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Introduction Methods Results Discussion and Conclusions This study explores the attitudes of psychologists towards psychedelics and psychedelic‐assisted therapy (PAT) following the world‐first regulatory changes in 2023 in Australia which permitted psilocybin and 3,4‐methylenedioxy‐methamphetamine (MDMA) to be used in clinical services.A purposive sample of 20 Australian psychologists was recruited using snowball sampling. Semi‐structured interviews were conducted which explored participants' attitudes, knowledge and concerns about PAT. Data were coded and analysed to identify and develop theme categories.Most psychologists exhibited positive attitudes towards psychedelics and their therapeutic potential, viewing them as promising for addressing chronic mental health conditions like depression. However, there was a notable concern regarding the limited evidence on efficacy and potential adverse experiences, as well as the complexity of the individualised treatment protocol. Despite enthusiasm, many psychologists had limited detailed knowledge about the interventions themselves. The need for comprehensive education and training programs, including exposure to psychedelic experiences and credible higher education institutions, was emphasised to ensure competence in administering PAT.Psychologists displayed notably positive attitudes towards PAT, likely reflecting both shifting perceptions of psychedelics and self‐selection bias within the sample. Despite this optimism, concerns were raised about psychiatric risks and the necessity for comprehensive and reputable training and supervision. The cohort showed openness to both novel treatments and innovative training methods, underscoring the importance of enhancing educational frameworks to ensure effective implementation of PAT. [ABSTRACT FROM AUTHOR]

Psychedelic drugs have seen a resurgence in interest as a next generation of psychiatric medicines with potential as rapid‐acting antidepressants (RAADs). Despite promising early clinical trials, the mechanisms which underlie the effects of psychedelics are poorly understood. For example, key questions such as whether antidepressant and psychedelic effects involve related or independent mechanisms are unresolved. Preclinical studies in relevant animal models are key to understanding the pharmacology of psychedelics and translating these findings to explain efficacy and safety in patients. Understanding the mechanisms of action associated with the behavioural effects of psychedelic drugs can also support the identification of novel drug targets and more effective treatments. Here we review the behavioural approaches currently used to quantify the psychedelic and antidepressant effects of psychedelic drugs. We discuss conceptual and methodological issues, the importance of using clinically relevant doses and the need to consider possible sex differences in preclinical psychedelic studies. [ABSTRACT FROM AUTHOR]

Psilocybin, the natural hallucinogen from Psilocybe (magic) mushrooms, is a highly promising drug candidate for the treatment of depression and several other mental health conditions. Biosynthesis of psilocybin from the amino acid l‐tryptophan involves four strictly sequential modifications. The third of these, ATP‐dependent phosphorylation of the intermediate 4‐hydroxytryptamine, is catalysed by PsiK. Here we present a crystallographic analysis and a structure‐based mutagenesis study of this kinase, providing insight into its mode of substrate recognition. The results of our work will support future bioengineering efforts aimed at generating variants of psilocybin with enhanced therapeutic properties. [ABSTRACT FROM AUTHOR]

Recent years have witnessed an unprecedented increase in the search for the use of psychedelics in improving physical and mental health. Anaesthesia has evolved since very early times, born from the need to eliminate pain and reduce suffering and there are reports of the use of anaesthetics to achieve mystical states since the nineteenth century. Nowadays, the renaissance of psychedelics in anaesthesia has been inspired by their potential in the treatment of chronic pain syndromes, palliative care and in the emergency department and pre‐hospital care with the administration of psychedelics in cases of ischaemia, given their potential in neuroprotection. Although there are already some published protocols for the administration of psychedelics in patients with mental illness, little has been addressed concerning non‐mental medical applications. In this sense, in patients with multiple comorbidities, functional limitations and polymedicated, the anaesthetist may play a fundamental role, not only in clinical practice, but also in translational research.This article focuses on the description of psychedelics, with a particular focus on dimethyltryptamine (DMT) and ayahuasca pharmacology, effects, safety and toxicity. A detailed description of the role of the anaesthetist in clinical and experimental research is provided, from participant's screening to preparation and dosing session, expected adverse effects and how to manage them, based on the protocol and standard procedures of a current study with neuroimaging during the psychedelic experience. Specific considerations regarding the management of psychedelic toxicity are also provided as well as future directions for safe psychedelic use in clinical practice. [ABSTRACT FROM AUTHOR]

Psychedelic drugs have profound effects on perception, cognition and mood. How psychedelics affect neural signaling to produce these effects remains poorly understood. We investigated the effect of the classic psychedelic psilocybin on neural activity patterns and spatial encoding in the retrosplenial cortex of head‐fixed mice navigating on a treadmill. The place specificity of neurons to distinct locations along the belt was reduced by psilocybin. Moreover, the stability of place‐related activity across trials decreased. Psilocybin also reduced the functional correlation among simultaneously recorded neurons. The 5‐HT2AR (serotonin 2A receptor) antagonist ketanserin blocked these effects. These data are consistent with proposals that psychedelics increase the entropy of neural signaling and provide a potential neural mechanism contributing to disorientation frequently reported by humans after taking psychedelics. [ABSTRACT FROM AUTHOR]

Artificial intelligence (AI) and psychedelic medicines are among the most high‐profile evolving disruptive innovations within mental healthcare in recent years. Although AI and psychedelics may not have historically shared any common ground, there exists the potential for these subjects to combine in generating innovative mental health treatment approaches. In order to inform our perspective, we conducted a scoping review of relevant literature up to late August 2024 via PubMed intersecting AI with psychomedical use of psychedelics. Our perspective covers the potential application of AI in psychedelic medicine for: drug discovery and clinical trial optimization (including pharmacodynamics); study design; understanding psychedelic experiences; personalization of treatments; clinical screening, delivery, and follow‐up (potentially delivered via chatbots/apps); application of psychological preparation, integration, and general mental health support; its role in enhancing treatment via brain modulatory devices (including virtual reality and haptic suits); and the consideration of ethical and security safeguards. Challenges include the need for sufficient data protection and security, and a range of necessary ethical protections. Future avenues of exploration could involve directly administering psychedelics (or providing algorithm‐generated effects) to inorganic AI‐interfaced neural networks that may exceed human brain activity (i.e., cognitive capacity) and intelligence. [ABSTRACT FROM AUTHOR]

Psilocybin is a classic psychedelic with demonstrated preliminary clinical efficacy in a range of psychiatric disorders. Evaluating the impact of psilocybin on cognitive function is essential to unravel its potential benefits and risks. In this systematic review, we assessed psilocybin's effect on cognitive function through a comprehensive search of electronic databases from inception to January 2024, identifying 20 articles involving 2,959 participants. While 85% of studies were conducted in healthy volunteers, most of these studies (85%) used macrodoses, ranging from 45 μg/kg to 30 mg/70 kg. Various cognitive aspects were evaluated and yielded mixed results. Global cognitive function, and processing speed remained mostly unchanged in healthy individuals; However, a limited number of studies reported improvements in certain areas such as sustained attention, working memory, and executive function especially in patients with treatment‐resistant depression (TRD). Emotional processing was positively modified, particularly in TRD patients. Psilocybin was observed to enhance emotional empathy without significantly altering cognitive empathy and social cognition. Cognitive flexibility and creative cognition were noted to initially decline but could potentially improve over time. Additionally, with respect to learning and memory skills, psilocybin showed promise in improving specific memory types such as semantic associations and associative learning, while its effects on episodic and verbal memory have been less pronounced compared to other cognitive enhancers. The observed mixed findings underscore the complexity of psilocybin's cognitive influence. Further research is essential to provide a clearer understanding of psilocybin's impact on cognitive domains and to guide the development of safe and effective interventions. [ABSTRACT FROM AUTHOR]

