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This meta-analysis investigates the effect of classic psychedelic drugs on empathy and focuses on cognitive and emotional empathy measured using the Multifaceted Empathy Test (MET). Empathy entails the ability to understand and share the feelings of another and is a significant component of social interaction. Several studies have examined the effects of psychedelic drugs such as LSD, psilocybin and ayahuasca on empathy, yet their overall effect has not been studied so far. In this meta-analysis, we reviewed data from studies up to November 2023 with the aim of examining the effects of various psychedelic drugs on empathic abilities broadly. Our findings suggest that classical psychedelics significantly enhance explicit and implicit emotional empathy without affecting measures of cognitive empathy. The results emphasize the need to continue testing the therapeutic potential of classic psychedelic drugs. [ABSTRACT FROM AUTHOR]

Psychedelics have a complex history marked by traditional use among indigenous cultures, early scientific interest, and subsequent prohibition. Despite their classification as controlled substances, recent decades have witnessed a resurgence of research into their therapeutic potential for various mental health conditions. However, most studies have focused on controlled clinical settings, leaving a significant gap in understanding how these substances are used in naturalistic contexts, particularly in Latin America. This study investigates the regular use of macrodoses of psychedelics among Latin American adults. We aimed to characterize the sociodemographic profiles, consumption practices, and subjective effects experienced by individuals who use psychedelics regularly. Data were collected via an online survey from 4,270 participants across several Latin American countries. Results indicated a diverse user base with varied motivations, predominantly psychological and spiritual well-being. The most frequently used substance was psilocybin mushrooms, with significant associations found between demographic variables and specific psychedelics used. The study provides new insights into the naturalistic use of psychedelics in Latin America, highlighting the need for informed, safe, and legal use frameworks. [ABSTRACT FROM AUTHOR]

This document is a compilation of summaries of four different articles from various medical journals. The first article discusses the use of a two-bag N-acetylcysteine (NAC) system for acetaminophen poisoning, comparing its effectiveness and safety to the FDA-approved three-bag system. The second article examines the use of physostigmine in the treatment of anticholinergic toxicity, finding that patients treated with physostigmine alone were less likely to be intubated. The third article explores the use of dexmedetomidine in non-intubated patients, concluding that it is a safe and useful adjunct in the care of agitated toxicological patients. The fourth article compares the acute effects of mescaline, lysergic acid diethylamide (LSD), and psilocybin in a randomized, double-blind, placebo-controlled study, finding that the subjective experiences were similar at the studied doses. These articles provide valuable insights for toxicologists and poison centers in the treatment of various toxicological conditions. [Extracted from the article]

Mental health disorders and substance use disorders (SUDs) in particular, contribute greatly to the global burden of disease. Psychedelics, including entactogens and dissociative substances, are currently being explored for the treatment of SUDs, yet with less empirical clinical evidence than for other mental health disorders, such as depression or post-traumatic stress disorder (PTSD). In this narrative review, we discuss the current clinical research evidence, therapeutic potential and safety of psilocybin, lysergic acid diethylamide (LSD), ketamine, 3,4-methylenedioxymethamphetamine (MDMA) and ibogaine, particularly in the context of the SUD treatment. Our aim was to provide a balanced overview of the current research and findings on potential benefits and harms of psychedelics in clinical settings for SUD treatment. We highlight the need for more clinical research in this particular treatment area and point out some limitations and challenges to be addressed in future research. [ABSTRACT FROM AUTHOR]

With the discovery of the antidepressive effects of ketamine and the increasing withdrawal of the pharmaceutical industry from the development of new psychotropic drugs, the psychiatric research into the clinical application of hallucinogens in psychiatry has literally blossomed in the last two decades. Promising results for various treatment approaches with psychedelic agents, such lysergic acid diethylamide (LSD) and psilocybin, and dissociative agents, such as ketamine and esketamine, have raised great hopes among researchers, clinicians and patients in recent years, so that there was already talk of a new era in psychiatry. As one of the first of these substances, in December 2019 intranasal esketamine was approved in the USA and the EU for the treatment of treatment-resistant depression and Switzerland followed in 2020. Recently, psilocybin was approved in Australia, Canada and Switzerland for compassionate use in exceptional cases for the treatment of depression, while large approval studies with various psychedelic agents are currently ongoing worldwide. The medical application of psychedelic agents and ketamine/esketamine is considered to be safe; however, as with all new forms of treatment it is of crucial importance that, in addition to the hopes, the specific challenges of these new treatment approaches must also be carefully considered and assessed. Excessive expectations and an insufficient risk-benefit estimation are detrimental to the patients and the reputation of the treating physician. Although a possible paradigm shift in the care of mental health is already being discussed, this review article consciously concentrates on the possible risks of treatment and the methodological weaknesses of the studies carried out so far. [ABSTRACT FROM AUTHOR]

Psychedelic substances, which can occasion mystical experiences, are sometimes used for religious and spiritual reasons. Despite strong links between psychedelics and spirituality, no previous systematic review has investigated connections between psychedelics and indicators of long-term spiritual growth. Thus, 34 empirical studies were analyzed with 19,724 total participants from 32 independent samples. A variety of methodologies were used among the reviewed studies, and some studies included international samples. Results showed that psychedelics—especially classic psychedelics (e.g., psilocybin, LSD, and DMT)—have been studied more often in this context than other substances. Findings indicate that psychedelic use is linked with a variety of subjective indicators of spiritual growth, including stronger perceived connections with the divine, a greater sense of meaning, increased spiritual faith, increased engagement in religious and spiritual practices, an increase in feelings of unity and self-transcendence, positive changes in worldview, increased connectedness with others, and reduced fear of death. Many studies that reported on one of these indicators also reported on others, implying a co-occurrence of these facets during and after psychedelic experiences. Spiritual growth was often related to mystical experiences, with higher mystical experience ratings associating positively with perceived spiritual growth. [ABSTRACT FROM AUTHOR]

As a proposed mediator between stigma-related stressors and negative mental health outcomes, HIV-related shame has been predictive of increased rates of substance use and difficulties adhering to antiretroviral treatment among people with HIV. These downstream manifestations have ultimately impeded progress toward national goals to End the HIV Epidemic, in part due to limited success of conventional psychotherapies in addressing HIV-related shame. In a pilot clinical trial (N = 12), receipt of psilocybin-assisted group therapy was associated with a large pre-post decrease in HIV-related shame as measured by the HIV and Abuse Related Shame Inventory, with a median (IQR) change of − 5.5 (− 6.5, − 3.5) points from baseline to 3-months follow-up (Z = − 2.6, p = 0.009, r = − 0.75). A paradoxical exacerbation of sexual abuse-related shame experienced by two participants following receipt of psilocybin raises critical questions regarding the use of psilocybin therapy among patients with trauma. These preliminary findings carry potential significance for the future of HIV care. [ABSTRACT FROM AUTHOR]

Rationale: Psychedelic-assisted psychotherapy (PAP) has emerged as a potential treatment for a variety of mental health conditions, including substance use disorders and depression. Current models of PAP emphasize the importance of psychotherapeutic support before, during, and after ingestion of a psychedelic to maximize safety and clinical benefit. Despite this ubiquitous assumption, there has been surprisingly little empirical investigation of the "psychotherapy" in PAP, leaving critical questions about the necessary and sufficient components of PAP unanswered. Objectives: As clinical trials for psychedelic compounds continue the transition from safety- and feasibility-testing to evaluating efficacy, the role of the accompanying psychotherapy must be better understood to enhance scientific understanding of the mechanisms underlying therapeutic change, optimize clinical outcomes, and inform cost-effectiveness. Results: The present paper first reviews the current status of psychotherapy in the PAP literature, starting with recent debates regarding "psychotherapy" versus "psychological support" and then overviewing published clinical trial psychotherapy models and putative models informed by theory. We then delineate lessons that PAP researchers can leverage from traditional psychotherapy research regarding standardizing treatments (e.g., publish treatment manuals, establish eligibility criteria for providers), identifying mechanisms of change (e.g., measure established mechanisms in psychotherapy), and optimizing clinical trial designs (e.g., consider dismantling studies, comparative efficacy trials, and cross-lagged panel designs). Throughout this review, the need for increased research into the psychotherapeutic components of treatment in PAP is underscored. Conclusions: PAP is a distinct, integrative, and transdisciplinary intervention. Future research designs should consider transdisciplinary research methodologies to identify best practices and inform federal guidelines for PAP administration. [ABSTRACT FROM AUTHOR]

