant action.

The understanding of biological responses to psychedelics with antidepressant potential is imperative. Here we report how a set of acute parameters, namely emotional (depressive symptoms), cognitive (psychedelic experience), and physiological (salivary cortisol), recorded during an ayahuasca dosing session, modulated serum brain-derived neurotrophic factor (BDNF), serum cortisol (SC), serum interleukin 6 (IL-6), plasma C-reactive protein (CRP), and salivary cortisol awakening response (CAR). Results were analyzed 2 days after the psychedelic intervention (ayahuasca) versus placebo in both patients with treatment-resistant depression and healthy volunteers. These measures were assessed as part of a randomized double-blinded, placebo-controlled trial ( Results revealed that larger reductions of depressive symptoms during the dosing session significantly moderated higher levels of SC in patients. Whereas lesser changes in salivary cortisol levels during the ayahuasca intervention were related to higher BDNF levels in patients with a larger clinical response in the reduction in depressive symptoms. No moderator was found for patients CAR, IL-6, and CRP responses to ayahuasca and for all biomarker responses to ayahuasca in healthy controls and in the placebo group. In summary, some specific emotional and physiological parameters during experimental ayahuasca session were revealed as critical moderators of the improvement of major depression biomarkers, mainly BDNF and SC two days after ayahuasca intake. These findings contribute to paving the way for future studies investigating the biological antidepressant response to psychedelic therapy.

Single-dose psilocybin for treatment-resistant obsessive-compulsive disorder A case report.

Classic psychedelics, such as psilocybin, act on the brains serotonin system and produce striking psychological effects. Early work in the 1950s and 1960s and more recent controlled studies suggest benefit from psychedelic treatment in a number of conditions. A few case reports in recreational users and a single experimental study suggest benefit in patients with obsessive-compulsive disorder (OCD), but careful clinical data and long-term follow-up have been lacking. Here we describe a case of a patient with refractory OCD treated with psilocybin and followed prospectively for a year, with marked symptomatic improvement. We provide qualitative and quantitative detail of his experience during and after treatment. Improvement in OCD symptoms (YBOCS declined from 24 to 0-2) was accompanied by broader changes in his relationship to his emotions, social and work function, and quality of life. This individual was an early participant in an ongoing controlled study of psilocybin in the treatment of OCD (NCT03356483). These results are preliminary but promising, motivating ongoing investigations of the therapeutic potential of appropriately monitored and supported psychedelic treatment in the treatment of patients with obsessions and compulsions.

Associations between MDMAecstasy, classic psychedelics, and suicidal thoughts and behaviors in a sample of U.S. adolescents.

Suicide is one of the leading causes of death amongst adolescents and decades of research have failed to curb suicide rates within this population. There is thus a need to better understand factors that correlate with adolescent suicidal thoughts and behaviors (STBs). MDMAecstasy and classic psychedelics represent two areas for exploration, as use of these substances has been associated with both increased and lowered odds of STBs. Thus, the goal of this study was to test the associations between MDMAecstasy and classic psychedelics (psilocybin, peyote, mescaline, LSD) and STBs in a nationally representative sample of U.S. adolescents. We tested these associations in a sample of adolescents aged 12-17 years old from the National Survey on Drug Use and Health (2004-2019) (N 262,617) using survey-weighted multivariable logistic regression models. Lifetime psilocybin use was associated with lowered odds of lifetime suicidal thinking, planning, and attempts (aOR range 0.77-0.85). Conversely, LSD was associated with increased odds of these same outcomes (aOR range 1.20-1.35). MDMAecstasy, peyote, and mescaline did not share associations with STBs. Our study demonstrates that individual classic psychedelics share varying relationships to STBs among adolescents. Future cross-sectional and longitudinal studies are needed to further elucidate the link between classic psychedelic use and STBs in youth.

Psychotherapists openness to engage their patients in Psilocybin-Assisted Therapy for mental health treatment.

Despite psychedelic research initially ceasing in the 1970-80s, the findings documented encouraged researchers to re-examine the safety and efficacy of treating mental health with psychedelics. Of particular focus, psilocybin has shown to have therapeutic potential for a variety of mental health problems and was granted breakthrough therapy status by the FDA. Should psilocybin eventually become legally licensed, the success of Psilocybin-Assisted Therapy (PAT) may largely rely on clinicians openness to engage their eligible patients with PAT. We therefore assessed 119 psychologists openness to recommend PAT, perceived barriersfacilitators to informing patients about PAT, and factors affecting their openness to involve patients with PAT if FDA approved. While 77.4 % of psychologists agreed they would inform eligible patients about PAT, 91.6 % stated they would still recommend psychotherapies that do not involve psilocybin first. 76.5 % endorsed that knowledge on psilocybin would increase their likelihood to inform patients about PAT. More positive attitudes and beliefs about psilocybin, greater self-reported knowledge of psilocybin, personal history of psychedelic usage, and more positive attitudes towards medical cannabis (MC) was associated with greater openness to engage patients with PAT. Our regression analysis revealed that attitudes towards MC and beliefs about psilocybin were the only significant predictors of psychotherapists openness towards PAT. These findings provide relevant information to institutions planning educational programs for mental health professionals about psilocybin and Psychedelic-Assisted Therapies.

Meditation trips A thematic analysis of the combined naturalistic use of psychedelics with meditation practices.

Similarities between meditative and psychedelic states have long been recognized. Recently, parallels in the psychological mechanisms mediating the beneficial effects of mindfulness and psychedelic treatments-as well as their potential therapeutic complementarity-have been noted. However, empirical research in this area remains limited. Here, we explore the naturalistic use of meditation practices among psychedelic users recruited outside of treatmentretreat or research settings. Participants with ≥ 1 psychedelic drug experience(s) were included in an online survey. The majority (

Research into Psychedelic-Assisted Psychotherapy for Anorexia Nervosa Should be Funded.

Eating disorders are debilitating diseases that have twin impacts on the body and mind and are associated with a number of physiological and psychological comorbidities (Blinder, Cumella, and Sanathara 2006 Casiero and Frishman 2006), including increased suicide risk (Arcelus et al. 2011 Lipson and Sonneville 2020). In addition, eating disorders are growing in prevalence (Gilmache et al. 2019) and impact women at much higher rates than men (Bearman, Martinez, and Stice 2006), especially in adolescence (Spriggs, Kettner, and Carhart-Harris 2021). Anorexia nervosa (AN) is a particularly devastating eating disorder, with one of the highest mortality rates of any psychiatric disorder (Sullivan 1995). Despite the severity of the condition, current treatments for AN are limited in their efficacy (Khalsa et al. 2017). Based on the growing body of evidence demonstrating the short-term and long-term efficacy of psychedelic-assisted psychotherapy for the treatment of other mental illnesses, I argue that research into psychedelic-assisted psychotherapy for AN should be funded.

Lower-dose psycholytic therapy - A neglected approach.

Lysergic acid diethylamide (LSD) and similar psychoactive drugs have been used in psychotherapy since 1949, when the first clinical study with lower-dose LSD showed therapeutically relevant effects. This caused an intense interest among psychotherapists and researchers, alike, on an international scale. In 1960, the use of serial lower-dose LSDpsilocybin sessions in a psychoanalytical framework, which was dominant at the time, was named

Therapeutic use of psilocybin Practical considerations for dosing and administration.

The interest in psilocybin as a therapeutic approach has grown exponentially in recent years. Despite increasing access, there remains a lack of practical guidance on the topic for health care professionals. This is particularly concerning given the medical complexity and vulnerable nature of patients for whom psilocybin-assisted psychotherapy may be considered. This article aims to provide health care professionals with an overview of practical considerations for psilocybin therapy, rooted in a patient safety focus. Within this piece we will review basic psilocybin pharmacology and pharmacokinetics, indications, practical therapeutic strategies (e.g., dosing, administration, monitoring) and safety considerations (e.g., contraindications, adverse events, and drug interactions). With this information, our goal is to increase the knowledge and comfort of health care professionals to discuss and counsel their patients on psilocybin therapy, ultimately improving patient care and safety.

Effect of psilocybin on decision-making and motivation in the healthy rat.

Psilocybin and its active metabolite psilocin are hallucinogenic serotonergic agonists with high affinity for several serotonin receptors. In addition to underlying the hallucinogenic effects of these compounds, serotonin receptor activation also has important effects on decision-making and goal-directed behaviors. The impact of psilocybin and psilocin on these cognitive systems, however, remains unclear. This study investigated the effects of psilocybin treatment on decision-making and motivation in healthy male and female rats. We compared probability and delay discounting performance of psilocybin treated (1 mgkg) to vehicle rats (n 10sexgroup), and further assessed motivation in each group using a progressive ratio task. We also confirmed drug action by assessing head twitch responses after psilocybin treatment (1 mgkg). Results from this study demonstrated that exposure to 1 mgkg psilocybin did not affect decision-making in the probability and delay discounting tasks and did not reduce response rates in the progressive ratio task. However, psilocybin treatment did cause the expected increase in head twitch responses in both male and female rats, demonstrating that the drug was delivered at a pharmacologically relevant dosage. Combined, these results suggest that psilocybin may not impair or improve decision-making and motivation. Considering recent interest in psilocybin as a potential fast-acting therapeutic for a variety of mental health disorders, our findings also suggest the therapeutic effects of this drug may not be mediated by changes to the brain systems underlying reward and decision-making. Finally, these results may have important implications regarding the relative safety of this compound, suggesting that widespread cognitive impairments may not be seen in subjects, even after chronic treatment.

Effects of prenatal exposure to THC on hippocampal neural development in offspring.

Cannabis use is a worldwide issue with the development of legalization. Prenatal exposure to Δ9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, is related to affect fetal nervous system development. In our present study, we administered THC to pregnant mice from gestational day 5.5-12.5. Differences in neuronal cell composition and organization between the two groups were found by staining sections of the offspring hippocampus at PND21. In addition, RNA-seq of hippocampal tissue also suggested differences in gene expression due to THC treatment, especially significant enrichment to neurogenesis and neural differentiation. Subsequently, the effect of THC treatment on the proliferation and differentiation capacity of neural stem cells (NSCs) was confirmed. Based on the RNA-seq results, we selected the differentially expressed transcription factor MEF2C for validation. The effect of THC treatment on NSCs differentiation was found to be regulated by knocking down the expression of MEF2C in NSCs. Considering that THC is an agonist of cannabinoid receptor (CB1R), the differentiation outcome of NSC after THC treatment was significantly rescued, by pretreating with the CB1R inhibitor Rimonabant. Notably, pretreatment with Rimonabant restored the expression of MEF2C. Taken together, the present results suggested that THC regulated the MEF2C pathway through CB1R and had an impact on hippocampal neurodevelopment.

Experimental strategies to discover and develop the next generation of psychedelics and entactogens as medicines.

Research on classical psychedelics (psilocybin, LSD and DMT) and entactogen, MDMA, has produced a renaissance in the search for more effective drugs to treat psychiatric, neurological and various peripheral disorders. Psychedelics and entactogens act though interaction with 5-HT

Determination of urinary metabolites of cannabidiol, Δ

In this study, an automated online micro-solid-phase extraction (μSPE)-liquid chromatography-tandem mass spectrometry (LC-MSMS) method was developed and validated for the detection of metabolites of cannabidiol (CBD), Δ

A unified model of ketamines dissociative and psychedelic properties.

Ketamine is an N-methyl-d-aspartate antagonist which is increasingly being researched and used as a treatment for depression. In low doses, it can cause a transitory modification in consciousness which was classically labelled as dissociation. However, ketamine is also commonly classified as an atypical psychedelic and it has been recently reported that ego dissolution experiences during ketamine administration are associated with greater antidepressant response. Neuroimaging studies have highlighted several similarities between the effects of ketamine and those of serotonergic psychedelics in the brain however, no unified account has been proposed for ketamines multi-level effects - from molecular to network and psychological levels. Here, we propose that the fast, albeit transient, antidepressant effects observed after ketamine infusions are mainly driven by its acute modulation of reward circuits and sub-acute increase in neuroplasticity, while its dissociative and psychedelic properties are driven by dose- and context-dependent disruption of large-scale functional networks. Computationally, as nodes of the salience network (SN) represent high-level priors about the body (minimal self) and nodes of the default-mode network (DMN) represent the highest-level priors about narrative self-experience (biographical self), we propose that transitory SN desegregation and disintegration accounts for ketamines

Application of machine learning and complex network measures to an EEG dataset from ayahuasca experiments.