This brief review highlights some of the structure–activity relationships of classic serotonergic psychedelics. In particular, we discuss structural features of three chemotypes: phenethylamines, ergolines and certain tryptamines, which possess psychedelic activity in humans. Where they are known, we point out the underlying molecular mechanisms utilized by each of the three chemotypes of psychedelic molecules. With a focus on the 5‐HT2A receptor subtype, a G‐protein coupled receptor known to be the primary target of psychedelics, we refer to several X‐ray and cryoEM structures, with a variety of ligands bound, to illustrate the underlying atomistic basis for some of the known pharmacological observations of psychedelic drug actions. [ABSTRACT FROM AUTHOR]

Background and Purpose: Demand for new antidepressants has resulted in a re‐evaluation of the therapeutic potential of psychedelic drugs. Several tryptamines found in psilocybin‐containing "magic" mushrooms share chemical similarities with psilocybin. Early work suggests they may share biological targets. However, few studies have explored their pharmacological and behavioural effects. Experimental Approach: We compared baeocystin, norbaeocystin and aeruginascin with psilocybin to determine if they are metabolized by the same enzymes, similarly penetrate the blood–brain barrier, serve as ligands for similar receptors and modulate behaviour in rodents similarly. We also assessed the stability and optimal storage and handling conditions for each compound. Key Results: In vitro enzyme kinetics assays found that all compounds had nearly identical rates of dephosphorylation via alkaline phosphatase and metabolism by monoamine oxidase. Further, we found that only the dephosphorylated products of baeocystin and norbaeocystin crossed a blood–brain barrier mimetic to a similar degree as the dephosphorylated form of psilocybin, psilocin. The dephosphorylated form of norbaeocystin was found to activate the 5‐HT2A receptor with similar efficacy to psilocin and norpsilocin in in vitro cell imaging assays. Behaviourally, only psilocybin induced head twitch responses in rats, a marker of 5‐HT2A‐mediated psychedelic effects and hallucinogenic potential. However, like psilocybin, norbaeocystin improved outcomes in the forced swim test. All compounds caused minimal changes to metrics of renal and hepatic health, suggesting innocuous safety profiles. Conclusions and Implications: Collectively, this work suggests that other naturally occurring tryptamines, especially norbaeocystin, may share overlapping therapeutic potential with psilocybin, but without causing hallucinations. [ABSTRACT FROM AUTHOR]

Background Aim and Objectives Method Findings Conclusions Research on psychedelics centres on two key areas: the action of psychedelics on the brain and the protocol for delivering therapy. There is little research that considers the implications of this novel therapy on the therapist delivering the treatment. This research study sought to explore this.The aim of this research was to explore the considerations for psychotherapists interested in delivering psychedelic therapy. Objectives were to examine the therapeutic conditions needed for effective outcomes, to explore the perceived differences between the practice of standard psychotherapy and psychedelic therapy and to determine the challenges for therapists working in the field.Six semi‐structured interviews were conducted with therapists who work in clinical or retreat settings. Interview transcripts were analysed using qualitative thematic analysis.Three themes emerged that highlight the importance of preparation for effective clinical outcomes, the differences in standard and psychedelic practice and the personal and professional implications for therapists.The results highlighted challenges and revealed the need for clear protocols for integrating psychedelics into psychotherapy practice. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Short‐lasting unilateral neuralgiform headache attacks (SUNHA) are trigeminal autonomic cephalalgias that feature intense and recurrent paroxysms of pain and autonomic symptoms. Many patients are left with debilitating symptoms despite best‐available treatment. Psychedelics, such as the serotonin 2A partial agonist psilocybin, have shown promise in related disorders such as migraine and cluster headache. In this open‐label phase Ib ascending dose study, we aimed to assess the effects of low‐dose oral psilocybin with psychological support in six to 12 patients with chronic SUNHA. Study objectives were to determine effects on cognition, as well as safety, tolerability, and effects on headache severity and frequency.Oral psilocybin in ascending doses of 5, 7.5, and 10 mg (one dose per session; three dosing sessions in total) were administered. Cognition was assessed via the Cambridge Neuropsychological Tests Automated Battery. Headache attacks were assessed via headache diaries and the six‐item Headache Impact Test (HIT‐6). Subjective dose intensity was assessed via the five‐Dimensional Altered States of Consciousness Questionnaire (5D‐ASC). The study was terminated early due to recruitment difficulties; four patients were enrolled, three of whom were study completers. Post hoc, we undertook a thematic analysis of the applicable free‐text clinical trial notes from the dosing and subsequent visits (n = 22). An inductive method was employed to establish emergent themes.No significant adverse events were recorded. We were unable to collect data as planned on cognitive function during the acute experience due to high ratings of subjective dose intensity (mean 5D‐ASC scores 37.8–45.7). The impact of the headaches remained severe throughout the duration of the trial (HIT‐6 mean scores 64.3–65.7). There were limited effects on headache duration and severity based on the diaries; however, mean daily attack frequency decreased by >50% in two participants at final follow‐up (22.9 to 11.0 and 56.4 to 28.0, respectively). Completing participants and their clinicians recorded “much” (two participants) or “minimal” improvements (one participant) at final follow‐up via the Clinical Global Impression rating scale. Thematic analysis indicated that psychological insights were key features of participants’ experience; these insights included re‐configured relationships to their headache pain.The study met with recruitment difficulties and cognition could not be assessed during the acute experience due to subjective dose intensity, likely mediated in part by expectancy effects. The clinical results provide no conclusive evidence for the use of psilocybin in SUNHA. We suggest that accounting for psychological factors in chronic SUNHA may be an important facet of treatment. [ABSTRACT FROM AUTHOR]

Psilocybin is the main psychoactive compound found in hallucinogenic/magic mushrooms and can bind to both serotonergic and tropomyosin receptor kinase b (TrkB) receptors. Psilocybin has begun to show efficacy for a range of neuropsychiatric conditions, including treatment‐resistant depression and anxiety disorders; however, neurobiological mechanisms are still being elucidated. Clinical research has found that psilocybin can alter functional connectivity patterns in human brains, which is often associated with therapeutic outcomes. However, preclinical research affords the opportunity to assess the potential cellular mechanisms by which psilocybin may exert its therapeutic effects. Preclinical rodent models can also facilitate a more tightly controlled experimental context and minimise placebo effects. Furthermore, where there is a rationale, preclinical researchers can investigate psilocybin administration in neuropsychiatric conditions that have not yet been researched clinically. As a result, we have systematically reviewed the knowledge base, identifying 82 preclinical studies which were screened based on specific criteria. This resulted in the exclusion of 44 articles, with 34 articles being included in the main review and another 2 articles included as Supporting Information materials. We found that psilocybin shows promise as a lead candidate molecule for treating a variety of neuropsychiatric conditions, albeit showing the most efficacy for depression. We discuss the experimental findings, and identify possible mechanisms whereby psilocybin could invoke therapeutic changes. Furthermore, we critically evaluate the between‐study heterogeneity and possible future research avenues. Our review suggests that preclinical rodent models can provide valid and translatable tools for researching novel psilocybin‐induced molecular and cellular mechanisms, and therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Psilocybin shows promise as a treatment for CRPS, offering significant pain relief and functional improvement in a patient with refractory symptoms. This case highlights the need for further research into psilocybin's efficacy and optimal dosing for chronic pain management. [ABSTRACT FROM AUTHOR]