Rationale: Treatments with the serotonergic psychedelic psilocybin are being investigated for multiple neuropsychiatric disorders. Because many patients with these disorders use selective serotonin reuptake inhibitors (SSRIs), understanding interactions between psilocybin and SSRIs is critical for evaluating the safety, efficacy, and scalability of psilocybin-based treatments. Current knowledge about these interactions is limited, as most clinical psilocybin research has prohibited concomittant SSRI use. Objectives: We aimed to explore potential interactions between psilocybin and SSRIs by characterizing peoples' real-world experiences using psilocybin mushrooms and SSRIs together. Methods: We conducted a systematic search of Reddit for posts describing psilocybin mushroom and SSRI coadministration. We identified 443 eligible posts and applied qualitative content analysis to each. Results: 8% of posts reported negative physical or psychological effects resulting from coadministration. These included 13 reports that may reflect serotonin toxicity, and 1 concerning for a psychotic/manic episode. 54% of posts described reduced intensity of the acute psilocybin experience, but 39% reported unchanged intensity with SSRI coadministration. Conclusions: Psilocybin's interactions with SSRIs are likely complex and may depend on multiple factors. Prospective studies are needed to evaluate whether psilocybin treatments are reliably safe and effective in the setting of SSRI use. [ABSTRACT FROM AUTHOR]

Purpose of Review: Self-awareness can be defined as the capacity of becoming the object of one's own awareness and, increasingly, it has been the target of scientific inquiry. Self-awareness has important clinical implications, and a better understanding of the neurochemical basis of self-awareness may help clarifying causes and developing interventions for different psychopathological conditions. The current article explores the relationship between neurochemistry and self-awareness, with special attention to the effects of psychedelics. Recent Findings: The functioning of self-related networks, such as the default-mode network and the salience network, and how these are influenced by different neurotransmitters is discussed. The impact of psychedelics on self-awareness is reviewed in relation to specific processes, such as interoception, body ownership, agency, metacognition, emotional regulation and autobiographical memory, within a framework based on predictive coding. Summary: Improved outcomes in emotional regulation and autobiographical memory have been observed in association with the use of psychedelics, suggesting higher-order self-awareness changes, which can be modulated by relaxation of priors and improved coping mechanisms linked to cognitive flexibility. Alterations in bodily self-awareness are less consistent, being potentially impacted by doses employed, differences in acute/long-term effects and the presence of clinical conditions. Future studies investigating the effects of different molecules in rebalancing connectivity between resting-state networks may lead to novel therapeutic approaches and the refinement of existing treatments. [ABSTRACT FROM AUTHOR]

Recent clinical trials have found that the serotonergic psychedelic psilocybin effectively alleviates anxiodepressive symptoms in patients with life-threatening illnesses when given in a supportive environment. These outcomes prompted Canada to establish legal pathways for therapeutic access to psilocybin, coupled with psychological support. Despite over one-hundred Canadians receiving compassionate access since 2020, there has been little examination of these 'real-world' patients. We conducted a prospective longitudinal survey which focused on Canadians who were granted Section 56 exemptions for legal psilocybin-assisted psychotherapy. Surveys assessing various symptom dimensions were conducted at baseline, two weeks following the session (endpoint), and optionally one day post-session. Participant characteristics were examined using descriptive statistics, and paired sample t-tests were used to quantify changes from baseline to the two-week post-treatment endpoint. Eight participants with Section 56 exemptions (four females, Mage = 52.3 years), all with cancer diagnoses, fully completed baseline and endpoint surveys. Significant improvements in anxiety and depression symptoms, pain, fear of COVID-19, quality of life, and spiritual well-being were observed. Attitudes towards death, medical assistance in dying, and desire for hastened death remained unchanged. While most participants found the psilocybin sessions highly meaningful, if challenging, one reported a substantial decrease in well-being due to the experience. These preliminary data are amongst the first to suggest that psilocybin-assisted psychotherapy can produce psychiatric benefits in real-world patients akin to those observed in clinical trials. Limited enrollment and individual reports of negative experiences indicate the need for formal real-world evaluation programs to surveil the ongoing expansion of legal access to psychedelics. [ABSTRACT FROM AUTHOR]

Aim: Recently, the relationship between diabetes and mental health has been widely studied. With the advent of continuous glucose monitoring (CGM), some researchers have been interested in exploring the association between glucose-related metrics and psychological aspects. These studies have primarily relied on self-report questionnaires which present some limitations. Therefore, the present multicenter study aims at testing potential associations between CGM metrics and affective processes derived from narratives about using a CGM sensor. Methods: An exploratory correlational design was used. Fifty-eight adults with type 1 diabetes using CGM were enrolled and invited to complete an online survey, where they replied to an open-ended question regarding their personal experience with the CGM sensor. Texts derived from the answers were analyzed through Linguistic Inquiry and Word Count, a widely used text analysis tool that can automatically identify and quantify linguistic patterns related to various psychological dimensions. Psycholinguistic measures were correlated with CGM metrics. Results: Higher levels of sadness/depression correlated with lower %TIR (r = − 339; p <.01) and higher %TAR (r =.342; p <.01). Conclusions: The study highlights the relationship between CGM metrics and psychological variables derived from patients' narratives. In particular, it is possible to hypothesize a positive role of %TIR in reducing depressive feelings in individuals with diabetes, as well as a negative role of depressive feelings in achieving desirable CGM outcomes. Additionally, there is a potential role of glycemic variability, particularly hyperglycemia, in the expression of depressive and sad feelings, which has been less studied compared to the effects of hypoglycemia. [ABSTRACT FROM AUTHOR]

Chronic pruritus (CP) is defined as an unpleasant sensation causing a desire to scratch and lasting > 6 weeks. It has a multifactorial etiology but is more frequently associated with chronic inflammatory dermatoses and systemic disorders. Psychogenic pruritus and neurological disorders are other less common etiologies, while, in some patients, it is idiopathic. CP appears to be processed by non-histaminergic pathway, contributing to its complexity and therapeutic challenge. Moreover, regardless of the etiology, it is multidimensional, including cognitive, motivational and affective components. There is a close link between psychological distress and pruritus, with particular clinical expression in chronic inflammatory dermatoses, involving the activation of the hypothalamic-pituitary-adrenal axis (and its cutaneous equivalent), the sympathetic nervous system, the release of hormones and peptides, the role of immune cells (T and B cells, macrophages) and immune-related cells in the skin (mast cells, dendritic cells and keratinocytes). Moreover, there is strong evidence that psychological factors influence the experience of pruritus. CP can also cause psychiatric disorders, including but not limited to anxiety and depression, and also lead to significant quality of life (QoL) impairment. Thereby, although a psychodermatological assessment should ideally be carried out in the context of a specific psychodermatology consultation, a brief mental health assessment could be part of the general dermatological approach to these patients. Considering that mental health, QoL and pruritus are closely linked, psychotherapeutic interventions and/or psychotropic drugs should thus be considered in some patients as an adjunct to the pharmacological treatment of CP. [ABSTRACT FROM AUTHOR]