Ayahuasca is a blend of Amazonian plants that has been used for traditional medicine by the inhabitants of this region for hundreds of years. Furthermore, this plant has been demonstrated to be a viable therapy for a variety of neurological and mental diseases. EEG experiments have found specific brain regions that changed significantly due to ayahuasca. Here, we used an EEG dataset to investigate the ability to automatically detect changes in brain activity using machine learning and complex networks. Machine learning was applied at three different levels of data abstraction (A) the raw EEG time series, (B) the correlation of the EEG time series, and (C) the complex network measures calculated from (B). Further, at the abstraction level of (C), we developed new measures of complex networks relating to community detection. As a result, the machine learning method was able to automatically detect changes in brain activity, with case (B) showing the highest accuracy (92%), followed by (A) (88%) and (C) (83%), indicating that connectivity changes between brain regions are more important for the detection of ayahuasca. The most activated areas were the frontal and temporal lobe, which is consistent with the literature. F3 and PO4 were the most important brain connections, a significant new discovery for psychedelic literature. This connection may point to a cognitive process akin to face recognition in individuals during ayahuasca-mediated visual hallucinations. Furthermore, closeness centrality and assortativity were the most important complex network measures. These two measures are also associated with diseases such as Alzheimers disease, indicating a possible therapeutic mechanism. Moreover, the new measures were crucial to the predictive model and suggested larger brain communities associated with the use of ayahuasca. This suggests that the dissemination of information in functional brain networks is slower when this drug is present. Overall, our methodology was able to automatically detect changes in brain activity during ayahuasca consumption and interpret how these psychedelics alter brain networks, as well as provide insights into their mechanisms of action.

Association of a Positive Drug Screening for Cannabis With Mortality and Hospital Visits Among Veterans Affairs Enrollees Prescribed Opioids.

Cannabis has been proposed as a therapeutic with potential opioid-sparing properties in chronic pain, and its use could theoretically be associated with decreased amounts of opioids used and decreased risk of mortality among individuals prescribed opioids. To examine the risks associated with cannabis use among adults prescribed opioid analgesic medications. This cohort study was conducted among individuals aged 18 years and older who had urine drug screening in 2014 to 2019 and received any prescription opioid in the prior 90 days or long-term opioid therapy (LTOT), defined as more than 84 days of the prior 90 days, through the Veterans Affairs health system. Data were analyzed from November 2020 through March 2022. Biologically verified cannabis use from a urine drug screen. The main outcomes were 90-day and 180-day all-cause mortality. A composite outcome of all-cause emergency department (ED) visits, all-cause hospitalization, or all-cause mortality was a secondary outcome. Weights based on the propensity score were used to reduce confounding, and hazard ratios HRs were estimated using Cox proportional hazards regression models. Analyses were conducted among the overall sample of patients who received any prescription opioid in the prior 90 days and were repeated among those who received LTOT. Analyses were repeated among adults aged 65 years and older. Among 297 620 adults treated with opioids, 30 514 individuals used cannabis (mean SE age, 57.8 10.5 years 28 784 94.3% men) and 267 106 adults did not (mean SE age, 62.3 12.3 years P < .001 247 684 92.7% men P < .001). Among all patients, cannabis use was not associated with increased all-cause mortality at 90 days (HR, 1.07 95% CI, 0.92-1.22) or 180 days (HR, 1.00 95% CI, 0.90-1.10) but was associated with an increased hazard of the composite outcome at 90 days (HR, 1.05 95% CI, 1.01-1.07) and 180 days (HR, 1.04 95% CI, 1.01-1.06). Among 181 096 adults receiving LTOT, cannabis use was not associated with increased risk of all-cause mortality at 90 or 180 days but was associated with an increased hazard of the composite outcome at 90 days (HR, 1.05 95% CI, 1.02-1.09) and 180 days (HR, 1.05 95% CI, 1.02-1.09). Among 77 791 adults aged 65 years and older receiving LTOT, cannabis use was associated with increased 90-day mortality (HR, 1.55 95% CI, 1.17-2.04). This study found that cannabis use among adults receiving opioid analgesic medications was not associated with any change in mortality risk but was associated with a small increased risk of adverse outcomes and that short-term risks were higher among older adults receiving LTOT.

Multinational Association of Supportive Care in Cancer (MASCC) expert opinionconsensus guidance on the use of cannabinoids for gastrointestinal symptoms in patients with cancer.

Gastrointestinal symptoms are common in patients with cancer, whether related to treatment or a direct effect of the disease itself. Patients may choose to access cannabinoids outside of their formal medical prescriptions to palliate such symptoms. However, clinical guidelines are lacking in relation to the use of such medicines for gastrointestinal symptoms in patients with cancer. A systematic review of the evidence for the use of cannabinoids for symptom control in patients with cancer was undertaken. Search strategies were developed for Medline, Embase, PsychINFO, and the Cochrane Central Register of Controlled Trials, including all publications from 1975 up to 12 November 2021. Studies were included if they were randomized controlled trials of cannabinoids compared with placebo or active comparator in adult patients with cancer, regardless of type, stage, or treatment status. Articles for inclusion were agreed by all authors, and data extracted and summarized by two authors. Each study was scored according to the Jadad scale. This review was specifically for the purpose of developing guidelines for the use of cannabis for gastrointestinal symptoms, including chemotherapy-induced nausea and vomiting (CINV), chronic nausea, anorexia-cachexia syndrome, and taste disturbance. Thirty-six randomized controlled trials were identified that met the inclusion criteria for this review of gastrointestinal symptoms 31 relating to CINV, one to radiotherapy-induced nausea and vomiting, and the remaining four to anorexia-cachexia and altered chemosensory disturbance. The populations for the randomized controlled trials were heterogeneous, and many studies were of poor quality, lacking clarity regarding method of randomization, blinding, and allocation concealment. For CINV, eleven RCTs showed improvement with cannabis compared to placebo, but out of 21 trials where cannabis was compared to other antiemetics for CINV, only 11 favoured cannabis. Tetrahydrocannabinol (THC) and nabilone were more effective in preventing CINV when compared to placebo but are not more effective than other antiemetics. For refractory CINV, one study of THCCBD demonstrated reduced nausea as an add-on treatment to guideline-consistent antiemetic therapy without olanzapine. The MASCC Guideline Committee found insufficient evidence to recommend cannabinoids for the management of CINV, nausea from advanced cancer, cancer-associated anorexia-cachexia, and taste disturbance. High-quality studies are needed to inform practice.

Reactivations after 5-methoxy-N,N-dimethyltryptamine use in naturalistic settings An initial exploratory analysis of the phenomenons predictors and its emotional valence.

The psychedelic 5-MeO-DMT has shown clinical potential due to its short duration and ability to induce mystical experiences. However, a phenomenon known as reactivations (similar to flashbacks) is a poorly understood and frequently reported phenomenon which appears associated with 5-MeO-DMT use and warranted further investigation. This study examined whether differences in age, gender, education, lifetime use, use location, and preparation strategies predict reactivations (primary outcome). Additionally, we explored how reactivations were perceived by survey respondents and whether demographic data predicted emotional valence (secondary outcome) of reported reactivations. This study used secondary quantitative data from a survey assessing epidemiological and behavioral associations of 5-MeO-DMT use in non-clinical settings ( Being female, older at the time of first 5-MeO-DMT dose, having higher educational attainment, and dosing in a structured group setting were associated with increased odds of reporting a reactivation event. Higher mystical experience scores, greater personal wellbeing and having had a non-dual awareness experience that was not substance-induced were associated with higher likelihood of reporting a neutral or positive emotional valence of a reactivation event. These findings suggest that reactivation phenomena, in this particular sample may most often represent a neutral or positive byproduct of the acute 5-MeO-DMT experience. More information is needed to best identify individuals most likely to experience a reactivation as a negative event to prevent such potential challenging outcomes.

Pharmacological Mechanism of the Non-hallucinogenic 5-HT

Ariadne is a non-hallucinogenic analog in the phenylalkylamine chemical class of psychedelics that is closely related to an established synthetic hallucinogen, 2,5-dimethoxy-4-methyl-amphetamine (DOM), differing only by one methylene group in the α-position to the amine. Ariadne has been tested in humans including clinical trials at Bristol-Myers Company that indicate a lack of hallucinogenic effects and remarkable therapeutic effects, such as rapid remission of psychotic symptoms in schizophrenics, relaxation in catatonics, complete remission of symptoms in Parkinsons disease (PD), and improved cognition in geriatric subjects. Despite these provocative clinical results, the compound has been abandoned as a drug candidate and its molecular pharmacology remained unknown. Here, we report a detailed examination of the in vitro and in vivo pharmacology of Ariadne and its analogs, and propose a molecular hypothesis for the lack of hallucinogenic effects and the therapeutic potential of this compound class. We also provide a summary of previous clinical and preclinical results to contextualize the molecular signaling data. Our results show that Ariadne is a serotonin 5-HT

Merging enzymatic and synthetic chemistry with computational synthesis planning.

Synthesis planning programs trained on chemical reaction data can design efficient routes to new molecules of interest, but are limited in their ability to leverage rare chemical transformations. This challenge is acute for enzymatic reactions, which are valuable due to their selectivity and sustainability but are few in number. We report a retrosynthetic search algorithm using two neural network models for retrosynthesis-one covering 7984 enzymatic transformations and one 163,723 synthetic transformations-that balances the exploration of enzymatic and synthetic reactions to identify hybrid synthesis plans. This approach extends the space of retrosynthetic moves by thousands of uniquely enzymatic one-step transformations, discovers routes to molecules for which synthetic or enzymatic searches find none, and designs shorter routes for others. Application to (-)-Δ

Cannabinoid CB1 Receptors Are Expressed in a Subset of Dopamine Neurons and Underlie Cannabinoid-Induced Aversion, Hypoactivity, and Anxiolytic Effects in Mice.

Cannabinoids modulate dopamine (DA) transmission and DA-related behavior, which has been thought to be mediated initially by activation of cannabinoid CB1 receptors (CB1Rs) on GABA neurons. However, there is no behavioral evidence supporting it. In contrast, here we report that CB1Rs are also expressed in a subset of DA neurons and functionally underlie cannabinoid action in male and female mice. RNAscope in situ hybridization (ISH) assays demonstrated CB1 mRNA in tyrosine hydroxylase (TH)-positive DA neurons in the ventral tegmental area (VTA) and glutamate decarboxylase 1 (GAD1)-positive GABA neurons. The CB1R-expressing DA neurons were located mainly in the middle portion of the VTA with the number of CB1-TH colocalization progressively decreasing from the medial to the lateral VTA. Triple-staining assays indicated CB1R mRNA colocalization with both TH and vesicular glutamate transporter 2 (VgluT2, a glutamate neuronal marker) in the medial VTA close to the midline of the brain. Optogenetic activation of this population of DA neurons was rewarding as assessed by optical intracranial self-stimulation. Δ

A sense of the bigger picture A qualitative analysis of follow-up interviews with people with bipolar disorder who self-reported psilocybin use.