Key Clinical Message: This case study describes the feasibility and safety of psychedelic‐assisted therapy (PAT) as a home‐based intervention for a patient with throat cancer experiencing significant existential distress. The patient tolerated the intervention well. This case supports the feasibility and safety of PAT for patients with life‐threatening conditions in a home setting. Psychedelic‐assisted therapy (PAT), as it is practiced today, merges traditional psychotherapeutic techniques with the use of psychedelics such as LSD, psilocybin, or MDMA with the aim of unlocking deeper insights in patients and treating mental conditions that are resistant to other forms of therapy. The present case study describes the safety of PAT as a home‐based intervention for a patient with throat cancer experiencing significant existential distress. The patient tolerated the intervention well and was asked to report on measures of anxiety, depression, and distress related to his somatic condition. The observations provided by this clinical case report align with previous findings, suggesting that PAT can be safely applied to potentially provide relief from existential distress in patients with life‐threatening conditions. As this is a single‐case study, generalizations should be made cautiously. Moreover, placebo effects, expectancy effects, and the natural course of the disease may influence outcomes. Future research should consider controlled trials to ascertain the efficacy and safety of such interventions in diverse settings. [ABSTRACT FROM AUTHOR]

Background and aims: Lysergic acid diethylamide (LSD) and psilocybin are used as recreational drugs, and there is renewed interest in their clinical use. The current study aimed to (1) determine the circumstances of death and case characteristics of LSD‐ and psilocybin‐related death in Australia, 2000–23; and (2) determine the toxicological profile and major autopsy findings of these cases. Methods: This was a retrospective exploratory study of all cases of LSD‐ and psilocybin‐related death in Australia, 2000–23, retrieved from the National Coronial Information System. Results: A total of 43 cases were identified: 33 LSD and 10 psilocybin. The median ages were 24 years [interquartile range (IQR) = 13, range = 16–53] (LSD) and 26 years (IQR = 18.5, range = 20–58) (psilocybin), and fewer than five cases were female. The most common circumstance of death among both groups was traumatic accident (LSD 36.4%, psilocybin 40.0%). There were 12 cases of self‐harm, all of which involved LSD, all by physical means. In a fifth, death was attributed to multiple drug toxicity (LSD 18.2%, psilocybin 20.0%). In one case, death was attributed solely to LSD toxicity, while in a further two cases death was attributed to a cardiovascular event following LSD consumption (one LSD only, one multiple drug toxicity). In four psilocybin cases, the cause of death was undetermined. The most common clinical presentation was severe agitation (LSD 27.3%, psilocybin 20.0%). Median blood concentrations were LSD 0.8 μg/l (IQR = 1.7, range = 0.1–3), psilocin 20 μg/l (IQR = 53.5, range = 6–83). LSD was the only drug present in 25.0% of LSD cases and psilocybin in 20.0% of psilocybin cases. Pre‐existing organ pathology was uncommon. Conclusions: Lysergic acid diethylamide (LSD)‐ and psilocybin‐related death in Australia from 2000 to 2023 was primarily due to traumatic injury, whether through accident or self‐harm. Cases of acute toxic reactions that were attributed solely to LSD were rare. [ABSTRACT FROM AUTHOR]

It is a paradox that psychotomimetic drugs can relieve symptoms that increase risk of and cooccur with psychosis, such as attention and motivational deficits (e.g., amphetamines), pain (e.g., cannabis) and symptoms of depression (e.g., psychedelics, dissociatives). We introduce the ideas of psychotomimetic compensation and psychotomimetic sensitization to explain this paradox. Psychotomimetic compensation refers to a short‐term stressor or drug‐induced compensation against stress that is facilitated by engagement of neurotransmitter/modulator systems (endocannabinoid, serotonergic, glutamatergic and dopaminergic) that mediate the effects of common psychotomimetic drugs. Psychotomimetic sensitization occurs after repeated exposure to stress and/or drugs and is evidenced by the gradual intensification and increase of psychotic‐like experiences over time. Theoretical and practical implications of this model are discussed. [ABSTRACT FROM AUTHOR]

Pain, a comorbidity of anxiety disorders, causes substantial clinical, social, and economic burdens. Emerging evidence suggests that propofol, the most commonly used general anesthetic, may regulate psychological disorders; however, its role in pain‐associated anxiety is not yet described. This study investigates the therapeutic potential of a single dose of propofol (100 mg kg−1) in alleviating pain‐associated anxiety and examines the underlying neural mechanisms. In acute and chronic pain models, propofol decreased anxiety‐like behaviors in the elevated plus maze (EPM) and open field (OF) tests. Propofol also reduced the serum levels of stress‐related hormones including corticosterone, corticotropin‐releasing hormone (CRH), and norepinephrine. Fiber photometry recordings indicated that the calcium signaling activity of CRH neurons in the paraventricular nucleus (PVNCRH) is reduced after propofol treatment. Interestingly, artificially activating PVNCRH neurons through chemogenetics interfered with the anxiety‐reducing effects of propofol. Electrophysiological recordings indicated that propofol decreases the activity of PVNCRH neurons by increasing spontaneous inhibitory postsynaptic currents (sIPSCs). Further, reducing the levels of γ‐aminobutyric acid type A receptor β3 (GABAAβ3) subunits in PVNCRH neurons diminished the anxiety‐relieving effects of propofol. In conclusion, this study provides a mechanistic and preclinical rationale to treat pain‐associated anxiety‐like behaviors using a single dose of propofol. [ABSTRACT FROM AUTHOR]

Psychoactive substances obtained from botanicals have been applied for a wide variety of purposes in the rituals of different cultures for thousands of years. Classical psychedelics from N,N′‐dimethyltryptamine, psilocybin, mescaline and various lysergamides cause specific alterations in perception, emotion and cognition by acting through serotonin 5‐HT2A receptor activation. Lysergic acid diethylamide, the first famous breakthrough in the field, was discovered by chance by Albert Hoffman in the Zurich Sandoz laboratory in 1943, and studies on its psychoactive effects began to take place in the literature. Studies in this area were blocked after the legislation controlling the use and research of psychedelic drugs came into force in 1967, but since the 1990s, it has started to be a matter of scientific curiosity again by various research groups. In particular, with the crucial reports of psychotherapy‐assisted psilocybin applications for life‐threatening cancer‐related anxiety and depression, a new avenues have been opened in the treatment of psychiatric diseases such as treatment‐resistant depression and substance addictions. An increasing number of studies show that psychedelics have a very promising potential in the treatment of neuropsychiatric diseases where the desired efficiency cannot be achieved with conventional treatment methods. In this context, we discuss psychedelic therapy, encompassing its historical development, therapeutic applications and potential treatment effects—especially in depression, trauma disorders and substance use disorders—within the framework of ethical considerations. [ABSTRACT FROM AUTHOR]