Psychedelics have experienced renewed interest following positive clinical effects, however the neurobiological mechanisms underlying effects remain unclear. The paraventricular nucleus of the hypothalamus (PVN) plays an integral role in stress response, autonomic function, social behavior, and other affective processes. We investigated the effect of psilocin, the psychoactive metabolite of psilocybin, on PVN reactivity in Sprague Dawley rats. Psilocin increased stimulus-independent PVN activity as measured by c-Fos expression in male and female rats. Psilocin increased PVN reactivity to an aversive air-puff stimulus in males but not females. Reactivity was restored at 2- and 7-days post-injection with no group differences. Additionally, prior psilocin injection did not affect PVN reactivity following acute restraint stress. Experimental groups sub-classified by baseline threat responding indicate that increased male PVN reactivity is driven by active threat responders. These findings identify the PVN as a significant site of psychedelic drug action with implications for threat responding behavior. The neurobiological mechanisms underlying the fast acting and long-lasting effects of these drugs are not fully understood. Here authors show that the psychedelic psilocin increases reactivity in the paraventricular nucleus of the hypothalamus (PVN) in male rats but does not change acute stress response. Male reactivity changes are driven by active threat responding, with clinical implications. [ABSTRACT FROM AUTHOR]

S-ketamine, a N-methyl-D-aspartate receptor (NMDAR) antagonist, and psilocybin, a 5-hydroxy-tryptamine (serotonin) 2A receptor (5-HT2AR) agonist, are reported as effective rapid-acting antidepressants. Both compounds increase glutamate signalling and evoke cortical hyperexcitation. S-ketamine induces neurotoxicity especially in the retrosplenial cortex (Olney's lesions). Whether psilocybin produces similar neurotoxic effects has so far not been investigated. We performed an immunohistochemical whole-brain mapping for heat shock protein 70 (HSP70) in rats treated with psilocybin, S-ketamine, and MK-801. In contrast to S-ketamine- and MK-801-treated animals, we did not detect any HSP70-positive neurons in retrosplenial cortex of rats treated with psilocybin. Our results suggest that psilocybin might be safer for clinical use compared to S-ketamine regarding neuronal damage. [ABSTRACT FROM AUTHOR]

Amanita phalloides is the primary species responsible for fatal mushroom poisoning, as its main toxin, α-amanitin, irreversibly and potently inhibits eukaryotic RNA polymerase II (RNAP II), leading to cell death. There is no specific antidote for α-amanitin, which hinders its clinical application. However, with the advancement of precision medicine in oncology, including the development of antibody–drug conjugates (ADCs), the potential value of various toxic small molecules has been explored. These ADCs ingeniously combine the targeting precision of antibodies with the cytotoxicity of small-molecule payloads to precisely kill tumor cells. We searched PubMed for studies in this area using these MeSH terms "Amanitins, Alpha-Amanitin, Therapeutic use, Immunotherapy, Immunoconjugates, Antibodies" and did not limit the time interval. Recent studies have conducted preclinical experiments on ADCs based on α-amanitin, showing promising therapeutic effects and good tolerance in primates. The current challenges include the not fully understood toxicological mechanism of α-amanitin and the lack of clinical studies to evaluate the therapeutic efficacy of ADCs developed based on α-amanitin. In this article, we will discuss the role and therapeutic efficacy of α-amanitin as an effective payload in ADCs for the treatment of various cancers, providing background information for the research and application strategies of current and future drugs. [ABSTRACT FROM AUTHOR]

Recent years have seen a resurgence in randomized, placebo controlled trials (RCTs) utilizing non-classical psychedelics (e.g. 3,4-methyl enedioxy methamphetamine [MDMA]), and classical psychedelics (e.g. psilocybin, lysergic acid diethylamide [LSD], and N,N-dimethyltryptamine [DMT/ayahuasca]) in conjunction with assisted therapy (AT) for psychiatric disorders. A notable methodological challenge in psychedelic AT, however, is the complexity of blinding procedures. The lack of efficacious blinding can introduce considerable response bias, reduce internal validity, and compromise participant retention. This systematic review examines design and blinding techniques in RCTs utilizing psychedelics and placebo for the treatment of psychiatric disorders. The aim of this work is to identify factors that may inform future RTC design for conducting psychedelics research. We conducted a systematic review of PubMed, MEDLINE, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), Psycinfo, Embase, and Web of Science Core Collection to examine: (1) placebo selection, (2) study design, and (3) integrity of blinding measures. Sixteen publications were identified as meeting the criteria for a systematic review. Our findings suggest that traditional placebo administration is insufficient to control for expectancy confounds. Consequently, experimental methodology that limits personnel unblinding and the use of an active placebo are important considerations when designing prospective clinical studies involving psychedelics. [ABSTRACT FROM AUTHOR]

Modern life is filled with radiofrequency electromagnetic radiation (RF-EMR) in various frequency bands, while the health risks are not clear. In this study, mice were whole-body exposed to 0.9/1.5/2.65 GHz radiofrequency radiation at 4 W/kg for 2 h per day for 4 weeks to investigate the emotional effects. It was found that the mice showed anxiety but no severe depression. The ELISA results showed a significant decrease in amino acid neurotransmitters (GABA, DA, 5-HT), although acetylcholine (ACH) levels were not significantly altered. Furthermore, Western blot results showed that BDNF, TrkB, and CREB levels were increased in the cerebral cortex, while NF-κB levels were decreased. In addition, pro-inflammatory factors (IL-6, IL-1β, TNF-α) were significantly elevated, and anti-inflammatory factors (IL-4, IL-10) tended to decrease. In conclusion, multi-frequency electromagnetic radiation induces an inflammatory response through the CREB-BDNF-TrkB and NF-κB pathways in the cerebral cortex and causes a decrease in excitatory neurotransmitters, which ultimately causes anxiety in mice. [ABSTRACT FROM AUTHOR]

DNA methylation plays an important role in the regulation of gene expression. Its deficits in the brain cause various neurological diseases, including autism, schizophrenia and mood disorders. The zebrafish (Danio rerio) is a promising model organism in biomedicine. Given its high genetic and physiological homology with humans, studying genome methylation deficits in zebrafish can help elucidate the molecular processes underlying the etiology and pathogenesis of various neurological diseases, as well as develop novel therapies. Here, we discuss the mechanisms of DNA methylation in the brain and the diseases associated with its dysregulation in humans, as well as their genetic and pharmacological models in zebrafish. We also evaluate the limitations of zebrafish models and possible directions for further research in this field. Mounting evidence summarized here supports zebrafish as an effective model for elucidating the molecular mechanisms of brain pathologies associated with compromised DNA methylation. [ABSTRACT FROM AUTHOR]

Several phase II studies have demonstrated that psilocybin-assisted therapy shows therapeutic potential across a spectrum of neuropsychiatric conditions, including major depressive disorder (MDD). However, the mechanisms underlying its often persisting beneficial effects remain unclear. Observational research suggests that improvements in psychological flexibility may mediate therapeutic effects. However, no psychedelic trials to date have substantiated this finding in a clinical sample. In an exploratory placebo-controlled, within-subject, fixed-order study, individuals with moderate to severe MDD were administered placebo (n = 19) followed by psilocybin (0.3 mg/kg) (n = 15) 4 weeks later. Dosing sessions were embedded within a manualized psychotherapy that incorporated principles of Acceptance and Commitment Therapy. Depression severity, psychological flexibility, mindfulness, and values-congruent living were measured over a 16-weeks study period. Psychological flexibility, several facets of mindfulness, and values-congruent living significantly improved following psilocybin and were maintained through week 16. Additionally, improvements in psychological flexibility and experiential acceptance were strongly associated with reductions in depression severity following psilocybin. These findings support the theoretical premise of integrating psilocybin treatment with psychotherapeutic platforms that target psychological flexibility and add to emerging evidence that increasing psychological flexibility may be an important putative mechanism of change in psilocybin-assisted therapy for MDD and potentially, other mental health conditions. [ABSTRACT FROM AUTHOR]