People with bipolar disorder (BD) spend more time depressed than manichypomanic, and depression is associated with greater impairments in psychosocial functioning and quality of life than maniahypomania. Emerging evidence suggests psilocybin, the psychoactive compound in magic mushrooms, is a promising treatment for unipolar depression. Clinical trials of psilocybin therapy have excluded people with BD as a precaution against possible adverse effects (e.g., mania). Our study centered the experiences of adults living with BD who consumed psilocybin-containing mushrooms, and aimed to (1) understand its subjective impacts on BD symptoms, (2) deepen understanding of Phase I survey results, and (3) elucidate specific contextual factors associated with adverse reactions in naturalistic settings. Following an international survey (Phase I), follow-up interviews were conducted with 15 respondents (Phase II) to further understand psilocybin use among adults with BD. As part of a larger mixed-methods explanatory sequential design study, reflexive thematic analysis was used to elaborate findings. Three major themes containing sub-themes were developed. (1) Mental Health Improvements (1.1) decreased impact and severity of depression, (1.2) increased emotion processing, (1.3) development of new perspectives, and (1.4) greater relaxation and sleep. (2) Undesired Mental Health Impacts (2.1) changes in sleep, (2.2) increased mania severity, (2.3) hospitalization, and (2.4) distressing sensory experiences. (3) Salient Contextual Factors for psilocybin use included (3.1) poly-substance use and psilocybin dose, (3.2) solo versus social experiences, and (3.3) pre-psilocybin sleep deprivation. Our findings demonstrate both benefits and risks of psilocybin use in this population. Carefully designed clinical trials focused on safety and preliminary efficacy are warranted.

Therapeutic uses of psychedelics for eating disorders and body dysmorphic disorder.

Clinical use of psychedelics has gained considerable attention, with promising benefits across a range of mental disorders. Current pharmacological and psychotherapeutic treatments for body dysmorphic disorder (BDD) and eating disorders (EDs) have limited efficacy. As such, other treatment options such as psychedelic-assisted therapies are being explored in these clinical groups. This systematic review evaluates evidence related to the therapeutic potential of psychedelics in individuals diagnosed with BDD and EDs. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a systematic review of all study designs published to the end of February 2022 that identified changes in EDBDD symptom severity from psychedelics using validated measures to assess symptom changes. Our search detected a total of 372 studies, of which five met inclusion criteria (two exploratory studies, two case reports, and one prospective study). These were included in the data evaluation. Effects of psychedelics on BDD and various ED symptoms were identified mostly through thematic analyses and self-reports. Our findings highlight that more research is needed to determine the safety and efficacy of psychedelics in BDD and EDs and we suggest avenues for future exploration.

Risks and benefits of psilocybin use in people with bipolar disorder An international web-based survey on experiences of magic mushroom consumption.

Psilocybin, the primary psychoactive component of psychedelic magic mushrooms, may have potential for treating depressive symptoms, and consequent applications for bipolar disorder (BD). Knowledge of the risks and benefits of psilocybin in BD is limited to case studies. To support the design of clinical trials, we surveyed experiences of psilocybin use in people with BD. An international web-based survey was used to explore experiences of psilocybin use in people with a self-reported diagnosis of BD. Quantitative findings were summarised using descriptive statistics. Qualitative content analysis was used to investigate free-text responses, with a focus on positive experiences of psilocybin use. A total of 541 people completed the survey (46.4% female, mean 34.1 years old). One-third (32.2% The subjective benefits of psilocybin use for mental health symptoms reported by survey participants encourage further investigation of psilocybin-based treatments for BD. Clinical trials should incorporate careful monitoring of symptoms, as data suggest that BD symptoms may emerge or intensify following psilocybin use.

Psilocybin-assisted therapy improves psycho-social-spiritual well-being in cancer patients.

While psychedelics have been shown to improve psycho-spiritual well-being, the underlying elements of this change are not well-characterized. The NIH-HEALS posits that psycho-social-spiritual change occurs through the factors of Connection, Reflection Introspection, and Trust Acceptance. This study aimed to evaluate the changes in NIH-HEALS scores in a cancer population with major depressive disorder undergoing psilocybin-assisted therapy. In this Phase II, single-center, open label trial, 30 cancer patients with major depressive disorder received a fixed dose of 25 mg of psilocybin. Participants underwent group preparation sessions, simultaneous psilocybin treatment administered in adjacent rooms, and group integration sessions, along with individual care. The NIH-HEALS, a self-administered, 35-item measure of psycho-social spiritual healing was completed at baseline and post-treatment at day 1, week 1, week 3, and week 8 following psilocybin therapy. NIH-HEALS scores, representing psycho-social-spiritual wellbeing, improved in response to psilocybin treatment (p < 0.001). All three factors of the NIH-HEALS (Connection, Reflection Introspection, and Trust Acceptance) demonstrated positive change by 12.7 %, 7.7 %, and 22.4 %, respectively. These effects were apparent at all study time points and were sustained up to the last study interval at 8 weeks (p < 0.001). The study lacks a control group, relies on a self-report measure, and uses a relatively small sample size with limited diversity that restricts generalizability. Findings suggest that psilocybin-assisted therapy facilitates psycho-social-spiritual growth as measured by the NIH-HEALS and its three factors. This supports the factors of Connection, Reflection Introspection, and Trust Acceptance as underlying elements for psycho-social-spiritual healing in cancer patients, and validates the use of the NIH-HEALS within psychedelic research.

Psychedelic-Assisted Therapy and Psychedelic Science A Review and Perspective on Opportunities in Neurosurgery and Neuro-Oncology.

After a decades-long pause, psychedelics are again being intensely investigated for treating a wide range of neuropsychiatric ailments including depression, anxiety, addiction, post-traumatic stress disorder, anorexia, and chronic pain syndromes. The classic serotonergic psychedelics psilocybin and lysergic acid diethylamide and nonclassic psychedelics 3,4-methylenedioxymethamphetamine and ketamine are increasingly appreciated as neuroplastogens given their potential to fundamentally alter mood and behavior well beyond the time window of measurable exposure. Imaging studies with psychedelics are also helping advance our understanding of neural networks and connectomics. This resurgence in psychedelic science and psychedelic-assisted therapy has potential significance for the fields of neurosurgery and neuro-oncology and their diverse and challenging patients, many of whom continue to have mental health issues and poor quality of life despite receiving state-of-the-art care. In this study, we review recent and ongoing clinical trials, the set and setting model of psychedelic-assisted therapy, potential risks and adverse events, proposed mechanisms of action, and provide a perspective on how the safe and evidence-based use of psychedelics could potentially benefit many patients, including those with brain tumors, pain syndromes, ruminative disorders, stroke, SAH, TBI, and movement disorders. By leveraging psychedelics neuroplastic potential to rehabilitate the mind and brain, novel treatments may be possible for many of these patient populations, in some instances working synergistically with current treatments and in some using subpsychedelic doses that do not require mind-altering effects for efficacy. This review aims to encourage broader multidisciplinary collaboration across the neurosciences to explore and help realize the transdiagnostic healing potential of psychedelics.

Receptor-mediated effects of Δ

Δ

Cannabis use in Attention - DeficitHyperactivity Disorder (ADHD) A scoping review.

Treatments for Adult ADHD include stimulants, two non-stimulant medications, as well as cognitive-behavioral therapy (CBT). These pharmacological agents are often associated with side effects, contributing to poor treatment adherence. Patients with ADHD have regularly stated that cannabis has helped improve their ADHD symptoms however, scientific literature describing the effects of cannabis on symptoms of ADHD is scarce. We systematically searched MEDLINE, EMBASE, EMCARE, PsycINFO, Web of Science, Cochrane Library, and Clinicaltrials.gov. The searches included all publications in English up to June 27, 2022. We included both experimental and observational studies that assessed the effect of cannabis on ADHD symptomatology and neuropsychiatric outcomes. To synthesize our current understanding of the potential effects of cannabis use on ADHD symptoms and pathophysiology, and the effects of ADHD on cannabis use, data was extracted from each study regarding the characteristics of its population, methods used to assess both cannabis consumption and ADHD symptoms, and key findings. Our scoping review included a total of 39 studies. Only one study employed a randomized and placebo-controlled design to directly measure the effect of cannabis on ADHD, and no significant effect was observed for the studys primary outcome, the QbTest (Est -0.17, 95% CI -0.40 to 0.07, p 0.16). Most of the literature consists of cross-sectional studies that evaluate the association between ADHD severity and cannabis use. 15 studies addressed the neuropsychiatric effects of cannabis on ADHD by employing either a battery of neuropsychiatric tests or neuroimaging. The concentration and amount of THC and CBD used were not well measured in most of the studies. Although some studies indicated that cannabis improved ADHD symptoms, most studies indicated it worsened or had no effect on ADHD symptoms. Given the current evidence, cannabis is not recommended for people with ADHD. Limitations of the literature include the absence of objective measurements for cannabis exposure and ADHD symptoms, heterogenous definitions, oversampling, and small sample sizes.

The C4EB study-Transvamix (10% THC 5% CBD) to treat chronic pain in epidermolysis bullosa A protocol for an explorative randomized, placebo controlled, and double blind intervention crossover study.

Patients with the genetic blistering skin condition epidermolysis bullosa (EB) report severe pain as a consequence of skin and mucous membrane lesions including blisters, wounds, and scars. Adequate symptom alleviation is not often achieved using conventional pharmacologic interventions. Finding novel approaches to pain care in EB is imperative to improve the quality of life of patients living with EB. There are several anecdotal reports on the use of cannabinoid-based medicines (CBMs) by EB patients to reduce the burden of symptoms. However, controlled clinical investigations assessing these reported effects are lacking. As the pain quality unpleasantness delineates EB pain, we hypothesize the modulation of affective pain processing in the brain by way of intervention with CBMs comprising the cannabinoids Δ-9-tetrahydrocannabinol and cannabidiol-objectified by functional magnetic resonance imaging (fMRI). The C4EB study is an investigator-initiated, single-centre, randomized, double-blind, placebo-controlled and crossover trial. Adult patients with the diagnosis epidermolysis bullosa, reporting chronic pain will be eligible to participate. Following baseline measurements, participants will be randomized to receive the sublingually administered interventions placebo and Transvamix® in forward or reversed orders, each for two weeks and separated by a washout. The primary outcome is the difference in numeric rating scale pain scores between grouped interventions, using affective descriptors within the Short-form McGill Pain Questionnaire-2. Secondary outcomes include pain self-efficacy, concomitant analgesic medication-use and adverse events. Additionally, fMRI will be employed to assess brain connectivity related to neuroanatomic pain circuits at baseline, placebo and Transvamix® interventions. The study was approved by the ethical committee at the University Medical Center of Groningen in the Netherlands. Results will be submitted for publication in a peer-reviewed journal. Trial registration number Netherlands Trial Register NL9347 (Acronym C4EB).

Integrated world modeling theory expanded Implications for the future of consciousness.

Integrated world modeling theory (IWMT) is a synthetic theory of consciousness that uses the free energy principle and active inference (FEP-AI) framework to combine insights from integrated information theory (IIT) and global neuronal workspace theory (GNWT). Here, I first review philosophical principles and neural systems contributing to IWMTs integrative perspective. I then go on to describe predictive processing models of brains and their connections to machine learning architectures, with particular emphasis on autoencoders (perceptual and active inference), turbo-codes (establishment of shared latent spaces for multi-modal integration and inferential synergy), and graph neural networks (spatial and somatic modeling and control). Future directions for IIT and GNWT are considered by exploring ways in which modules and workspaces may be evaluated as both complexes of integrated information and arenas for iterated Bayesian model selection. Based on these considerations, I suggest novel ways in which integrated information might be estimated using concepts from probabilistic graphical models, flow networks, and game theory. Mechanistic and computational principles are also considered with respect to the ongoing debate between IIT and GNWT regarding the physical substrates of different kinds of conscious and unconscious phenomena. I further explore how these ideas might relate to the Bayesian blur problem, or how it is that a seemingly discrete experience can be generated from probabilistic modeling, with some consideration of analogies from quantum mechanics as potentially revealing different varieties of inferential dynamics. I go on to describe potential means of addressing critiques of causal structure theories based on network unfolding, and the seeming absurdity of conscious expander graphs (without cybernetic symbol grounding). Finally, I discuss future directions for work centered on attentional selection and the evolutionary origins of consciousness as facilitated unlimited associative learning. While not quite solving the Hard problem, this article expands on IWMT as a unifying model of consciousness and the potential future evolution of minds.

Holding on or letting go Patient experiences of control, context, and care in oral esketamine treatment for treatment-resistant depression A qualitative study.