The turn of the century brought a resurgence of interest in psychedelics as a treatment for addiction and other psychiatric conditions, accompanied by extensive positive media attention and private equity investment. Government regulatory bodies in Australia, Israel, Canada and the United States now permit use of psychedelics for medical purposes. In the United States, citizen action and corporate financing have led to petitions and ballot initiatives to legalize psilocybin and other psychedelics for medical and recreational use. Given this momentum, policymakers must grapple with important questions that define whether and how psychedelics are made available to the public, as well as how companies produce and promote them. The current push to broaden the production, sale, and use of psychedelics bears many parallels to the movement to legalize cannabis in the United States and other nations—most notably, the use of poorly‐evidenced therapeutic claims to create a de facto recreational market via the health care system. Experience with cannabis highlights the value of debating the question of legalization for nonmedical use as such rather than misrepresenting it as a medical issue. The lessons of cannabis policy also suggest a need to challenge hyping of psychedelic research findings; to promote rigorous clinical research on dosing and potency; to minimize the influence of for‐profit industry in shaping policies to their economic advantage; and to coordinate federal, state, and local governments to regulate the manufacture, sale and distribution of psychedelic drugs (regardless of whether they are legalized for medical and/or recreational use). [ABSTRACT FROM AUTHOR]

Key Clinical Message: Long‐COVID syndrome lacks effective holistic treatment options. We present a case of a 41‐year‐old fully vaccinated female with Long‐COVID syndrome who obtained significant symptomatic relief after self‐medicating with psilocybin and MDMA. Long‐COVID, a syndrome persisting after the acute phase of coronavirus disease 2019 (COVID‐19), lacks effective holistic treatment options. We present a case of a 41‐year‐old fully vaccinated female with Long‐COVID syndrome who obtained significant symptomatic relief by self‐prescribing psilocybin and MDMA. Future research is needed to assess safety and efficacy. [ABSTRACT FROM AUTHOR]

The article argues for safety monitoring systems and regulation of services when expanding access to psychedelics to reduce harm, with reference to a study which characterized lysergic acid diethyl acid dietylamide and psilocybin-related deaths in Australia. It urges for better systems for assessing population risks in regulated and unregulated settings, tracking of adverse effects and benefits, and enrollment of people who use psychedelics in secure data collection systems.

For some patients with psoriasis, orally administered small molecule inhibitors of interleukin (IL)‐17A may represent a convenient alternative to IL‐17A‐targeting monoclonal antibodies. This first‐in‐human study assessed the safety, tolerability, pharmacokinetics (PKs), and peripherally circulating IL‐17A target engagement profile of single or multiple oral doses of the small molecule IL‐17A inhibitor LY3509754 (NCT04586920). Healthy participants were randomly assigned to receive LY3509754 or placebo in sequential escalating single ascending dose (SAD; dose range 10–2,000 mg) or multiple ascending dose (MAD; dose range 100–1,000 mg daily for 14 days) cohorts. The study enrolled 91 participants (SAD, N = 51 and MAD, N = 40) aged 21–65 years (71% men). LY3509754 had a time to maximum concentration (Tmax) of 1.5–3.5 hours, terminal half‐life of 11.4–19.1 hours, and exhibited dose‐dependent increases in exposure. LY3509754 had strong target engagement, indicated by elevated plasma IL‐17A levels within 12 hours of dosing. Four participants from the 400‐mg (n = 1) and 1,000‐mg (n = 3) MAD cohorts experienced increased liver transaminases or acute hepatitis (onset ≥ 12 days post‐last LY3509754 dose), consistent with drug‐induced liver injury (DILI). One case of acute hepatitis was severe, resulted in temporary hospitalization, and was classified as a serious adverse event. No adverse effects on other major organ systems were observed. Liver biopsies from three of the four participants revealed lymphocyte‐rich, moderate‐to‐severe lobular inflammation. We theorize that the DILI relates to an off‐target effect rather than IL‐17A inhibition. In conclusion, despite strong target engagement and a PK profile that supported once‐daily administration, this study showed that oral dosing with LY3509754 was poorly tolerated. [ABSTRACT FROM AUTHOR]

Background: Depression is common in patients with cancer and is associated with lower treatment adherence and reduced quality of life. Antidepressants and psychotherapy have limited success in improving depression among patients with cancer. This study explored the safety, feasibility, and efficacy of psilocybin‐assisted therapy in patients with cancer and major depressive disorder. Methods: This phase 2, open‐label trial enrolled patients with curable and noncurable cancer and major depressive disorder at a single community oncology practice site. A single 25‐mg dose of psilocybin was administered simultaneously to cohorts of three to four participants with individual (4.25 hours in 1:1 therapist‐to‐patient ratio) and group therapeutic support (3.75 hours) before, during, and after psilocybin administration. Outcomes included depression severity, anxiety, pain, demoralization, and disability. Results: Thirty participants completed the study. No psilocybin‐related serious adverse events occurred; treatment‐related adverse events (e.g., nausea, headache) were generally mild and expected. There were no laboratory or electrocardiogram abnormalities. No suicidality was reported. Efficacy was suggested with a robust reduction in depression severity scores from baseline to posttreatment of 19.1 points (95% CI, 22.3 to –16.0; p <.0001) by week 8. Eighty percent of participants demonstrated a sustained response to psilocybin treatment; 50% showed full remission of depressive symptoms at week 1, which was sustained for 8 weeks. Conclusions: Psilocybin‐assisted therapy in group cohort administration was safe and feasible in patients with cancer and depression. Efficacy was suggested based on clinically meaningful reductions in depressive symptoms. The novel, group‐oriented format, compact delivery time, community cancer center setting, and one‐to‐one therapist‐to‐patient ratio could also add to therapeutic gains and efficiency of administration. Trial Registration: NCT04593563. Plain Language Summary: Depression is common in patients with cancer and associated with lower treatment adherence, reduced quality of life, and limited response to antidepressants and psychotherapy.We conducted a phase 2 trial to study a single dose of psilocybin administered in a group therapy setting with one‐to‐one therapist‐to‐participant psychological support to patients with curable and noncurable cancer and major depressive disorder.Findings of the study showed safety (no treatment‐related serious adverse events or suicidality) with psilocybin and suggested efficacy, with a significant reduction in depression severity scores from baseline to posttreatment. Further investigation is warranted. A phase 2 study explored the safety, feasibility, and efficacy of psilocybin‐assisted therapy in a community cancer setting in 30 patients with cancer and major depressive disorder. Psilocybin‐assisted therapy in group cohort administration was safe and feasible, as demonstrated by a robust reduction in depression severity scores from baseline to posttreatment of 19.1 points (95% CI, 22.3 to –16.0; p <.0001) by week 8. [ABSTRACT FROM AUTHOR]

Summary: Sleep bruxism (SB) has been associated with biological and psychosocial factors. The assessment of SB includes self‐report, clinical evaluation, and polysomnography. This study aimed to investigate the associations of self‐reported SB with other sleep disorders and demographic, psychological, and lifestyle factors in the adult general population, and to investigate whether self‐reported SB and polysomnographically (PSG) confirmed SB provide similar outcomes in terms of their associated factors. We recruited 915 adults from the general population in Sao Paulo, Brazil. All participants underwent a one‐night PSG recording and answered questions about sex, age, BMI, insomnia, OSA risk, anxiety, depression, average caffeine consumption, smoking frequency, and alcohol consumption frequency. We investigated the link between SB and the other variables in univariate, multivariate, and network models, and we repeated each model once with self‐reported SB and once with PSG‐confirmed SB. Self‐reported SB was only significantly associated with sex (p = 0.042), anxiety (p = 0.002), and depression (p = 0.03) in the univariate analysis, and was associated with insomnia in the univariate (p < 0.001) and multivariate (β = 1.054, 95%CI 1.018–1.092, p = 0.003) analyses. Network analysis showed that self‐reported SB had a direct positive edge to insomnia, while PSG‐confirmed SB was not significantly associated with any of the other variables. Thus, sleep bruxism was positively associated with insomnia only when self‐reported, while PSG‐confirmed SB was not associated with any of the included factors. [ABSTRACT FROM AUTHOR]