The hydrocarbon group-type composition (saturated and aromatic hydrocarbons, resins, asphaltenes) of oil dispersed systems is predominantly determined using chromatographic methods: liquid adsorption chromatography, high-performance liquid chromatography, thin-layer chromatography with flame ionization detection. The specificity of standard procedures developed for analyzing petroleum feedstocks and products by various methods often leads to the incomparability of the results, both in terms of the nomenclature of the identified hydrocarbon groups and the determined concentrations. This review assesses chromatographic methods for analyzing the hydrocarbon group-type composition of petroleum feedstocks and products, highlighting their features, advantages, and disadvantages. The main modifications of standard procedures aimed at achieving a correlation between the results obtained by different analytical methods are described. [ABSTRACT FROM AUTHOR]

The mechanisms by which Psilocybin Therapy (PT) improves depression remain an important object of study, with scientists actively exploring acute psychological experiences and neurobiological processes as candidates. In a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we investigated whether acute psychological experiences could meaningfully account for the unique efficacy of PT versus Escitalopram Treatment over a core 6-week trial period. An exploratory-factor-analysis-derived single-factor of depression was used as the outcome. Among a comprehensive set of acute experiences related to psilocybin, so-called "mystical experience" and "ego dissolution" were unique in mediating the effect of treatment condition on depressive response with high specificity. Higher reported levels of mystical experience, emotional breakthrough, and intense responses to music-listening were furthermore associated with greater antidepressant response. These results provide qualified support for the causal mechanistic role of acute psychological experiences in the treatment of depression via PT. [ABSTRACT FROM AUTHOR]

The ethical value—and to some scholars, necessity—of providing trial patients with post-trial access (PTA) to an investigational drug has been subject to significant attention in the field of research ethics. Although no consensus has emerged, it seems clear that, in some trial contexts, various factors make PTA particularly appropriate. We outline the atypical aspects of psychedelic clinical trials that support the case for introducing the provision of PTA within research in this field, including the broader legal status of psychedelics, the nature of the researcher-therapist/participant relationship, and the extended time-frame of the full therapeutic process. As is increasingly understood, the efficacy of psychedelic-assisted psychotherapy is driven as much by extrapharmacological elements and the cultural therapeutic container as by the drug itself. As such, we also advocate for a refocusing of attention from post-trial access to a broader concept encompassing other elements of post-trial care. We provide an overview of some of the potential post-trial care provisions that may be appropriate in psychedelic clinical trials. Although the World Medical Association’s Declaration of Helsinki calls on researchers, sponsors, and governments to make provisions for post-trial access, such provision may feel impracticable or out-of-reach within psychedelic trials that are already constrained by a high resource demand and significant bureaucratic burden. We show how conceiving of post-trial provision as an integral site of the research process, and an appropriate destination for research funding, will serve to develop the infrastructure necessary for the post-legalisation psychedelic medicine ecosystem. [ABSTRACT FROM AUTHOR]

Gamma-aminobutyric acid (GABA) plays a crucial role in the central nervous system as an inhibitory neurotransmitter. Imbalances of this neurotransmitter are associated with neurological diseases, such as Alzheimer's and Parkinson's disease, and psychological disorders, including anxiety, depression, and stress. Since GABA has long been believed to not cross the blood–brain barrier, the effects of circulating GABA on the brain are neglected. However, emerging evidence has demonstrated that changes in both circulating and brain levels of GABA are associated with changes in gut microbiota composition and that changes in GABA levels and microbiota composition play a role in modulating mental health. This recent research has raised the possibility that GABA may be a potent mediator of the gut–brain axis. This review article will cover up-to-date information about GABA-producing microorganisms isolated from human gut and food sources, explanation why those microorganisms produce GABA, food factors inducing gut–GABA production, evidence suggesting GABA as a mediator linking between gut microbiota and mental health, including anxiety, depression, stress, epilepsy, autism spectrum disorder, and attention deficit hyperactivity disorder, and novel information regarding homocarnosine-a predominant brain peptide that is a putative downstream mediator of GABA in regulating brain functions. This review will help us to understand how the gut microbiota and GABA-homocarnosine metabolism play a significant role in brain functions. Nonetheless, it could support further research on the use of GABA production-inducing microorganisms and food factors as agents to treat neurological and psychological disorders. [ABSTRACT FROM AUTHOR]

In this study, for the first time, we explored a dataset of functional magnetic resonance images collected during focused attention and open monitoring meditation before and after a five-day psilocybin-assisted meditation retreat using a recently established approach, based on the Mapper algorithm from topological data analysis. After generating subject-specific maps for two groups (psilocybin vs. placebo, 18 subjects/group) of experienced meditators, organizational principles were uncovered using graph topological tools, including the optimal transport (OT) distance, a geometrically rich measure of similarity between brain activity patterns. This revealed characteristics of the topology (i.e. shape) in space (i.e. abstract space of voxels) and time dimension of whole-brain activity patterns during different styles of meditation and psilocybin-induced alterations. Most interestingly, we found that (psilocybin-induced) positive derealization, which fosters insightfulness specifically when accompanied by enhanced open-monitoring meditation, was linked to the OT distance between open-monitoring and resting state. Our findings suggest that enhanced meta-awareness through meditation practice in experienced meditators combined with potential psilocybin-induced positive alterations in perception mediate insightfulness. Together, these findings provide a novel perspective on meditation and psychedelics that may reveal potential novel brain markers for positive synergistic effects between mindfulness practices and psilocybin. [ABSTRACT FROM AUTHOR]

Psilocybin, the natural hallucinogen produced by Psilocybe ("magic") mushrooms, holds great promise for the treatment of depression and several other mental health conditions. The final step in the psilocybin biosynthetic pathway, dimethylation of the tryptophan-derived intermediate norbaeocystin, is catalysed by PsiM. Here we present atomic resolution (0.9 Å) crystal structures of PsiM trapped at various stages of its reaction cycle, providing detailed insight into the SAM-dependent methylation mechanism. Structural and phylogenetic analyses suggest that PsiM derives from epitranscriptomic N6-methyladenosine writers of the METTL16 family, which is further supported by the observation that bound substrates physicochemically mimic RNA. Inherent limitations of the ancestral monomethyltransferase scaffold hamper the efficiency of psilocybin assembly and leave PsiM incapable of catalysing trimethylation to aeruginascin. The results of our study will support bioengineering efforts aiming to create novel variants of psilocybin with improved therapeutic properties. The natural hallucinogen psilocybin — produced by so-called magic mushrooms — holds promise for the treatment of depression and other mental health conditions. Here, the authors provide a structural and biochemical analysis of the Psilocybe methyl transferase PsiM that provides mechanistic insight into the last step of psilocybin biosynthesis. [ABSTRACT FROM AUTHOR]

Rationale: The 5-methoxy-N-methyl-N-isopropyltryptamine (5-MeO-MiPT, known online as "Moxy") is a new psychedelic tryptamine first identified on Italian national territory in 2014. Its hallucinogen effects are broadly well-known; however, only few information is available regarding its pharmaco-toxicological effects. Objectives: Following the seizure of this new psychoactive substances by the Arm of Carabinieri and the occurrence of a human intoxication case, in the current study we had the aim to characterize the in vivo acute effects of systemic administration of 5-MeO-MiPT (0.01–30 mg/kg i.p.) on sensorimotor (visual, acoustic, and overall tactile) responses, thermoregulation, and stimulated motor activity (drag and accelerod test) in CD-1 male mice. We also evaluated variation on sensory gating (PPI, prepulse inhibition; 0.01–10 mg/kg i.p.) and on cardiorespiratory parameters (MouseOx and BP-2000; 30 mg/kg i.p.). Lastly, we investigated the in silico ADMET (absorption, distribution, metabolism, excretion, toxicity) profile of 5-MeO-MiPT compared to 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) and N,N-dimethyltryptamine (DMT). Results: This study demonstrates that 5-MeO-MiPT dose-dependently inhibits sensorimotor and PPI responses and, at high doses, induces impairment of the stimulated motor activity and cardiorespiratory changes in mice. In silico prediction shows that the 5-MeO-MiPT toxicokinetic profile shares similarities with 5-MeO-DIPT and DMT and highlights a cytochrome risk associated with this compound. Conclusions: Consumption of 5-MeO-MiPT can affect the ability to perform activities and pose a risk to human health status, as the correspondence between the effects induced in mice and the symptoms occurred in the intoxication case suggests. However, our findings suggest that 5-MeO-MiPT should not be excluded from research in the psychiatric therapy field. [ABSTRACT FROM AUTHOR]