Ketamine and its enantiomer esketamine represent promising new treatments for treatment-resistant depression (TRD). Esketamine induces acute, transient psychoactive effects. How patients perceive esketamine treatment, and which conditions facilitate optimal outcomes, remains poorly understood. Understanding patient perspectives on these phenomena is important to identify unmet needs, which can be used to improve (es)ketamine treatments. To explore the perspectives of TRD patients participating in off label oral esketamine treatment. In-depth interviews were conducted with 17 patients (11 women) after a six-week, twice-weekly esketamine treatment program, and subsequently after six months of at-home use. Interviews explored participants perspectives, expectations, and experiences with esketamine treatment. Audio interviews were transcribed verbatim and analysed following an Interpretative Phenomenological Analysis (IPA) framework. Key themes included overwhelming experiences inadequate preparation letting go of control mood states influencing session experiences presence and emotional support, and supportive settings. Patients attempts to let go and give into vs. attempts to maintain control over occasionally overwhelming experiences was a central theme. Multiple factors influenced patients ability to give into the experience and appeared to impact their mood and anxiety about future sessions, including level of preparation and education, physical and emotional support, and setting during the session. Better preparation beforehand, an optimized treatment setting, and emotional and psychological support during (es)ketamine sessions can help patients to let go and may lead to better quality of care and outcomes. Recommendations to improve quality of patient care in (es)ketamine treatment are provided, including suggestions for the training of nurses and other support staff.

Assessment of clinical outcomes in patients with post-traumatic stress disorder analysis from the UK Medical Cannabis Registry.

The current paucity of clinical evidence limits the use of cannabis-based medicinal products (CBMPs) in post-traumatic stress disorder (PTSD). This study investigates health-related quality of life (HRQoL) changes and adverse events in patients prescribed CBMPs for PTSD. A case-series of patients from the UK Medical Cannabis Registry was analyzed. HRQoL was assessed at 1-, 3-, and 6-months using validated patient reported outcome measures (PROMs). Adverse events were analyzed according to the Common Terminology Criteria for Adverse Events version 4.0. Statistical significance was defined as p < 0.050. Of 162 included patients, 88.89% (n 144) were currentprevious cannabis users. Median daily CBMP dosages were 5.00 (IQR 0.00-70.00) mg of cannabidiol and 145.00 (IQR 100.00-200.00) mg of Δ9-tetrahydrocannabinol. Significant improvements were observed in PTSD symptoms, sleep, and anxiety across all follow-up periods (p < 0.050). There were 220 (135.8%) adverse events reported by 33 patients (20.37%), with the majority graded mild or moderate in severity (n 190, 117.28%). Insomnia and fatigue had the greatest incidence (n 20, 12.35%). Associated improvements in HRQoL were observed in patients who initiated CBMP therapy. Adverse events analysis suggests acceptability and safety up to 6 months. This study may inform randomized placebo-controlled trials, required to confirm causality and determine optimal dosing.

Maternal behaviours and adult offspring behavioural deficits are predicted by maternal TNFα concentration in a rat model of neurodevelopmental disorders.

Exposure to inflammatory stressors during fetal development is a major risk factor for neurodevelopmental disorders (NDDs) in adult offspring. Maternal immune activation (MIA), induced by infection, causes an acute increase in pro-inflammatory cytokines which can increase the risk for NDDs directly by inducing placental and fetal brain inflammation, or indirectly through affecting maternal care behaviours thereby affecting postnatal brain development. Which of these two potential mechanisms dominates in increasing offspring risk for NDDs remains unclear. Here, we show that acute systemic maternal inflammation induced by the viral mimetic polyinosinicpolycytidylic acid (poly IC) on gestational day 15 of rat pregnancy affects offspring and maternal behaviour, offspring cognition, and expression of NDD-relevant genes in the offspring brain. Dams exposed to poly IC elicited an acute increase in the pro-inflammatory cytokine tumour necrosis factor (TNF referred to here as TNFα), which predicted disruption of key maternal care behaviours. Offspring of poly IC-treated dams showed early behavioural and adult cognitive deficits correlated to the maternal TNFα response, but, importantly, not with altered maternal care. We also found interacting effects of sex and treatment on GABAergic gene expression and DNA methylation in these offspring in a brain region-specific manner, including increased parvalbumin expression in the female adolescent frontal cortex. We conclude that the MIA-induced elevation of TNFα in the maternal compartment affects fetal neurodevelopment leading to altered offspring behaviour and cognition. Our results suggest that a focus on prenatal pathways affecting fetal neurodevelopment would provide greater insights into the mechanisms underpinning the TNFα-mediated genesis of altered offspring behaviour and cognition following maternal inflammation.

Rumors of Psychedelics, Psychotropics and Related Derivatives in

There are almost 1000 species of

Development and Validation of the LC-MSMS Method for Determination of 130 Natural and Synthetic Cannabinoids in Cannabis Oil.

Dietary supplements are widely available products used by millions of people around the world. Unfortunately, the procedure of adding pharmaceutical and psychoactive substances has recently been observed, in order to increase the effectiveness of supplements in the form of hemp oils. For this reason, it is extremely important to develop analytical methods for the detection of substances prohibited in dietary supplements and food products. In the present study, using the LC-MSMS technique, an innovative method for the detection and quantification of 117 synthetic cannabinoids and 13 natural cannabinoids in dietary supplements and food products in the form of oils during one 13-min chromatographic run was developed. Each method was fully validated by characterization of the following parameters The limit of detection was set to 0.1 ngmL (100 µgg, 0.01%). The limit of quantification ranged from 0.05 ngmL to 50 ngmL. The criteria assumed for systematic error caused by methodological bias (±20%) resulting from the recovery of analytes after the extraction process, as well as the coefficient of variation (CV) (≤20%), were met for all 130 tested compounds. The positive results of the validation confirmed that the developed methods met the requirements related to the adequacy of their application in a given scope. Additionally, methods developed using the LC-MSMS technique were verified via proficiency tests. The developed analytical procedure was successfully used in the analysis of hemp oils and capsules containing them in the studied dietary supplements.

Psychedelic-Induced Serotonin 2A Receptor Downregulation Does Not Predict Swim Stress Coping in Mice.

Serotoninergic psychedelics such as psilocybin have been reported to elicit a long-lasting reduction in depressive symptoms. Although the main target for serotoninergic psychedelics, serotonin type 2A receptor (5-HT

Genetic Variants Associated with Long-Terminal Repeats Can Diagnostically Classify

Social genetic effects for drug use disorder among spouses.

Preclinical and human studies suggest that a social partners genotype may be associated with addiction-related outcomes. This study measured whether spousal genetic makeup is associated with risk of developing drug use disorder (DUD) during marriage and whether the risk associated with a spouses genotype could be disentangled from potentially confounding rearing environmental effects. Univariable and multivariable logistic regression analyses. Sweden. Men and women born between 1960 and 1990 and in opposite-sex first marriages before age 35 (n 294 748 couples). Outcome was DUD diagnosis (inclusive of opioids, sedativeshypnoticsanxiolytics, cocaine, cannabis, amphetamine and other psychostimulants, hallucinogens, other drugs of abuse and combinations thereof) obtained from legal, medical and pharmacy registries. The focal predictor was family genetic risk scores for DUD (FGRS-DUD), which were inferred from diagnoses in first- through fifth-degree relatives and weighted by degree of genetic sharing. FGRS-DUD were calculated separately for each partner in a couple. Marriage to a spouse with a high FGRS-DUD was associated with increased risk of developing DUD during marriage, OR There is relatively robust evidence that a persons risk for developing drug use disorder is associated with the genetic makeup of the persons spouse.

Egocentric Network Characteristics and Cannabis Use in a Sample of Young Adult Medical Cannabis Patients and Nonpatient Users.

Social factors play an important role in young adults substance use behaviors, but little is known about how egocentric social network factors are related to young adults cannabis use. Young adults also report medicinal and recreational uses of cannabis, which may alter the strength of these relationships. Therefore, medical cannabis patient status and medicinalrecreational orientation toward cannabis were examined as moderators of these relationships. Young adult medical cannabis patients ( Only descriptive norms (adjusted incidence rate ratio aIRR 1.19, 95% confidence interval CI 1.06, 1.33) were associated with more frequent use, but not problematic use. Descriptive norms interacted with cannabis use orientation descriptive norms were positively associated with cannabis use days among medicinally oriented users (aIRR 1.22, 95% CI 1.02, 1.46). However, this relationship was stronger for recreationally oriented users (aIRR 1.62, 95% CI 1.31, 2.01). No interactions were found predicting problematic use. Descriptive cannabis use norms among ones personal network members are an important variable predicting young adults cannabis use, but not problematic use. Perceived descriptive norms may be a stronger motivator to use for recreational users than medicinal users.

Nasal accumulation and metabolism of Δ

Passive aerosol exposure to Δ

Patients recovery and non-recovery narratives after intravenous ketamine for treatment-resistant depression.

Intravenous (IV) ketamine is an effective therapy for treatment-resistant depression. A large data base is confirmatory and steadily expanding. Qualitative studies can inform best practices and suggest new research directions. As part of a clinical trial designed to identify biomarkers of ketamine response, a qualitative study was conducted to characterize experiences with receiving infusions recovering or not recovering from depression and beliefs about why ketamine worked or did not work. Adults with treatment-resistant depression received three IV ketamine infusions in a two-week period and were characterized as remitters or non-remitters via symptom reduction 24 h after the third infusion. Qualitative interviews of a subset of participants were audio recorded, transcribed verbatim, and coded using deductive and inductive methods. Themes were derived and compared across a broader construct of recovery status. Of the 21 participants, nine (43 %) were characterized as having experienced remission and 12 (57 %) non-remission. Of the 12 non-remitters, five were characterized as having experienced partial recovery based on their subjective experiences, reporting substantial benefit from ketamine infusions despite non-remission status based on scale measurements. Attributions for ketamines effects included biological and experiential mechanisms. Among non-remitters there was risk of disappointment when adding another failed treatment. A more diverse sample may have yielded different themes. Different patients had different amounts of time elapsed between ketamine infusions and qualitative interview. Qualitative methods may enhance researchers characterization of IV ketamines impact on treatment-resistant depression. While requiring confirmation, patients may benefit from a preparatory milieu that prepares them for multiple recovery pathways decouples the psychedelic experience from clinical outcomes and addresses potential risks of another failed treatment.

The therapeutic potential of psychedelics.

The development of psychedelics as medicines faces several challenges.

Use of the head-twitch response to investigate the structure-activity relationships of 4-thio-substituted 2,5-dimethoxyphenylalkylamines.

4-Thio-substituted phenylalkylamines such as 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2) and 2,5-dimethoxy-4-n-propylthiophenethylamine (2C-T-7) produce psychedelic effects in humans and have been distributed as recreational drugs. The present studies were conducted to examine the structure-activity relationships (SAR) of a series of 4-thio-substituted phenylalkylamines using the head twitch response (HTR), a 5-HT HTR dose-response studies with twelve different 4-thio-substituted phenylalkylamines were conducted in male C57BL6 J mice. To detect the HTR, head movement was recorded electronically using a magnetometer coil and then head twitches were identified in the recordings using a validated method based on artificial intelligence. 2C-T, the parent compound of this series, had relatively low potency in the HTR paradigm, but adding an α-methyl group increased potency fivefold. Potency was also increased when the 4-methylthio group was extended by one to three methylene units. Fluorination of the 4-position alkylthio chain, however, was detrimental for activity, as was the presence of a 4-allylthio substituent versus a propylthio group. 2C-T analogs containing a 4-benzylthio group showed little or no effect in the HTR paradigm, which is consistent with evidence that bulky 4-substituents can dampen agonist efficacy at the 5-HT In general, there were close parallels between the HTR data and the known SAR governing activity of phenylalkylamines at the 5-HT

Psychedelic Drug Legislative Reform and Legalization in the US.