Point mutations in the α‐synuclein coding gene may lead to the development of Parkinson's disease (PD). PD is often accompanied by other psychiatric conditions, such as anxiety, depression, and drug use disorders, which typically emerge in adulthood. Some of these point mutations, such as SNCA and A30T, have been linked to behavioral effects that are not commonly associated with PD, especially regarding alcohol consumption patterns. In this study, we investigated whether the familial PD point mutation A53T is associated with changes in alcohol consumption behavior and emotional states at ages not yet characterized by α‐synuclein accumulation. The affective and alcohol‐drinking phenotypes remained unaltered in female PDGF‐hA53T‐synuclein‐transgenic (A53T) mice during both early and late adulthood. Brain region‐specific activation of ceramide‐producing enzymes, acid sphingomyelinase (ASM), and neutral sphingomyelinase (NSM), known for their neuroprotective properties, was observed during early adulthood but not in late adulthood. In males, the A53T mutation was linked to a reduction in alcohol consumption in both early and late adulthood. However, male A53T mice displayed increased anxiety‐ and depression‐like behaviors during both early and late adulthood. Enhanced ASM activity in the dorsal mesencephalon and ventral hippocampus may potentially contribute to these adverse behavioral effects of the mutation in males during late adulthood. In summary, the A53T gene mutation was associated with diverse changes in emotional states and alcohol consumption behavior long before the onset of PD, and these effects varied by sex. These alterations in behavior may be linked to changes in brain ceramide metabolism. [ABSTRACT FROM AUTHOR]

There has been burgeoning interest in psilocybin‐use for the treatment of various neurological and neurodegenerative diseases. Psilocybin is mistakenly perceived as the principal pharmacologically active compound due to its high concentrations found in magic mushrooms; however, it is the prodrug of psilocin. Despite the expanding body of clinical research seeking to understand the pharmacodynamic/pharmacokinetic properties of psilocin, and its role in inducing dramatic changes to cognitive function, there has not been a corresponding increase in the development of sensitive analytical methods that can quantify psilocin in different biological fluids. Existing analytical methods have been developed using plasma, serum, and urine as the matrix of choice, but with the unknown blood‐to‐plasma ratio of psilocin, any pharmacokinetic conclusions drawn solely on plasma data may be misleading. Thus, the main objective of this study is to develop the first analytical method that utilizes SPE and LC–MS/MS to quantify psilocin in human whole blood. The SPE procedure yielded a high recovery efficiency (≥89%) with minimal matrix effects. The method was validated according to ANSI/ASB 036 guidelines. Linearity was between 0.7–200 ng/mL and encompassed previously reported ranges found in plasma/serum. Bias, within‐ and between‐run precision for all quality controls met ANSI/ASB 036 acceptability criteria. Endogenous/exogenous interferences and carryover were negligible. Psilocin stability was assessed at 4°C over 48 h and was considered stable. Although a proof‐of‐concept study will need to be performed to characterize the method, this analytical workflow was able to detect and quantify psilocin in human whole blood at low limits of quantification. [ABSTRACT FROM AUTHOR]

Serotonergic psychedelics, such as lysergic acid diethylamide (LSD), psilocybin, dimethyltryptamine (DMT), and 5‐methoxy‐N,N‐dimethyltryptamine (5‐MeO‐DMT), are currently being investigated for the treatment of psychiatric disorders such as depression and anxiety. Clinical trials with psilocybin and LSD have shown improvement in emotional and psychological scores. Although these drugs are reported to be safe in a controlled environment (such as clinical trials), exposure to low doses of these drugs can result in psychedelic effects, and therefore, occupational safety is an important consideration to prevent adverse effects in the workplace from low daily exposure. This article will discuss the factors involved in the derivation of occupational exposure limits (OELs) and risk assessment of these psychedelic drugs. To support the OEL derivations of psychedelic drugs, information regarding their mechanism of action, adverse effect profiles, pharmacokinetics, clinical effects, and nonclinical toxicity were considered. Additionally, psilocybin and LSD, which are the most extensively researched psychedelic substances, are employed as illustrative examples in case studies. The OELs derived for psilocybin and for LSD are 0.05 and 0.002 μg/m3, respectively, which indicates that these are highly hazardous compounds, and it is important to take into account suitable safety measures and risk‐management strategies in order to minimize workplace exposure. Clinical trials are currently exploring the potential of psychedelics such as LSD, psilocybin, DMT, and 5‐MeO‐DMT for treating psychiatric disorders. It is crucial to consider the occupational risks associated with these drugs, especially their psychedelic effects at low doses. This article focuses on establishing occupational exposure limits (OELs) for psychedelic substances, with psilocybin and LSD as examples. The derived OELs for both compounds are below 0.05 μg/m3, indicating the importance of effectively controlling occupational exposure to these substances. [ABSTRACT FROM AUTHOR]

Objective: Can machine learning (ML) enable data-driven discovery of how changes in sentiment correlate with different psychoactive experiences? We investigate by training models directly on text testimonials from a diverse 52-drug pharmacopeia. Methods: Using large language models (i.e. BERT) and 11,816 publicly-available testimonials, we predicted 28-dimensions of sentiment across each narrative, and then validated these predictions with adjudication by a clinical psychiatrist. BERT was then fine-tuned to predict biochemical and demographic information from these narratives. Lastly, canonical correlation analysis linked the drugs' receptor affinities with word usage, revealing 11 statistically-significant latent receptorexperience factors, each mapped to a 3D cortical Atlas. Results: These methods elucidate a neurobiologically-informed, sequence-sensitive portrait of drug-induced subjective experiences. The models' results converged, revealing a pervasive distinction between the universal psychedelic heights of feeling in contrast to the grim, mundane, and personal experiences of addiction and mental illness. Notably, MDMA was linked to "Love", DMT and 5-MeO-DMT to "Mystical Experiences" and "Entities and Beings", and other tryptamines to "Surprise", "Curiosity" and "Realization". Conclusions: ML methods can create unified and robust quantifications of subjective experiences with many different psychoactive substances and timescales. The representations learned are evocative and mutually confirmatory, indicating great potential for ML in characterizing psychoactivity. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the feasibility and prophylactic effect of psilocybin as well as its effects on hypothalamic functional connectivity (FC) in patients with chronic cluster headache (CCH). Background: CCH is an excruciating and difficult‐to‐treat disorder with incompletely understood pathophysiology, although hypothalamic dysfunction has been implicated. Psilocybin may have beneficial prophylactic effects, but clinical evidence is limited. Methods: In this small open‐label clinical trial, 10 patients with CCH were included and maintained headache diaries for 10 weeks. Patients received three doses of peroral psilocybin (0.14 mg/kg) on the first day of weeks five, six, and seven. The first 4 weeks served as baseline and the last 4 weeks as follow‐up. Hypothalamic FC was determined using functional magnetic resonance imaging the day before the first psilocybin dose and 1 week after the last dose. Results: The treatment was well tolerated. Attack frequency was reduced by mean (standard deviation) 31% (31) from baseline to follow‐up (pFWER = 0.008). One patient experienced 21 weeks of complete remission. Changes in hypothalamic–diencephalic FC correlated negatively with a percent change in attack frequency (pFWER = 0.03, R = −0.81), implicating this neural pathway in treatment response. Conclusion: Our results indicate that psilocybin may have prophylactic potential and implicates the hypothalamus in possible treatment response. Further clinical studies are warranted. [ABSTRACT FROM AUTHOR]