Psychedelic substances induce profound alterations in consciousness. Careful preparation is therefore essential to limit adverse reactions, enhance therapeutic benefits, and maintain user safety. This paper describes the development of a self-directed, digital intervention for psychedelic preparation. Drawing on elements from the UK Medical Research Council (MRC) framework for developing complex interventions, the design was informed by a four-factor model of psychedelic preparedness, using a person-centred approach. Our mixed-methods investigation consisted of two studies. The first involved interviews with 19 participants who had previously attended a ‘high-dose’ psilocybin retreat, systematically exploring their preparation behaviours and perspectives on the proposed intervention. The second study engaged 28 attendees of an ongoing psilocybin retreat in co-design workshops, refining the intervention protocol using insights from the initial interviews. The outcome is a co-produced 21-day digital course (Digital Intervention for Psychedelic Preparation (DIPP)), that is organised into four modules: Knowledge–Expectation, Psychophysical–Readiness, Safety–Planning, and Intention–Preparation. Fundamental components of the course include daily meditation practice, supplementary exercises tied to the weekly modules, and mood tracking. DIPP provides a comprehensive and scalable solution to enhance psychedelic preparedness, aligning with the broader shift towards digital mental health interventions. [ABSTRACT FROM AUTHOR]

Summary 1: The first article discusses a study comparing biodosimetry and physical dosimetry techniques for estimating radiation dose in emergency situations. The study found that physical dosimetry using smartphone components can estimate high-energy (gamma ray) exposure well, but overestimates x-ray exposure.Summary 2: The second article presents a cross-sectional study of suicides in Australia, focusing on substances detected during postmortem toxicology analyses. The study found that psychotropic medications and potentially intoxicating medications/drugs were found at high rates in both poisoning- and non-poisoning-related suicides.Summary 3: The third article examines the administration of Centruroides (scorpion) antivenom and investigates the rate of serious adverse events when the antivenom is given as a slow intravenous push. The study found that the administration of antivenom via slow intravenous push (sIVP) was safe and effective when given by trained staff. [Extracted from the article]

Psoriasis is a chronic immune-mediated disorder that commonly affects adults and children. In recent years, pediatric psoriasis has increased in prevalence and the disease is often associated with various comorbidities and psychological distress. The conventional topical treatments for psoriasis, such as corticosteroids, calcineurin inhibitors, vitamin D analogs, anthralin, and coal tar, are often limited by their side effects, tolerability, and/or efficacy, particularly for use in children and on sensitive and intertriginous areas. Recently, the US Food and Drug Administration approved two new topical non-steroidal agents for treating psoriasis that target different pathogenic pathways than the conventional treatments. Roflumilast is a phosphodiesterase type 4 inhibitor approved for the treatment of plaque psoriasis in patients aged 12 years and older. Tapinarof is a novel aryl hydrocarbon receptor modulator approved for adult psoriasis and currently undergoing studies for pediatric psoriasis. Ongoing efforts are also being made to optimize conventional treatments, for instance, a new foam formulation of halobetasol propionate was recently approved for pediatric psoriasis. Clinical trials of various new drugs targeting one or multiple pathogenic pathways of psoriasis, such as Janus kinase inhibitors, different formulations of phosphodiesterase type 4 inhibitors, and aryl hydrocarbon receptor modulators have also been explored. The recent emergence of novel topical agents provides promising new options for managing pediatric psoriasis with the potential to improve clinical outcomes and quality of life. In this article, we review the mechanism of action, efficacy, and safety profile of novel topical agents and discuss their potential roles in the management of pediatric psoriasis. [ABSTRACT FROM AUTHOR]

Despite the longstanding use of nitrous oxide and descriptions of its psychological effects more than a century ago, there is a paucity of neurobiological investigation of associated psychedelic experiences. We measure the brain's functional geometry (through analysis of cortical gradients) and temporal dynamics (through analysis of co-activation patterns) using human resting-state functional magnetic resonance imaging data acquired before and during administration of 35% nitrous oxide. Both analyses demonstrate that nitrous oxide reduces functional differentiation in frontoparietal and somatomotor networks. Importantly, the subjective psychedelic experience induced by nitrous oxide is inversely correlated with the degree of functional differentiation. Thus, like classical psychedelics acting on serotonin receptors, nitrous oxide flattens the functional geometry of the cortex and disrupts temporal dynamics in association with psychoactive effects. Like classical psychedelics, nitrous oxide reduces functional differentiation in human frontoparietal and somatomotor networks, flattening functional brain geometry and disrupting temporal dynamics in association with the psychedelic experience. [ABSTRACT FROM AUTHOR]

A recent review by Pouyan et al. examined the effects of lysergic acid diethylamide (LSD) using the Research Domain Criteria (RDoC) framework. The review found that LSD can alter reward processing systems to enhance reward responsiveness. However, the review also highlighted the lack of attention given to contextual factors in psychedelic studies, such as the use of music during dosing sessions. The article emphasizes the importance of considering extrapharmacological variables, or the "set and setting," in understanding the effects of psychoactive drugs. It suggests that researchers and clinicians should be mindful of context and work towards developing standardized reporting guidelines for psychoactive drug studies. [Extracted from the article]

Background and Objectives: The renewed interest in psychedelic research provides growing evidence of potentially unique effects on various aspects of reward processing systems. Using the Research Domain Criteria (RDoC) framework, as proposed by the National Institute of Mental Health, we aim to synthesize the existing literature concerning the impact of lysergic acid diethylamide (LSD) on the RDoC's Positive Valence Systems (PVS) domain, and to identify potential avenues for further research. Methods: Two LSD-related terms (lysergic acid diethylamide and LSD) and 13 PVS-related terms (reward, happiness, bliss, motivation, reinforcement learning, operant, conditioning, satisfaction, decision making, habit, valence, affect, mood) were used to search electronic databases such as PubMed, Scopus, PsychINFO, and Web of Science for relevant articles. A manual search of the reference list resulted in nine additional articles. After screening, articles and data were evaluated and included based on their relevance to the objective of investigating the effects of LSD on the PVS. Articles and data were excluded if they did not provide information about the PVS, were observational in nature, lacked comparators or reference groups, or were duplicates. A risk of bias assessment was performed using the National Toxicology Program's Office of Health Assessment and Translation (NTP OHAT) risk of bias (RoB) tool. Data from the included articles were collected and structured based on the RDoC bio-behavioral matrix, specifically focusing on the PVS domain and its three constituent constructs: reward responsiveness, reward learning, and reward valuation. Results: We reviewed 28 clinical studies with 477 participants. Lysergic acid diethylamide, assessed at self-report (23 studies), molecular (5 studies), circuit (4 studies), and paradigm (3 studies) levels, exhibited dose-dependent mood improvement (20 short-term and 3 long-term studies). The subjective and neural effects of LSD were linked to the 5-HT2A receptor (molecular). Animal studies (14 studies) suggested LSD could mildly reinforce conditioned place preference without aversion and reduce responsiveness to other rewards. Findings on reward learning were inconsistent but hinted at potential associative learning enhancements. Reward valuation measures indicated potential reductions in effort expenditure for other reinforcers. Conclusion: Our findings are consistent with our previous work, which indicated classical psychedelics, primarily serotonin 2A receptor agonists, enhanced reward responsiveness in healthy individuals and patient populations. Lysergic acid diethylamide exhibits a unique profile in the reward learning and valuation constructs. Using the RDoC-based framework, we identified areas for future research, enhancing our understanding of the impact of LSD on reward processing. However, applying RDoC to psychedelic research faces limitations due to diverse study designs that were not initially RDoC-oriented. Limitations include subjective outcome measure selection aligned with RDoC constructs and potential bias in synthesizing varied studies. Additionally, some human studies were open-label, introducing potential bias compared to randomized, blinded studies. [ABSTRACT FROM AUTHOR]