Psychedelic drugs are becoming accessible in the US through a patchwork of state legislative reforms. This shift necessitates consensus on treatment models, education and guidance for health care professionals, and planning for implementation and regulation. To assess trends in psychedelics legislative reform and legalization in the US to provide guidance to health care professionals, policy makers, and the public. Data were compiled from legislative databases (BillTrack50, LexisNexis, and Ballotpedia) from January 1, 2019, to September 28, 2022. Legislation was identified by searching for terms related to psychedelics (eg, psilocybin, MDMA, peyote, mescaline, ibogaine, LSD, ayahuasca, and DMT). Bills were coded by an attorney along 2 axes which psychedelic drugs would be affected and in what ways (eg, decriminalization, funding for medical research, and right to try). To explore drivers and rates of legislative reform, data were compared with other state indices including 2020 presidential voting margins and marijuana legislative reform. Twenty-five states have considered 74 bills (69 legislative initiatives, 5 ballot measures) 10 bills were enacted, and 32 were still active. The number of psychedelic reform bills introduced during each calendar year increased steadily from 5 in 2019 to 6 in 2020, 27 in 2021, and 36 in 2022. Nearly all bills specified psilocybin (67 90%), and many also included MDMA (3,4-methylenedioxy-methamphetamine 27 36%). While bills varied in their framework, most (43 58%) proposed decriminalization, of which few delineated medical oversight (10 of 43 23%) or training andor licensure requirements (15 of 43 35%). In general, bills contained less regulatory guidance than the enacted Oregon Measure 109. While early legislative efforts occurred in liberal states, the margin between liberal and conservative states has decreased over time (although the difference was not significant), suggesting that psychedelic drug reform is becoming a bipartisan issue. In addition, an analytic model based on marijuana legalization projected that a majority of states will legalize psychedelics by 2034 to 2037. Legislative reform for psychedelic drugs has been proceeding in a rapid, patchwork fashion in the US. Further consideration should be given to key health care issues such as establishing (1) standards for drugs procured outside the medical establishment, (2) licensure criteria for prescribers and therapists, (3) clinical and billing infrastructure, (4) potential contraindications, and (5) use in special populations like youths, older adults, and pregnant individuals.

Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes.

Anxiety is a troublesome symptom for many patients, especially those suffering from schizophrenia. Its regulation involves serotonin receptors, targeted e.g. by antipsychotics or psychedelics such as LSD. 5-HT

Rapid antidepressant-like effect of non-hallucinogenic psychedelic analog lisuride, but not hallucinogenic psychedelic DOI, in lipopolysaccharide-treated mice.

Classical psychedelics with 5-hydroxytryptamine-2A receptor (5-HT

Effects of ketamine optical isomers, fluoxetine and naloxone on timing in differential reinforcement of low-rate response (DRL) 72-s task in rats.

(S)-ketamine-induced rapid-acting antidepressant effects have revolutionized the pharmacotherapy of major depression however, this medication also produces psychotomimetic effects such as timing distortion. While (R)-ketamine produces fewer dissociative effects, its antidepressant actions are less studied. Depression is associated with time overestimation (i.e., subjectively, time passes slowly). Our recent report suggests that while (S)-ketamine induces an opposite effect, i.e., time underestimation, the (R)-isomer does not affect timing. It has been suggested that opioid receptors are involved in the antidepressant effect of ketamine. In the present study we tested (R)- and (S)-ketamine, and fluoxetine as a positive control in the differential-reinforcement-of-low-rate (DRL) 72-s schedule of reinforcement in male rats following naloxone pretreatment. DRL classic metrics as well as peak deviation analyses served to determine antidepressant-like actions and those associated with timing. We report antidepressant-like effects of (S)-ketamine (30-60 mgkg) that resemble fluoxetines (2.5-10 mgkg), as both compounds increased reinforcement rate and peak location (suggesting increased performance), reduced premature responses (suggesting time underestimation) and decreased Webers fraction (suggesting increased timing precision). (R)-ketamine (30, but not 60 mgkg) increased only the reinforcement rate and peak location but did not affect timing. Only fluoxetine decreased burst responses, suggesting decreased impulsivity. Naloxone pretreatment did not block ketamine enantiomers actions, but unexpectedly, increased fluoxetine performance. Thus, while all three medications produced antidepressant-like effects in DRL 72-s, fluoxetine- and (S)- but not (R)- ketamine-induced time underestimation (the subject experiences the time as passing quickly). The potentiation of DRL performance of fluoxetine by naloxone was unexpected and warrants clinical studies.

Oxygen and the Spark of Human Brain Evolution Complex Interactions of Metabolism and Cortical Expansion across Development and Evolution.

Scientific theories on the functioning and dysfunction of the human brain require an understanding of its development-before and after birth and through maturation to adulthood-and its evolution. Here we bring together several accounts of human brain evolution by focusing on the central role of oxygen and brain metabolism. We argue that evolutionary expansion of human transmodal association cortices exceeded the capacity of oxygen delivery by the vascular system, which led these brain tissues to rely on nonoxidative glycolysis for additional energy supply. We draw a link between the resulting lower oxygen tension and its effect on cytoarchitecture, which we posit as a key driver of genetic developmental programs for the human brain-favoring lower intracortical myelination and the presence of biosynthetic materials for synapse turnover. Across biological and temporal scales, this protracted capacity for neural plasticity sets the conditions for cognitive flexibility and ongoing learning, supporting complex group dynamics and intergenerational learning that in turn enabled improved nutrition to fuel the metabolic costs of further cortical expansion. Our proposed model delineates explicit mechanistic links among metabolism, molecular and cellular brain heterogeneity, and behavior, which may lead toward a clearer understanding of brain development and its disorders.

Journeying to Ixtlan Ethics of Psychedelic Medicine and Research for Alzheimers Disease and Related Dementias.

In this paper, we examine the case of psychedelic medicine for Alzheimers disease and related dementias (ADADRD). These mind-altering drugs are not currently offered as treatments to persons with ADADRD, though there is growing interest in their use to treat underlying causes and associated psychiatric symptoms. We present a research agenda for examining the ethics of psychedelic medicine and research involving persons living with ADADRD, and offer preliminary analyses of six ethical issues the impact of psychedelics on autonomy and consent the impact of ego dissolution on persons experiencing a pathology of self how psychedelics might impact caregiving the potential exploitation of patient desperation institutional review boards orientation to psychedelic research and methods to mitigate inequity. These ethical issues are magnified for ADADRD but bear broader relevance to psychedelic medicine and research in other clinical populations.

The Next Day Effects of Cannabis Use A Systematic Review.

Psychedelics and fNIRS neuroimaging exploring new opportunities.

In this Outlook paper, we explain to the optical neuroimaging community as well as the psychedelic research community the great potential of using optical neuroimaging with functional near-infrared spectroscopy (fNIRS) to further explore the changes in brain activity induced by psychedelics. We explain why we believe now is the time to exploit the momentum of the current resurgence of research on the effects of psychedelics and the momentum of the increasing progress and popularity of the fNIRS technique to establish fNIRS in psychedelic research. With this article, we hope to contribute to this development.

Role of cyclin-dependent kinase 5 in psychosis and the modulatory effects of cannabinoids.

Cyclin-dependent kinase 5 (CDK5) is a serinethreonine kinase that has emerged as a key regulator of neurotransmission in complex cognitive processes. Its expression is altered in treated schizophrenia patients, and cannabinoids modulate CDK5 levels in the brain of rodents. However, the role of this kinase, and its interaction with cannabis use in first-episode psychosis (FEP) patients is still not known. Hence, we studied the expression changes of CDK5 and its signaling partner, postsynaptic density protein 95 (PSD95) in olfactory neuroepithelial (ON) cells of FEP patients with (FEPc) and without (FEPnc) prior cannabis use, and in a dual-hit mouse model of psychosis. In this model, adolescent mice were exposed to the cannabinoid receptor 1 agonist (CB1R) WIN-55,212-2 (WIN 1 mgkg) during 21 days, and to the N-methyl-d-aspartate receptor (NMDAR) blocker phencyclidine (PCP 10 mgkg) during 10 days. FEPc showed less social functioning deficits, lower CDK5 and higher PSD95 levels than FEPnc. These changes correlated with social skills, but not cognitive deficits. Consistently, exposure of ON cells from FEPnc patients to WIN in vitro reduced CDK5 levels. Convergent results were obtained in mice, where PCP by itself induced more sociability deficits, and PSD95CDK5 alterations in the prefrontal cortex and hippocampus than exposure to PCP-WIN. In addition, central blockade of CDK5 activity with roscovitine in PCP-treated mice restored both sociability impairments and PSD95 levels. We provide translational evidence that increased CDK5 could be an early indicator of psychosis associated with social deficits, and that this biomarker is modulated by prior cannabis use.

Exploring Potential Bellwethers for Drug-Related Mortality in the General Population A Case for Sentinel Surveillance of Trends in Drug Use among NightclubFestival Attendees.

Psilocybin mitigates the cognitive deficits observed in a rat model of Fragile X syndrome.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID) and the leading monogenic cause of autism spectrum disorder (ASD). Serotonergic neurotransmission has a key role in the modulation of neuronal activity during development, and therefore, it has been hypothesized to be involved in ASD and co-occurring conditions including FXS. As serotonin is involved in synaptic remodeling and maturation, serotonergic insufficiency during childhood may have a compounding effect on brain patterning in neurodevelopmental disorders, manifesting as behavioral and emotional symptoms. Thus, compounds that stimulate serotonergic signaling such as psilocybin may offer promise as effective early interventions for developmental disorders such as ASD and FXS. The aim of the present study was to test whether different protocols of psilocybin administration mitigate cognitive deficits displayed by the recently validated Fmr1- Our results revealed that systemic and oral administration of psilocybin microdoses normalizes the aberrant cognitive performance displayed by adolescent Fmr1- These data support the hypothesis that serotonin-modulating drugs such as psilocybin may be useful to ameliorate ASD-related cognitive deficits. Overall, this study provides evidence of the beneficial effects of different schedules of psilocybin treatment in mitigating the short-term cognitive deficit observed in a rat model of FXS.

Music programming for psilocybin-assisted therapy Guided Imagery and Music-informed perspectives.

The psychedelic drug psilocybin has been successfully explored as a novel treatment for a range of psychiatric disorders. Administration of psilocybin requires careful attention to psychological support and the setting in which the drug is administered. The use of music to support the acute psychoactive effects of psilocybin is recommended in current guidelines, but descriptions of how to compile music programs for the 4-6 h long sessions are still scarce. This article describes the procedural steps and considerations behind the curation of a new music program, the Copenhagen Music Program, tailored to the intensity profile of a mediumhigh dose psilocybin. The method of Guided Imagery and Music is presented as a music therapeutic framework for choosing and sequencing music in music programming and the Taxonomi of Therapeutic Music is presented as a rating tool to evaluate the music-psychological intensity of music pieces. Practical examples of how to organize the process of music programming are provided along with a full description of the Copenhagen Music Program and its structure. The aim of the article is to inspire others in their endeavours to create music programs for psychedelic interventions, while proposing that an informed music choice may support the therapeutic dynamics during acute effects of psilocybin.

Classic psychedelics, health behavior, and physical health.

Preliminary evidence suggests that classic psychedelics may be effective in the treatment of some psychiatric disorders, yet little remains known about their effects on health behavior and physical health. The purpose of this study was to investigate associations of lifetime classic psychedelic use and psychological insight during ones most insightful classic psychedelic experience with health behavior and physical health. Using data representative of the US population with regard to sex, age, and ethnicity ( Lifetime classic psychedelic use was associated with more healthy tobacco-related and diet-related behavior ( Although these results cannot demonstrate causality, they suggest that psychological insight during a classic psychedelic experience may lead to positive health behavior change and better physical health in some domains, in particular in those related to weight management.

The Efficacy of Psychedelic-Assisted Therapy in Managing Post-traumatic Stress Disorder (PTSD) A New Frontier

Post-traumatic stress disorder (PTSD) is a significant public health concern for which existing therapies are only marginally effective. Indisputably, the primary line of treatment for PTSD is psychotherapy, according to current treatment guidelines. However, PTSD continues to be a chronic condition even after psychotherapy, with high psychiatric and medical illness rates. There is a dire need to search for new compounds and approaches for managing PTSD. The usage of psychedelic substances is a potential new method. This article reviews the efficacy of psychedelic-assisted therapy in treating PTSD and improving patient outcomes. It will examine current research on the topic and evaluate the benefits and drawbacks of different therapies. The current evidence for the use of four different types of psychedelics (3,4-methylenedioxymethamphetamine, ketamine, classical psychedelics, and cannabis) in the treatment of PTSD will be reviewed. It will also include an overview of the therapeutic justification, context of use, and level of evidence available for each drug. Several questions are formulated that could be studied in future research in order to gain a better understanding of the topic.