Music and psychedelics have been intertwined throughout the existence of Homo sapiens, from the early shamanic rituals of the Americas and Africa to the modern use of psychedelic‐assisted therapy for a variety of mental health conditions. Across such settings, music has been highly prized for its ability to guide the psychedelic experience. Here, we examine the interplay between music and psychedelics, starting by describing their association with the brain's functional hierarchy that is relied upon for music perception and its psychedelic‐induced manipulation, as well as an exploration of the limited research on their mechanistic neural overlap. We explore music's role in Western psychedelic therapy and the use of music in indigenous psychedelic rituals, with a specific focus on ayahuasca and the Santo Daime Church. Furthermore, we explore work relating to the evolution and onset of music and psychedelic use. Finally, we consider music's potential to lead to altered states of consciousness in the absence of psychedelics as well as the development of psychedelic music. Here, we provide an overview of several perspectives on the interaction between psychedelic use and music—a topic with growing interest given increasing excitement relating to the therapeutic efficacy of psychedelic interventions. [ABSTRACT FROM AUTHOR]

This perspective paper explores the choice of psychotherapy for psilocybin‐assisted psychotherapy for treatment‐resistant depression. There is evidence to support the use of some psychotherapies in treating 'treatment‐resistant' depression, and emerging evidence for the efficacy of psilocybin. The next step which is the focus of this paper is to identify psychotherapies that are both effective and congruent with the psilocybin experience. The evidence for the efficacy of the psychotherapies is drawn from a Cochrane review and the analysis of their congruence with the psilocybin experience is drawn from a qualitative meta‐synthesis of the experience of psilocybin. The paper will examine whether three one‐to‐one psychotherapies identified as effective in the treatment of treatment‐resistant depression are compatible with the psilocybin experience. Each psychotherapy will be examined in relation to its congruence with the qualitative evidence that suggests the choice of psychotherapy needs to give priority to the subjective experience, facilitate emotional processing, support connectedness with others, acceptance of the self as emotional and support change based on the person's insights into their relationships with others and the world in which they live. We conclude that interpersonal psychotherapy and intensive short‐term dynamic psychotherapy align with that experience, although others are currently being trialled. [ABSTRACT FROM AUTHOR]

Several recent studies have investigated psilocybin as a novel therapeutic compound for the treatment of existential distress in patients with cancer, demonstrating persistent, positive effects on mood. This editorial discusses two articles in the current issue of Cancer that report findings of a group‐based psilocybin‐assisted intervention for treatment of depression in patients diagnosed with cancer. [ABSTRACT FROM AUTHOR]

This article explores the potential effects of psychedelic substances on the release of glucagon, a hormone involved in regulating glucose levels in the body. The author discusses the role of neurotransmitters in the pancreas and how they influence glucagon release. They propose several mechanisms through which psychedelics could impact glucagon secretion, including direct targeting of neurotransmitter receptors, effects on the autonomic nervous system, and modulation of the sensitivity of neurotransmitter receptors. The article suggests that further research is needed to understand the potential metabolic impacts of psychedelics and their implications for conditions like diabetes. However, the use of psychedelics in a clinical setting would require thorough evaluation of their effectiveness and safety, as well as consideration of potential interactions with existing medications and mental health conditions. The author emphasizes the need for scientifically robust and ethically responsible research in this field. [Extracted from the article]

Objective: This study invited providers who care for patients with eating disorders to inform engagement, communication, and collaboration with psilocybin‐assisted psychotherapy interventions. Method: Medical and mental health providers who treat patients with eating disorders were recruited via professional referral networks and participant driven sampling from across California to participate in one of five focus groups. Discussion topics included prior knowledge of psychedelic therapy, interest/concerns related to psilocybin therapy, and opportunities for collaboration. Study team members completed iterative rounds of coding with a grounded theory approach. Results: A total of 32 participants reported a range of familiarity with psychedelics. Some raised concerns about the risks of administering psilocybin to malnourished patients and to those with psychological comorbidities. Despite these concerns, participants were hopeful to see psilocybin therapy as a treatment for patients with eating disorders. In anticipating challenges, providers had concerns about equity in access to care among publicly insured and non‐English speaking patients. They requested opportunities for continuing education about psilocybin therapy. Discussion: Our findings demonstrate provider interest in psilocybin therapy for the treatment of patients with eating disorders. As psilocybin therapy interventions are developed, providers caring for patients with eating disorders value collaboration to improve longitudinal patient outcomes. Public Significance: This study invited healthcare providers of patients with eating disorders to discuss their thoughts around the use of psilocybin‐assisted psychotherapy in this population. Findings will help inform emerging psilocybin therapy clinical trials with the goal of successful translation and adoption in real world clinical settings. [ABSTRACT FROM AUTHOR]

Fluorescence microscopy has revolutionized the visualization of physiological processes in live‐cell systems. With the recent innovations in super resolution microscopy, these events can be examined with high precision and accuracy. The development of fluorescently labelled small molecules has provided a significant advance in understanding the physiological relevance of targeted proteins that can now be visualized at the cellular level. One set of physiologically important target proteins are the monoamine transporters (MATs) that play an instrumental role in maintaining monoamine signalling homeostasis. Understanding the mechanisms underlying their regulation and dysregulation is fundamental to treating several neuropsychiatric conditions such as attention deficit hyperactivity disorder (ADHD), anxiety, depression and substance use disorders. Herein, we describe the rationale behind the small molecule design of fluorescently labelled ligands (FLL) either as MAT substrates or inhibitors as well as their applications to advance our understanding of this class of transporters in health and disease. [ABSTRACT FROM AUTHOR]

Introduction: High levels of sugar intake are associated with multiple maladaptive health outcomes in adult and younger populations. Identifying the psychological determinants of sugar intake in adolescents, and the processes involved, may help identify potentially modifiable targets and inform intervention development. We tested the predictions of an extended theoretical model based on the theory of planned behavior (TPB), which specified social cognition constructs, habit, and self‐control as correlates of sugar intake in an adolescent sample. Methods: Adolescents aged 12 to 14 years (N = 88) recruited via a survey panel company and consenting to participate in the study completed online self‐report measures of constructs from the TPB alongside measures of habit and self‐control. One month later, participants completed a follow‐up measure of free‐sugar intake. Hypothesized effects of our proposed extended model were tested using partial least squares structural equation modeling. Results: We found statistically significant effects of attitude, subjective norm, and perceived behavioral control on sugar intake intentions. We also found significant effects of habit and self‐control on sugar intake measured at follow‐up, but no effect for intention. Perceived behavioral control moderated the intention–behavior relationship such that intention effects on behavior were larger when perceived behavioral control was high. However, self‐control did not moderate the intention–behavior relationship. Conclusion: Results indicate that sugar intake in this sample was a function of habits and self‐control, and the effect of sugar intake intentions was conditional on perceived behavioral control. Results contribute to an evidence base of determinants and associated processes that relate to sugar intake in adolescents and may signal potentially modifiable targets for intervention. [ABSTRACT FROM AUTHOR]