Research into the use of psilocybin for the treatment of psychiatric disorders is a growing field. Nevertheless, robust brain–behavior relationships linking psilocybin-induced brain changes to subjective drug-induced effects have not been established. Furthermore, it is unclear if the acute neural effects are dependent on individual heterogeneity in baseline characteristics. To address this, we assessed the effects of three oral doses of psilocybin vs. placebo on cerebral blood flow (CBF) using arterial spin labeling in healthy participants (N = 70; n = 31, 0.16 mg/kg; n = 10, 0.2 mg/kg; n = 29, 0.215 mg/kg). First, we quantified psilocybin-induced changes in relative and absolute CBF. Second, in an exploratory analysis, we assessed whether individual baseline characteristics and subjective psychedelic experience are associated with changes in CBF. Psychological and neurobiological baseline characteristics correlated with the psilocybin-induced reduction in relative CBF and the psilocybin-induced subjective experience. Furthermore, the psilocybin-induced subjective experience was associated with acute changes in relative and absolute CBF. The results demonstrated that inter-individual heterogeneity in the neural response to psilocybin is associated with baseline characteristics and shed light on the mechanisms underlying the psychedelic-induced altered state. Overall, these findings help guide the search for biomarkers, paving the way for a personalized medicine approach within the framework of psychedelic-assisted therapy. [ABSTRACT FROM AUTHOR]

Previous research has suggested that classical psychedelics can foster significant and enduring changes in personality traits and subjective wellbeing. Despite the lack of evidence for adverse effects on mental health stemming from psychedelic use, concerns persist regarding the capacity of these substances to modulate information processing and attitudes towards factual data. The aim of the present study was to investigate the propensity for accepting alternative facts and the general treatment of knowledge within a sample of 392 participants, 233 of whom reported at least a single incidence of psychedelic use in their lifetime. To do this, we leveraged step-wise methods of linear modelling investigating effects of demographics, psychiatric conditions and concomitant drug use. Our findings revealed a moderate positive association between psychedelic use and beliefs in alternative facts, as well as the specific belief that facts are politically influenced. However, no links were found for favouring intuition over evidence when confirming facts. Among other investigated drugs, only alcohol was negatively associated with beliefs in alternative facts. Taken together, our results support the link between psychedelic use and non-conformist thinking styles, which can be attributed to the psychological effects of the drugs themselves, but may also mirror a common trait related to unconventional beliefs and illicit substance use. [ABSTRACT FROM AUTHOR]

Recent controversies have arisen regarding claims of uncritical positive regard and hype surrounding psychedelic drugs and their therapeutic potential. Criticisms have included that study designs and reporting styles bias positive over negative outcomes. The present study was motivated by a desire to address this alleged bias by intentionally focusing exclusively on negative outcomes, defined as self-perceived 'negative' psychological responses lasting for at least 72 h after psychedelic use. A strong justification for this selective focus was that it might improve our ability to capture otherwise missed cases of negative response, enabling us to validate their existence and better examine their nature, as well as possible causes, which could inspire risk-mitigation strategies. Via advertisements posted on social media, individuals were recruited who reported experiencing negative psychological responses to psychedelics (defined as classic psychedelics plus MDMA) lasting for greater than 72 h since using. Volunteers were directed to an online questionnaire requiring quantitative and qualitative input. A key second phase of this study involved reviewing all of the submitted cases, identifying the most severe—e.g., where new psychiatric diagnoses were made or pre-existing symptoms made worse post psychedelic-use—and inviting these individuals to participate in a semi-structured interview with two members of our research team, during which participant experiences and backgrounds were examined in greater depth. Based on the content of these interviews, a brief summary of each case was compiled, and an explorative thematic analysis was used to identify salient and consistent themes and infer common causes. 32 individuals fully completed an onboarding questionnaire (56% male, 53% < age 25); 37.5% of completers had a psychiatric diagnosis that emerged after their psychedelic experience, and anxiety symptoms arose or worsened in 87%. Twenty of the seemingly severer cases were invited to be interviewed; of these, 15 accepted an in-depth interview that lasted on average 60 min. This sample was 40% male, mean age = 31 ± 7. Five of the 15 (i.e., 33%) reported receiving new psychiatric diagnoses after psychedelic-use and all fifteen reported the occurrence or worsening of psychiatric symptoms post use, with a predominance of anxiety symptoms (93%). Distilling the content of the interviews suggested the following potential causal factors: unsafe or complex environments during or surrounding the experience, unpleasant acute experiences (classic psychedelics), prior psychological vulnerabilities, high- or unknown drug quantities and young age. The current exploratory findings corroborate the reality of mental health iatrogenesis via psychedelic-use but due to design limitations and sample size, cannot be used to infer on its prevalence. Based on interview reports, we can infer a common, albeit multifaceted, causal mechanism, namely the combining of a pro-plasticity drug—that was often 'over-dosed'—with adverse contextual conditions and/or special psychological vulnerability—either by young age or significant psychiatric history. Results should be interpreted with caution due to the small sample size and selective sample and study focus. [ABSTRACT FROM AUTHOR]

Purpose: Evidence suggests an increase of depression and anxiety symptoms during the Covid-19 pandemic but most studies relied on cross-sectional designs and/or small samples, and they often overlooked subgroup effects in the impact of the lockdown. We investigated the effect of the pandemic on depression and anxiety symptoms, and whether it differed by employment situation and alcohol consumption. Methods: This longitudinal study used 23 waves of the Covid-Questionnaire (April 2020—July 2021), within the Lifelines cohort from the Netherlands (n = 76,254). Depression and anxiety symptoms were combined in a "mental health score". Linear fixed-effects models were fitted to analyse trends in mental health throughout the observation period. The moderating role of pre-existing mental health, employment situation, and alcohol consumption was tested. Results: Depression and anxiety symptoms fluctuated considerably during the observation period, with clear peaks in winter 2021, during the strictest lockdown period. Moreover, temporal patterns differed by employment situation and alcohol consumption patterns, suggesting that various subgroups reacted to the pandemic and the lockdown in different ways. Conclusion: Lockdowns increased depression and anxiety symptoms in the Netherlands. The effect was particularly strong for unemployed individuals, those with risky alcohol consumption patterns and those with pre-existing mental health disorders. [ABSTRACT FROM AUTHOR]