Genetic support of a causal relationship between cannabis use and educational attainment a two-sample Mendelian randomization study of European ancestry.

Excessive cannabis use may lead to lower educational attainment. However, this association may be due to confounders and reverse causality. We tested the potential causal relationship between cannabis use disorder (CUD) or life-time cannabis use (LCU) and educational attainment. Bidirectional two-sample Mendelian randomization (MR) study was conducted. Our primary method was inverse-variance weighted (IVW) MR, with a series of sensitivity analyses. Multivariable MR (MVMR) was performed to estimate any direct effect independent of intelligence, smoking initiation or attention deficit hyperactivity disorder (ADHD). European ancestry individuals. The sample sizes of the genome-wide association study ranged from 55 374 to 632 802 participants. Genetic variants of CUD, LCU or educational attainment. Using univariable MR, we found evidence of a potential causal effect of genetic liability to CUD on a lower educational attainment MR, 95% confidence interval (CI) Genetic liability to cannabis use disorder may lead to lower educational attainment. Genetic liability to higher educational attainment may also lead to higher life-time cannabis use risk and lower cannabis use disorder risk. However, the bidirectional effect between cannabis use disorder and educational attainment may be due to shared risk factors (e.g. attention-deficit hyperactivity disorder).

The future of hallucination research Can hallucinogens and psychedelic drugs teach us anything

Hallucinations are one of the most interesting and least understood of all human experiences. This commentary addresses the ideas which most influenced my thinking in the past 20 years and what I believe to be the most currently promising area of enquiry. Interest in hallucinations reaches far back into antiquity and across cultures. The similarity of hallucinations in mental illness with the perceptual experiences reported by individuals who not mentally unwell has long been recognized. Early scientific research on hallucinogen drugs such as lysergic acid diethylamide (LSD) was criticized and then withdrawn, but its recent revival offers new opportunities to examine the mechanism and process of hallucinating. Many psychedelic compounds can elicit intense and realistic hallucinations. The study of hallucinogens conducted in carefully controlled and supervised settings and with individuals who are not mentally unwell opens exciting new possibilities. For example, it may be possible to study the temporal shifts in perceptual awareness, decode what influences the contents, affect, meaning, and appraisals of hallucinations and guide novel psychotherapy techniques and drug therapy.

Validation of analytical method of cannabinoids Novel approach using turbo-extraction.

The development of simple, efficient, and low-cost analytical methods is essential for the evaluation and monitoring of the main cannabinoids in Cannabis-based products. In this sense, the objectives of this study were to develop and validate an analytical method for obtaining and determining cannabinoids in a pool sample. Two extraction techniques were used, ultrasound and turbo-extraction, and two system-solvents, methanolchloroform (91 vv) and ethanol. The analytical method used and validated was carried out in High Performance Liquid Chromatography with Diodes Array Detector. The cannabidiol standard was characterized by a nuclear magnetic resonance. The use of the proposed method makes it possible to identify cannabinoids, both in the acid form and in the neutral form, in 7 min of analysis. The results confirmed high precision and accuracy. The detection and quantification limits were 0.19 μgmL and 5 μgmL, respectively. The method developed proved to be selective and robust for the evaluation of cannabinoids. It is hoped that the methods developed can be used to obtain and analyze cannabinoids, both for medicinal purposes and for forensic analysis.

Assessing the prevalence and risk factors of marijuana use in adults with disabilities.

Public support for the legalization of marijuana (cannabis) for medical or recreational use by adults has grown rapidly over the past two decades. Given the growing prevalence and concerns about potential harms, a better understanding is needed of disparities in marijuana use among adults by disability status. Using 2015-2019 data from the National Survey on Drug Use and Health (NSDUH), we obtained a national sample of 195,130 working-age (18-64 year) adults. Descriptive and multivariable analyses were conducted to assess the prevalence and risk factors associated with marijuana use among adults by disability status and type. We found the prevalence of marijuana use was higher among adults with disabilities (16.6% vs 10.9%) compared to those without disabilities, and this disparity widened from 2015 to 2019. Furthermore, the odds of marijuana use varied by disability type. Specifically, adults with vision disability only (OR 1.28 95% CI 1.14-1.44), cognitive disability only (OR 1.24 95% CI 1.13-1.35), and those with multiple disabilities (OR 1.22 95% CI 1.11-1.34) had higher odds of marijuana use compared to adults without any disability. Adults with disabilities have a higher prevalence of marijuana use compared to those without disabilities. Living in a state with legalized medical marijuana also increased the odds of marijuana use. These findings can help to inform policy and public health surveillance of marijuana use in the U.S. Further studies are needed to monitor the rising prevalence of marijuana use and examine how intensity of marijuana use affects health outcomes in adults with and without disabilities.

Matrix-assisted laser-desorptionionization-mass spectrometric imaging of psilocybin and its analogues in psychedelic mushrooms using a cesium chloride-coated target plate.

Fungi with hallucinogenic properties and neurotoxicity have been listed as prohibited drugs in recent years, but there is a lack of in situ quantification of psilocybin and analogues in these samples to avoid the decomposition of these psychoactive tryptamines in time-consuming sample preparation. In this study, matrix-assisted laser-desorptionionization (MALDI)-Fourier transform ion cyclotron resonance (FT ICR) mass spectrometric imaging (MSI) was used to analyze the distribution of psilocybin and its analogues in hallucinogenic Psilocybe mushrooms. A cesium chloride (CsCl)-coated target plate was prepared to improve the detection sensitivity and reduce the interference of other compounds or decomposition products with very similar mz values in MALDI-FT ICR MS analysis. Psilocybin and other tryptamines with structurally similar compounds, including psilocin, baeocystin, tryptophan, tryptamine, and aeruginascin, were identified and imaged in the psilocybe tissue section the semiquantitative analysis of the distribution of psilocybin was also investigated using a homemade 75-well CsCl-coated plate and the target plate can be placed on the mass spectrometry target carrier along with the indium-tin oxide (ITO) conductive slide, which can simultaneously carry out matrix vapor deposition, thus ensuring the parallelism between the standards and samples in the pretreatment experiment and MSI. The contents of psilocybin and its analogues in the psilocybe tissue section can be evaluated from the color changes corresponding to different concentration standard curves. Furthermore, a comprehensive comparison between MALDI-FT ICR MS and ultra-performance liquid chromatography-quadrupole time of flight mass spectrometry (UPLC-QTOF MS) analysis was performed for quantification and validation. This study reduces the decomposition in time-consuming sample pretreatment and provides a powerful tool for drug abuse control and forensic analysis.

The β-carboline Harmine improves the therapeutic benefit of anti-PD1 in melanoma by increasing the MHC-I-dependent antigen presentation.

Harmine is a dual-specificity tyrosine-regulated kinase 1A (DYRK1A) inhibitor that displays a number of biological and pharmacological properties. Also referred to as ACB1801 molecule, we have previously reported that harmine increases the presentation of major histocompatibility complex (MHC)-I-dependent antigen on melanoma cells. Here, we show that ACB1801 upregulates the mRNA expression of several proteins of the MHC-I such as Transporter Associated with antigen Processing TAP1 and 2, Tapasin and Lmp2 (hereafter referred to as MHC-I signature) in melanoma cells. Treatment of mice bearing melanoma B16-F10 with ACB1801 inhibits the growth and weight of tumors and induces a profound modification of the tumor immune landscape. Strikingly, combining ACB1801 with anti-PD1 significantly improves its therapeutic benefit in B16-F10 melanoma-bearing mice. These results suggest that, by increasing the MHC-I, ACB1801 can be combined with anti-PD1PD-L1 therapy to improve the survival benefit in cancer patients displaying a defect in MHC-I expression. This is further supported by data showing that

Sexualized drug use among men who have sex with men in Madrid and Barcelona The gateway to new drug use

This original study compares the prevalences of drug use for any purpose and for sexualized drug use (SDU) among MSM. It also describes relevant characteristics of first SDU, analyzes to what extent SDU has been the first experience (the gateway) with different drugs by age and explores the correlates of SDU. Study participants included 2,919 HIV-negative MSM attending four HIVSTI diagnosis services in Madrid and Barcelona. They answered an online, self-administered questionnaire. Poisson regression models with robust variance were used. About 81.4% had ever used any drug, and 71.9% had done so in the last-12-months, while 56% had ever engaged in SDU, and 50% had done so in the last-12-months. Participants under 25 years old had the lowest prevalences of SDU, and the 25-39 age group the highest, except for Viagra, which was higher among those over age 40. The most frequently used drugs for first SDU were poppers (53.6%), cannabis (19.6%) and Viagra (12.2%). These drugs were also the most ever consumed for SDU. Among sexualized users, methamphetamine (78.3%) and Mephedrone (75.4%) were used alwaysmost of the times for sex in the last-12-months. Around 72.2% of Mephedrone sexualized users and 69.6% of Methamphetamine vs 23.1% of ecstasy users first consumption of these drugs involved use for sex. These drugs were provided to them free where they have sex for 66.8, 79.1, and 31.9%, respectively. On that occasion, 8.1% of Mephedrone, 6.8% of Methamphetamine and 18.4% of ecstasy users had sex only with steady partner with 50.2, 56.2, and 26.2% respectively using a condom with any partner. SDU in the first use was associated with similar variables for recreational and chemsex drugs. The highest prevalence ratios were for having ever been penetrated by >20 men and having ever injected drugs. It can be concluded that the prevalence of SDU was more than half of the prevalence for any purpose. Thus SDU was the gateway to use for many drugs in an important proportion of users, who frequently consumed drugs that were free and had condomless anal sex with occasional and multiple partners. These circumstances were much more common for chemsex than for recreational drugs.

Stable isotope characterisation of 3,4-methylenedioxyphenyl-2-propanone and 3,4-methylenedioxyamphetamine prepared from piperonal.

Stable isotopic ratios can provide information for illicit drug profiling. The research presented here investigated the variations in stable isotopic ratios of hydrogen (δ Samples of MDA and MDP2P were synthesised from two isotopically characterised starting materials, piperonal and nitroethane. The isotopic compositions of the nitrostyrene intermediate (3,4-methylenedioxyphenyl-2-nitropropene, MDP2NP) and products MDP2P and MDA were also measured by isotope ratio mass spectrometry. A significantly negative change occurred to δ The changes to stable isotopic ratios observed during the preparation of MDA and MDP2P from piperonal may prove useful when attempting to compare batch-to-batch variations between seizures and provide information with tactical intelligence applications.

Underground ibogaine use for the treatment of substance use disorders A qualitative analysis of subjective experiences.

Ibogaine is one of the alkaloids naturally found in plants such as Tabernanthe iboga, which has been traditionally used by members of the Bwiti culture. Since the discovery of its anti-addictive properties by Howard S. Lotsof in 1962, ibogaine has been used experimentally to treat substance use disorders (SUD), especially those involving opioids. We aim to provide a detailed understanding of the underlying psychological aspects of underground ibogaine use for the treatment of SUD. Semi-structured interviews were carried out with 13 participants with SUD, which motivated their self-treatment with ibogaine. The data were analysed using the grounded theory approach and considered the context of the treatment, and the nature of the occurring hallucinogenic and cognitive phenomena during the treatment experience. We identified several psychological effects that the study respondents experienced, which seem to play a substantial role in the therapeutic process concerning SUD. The evoking of interpersonal and transpersonal experiences, autobiographical memories, and preparation, integration and motivation for a lifestyle change are important components that participants reported during and after ibogaine intake. Ibogaine is increasingly being used for the treatment of SUD, due in part to the limited treatment options currently available. Its beneficial effects seem to be related not only to its complex pharmacology but also to the subjective experience that ibogaine induces. The main aspects of this experience are related to autobiographical memories and valuable personal insights, which together appear to help individuals cope with their SUD.

Considerations in assessing the abuse potential of psychedelics during drug development.