Psychoactive substances such as psilocybin and 3,4‐methylenedioxy‐methamphetamine (MDMA) are currently being investigated for a variety of psychiatric indications including major depressive disorder and post‐traumatic stress disorder. It is critical that clinicians working in the mental health field understand the regulatory framework that balances access and control for such substances. While both psilocybin and MDMA are designated as "Breakthrough Therapy" by the Food and Drug Administration (FDA), they remain classified as Schedule I substances under the Controlled Substances Act (CSA) of 1970. There are programs such as Expanded Access (EA) and federal Right‐to‐Try (RTT) legislation that can accommodate patient access to investigational drugs under certain circumstances, but these programs are not without their limits—particularly for Schedule I substances that do not currently have an accepted medical use per the CSA. It is in the clinical community's best interest to understand the administrative procedures, key court cases, and federal legislative initiatives related to these substances in order to make well‐informed decisions for themselves and their patients. Furthermore, understanding the administrative proceedings related to controlled substances will also allow subject matter experts to participate in and shape the policies governing such substances. [ABSTRACT FROM AUTHOR]

This paper addresses the possible effects of psychedelic drugs, notably psilocybin, on moral bio‐enhancement (MBE). It will be argued that non‐psychedelic substances, such as oxytocin, serotonin/serotonin reuptake inhibitors, or vasopressin, have indirect effects on M(B)E, whereas psilocybin has direct effects. Additionally, morality and happiness have been shown to operate in a circularly supportive relationship. It will be argued that psilocybin also has more direct effects on the augmentation of human happiness than non‐psychedelic substances. Hence, psilocybin multiplies its effects on morality and on moral enhancement (as well as on happiness) if compared with non‐psychedelic substances. Still, caution is advised if psilocybin is being used, and the correct dosage should be prescribed by an appropriate physician. Furthermore, the use of psilocybin has additional effects on moral enhancement and happiness if combined with meditation, preferably under the guidance of an experienced meditation specialist. [ABSTRACT FROM AUTHOR]

This article discusses a study that aimed to investigate the use of low-dose psilocybin combined with psychological support as a potential treatment for short-lasting unilateral neuralgiform headache attacks (SUNHA). The study faced challenges in recruiting participants, and only three individuals were able to complete the trial. The participants reported intense psychedelic experiences, and data collection for cognitive tests was problematic. While there may have been modest improvements in headache severity and frequency for some participants, the study was unable to draw firm conclusions about the effectiveness of psilocybin as a treatment for SUNHA. The results of this small study may provide insights for future researchers facing similar recruitment challenges in studying SUNHA. [Extracted from the article]

There is increasing clinical interest in the use of psilocybin. There is emerging evidence of the efficacy of psilocybin for the treatment of a range of clinical conditions. Mental health nurses have a unique set of skills for caring for people who are hallucinating. To expand these skills to meet the developing clinical interest in the therapeutic use of psilocybin, it is helpful to understand the experience from the perspective of the person being treated with psilocybin. A qualitative meta‐synthesis was conducted to examine how those with psilocybin described their experiences to identify whether its effects are similar across different health conditions. Ten studies were included in the review. The health conditions studied were cancer, depression, HIV, substance use disorder, smoking cessation and trauma. The synthesis of findings identified three themes that were common across the studies despite the health condition: acceptance, connection and transformation. The review provides helpful insights into how people experience psilocybin and its effects on their health condition. [ABSTRACT FROM AUTHOR]

2,5‐dimethoxy‐4‐bromophenethylamine (2C‐B) is a hallucinogenic phenethylamine derived from mescaline. Observational and preclinical data have suggested it to be capable of producing both subjective and emotional effects on par with other classical psychedelics and entactogens. Whereas it is the most prevalently used novel serotonergic hallucinogen to date, it's acute effects and distinctions from classical progenitors have yet to be characterized in a controlled study. We assessed for the first time the immediate acute subjective, cognitive, and cardiovascular effects of 2C‐B (20 mg) in comparison to psilocybin (15 mg) and placebo in a within‐subjects, double‐blind, placebo‐controlled study of 22 healthy psychedelic‐experienced participants. 2C‐B elicited alterations of waking consciousness of a psychedelic nature, with dysphoria, subjective impairment, auditory alterations, and affective elements of ego dissolution largest under psilocybin. Participants demonstrated equivalent psychomotor slowing and spatial memory impairments under either compound compared with placebo, as indexed by the Digit Symbol Substitution Test, Tower of London, and Spatial Memory Task. Neither compound produced empathogenic effects on the Multifaceted Empathy Test. 2C‐B induced transient pressor effects to a similar degree as psilocybin. The duration of self‐reported effects of 2C‐B was shorter than that of psilocybin, largely resolving within 6 hours. Present findings support the categorization of 2C‐B as a psychedelic of moderate experiential depth at doses given. Tailored dose‐effect studies are needed to discern the pharmacokinetic dependency of 2C‐B's experiential overlaps. [ABSTRACT FROM AUTHOR]

Traditional psychedelics are undergoing a transformation from recreational drugs, to promising pharmaceutical drug candidates with the potential to provide an alternative treatment option for individuals struggling with mental illness. Sustainable and economic production methods are thus needed to facilitate enhanced study of these drug candidates to support future clinical efforts. Here, we expand upon current bacterial psilocybin biosynthesis by incorporating the cytochrome P450 monooxygenase, PsiH, to enable the de novo production of psilocybin as well as the biosynthesis of 13 psilocybin derivatives. The substrate promiscuity of the psilocybin biosynthesis pathway was comprehensively probed by using a library of 49 single‐substituted indole derivatives, providing biophysical insights to this understudied metabolic pathway and opening the door to the in vivo biological synthesis of a library of previously unstudied pharmaceutical drug candidates. [ABSTRACT FROM AUTHOR]

The microbiota‐gut‐brain axis (MGBA) has been the subject of much research over the past decade, offering an exciting new paradigm for the treatment of psychiatric disorders. In this review, the MGBA is extended to include skeletal muscle and the potential role of an expanded "muscle‐gut‐brain axis" (MuGBA) in conditions such as anxiety and depression is discussed. There is evidence, from both preclinical and human studies, of bidirectional links between the gut microbiome and skeletal muscle function and structure. The therapeutic role of exercise in reducing depressive and anxiety symptoms is widely recognised, and the potential role of the gut microbiota‐skeletal muscle link is discussed within this context. Potential pathways of communication involved in the MuGBA including the tryptophan‐kynurenine pathway, intestinal permeability, immune modulation, and bacterial metabolites such as short‐chain‐fatty‐acids are explored. [ABSTRACT FROM AUTHOR]

Aims: We aim to provide an evidence‐based overview of the use of psychedelics in chronic pain, specifically LSD and psilocybin. Content: Chronic pain is a common and complex problem, with an unknown etiology. Psychedelics like lysergic acid diethylamide (LSD) and psilocybin, may play a role in the management of chronic pain. Through activation of the serotonin‐2A (5‐HT2A) receptor, several neurophysiological responses result in the disruption of functional connections in brain regions associated with chronic pain. Healthy reconnections can be made through neuroplastic effects, resulting in sustained pain relief. However, this process is not fully understood, and evidence of efficacy is limited and of low quality. In cancer and palliative related pain, the analgesic potential of psychedelics was established decades ago, and the current literature shows promising results on efficacy and safety in patients with cancer‐related psychological distress. In other areas, patients suffering from severe headache disorders like migraine and cluster headache who have self‐medicated with psychedelics report both acute and prophylactic efficacy of LSD and psilocybin. Randomized control trials are now being conducted to study the effects in cluster headache Furthermore, psychedelics have a generally favorable safety profile especially when compared to other analgesics like opioids. In addition, psychedelics do not have the addictive potential of opioids. Implications: Given the current epidemic use of opioids, and that patients are in desperate need of an alternative treatment, it is important that further research is conducted on the efficacy of psychedelics in chronic pain conditions. [ABSTRACT FROM AUTHOR]