Purpose: The non-medical use of prescription medications among adolescents has become a concerning public health issue. This study assessed the prevalence of the non-medical use of prescription medications in Ontario high school students, and explored the moderating effect of this use on the relationship between psychological distress and unmet mental health needs. Methods: Cross-sectional data for 4896 students, age 14–18, were drawn from the 2019 Ontario Student Drug Use and Health Survey. Psychological distress was measured using the Kessler-6 Distress Scale, unmet mental health needs were defined by self-report (yes/no), and non-prescription medication use was defined by self-reported frequency of use. Using logistic regression, we explored the effect of the non-medical use of prescription medications on the relationship between psychological distress and unmet mental health needs. Results: High proportions of Ontario students reported serious psychological distress (22%), some degree of unmet mental health need (38%), and/or non-medical use of prescription medications (13%). While there were strong associations between psychological distress and unmet mental health need, this association was weaker among those reporting non-medical use of prescription medications (OR = 3.3, 95% CI 1.9–5.7) compared to non-users (OR = 5.6, 95% CI 4.5–7.1). Conclusion: Our findings suggest that Ontario students experiencing distress and using non-prescribed medications are less likely to identify a need for mental health support, highlighting the consequences of apparent self-medication through misuse of prescription medications. To assist in the redirection of adolescent perceptions of healthy coping strategies, population-based educational programming, with targeted promotion of both formal and informal mental health care resources, should be considered. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review discusses the current and projected landscape of psychedelic-assisted therapy (PAT), with a focus on clinical, legal, and implementation considerations in Department of Defense (DoD) and Department of Veterans Affairs (VA) healthcare systems. Recent Findings: 3,4-Methylenedioxymethamphetamine (MDMA)- and psilocybin-assisted therapy have shown promising outcomes in efficacy, safety, tolerability, and durability for PTSD and depression, respectively. MDMA-assisted therapy is already approved by the Food and Drug Administration (FDA) on an Expanded Access ("compassionate use") basis for PTSD, with full approval projected for 2024. Psilocybin-assisted therapy is projected to be FDA-approved for depression soon thereafter. Other psychedelics are in earlier stages of development. The VA is currently conducting PAT clinical trials. Summary: Although there are clear legal pathways for the VA and DoD to conduct PAT trials, a number of implementation barriers exist, such as the very high number of clinical hours necessary to treat each patient, resource requirements to support treatment infrastructure, military-specific considerations, and the high level of evidence necessary for PAT to be recommended in clinical practice guidelines. Ongoing considerations are whether and how PAT will be made available to VA and DoD beneficiaries, feasibility and cost-effectiveness, and ethical safeguards that must be implemented to prioritize access to PAT given the likelihood of extremely limited initial availability. However, with imminent FDA approval of PATs and considerable national interest in these treatments, DoD and VA policymakers must be prepared with clearly delineated policies and plans for how these healthcare systems will approach PAT. [ABSTRACT FROM AUTHOR]

Psilocybin and lysergic acid diethylamide (LSD) experiences can range from very positive to highly challenging (e.g., fear, grief, and paranoia). These challenging experiences contribute to hesitancy toward psychedelic-assisted psychotherapy among health care providers and patients. Co-use of 3,4-Methylenedioxy methamphetamine (MDMA) with psilocybin/LSD anecdotally reduces challenging experiences and enhances positive experiences associated with psilocybin/LSD. However, limited research has investigated the acute effects of co-use of MDMA and psilocybin/LSD. In a prospective convenience sample (N = 698) of individuals with plans to use psilocybin/LSD, we examined whether co-use of MDMA with psilocybin/LSD (n = 27) is associated with differences in challenging or positive experiences. Challenging experiences were measured using the Challenging Experiences Questionnaire and positive experiences were measured using the Mystical Experience Questionnaire and single-item measures of self-compassion, compassion, love, and gratitude. Potentially confounding variables were identified and included as covariates. Relative to psilocybin/LSD alone, co-use of psilocybin/LSD with a self-reported low (but not medium–high) dose of MDMA was associated with significantly less intense total challenging experiences, grief, and fear, as well as increased self-compassion, love and gratitude. Co-use of psilocybin/LSD and MDMA was not associated with differences in mystical-type experiences or compassion. Findings suggest co-use of MDMA with psilocybin/LSD may buffer against some aspects of challenging experiences and enhance certain positive experiences. Limitations include use of a convenience sample, small sample size, and non-experimental design. Additional studies (including controlled dose–response studies) that examine the effects and safety of co-administering MDMA with psilocybin/LSD (in healthy controls and clinical samples) are warranted and may assist the development of personalized treatments. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has had a devastating impact on the health and wellbeing of the global population. This paper presents the results of a longitudinal transcultural study that was begun at the peak of the pandemic (in April, 2020). An online survey was used to collect data from English-, Spanish-, and Portuguese-speaking participants. The survey collected information about sociodemographics, lifestyle activities, COVID-19-related circumstances, and drug use (with an emphasis on hallucinogenic drugs), as well as involving psychometric questionnaires. Users of hallucinogenic drugs had higher psychological well-being and lower scores on psychopathology scales, both at baseline and during follow-ups. This difference was larger when users were distinguished by frequency of use, as regular users scored higher on psychological well-being and lower on psychopathology scales. Subjects with more psychological distress had lower scores for all scales of post-traumatic growth, but if they were regular hallucinogens users, they had higher scores for post-traumatic growth. When comparing the results between cultural contexts, heterogeneous results were obtained. There were more English-speaking regular users of hallucinogenic drugs. Further research should analyse the potential role of hallucinogens in large-scale catastrophes, with a special focus on post-traumatic growth. [ABSTRACT FROM AUTHOR]

Objectives: The mindfulness-informed intervention that has so far received the most attention as an adjunct to psychedelic-assisted psychotherapy is Acceptance and Commitment Therapy (ACT), but little remains known about potential synergies between psychedelic-assisted psychotherapy and mindfulness-based interventions such as Mindfulness-Based Cognitive Therapy (MBCT). This paper examines and evaluates the therapeutic compatibility of MBCT with psychedelic-assisted psychotherapy, and their potential synergies. Methods: This study represents a narrative review of the current literature on psychedelic-assisted psychotherapy and MBCT. Results: We demonstrate how MBCT targets core processes including acceptance, being present, concentration, decentering and embracing difficulties — and outline why strengthening these capacities with systematic meditation training may prove invaluable during the preparation, dosing and integration phases of psychedelic-assisted psychotherapy. Conclusions: MBCT's emphasis on systematic training in mindfulness meditation and fostering nonjudgmental presence aligns well with the states of consciousness induced by psychedelics, highlighting its potential to enhance various stages of both the psychedelic experience and subsequent integration. By equipping individuals with effective mindfulness and cognitive restructuring techniques, MBCT may offer advantages beyond those provided by ACT, such as the ability to skillfully navigate and manage challenging experiences that can emerge during different phases of the psychedelic experience and integration. This suggests that MBCT's unique approach may complement psychedelic-assisted psychotherapy in ways that ACT may not fully address, particularly in the context of handling challenging experiences. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review presents the existing literature of and a framework for how psychedelic drugs might be applied as therapeutic agents in episodic migraine. Recent Findings: The therapeutic effects of psychedelics in headache disorders have been reported for decades and controlled investigations are now beginning. In the first and only clinical trial of a psychedelic drug in migraine, the single administration of low-dose psilocybin reduced weekly migraine days and pain intensity for the following 2 weeks in episodic subjects. These transitional effects, along with abortive effects in two subjects and additional findings in cluster headache, offer insight into the potential medicinal use of this and other psychedelic drugs in episodic migraine. Summary: The existing evidence supports the continued investigation of psilocybin and other psychedelics as transitional treatments in episodic migraine. Acute and preventive effects also exist, but the risks may outweigh benefits with these applications. Future research of psychedelics in episodic migraine should be tailored for this condition and not modeled after protocols used in other medical or psychiatric conditions. [ABSTRACT FROM AUTHOR]

A renewed interest in the use of psychedelics for treating obsessive compulsive disorder (OCD) has emerged in the last 20 years. But pre-clinical and clinical evidence remain scarce, and little is known about the factor determining the magnitude and persistence of the therapeutic effect. We therefore designed a retrospective online survey to explore, in the general population using psychoactive drugs, their impact on OCD symptoms. We also assessed the attitude of the participants towards the substance in term of frequency of intakes. In a sample of 174 participants, classic psychedelics were reported as the only substances effective at reducing OCD symptoms. In classic psychedelics users, symptoms reduction was associated with the intensity of acute effects, itself correlated to the dose. Reports on the persistence of the therapeutic effect varied from weeks to months, but we could not find any predicting factor. Finally, the occurrence and frequency of subsequent intakes, which seemed to be limited in our sample, were predicted by the magnitude and persistence of the therapeutic effect, respectively. Our observations support the hypothesis of classic psychedelics efficacy in reducing OCD symptoms but a careful evaluation of the persistence of this effect is still needed. [ABSTRACT FROM AUTHOR]