The recent increase in clinical research on the potential therapeutic uses of classic psychedelics has prompted the need to revisit the assessment of the abuse potential of these drugs. The term classic psychedelic is used in this manuscript to describe serotonergic 5-HT

Thin-layer chromatography on silver nitrate-impregnated silica gel for analysis of homemade tetrahydrocannabinol mixtures.

Various forms of cannabidiol (CBD)-containing products are sold in Japan. CBD is easily converted to mixtures of ∆ To evaluate potential separation ability, standards of five THC isomers (∆ System A showed clear separation between the five THC isomers and between ∆ AgNO

High-sensitivity method for the determination of LSD and 2-oxo-3-hydroxy-LSD in oral fluid by liquid chromatography‒tandem mass spectrometry.

We have developed and validated a high-sensitivity method to quantify lysergic acid diethylamide (LSD) and 2-oxo-3-hydroxy-LSD (OH-LSD) in oral fluid samples using liquid-liquid extraction and liquid chromatography-tandem mass spectrometry (LC‒MSMS). The method was applied to the quantification of both substances in 42 authentic oral fluid samples. A liquid-liquid extraction was performed using 500 µL each of samples (oral fluid samples collected using Quantisal™ device) and dichloromethaneisopropanol mixture (11, vv). Enzymatic hydrolysis was evaluated to cleave glucuronide metabolites. The limit of quantification was 0.01 ngmL for both LSD and OH-LSD. The linearity was assessed between 0.01 and 5 ngmL. Imprecision and bias were not higher than 10.2% for both analytes. Extraction recovery was higher than 69%. The analytes were stable in the autosampler at 10 °C for 24 h, and up to 30 days at 4 and -20 °C. The method was applied to the analysis of 42 oral fluid samples. LSD was detected in all samples (concentrations between 0.02 and 175 ngmL), and OH-LSD was detected in 20 samples (concentrations between 0.01 and 1.53 ngmL). A high-sensitive method was fully validated and applied to authentic samples. To our knowledge, this is the first work to report concentrations of LSD and OH-LSD in authentic oral fluid samples.

Cannabinoid Poisoning-Related Emergency Department Visits and Inpatient Hospitalizations in Kentucky, 2017 to 2019.

Self-transcendent experiences as promoters of ecological wellbeing Exploration of the evidence and hypotheses to be tested.

In recent years, much has been written on the role of different mental states and their potential to influence our way of thinking and, perhaps more importantly, the way we act. With the recent acceleration of environmental and mental health issues, alongside the limited effectiveness of existing interventions, an exploration of new approaches to deliver transformative change is required. We therefore explore the emerging potential of a type of mental state known as self-transcendent experiences (STEs) as a driver of ecological wellbeing. We focus on four types of STEs those facilitated by experiences of flow, awe, and mindfulness, as well as by psychedelic-induced experiences. Some of these experiences can occur naturally, through sometimes unexpected encounters with nature or during immersion in every-day activities that one intrinsically enjoys, as well as through more intentional practices such as meditation or the administration of psychedelics in controlled, legal settings. We explore the evidence base linking each of the four types of STE to ecological wellbeing before proposing potential hypotheses to be tested to understand why STEs can have such beneficial effects. We end by looking at the factors that might need to be considered if STEs are going to be practically implemented as a means of achieving ecological wellbeing.

Analgesic potential of macrodoses and microdoses of classical psychedelics in chronic pain sufferers a population survey.

Although several studies and reports have shown the potential analgesic use of serotonergic psychedelics in cancer pain, phantom limb pain and cluster headache, evidence supporting their use for chronic pain is still limited. The past years have seen a considerable renewal of interest toward the therapeutic use of these compounds for mood disorders, resulting in a marked increase in the number of people turning to psychedelics in an attempt to self-medicate a health condition or improve their wellbeing. In western countries particularly, this population of users overlaps substantially with chronic pain sufferers, representing a unique opportunity to evaluate the effects these compounds have on pain and wellbeing. Here, we report results from an online survey conducted between August 2020 and July 2021 in a population of 250 chronic pain sufferers who had experience with psychedelics, either in microdoses (small sub-hallucinogenic doses), macrodoses (hallucinogenic doses), or both. Macrodoses, while less often used for analgesic purposes than microdoses, were reported to induce a higher level of pain relief than both microdoses and conventional pain medications (including opioids and cannabis). Although the effects were weaker and potentially more prone to expectation bias than with macrodoses, our results also suggested some benefits of psychedelics in microdoses for pain management. The reported analgesic effect appeared unrelated to mood improvements associated with psychedelic use, or the advocacy of psychedelic use. Taken together, our findings indicate interesting potential analgesic applications for psychedelics that warrant further clinical research.

Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use Disorder A Review.

Novel treatments for opioid use disorder (OUD) are needed to address both the ongoing opioid epidemic and long-standing barriers to existing OUD treatments that target the endogenous μ-opioid receptor (MOR) system. The goal of this review is to highlight unique clinical trial design considerations for the study of emerging treatments for OUD that address targets beyond the MOR system. In November 2019, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration sponsored a meeting to discuss the current evidence regarding potential treatments for OUD, including cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics, such as vaccines. Consensus recommendations are presented regarding the most critical elements of trial design for the evaluation of novel OUD treatments, such as (1) stage of treatment that will be targeted (eg, seeking treatment, early abstinencedetoxification, long-term recovery) (2) role of treatment (adjunctive with or independent of existing OUD treatments) (3) primary outcomes informed by patient preferences that assess opioid use (including changes in patterns of use), treatment retention, andor global functioning and quality of life and (4) adverse events, including the potential for opioid-related relapse or overdose, especially if the patient is not simultaneously taking maintenance MOR agonist or antagonist medications. Applying the recommendations provided here as well as considering input from people with lived experience in the design phase will accelerate the development, translation, and uptake of effective and safe therapeutics for individuals struggling with OUD.

Smoking Behaviors and Prognosis in Patients With Non-Muscle-Invasive Bladder Cancer in the Be-Well Study.

Tobacco smoking is an established risk factor associated with bladder cancer, yet its impact on bladder cancer prognosis is unclear. To examine associations of use of tobacco (cigarettes, pipes, and cigars), e-cigarettes, and marijuana with risk of recurrence and progression of non-muscle-invasive bladder cancer (NMIBC) and to explore use of smoking cessation interventions. The Be-Well Study is a prospective cohort study of patients with NMIBC diagnosed from 2015 to 2019 and followed-up for 26.4 months in the Kaiser Permanente Northern and Southern California integrated health care system. Eligibility criteria were age at least 21 years, first NMIBC diagnosis (stages Ta, Tis, or T1), alive, and not in hospice care. Exclusion criteria were previous diagnosis of bladder cancer or other cancer diagnoses within 1 year prior to or concurrent with NMIBC diagnosis. Data were analyzed from April 1 to October 4, 2022. Use of cigarettes, pipes, cigars, e-cigarettes, and marijuana was reported in the baseline interview. Use of smoking cessation interventions (counseling and medications) was derived from electronic health records. Hazard ratios (HRs) and 95% CIs of recurrence and progression of bladder cancer were estimated by multivariable Cox proportional hazards regression. A total of 1472 patients (mean SD age at diagnosis, 70.2 10.8% years 1129 76.7% male patients) with NMIBC were enrolled at a mean (SD) of 2.3 (1.3) months after diagnosis, including 874 patients (59.4%) who were former smokers and 111 patients (7.5%) who were current cigarette smokers 67 patients (13.7%) smoked pipes andor cigars only, 65 patients (4.4%) used e-cigarettes, 363 patients (24.7%) used marijuana. Longer cigarette smoking duration and more pack-years were associated with higher risk of recurrence in a dose-dependent manner, with the highest risks for patients who had smoked for 40 or more years (HR, 2.36 95% CI, 1.43-3.91) or 40 or more pack-years (HR, 1.97 95% CI, 1.32-2.95). There was no association of having ever smoked, being a former or current cigarette smoker, and years since quit smoking with recurrence risk. No associations with pipes, cigars, e-cigarettes, or marijuana were found. Of 102 patients offered a smoking cessation intervention, 57 (53.8%) received an interventions after diagnosis, with female patients more likely than male patients to engage in such interventions (23 of 30 female patients 76.7% vs 34 of 76 male patients 44.7% P .003). These findings suggest that longer duration and more pack-years of cigarette smoking were associated with higher risk of NMIBC recurrence. Cigarette smoking remains a critical exposure before and after diagnosis in survivors of NMIBC.

Maternal and Fetal Exposure to (-)-Δ

(-)-Δ

Trends in cannabis use intention around the period of cannabis legalisation in Australia An age-period-cohort model.

This study examines age, time period and birth cohort trends in cannabis use intention and weekly use in Australia over a period in which medicinal cannabis was legalised. Hierarchical age-period-cohort models were used to analyse the National Drug Strategy Household Survey between 2001 and 2019, including 158,395 participants aged 18-79 years. The hierarchical age-period-cohort model demonstrated a decrease in likelihood of intending to try cannabis as age increases. Similar age effects were found in intending to use cannabis as often or less often. There was broad-based shift in attitudes for people wanting to try cannabis (2007 b -0.51 -0.82, -0.21 2019 b 0.68 0.38, 0.98) or use cannabis more often (2007 b -0.15 -0.50, 0.20 2019 b 0.83 0.49, 1.18). The population trend of weekly cannabis use decreased in the earlier periods but increased since 2013 (b -0.13 -0.25, -0.02 vs 2019 b 0.06 -0.09, 0.20). This suggests that legalisation would increase uptake of cannabis and consumption among current consumers. There were distinctive inter-generation variations people born between 1950s and 1960s had more liberal views towards cannabis use than people born before or after (p < 0.05). There were indications that young people born in the 1990 s are catching up with the baby boomers in using cannabis more often if it was legal. There has been a population-based shift in Australia in favourable attitudes towards cannabis use, more so among those born in the 1950s to 1960s than other generations. Liberal attitudes and more frequent cannabis use may put certain cohorts at higher risks of cannabis dependence and related harms.

Geographic Accessibility of Retail Cannabis in Northern California and Prenatal Cannabis Use During the COVID-19 Pandemic.

Prenatal cannabis use is associated with health risks for mothers and their children. Prior research suggests that rates of prenatal cannabis use in Northern California increased during the COVID-19 pandemic, but it is unknown whether increases varied with the local cannabis retail and policy environment. To test whether pandemic-related increases in prenatal cannabis use were greater among pregnant individuals with greater retail availability of cannabis around their homes or among those living in jurisdictions that allowed storefront retailers. A cross-sectional, population-based time series study used data from pregnancies in the Kaiser Permanente Northern California health care system screened for cannabis use before (January 1, 2019, to March 31, 2020) and during (April 1 to December 31, 2020) the early COVID-19 pandemic. Proximity to the nearest retailer and number of retailers within a 15-minute drive from ones home and local cannabis storefront retailer policy (banned vs permitted) were calculated. Interrupted time series models were fit using multiplicative and additive Poisson regression, adjusting for age and race and ethnicity. The COVID-19 pandemic. Prenatal cannabis use based on universal urine toxicology tests conducted during early pregnancy at entrance to prenatal care. The sample (n 99 127 pregnancies) included 26.2% Asian or Pacific Islander, 6.8% Black, 27.6% Hispanic, 34.4% non-Hispanic White, and 4.9% other, unknown, or multiracial individuals, with a mean (SD) age of 30.8 (5.3) years. Prenatal cannabis use before (6.8%) and during (8.2%) the pandemic was associated with closer proximity to a retailer, greater retailer density, and residing in a jurisdiction that permitted vs banned retailers. There was a greater absolute increase in cannabis use from before to during the pandemic among those within a 10-minute drive (<10 minutes adjusted rate difference aRD, 0.93 cases100 patients 95% CI, 0.56-1.29 cases100 patients ≥10 minutes aRD, 0.40 cases100 patients 95% CI, 0.12-0.68 cases100 patients interaction P .02). Otherwise, relative and absolute rates increased similarly across categories of cannabis retailer proximitydensity and local policy (interaction P > .05). Prenatal cannabis use was more common among individuals living in areas with greater retail availability of cannabis. Although relative rates increased similarly during the pandemic regardless of local cannabis retail and policy environment, there was a larger absolute increase associated with living closer to a storefront cannabis retailer. Continued monitoring of local cannabis policy, the retail environment, and prenatal cannabis use is needed.