N,N‐dimethyltryptamine (DMT) is a psychedelic substance and is being used as a research tool in investigations of the neurobiology behind the human consciousness using different brain imaging techniques. The effects of psychedelics have commonly been studied using electroencephalography (EEG) and have been shown to produce suppression of alpha power and increase in signal diversity. However, the relationship between DMT exposure and its EEG effects has never been quantified. In this work, a population pharmacokinetic/pharmacodynamic analysis was performed investigating the relationship between DMT plasma concentrations and its EEG effects. Data were obtained from a clinical study where DMT was administered by intravenous bolus dose to 13 healthy subjects. The effects on alpha power, beta power, and Lempel‐Ziv complexity were evaluated. DMT was shown to fully suppress alpha power. Beta power was only partially suppressed, whereas an increase in Lempel‐Ziv complexity was observed. The relationship between plasma concentrations and effects were described using effect compartment models with sigmoidal maximum inhibitory response or maximum stimulatory response models. Values of the concentration needed to reach half of the maximum response (EC50,e) were estimated at 71, 137, and 54 nM for alpha, beta, and Lempel‐Ziv complexity, respectively. A large amount of between‐subject variability was associated with both beta power and Lempel‐Ziv complexity with coefficients of variability of 75% and 77% for the corresponding EC50,e values, respectively. Alpha power appeared to be the most robust response, with a between‐subject variability in EC50,e of 29%. Having a deeper understanding of these processes might prove beneficial in choosing appropriate doses and response biomarkers in the future clinical development of DMT. [ABSTRACT FROM AUTHOR]

Psilocybin is being investigated as a potential treatment for psychiatric and neurological disorders. Only a few studies have evaluated the pharmacokinetics (PKs) of psilocybin and have used body weight‐adjusted dosing. Data on PKs and the PK‐pharmacodynamic (PD) relationship of fixed doses that are commonly used are unavailable. The present study characterized the PKs and PK‐PD relationship of 15, 25, and 30 mg of orally administered psilocybin in 28, 23, and 28 healthy subjects, respectively. Plasma levels of unconjugated psilocin (the psychoactive metabolite of psilocybin) and corresponding subjective effects were repeatedly assessed up to 24 hours. PK parameters were determined using compartmental modeling. Concentration‐subjective effect relationships were described using PK‐PD modeling. Mean (95% confidence interval) maximal psilocin concentrations were 11 ng/mL (10‐13), 17 ng/mL (16‐19), and 21 ng/mL (19‐24) after the administration of 15, 25, and 30 mg psilocybin, respectively. Maximal concentrations were reached after an average of 2 hours. Elimination half‐lives were 1.8 hours (1.7–2.0), 1.4 hours (1.2–1.7), and 1.8 hours (1.6–1.9) for 15, 25, and 30 mg psilocybin, respectively. Mean (± SD) durations of subjective effects were 5.6 ± 2.2 hours, 5.5 ± 1.6 hours, and 6.4 ± 2.2 hours, and maximal effects ("any drug" effects) were 58% ± 25%, 73% ± 27%, and 80% ± 18% after 15, 25, and 30 mg psilocybin, respectively. Psilocin exhibited dose‐proportional PKs. The duration and intensity of subjective effects were dose‐dependent. Body weight did not influence pharmacokinetics or the response to psilocybin. These data may serve as a reference for future clinical trials. [ABSTRACT FROM AUTHOR]

In the past decade, the consumption of psilocybin mushrooms has become a popular therapeutic tool for people looking to deal with mental and emotional health issues. The emerging interest in psilocybin therapy in the global north has led to the development of retreat centers in locations where psilocybin is legal or unregulated. Drawing on ethnographic research at a psilocybin retreat center in Jamaica, this article examines the emotional and somatic reactions attributed to psilocybin that influence the social interactions and the mental and emotional state of the guests at this retreat center. We argue that guests go through a symbolic healing process that involves the construction of a meaning response based on internal and collective experiences of altered consciousness via psilocybin. Additionally, we emphasize how both attending the retreat and the psychedelic experience there can be considered a liminal state that leads to different modes of relation while in Jamaica. [ABSTRACT FROM AUTHOR]

Aim: Psilocin is an active metabolite form of psilocybin and exerts psychoactive effects. Recent studies suggest that psilocin may have regulatory effects on abuse drugs, but the mechanisms remain unclear. In this study, we want to explore the effects of psilocin on methamphetamine (METH)‐induced alterations of behavior in mice and its molecular mechanisms. Methods: Acute METH administration model and conditioned place preference (CPP) model were used to investigate the effects of psilocin on METH‐induced alterations of behavior. Western blot was used to detect the expression of proteins. Results: In the acute 2 mg/kg METH administration model, 1 mg/kg psilocin counteracted METH‐induced elevation of activity. In the 1 mg/kg METH‐induced CPP model, 1 mg/kg psilocin inhibited CPP formation during the acquisition phase. However, psilocin did not impact METH extinction and relapse. Molecular results showed that the regulatory effect of psilocin on METH was underscored by altered expression of dopamine 2 receptor (D2R) and phosphorylated extra‐cellular signal‐regulated kinase (p‐ERK) in the prefrontal cortex (PFC), nucleus accumbens (NAc), and ventral tegmental area (VTA). Trifluoperazine (TFP)‐2HCl is a D2R inhibitor, and SCH772984 is a selective extra‐cellular signal‐regulated kinase (ERK) inhibitor that effectively inhibits ERK1/2 phosphorylation. The results indicated that 2 mg/kg TFP‐2HCl and 10 mg/kg SCH772984 blocked METH‐induced hyperactivity and acquisition of METH‐induced CPP. Conclusion: Psilocin has regulatory effects on METH‐induced alterations of behavior in mice via D2R‐mediated signal regulation of ERK phosphorylation. [ABSTRACT FROM AUTHOR]

Relatedly, traditional RCTs report the between-treatment I P i -value, which is the 'probability of obtaining the observed or more extreme data assuming that the treatment is no better than placebo'. Moreover, placebo-controlled RCTs raise ethical concerns when an ineffective treatment as in the placebo arm could have severe consequences, for example, suicide in depression or status epilepticus in epilepsy. Percentage of heavy drinking days following psilocybin-assisted psychotherapy vs placebo in the treatment of adult patients with alcohol use disorder: a randomized clinical trial. Keywords: Bayesian analysis; depression; medical cannabis; psilocybin; RCTs; Sir Michal Rawlins EN Bayesian analysis depression medical cannabis psilocybin RCTs Sir Michal Rawlins 2646 2648 3 08/17/23 20230901 NES 230901 The two pillars of modern medical research are where in most randomized controlled trials (RCTs), the active treatment is compared with placebo. [Extracted from the article]

This article discusses the regulation of medical and non-medical use of psychedelic drugs from a clinical research perspective. The author highlights the parallels between the deregulation of cannabis and the current situation with psychedelics, emphasizing the need to distinguish between medical and non-medical use. The article also addresses the off-label use of ketamine and the challenges faced in research with MDMA and psilocybin. The author suggests that comprehensive risk evaluation and mitigation strategies should be implemented if psychedelics are approved for clinical use. The article concludes by emphasizing the importance of improving the quality of clinical research to understand the potential roles of psychedelic drugs as medicines. [Extracted from the article]