Premenstrual dysphoric disorder (PMDD) is characterized by the predictable onset of mood and physical symptoms secondary to gonadal steroid fluctuation during the luteal phase of the menstrual cycle. Although menstrual-related affective dysfunction is responsible for considerable functional impairment and reduction in quality of life worldwide, currently approved treatments for PMDD are suboptimal in their effectiveness. Research over the past two decades has suggested that the interaction between allopregnanolone, a neurosteroid derivative of progesterone, and the gamma-aminobutyric acid (GABA) system represents an important relationship underlying symptom genesis in reproductive-related mood disorders, including PMDD. The objective of this narrative review is to discuss the plausible link between changes in GABAergic transmission secondary to the fluctuation of allopregnanolone during the luteal phase and mood impairment in susceptible individuals. As part of this discussion, we explore promising findings from early clinical trials of several compounds that stabilize allopregnanolone signaling during the luteal phase, including dutasteride, a 5-alpha reductase inhibitor; isoallopregnanolone, a GABA-A modulating steroid antagonist; and ulipristal acetate, a selective progesterone receptor modulator. We then reflect on the implications of these therapeutic advances, including how they may promote our knowledge of affective regulation more generally. We conclude that these and other studies of PMDD may yield critical insight into the etiopathogenesis of affective disorders, considering that (1) symptoms in PMDD have a predictable onset and offset, allowing for examination of affective state kinetics, and (2) GABAergic interventions in PMDD can be used to better understand the relationship between mood states, network regulation, and the balance between excitatory and inhibitory signaling in the brain. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental condition that is characterized by difficulty in social behavior and restricted behaviors. Also, in ASD, several accompanying disorders such as anxiety are observed. Considering the important role of amygdala in the pathophysiology of ASD, the present study focused on the neuronal changes and it possible signaling pathway in amygdala. After prenatal exposure to valproate (VPA; 600 mg/kg, i.p, on embryonic day 12.5), amount of ROS, MMP, caspase-3 activity, AMPK, SIRT1 and PGC1α proteins, and parvalbumin interneurons in the amygdala were assessed following evaluation of ASD and anxiety-like behaviors. Amygdala analysis revealed ROS accumulation and decreased MMP in autistic rats. In addition, caspase-3 activation elevated and immunoreactivity for parvalbumin interneurons decreased. These were accompanied by anxiety and autistic-like behaviors in open field test, elevated zero maze and U-Shaped 2 Choice Field maze. Also, our data showed that in the valproate group, protein levels of AMPK, SIRT1 and PGC1α reduced. Collectively, our results indicate that prenatal exposure to valproate leads to anxiety and autistic-like behaviors, partly through its targeting amygdala parvalbumin interneurons dysfunction and this might be affected by disturbed AMPK/SIRT1/PGC1α signaling pathway. [ABSTRACT FROM AUTHOR]

Rationale: Availability of the dopamine and noradrenaline precursor tyrosine is critical for normal functioning, and deficit in tyrosine transport across cell membrane and the blood-brain barrier has been reported in bipolar disorder and schizophrenia. Clozapine and lithium are two psychoactive agents used to treat psychosis, mood disorders and suicidal behavior, but their mechanism of action remains largely unknown. Objective: To characterize immediate and delayed differences in tyrosine uptake between healthy controls (HC) and bipolar patients (BP) and see if these differences could be normalized by either clozapine, lithium or both. A second objective was to see if clozapine and lithium have additive, antagonistic or synergistic effects in this. Method: Fibroblasts from five HC and five BP were incubated for 5 min or 6 h with clozapine, lithium, or combination of both. Radioactive labelled tyrosine was used to quantify tyrosine membrane transport. Results: There was significantly reduced tyrosine uptake at baseline in BP compared to HC, a deficit that grew with increasing incubation time. Clozapine selectively increased tyrosine uptake in BP and abolished the deficit seen under baseline conditions, while lithium had no such effect. Combination treatment with clozapine and lithium was less effective than when clozapine was used alone. Conclusions: There was significant deficit in tyrosine transport in BP compared to HC that was reversed by clozapine but not lithium. Clozapine was more effective when used alone than when added together with lithium. Potential clinical implications of this will be discussed. [ABSTRACT FROM AUTHOR]

In medical trials, 'blinding' ensures the equal distribution of expectancy effects between treatment arms in theory; however, blinding often fails in practice. We use computational modelling to show how weak blinding, combined with positive treatment expectancy, can lead to an uneven distribution of expectancy effects. We call this 'activated expectancy bias' (AEB) and show that AEB can inflate estimates of treatment effects and create false positive findings. To counteract AEB, we introduce the Correct Guess Rate Curve (CGRC), a statistical tool that can estimate the outcome of a perfectly blinded trial based on data from an imperfectly blinded trial. To demonstrate the impact of AEB and the utility of the CGRC on empirical data, we re-analyzed the 'self-blinding psychedelic microdose trial' dataset. Results suggest that observed placebo-microdose differences are susceptible to AEB and are at risk of being false positive findings, hence, we argue that microdosing can be understood as active placebo. These results highlight the important difference between 'trials with a placebo-control group', i.e., when a placebo control group is formally present, and 'placebo-controlled trials', where patients are genuinely blind. We also present a new blinding integrity assessment tool that is compatible with CGRC and recommend its adoption. [ABSTRACT FROM AUTHOR]

The profound changes in perception and cognition induced by psychedelic drugs are thought to act on several levels, including increased glutamatergic activity, altered functional connectivity and an aberrant increase in high-frequency oscillations. To bridge these different levels of observation, we have here performed large-scale multi-structure recordings in freely behaving rats treated with 5-HT2AR psychedelics (LSD, DOI) and NMDAR psychedelics (ketamine, PCP). While interneurons and principal cells showed disparate firing rate modulations for the two classes of psychedelics, the local field potentials revealed a shared pattern of synchronized high-frequency oscillations in the ventral striatum and several cortical areas. Remarkably, the phase differences between structures were close to zero, corresponding to <1 ms delays. Likely, this hypersynchrony has major effects on the integration of information across neuronal systems and we propose that it is a key contributor to changes in perception and cognition during psychedelic drug use. Potentially, similar mechanisms could induce hallucinations and delusions in psychotic disorders and would constitute promising targets for new antipsychotic treatments. Large-scale multi-structure recordings in freely behaving rats reveal that 5-HT2AR and NMDAR psychedelics induce similar hyper-synchronous states in the cognitive-limbic cortex-basal ganglia system [ABSTRACT FROM AUTHOR]

A fast and simple procedure based on microextraction by packed sorbent (MEPS) and liquid chromatography–tandem mass spectrometry (LC–MS/MS) has been developed for the simultaneous quantification of 28 synthetic hallucinogens in oral fluids, including lysergic acid diethylamide and substances from NBOMe, NBOH, NBF, 2C, and substituted amphetamine categories. Extraction conditions such as type of sorbent, sample pH, number of charge/discharge cycles, and elution volume were studied. Hallucinogenic compounds were extracted from oral fluid samples using C18 MEPS, loading with 100 μL sample (adjusted to pH 7) in 3 cycles, washing with 100 μL deionized water, and eluting with 50 μL methanol in 1 cycle, giving quantitative recoveries and no significant matrix effects. Limits of detection from 0.09 to 1.22 μg L−1; recoveries from 80 to 129% performed in spiked oral fluid samples at 20, 50, and 100 μg L−1; and high precision with relative standard deviations lower than 9% were obtained. The proposed methodology was demonstrated to be appropriate for the simple and sensitive determination of NBOMe derivates and other synthetic hallucinogenic substances in oral fluid samples. [ABSTRACT FROM AUTHOR]