DNA Authentication and Chemical Analysis of

The mushroom genus

Cannabis use, risk behaviours and harms in Brazil A comprehensive review of available data indicators.

Cannabis use and related healthsocial outcome indicator data for Brazil-where non-medical cannabis is generally illegal-are limited. Towards a comprehensive overview of relevant indicators, we searched primary databases by combining MeSH-index terms related to cannabis, geographic location and subtopic terms (e.g., use, health, mortality) focusing on cannabis use and key outcome indicators in Brazil since 2010. In addition, relevant grey literature (e.g., survey reports) was identified. Key indicator data were mainly narratively summarised. Overall, cannabis use has increased somewhat since pre-2010, with (past-year) use rates measured at 2-3% for general population adults, yet 5% or higher among youth andor (e.g., post-secondary) student populations. For key risk behaviours, the presence of tetrahydrocannabinol-positivity among motor-vehicle drivers has been measured at <2%. While the prevalence of cannabis use disorder appears to have decreased, the relative proportion of treatment provided for cannabis-related problems increased. National- and local-based studies indicated an association of cannabis use with mental health harms, including depression and suicidality. Although some non-representative andor local studies contain information, other monitoring data, including cannabis-related risks and harms (e.g., cannabis-related driving, mortality, hospitalisations), are limited in availability. The prevalence of cannabis use in Brazil is comparably low (e.g., relative to elsewhere in the Americas). Data on numerous key cannabis-related indicators is absent, or limited in scope for Brazil. Considering ongoing evolutions in cannabis control and its status as the most common illicit drug, more comprehensive surveillance of cannabis use and related outcomes is advised.

Thalamocortical functional connectivity and cannabis use in men with childhood attention-deficithyperactivity disorder.

Disruptions of the cortico-striato-thalamo-cortical circuit has been implicated in both attention-deficithyperactivity disorder and substance use disorder. Given the high prevalence of cannabis use among patients with attention-deficithyperactivity disorder, we set out to investigate the relationship between the two in the thalamus. We analyzed resting-state functional magnetic resonance imaging data obtained from the Addiction Connectome Preprocessed Initiative Multimodal Treatment Study of Attention-DeficitHyperactivity Disorder database. Functional connectivity maps were extracted to compare thalamic connectivity among adults who had been diagnosed with attention-deficithyperactivity disorder during childhood according to whether or not they used cannabis. The study participants included 18 cannabis users and 15 cannabis non-users with childhood attention-deficithyperactivity disorder. Our results revealed that adults with attention-deficithyperactivity disorder who used cannabis (n 18) had significantly decreased functional connectivity between the thalamus and parietal regions, which was particularly prominent in the inferior parietal areas, in comparison with those who did not use cannabis (n 15). Left thalamic functional connectivity with the inferior parietal and middle frontal areas and right thalamic functional connectivity with the inferior parietal and superior frontal areas were increased in non-users of cannabis with attention-deficithyperactivity disorder compared with a local normative comparison group (n 7). In conclusion, adults with a childhood history of attention-deficithyperactivity disorder who do not use cannabis often have relatively stronger thalamoparietal and thalamofrontal connectivity, which may help reduce the risk of cannabis use.

What We Have Gained from Ibogaine α3β4 Nicotinic Acetylcholine Receptor Inhibitors as Treatments for Substance Use Disorders.

For decades, ibogaine─the main psychoactive alkaloid found in

MDMA for the treatment of misophonia, a proposal.

Misophonia is a disorder characterized by negative physical and emotional reactions to certain trigger sounds, such as chewing food. Up to 50% of population samples endorse some symptoms of misophonia, with about 20% having symptoms that impair normal life functioning. Most misophonia patients exhibit intense negative emotions and autonomic arousal (the fight-flight-freeze response) in response to a trigger, similarly to how someone with post-traumatic stress disorder (PTSD) might respond to a trauma trigger. Curiously, misophonia trigger sounds are often most distressing when coming from a specific person, suggesting the disorder may be responsive to interpersonal relationship factors. Treatment of misophonia is currently limited to the use of hearing modifications (e.g., earplugs or headphones) and psychotherapy, but many patients continue to suffer despite these best efforts. Phase 3 clinical trials suggest that MDMA is efficacious at treating the symptoms of autonomic arousal, negative emotions, and interpersonal suffering found in PTSD. As such, we propose that MDMA may represent an ideal treatment for some suffering from severe misophonia. In this perspective article, we review the symptoms of misophonia, and outline how MDMA may be uniquely suited for treating it, perhaps using a protocol analogous to the MAPS Phase 3 studies for PTSD.

Antitumorigenic Effect of Cannabidiol in Lung Cancer What Do We Know So Far–A Mini Review.

Lung cancer remains a major factor contributing to morbidity and mortality worldwide. cannabidiol (CBD) and Δ9-tetrahydrocannabinol could serve as a specific treatment for lung cancer, owing to their essential role in lung cancer cell apoptosis. This review evaluated the antitumorigenic mechanisms of CBD in lung cancer cells. We searched the databases MEDLINE, clinicaltrials.gov, Cochrane Central Register of Controlled Trials, and Google Scholar using specific terms. Of 246 studies screened, nine were included and assessed using the ToxRTool. All the selected studies were conducted in vitro, and four of which also had an in vivo content. The most common cell line used in all the studies was A549 however, some studies contained other cell lines, including H460 and H358. Our findings suggested that CBD has direct antineoplastic effects on lung cancer cells through various mechanisms mediated by cannabinoid receptors or independent of these receptors. All studies were referred to an in vitro model hence, further research in animals is required.

Liquid chromatography-tandem mass spectrometry method for the bioanalysis of N,N-dimethyltryptamine (DMT) and its metabolites DMT-N-oxide and indole-3-acetic acid in human plasma.

The indole alkaloid N,N-dimethyltryptamine (DMT) induces psychedelic effects in humans. In addition to ceremonial and recreational use, DMT is subject to clinical investigations. Sensitive bioanalytical methods are required to assess the pharmacokinetics of DMT and its metabolites in human plasma. Here, a high performance liquid chromatography-tandem mass spectrometry (LC-MSMS) method for the quantification of DMT and its major metabolites indole-3-acetic acid (IAA) and DMT-N-oxide (DMT-NO) was developed and validated. As IAA is an endogenous component of human plasma,

Alleviation of opioid withdrawal by cannabis and delta-9-tetrahydrocannabinol A systematic review of observational and experimental human studies.

While six U.S. states have already officially authorized cannabinoids to substitute opioids and treat opioid use disorder, the therapeutic benefits of cannabinoids remain unclear, especially when weighted against their adverse effects. We conducted a systematic review of studies examining the association between opioid withdrawal and cannabis use or delta-9-tetrahydrocannabinol (THC) administration. We searched multiple databases from inception to July 30, 2022, and assessed study quality. Eleven studies were identified, with a total of 5330 participants, of whom 64 % were male. Nine observational studies examined the association between cannabis use and opioid withdrawal. Two randomized, placebo-controlled clinical trials (RCTs) investigated the withdrawal-alleviating effects of dronabinol, a synthetic form of THC. Four observational studies found an association between cannabis use and the alleviation of opioid withdrawal one reported exacerbation of opioid withdrawal symptoms and four reported no association. RCTs reported that THC alleviated opioid withdrawal, albeit with dose-dependent increases in measures of abuse liability, dysphoria, and tachycardia. There was high heterogeneity in measurements of opioid withdrawal and the type and dose of opioid at baseline. Although there is preliminary evidence that cannabis and its main psychoactive constituent, THC, may alleviate opioid withdrawal, these effects are likely to have a narrow therapeutic window. Further, the potential of cannabinoids to alleviate opioid withdrawal is determined by complex interactions between patient characteristics and pharmacological factors. Collectively, these findings have clinical, methodological, and mechanistic implications for treating opioid withdrawal during cannabinoid use, and for efforts to alleviate opioid withdrawal using non-opioid therapeutics.

Changes in music-evoked emotion and ventral striatal functional connectivity after psilocybin therapy for depression.

Music listening is a staple and valued component of psychedelic therapy, and previous work has shown that psychedelics can acutely enhance music-evoked emotion. The present study sought to examine subjective responses to music before and after psilocybin therapy for treatment-resistant depression, while functional magnetic resonance imaging (fMRI) data was acquired. Nineteen patients with treatment-resistant depression received a low oral dose (10 mg) of psilocybin, and a high dose (25 mg) 1 week later. fMRI was performed 1 week prior to the first dosing session and 1 day after the second. Two scans were conducted on each day one with music and one without. Visual analogue scale ratings of music-evoked pleasure plus ratings of other evoked emotions (21-item Geneva Emotional Music Scale) were completed after each scan. Given its role in musical reward, the nucleus accumbens (NAc) was chosen as region of interest for functional connectivity (FC) analyses. Effects of drug (vs placebo) and music (vs no music) on subjective and FC outcomes were assessed. Anhedonia symptoms were assessed pre- and post-treatment (Snaith-Hamilton Pleasure Scale). Results revealed a significant increase in music-evoked emotion following treatment with psilocybin that correlated with post-treatment reductions in anhedonia. A post-treatment reduction in NAc FC with areas resembling the default mode network was observed during music listening (vs no music). These results are consistent with current thinking on the role of psychedelics in enhancing music-evoked pleasure and provide some new insight into correlative brain mechanisms.

Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 Receptors in the Head Twitch Response Induced by 5-Hydroxytryptophan and Psilocybin Translational Implications.

There is increasing interest in the therapeutic potential of psilocybin. In rodents, the serotonin precursor, 5-hydroxytryptophan (5-HTP) and psilocybin induce a characteristic 5-HT2A receptor (5-HT2AR)-mediated head twitch response (HTR), which is correlated with the human psychedelic trip. We examined the role of other serotonergic receptors and the trace amine -associated receptor 1 (TAAR1) in modulating 5-HTP- and psilocybin-induced HTR. Male C57BL6J mice (11 weeks, 30 g) were administered 5-HTP, 50-250 mgkg i.p., 200 mgkg i.p. after pretreatment with 5-HTTAAR1 receptor modulators, psilocybin 0.1-25.6 mgkg i.p. or 4.4 mgkg i.p., immediately preceded by 5-HTTAAR1 receptor modulators. HTR was assessed in a custom-built magnetometer. 5-HTP and psilocybin induced a dose-dependent increase in the frequency of HTR over 20 min with attenuation by the 5-HT2AR antagonist, M100907, and the 5-HT1AR agonist, 8-OH-DPAT. The 5-HT2CR antagonist, RS-102221, enhanced HTR at lower doses but reduced it at higher doses. The TAAR1 antagonist, EPPTB, reduced 5-HTP- but not psilocybin-induced HTR. We have confirmed the key role of 5-HT2AR in HTR, an inhibitory effect of 5-HT1AR, a bimodal contribution of 5-HT2CR and a role of TAAR1 in modulating HTR induced by 5-HTP. Compounds that modulate psychedelic-induced HTR have important potential in the emerging therapeutic use of these compounds.

Extensive Collection of Psychotropic Mushrooms with Determination of Their Tryptamine Alkaloids.

Since not only psilocybin (PSB) but also PSB-containing mushrooms are used for psychedelic therapy and microdosing, it is necessary to know their concentration variability in wild-grown mushrooms. This article aimed to determine the PSB, psilocin (PS), baeocystin (BA), norbaeocystin (NB), and aeruginascin (AE) concentrations in a large sample set of mushrooms belonging to genera previously reported to contain psychotropic tryptamines. Ultra-high performance liquid chromatography coupled with tandem mass spectrometry was used to quantify tryptamine alkaloids in the mushroom samples. Most mushroom collections were documented by fungarium specimens andor ITS rDNALSUEF1-α sequencing. Concentrations of five tryptamine alkaloids were determined in a large sample set of 226 fruiting bodies of 82 individual collections from seven mushroom genera. For many mushroom species, concentrations of BA, NB, and AE are reported for the first time. The highest PSBPS concentrations were found in