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A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1-4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5-8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6-12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.

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.

There has been renewed interest in the use of 3,4-methylenedioxy-methamphetamine (MDMA) and serotonergic psychedelics in the treatment of multiple psychiatric disorders. Many of these compounds are known to produce prosocial effects, but how these effects relate to therapeutic efficacy and the extent to which prosocial effects are unique to a particular drug class is unknown. In this article, we present a narrative overview and compare evidence for the prosocial effects of MDMA and serotonergic psychedelics to elucidate shared mechanisms that may underlie the therapeutic process. We discuss 4 categories of prosocial effects: altered self-image, responses to social reward, responses to negative social input, and social neuroplasticity. While both categories of drugs alter self-perception, MDMA may do so in a way that is less related to the experience of mystical-type states than serotonergic psychedelics. In the case of social reward, evidence supports the ability of MDMA to enhance responses and suggests that serotonergic psychedelics may also do so, but more research is needed in this area. Both drug classes consistently dampen reactivity to negative social stimuli. Finally, preclinical evidence supports the ability of both drug classes to induce social neuroplasticity, promoting adaptive rewiring of neural circuits, which may be helpful in trauma processing. While both MDMA and serotonergic psychedelics produce prosocial effects, they differ in the mechanisms through which they do this. These differences affect the types of psychosocial interventions that may work best with each compound.

BACKGROUND: There is growing evidence for the therapeutic effects of the psychedelic drug psilocybin for major depression. However, due to the lack of safety data on combining psilocybin with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and concerns that there may be a negative interaction on efficacy, participants enrolling in psychedelic trials are usually required to discontinue SNRI/SNRIs prior to enrolling. AIMS: Using data from a recent clinical trial examining the comparative efficacy the psychedelic drug psilocybin (P) combined with approximately 20 h of psychological support to a 6-week (daily) course of the SSRI escitalopram plus matched psychological support for major depressive disorder, we explored the effects of discontinuing SSRI/SNRIs prior to study enrolment on study outcomes. METHODS: Exploratory post hoc analyses using linear mixed effects model were performed to investigate the discontinuation effect on various validated depression symptom severity scales and well-being. The impact of SSRI/SNRIs discontinuation on the acute psychedelic experience was also explored. RESULTS/OUTCOMES: In the psilocybin group, there was a reduced treatment effect on all outcome measures for SSRI/SNRIs discontinuers compared with unmedicated patients at trial entry. However, no effects of discontinuation on measures of the acute psychedelic experience were found. CONCLUSION: Discontinuation of SSRI/SNRIs before psilocybin might diminish response to treatment; however, as we did not test SSRI/SNRI continuation in our trial, we cannot infer such causation. Moreover, the exploratory nature of the analyses makes them hypothesis generating, and not confirmatory. A controlled trial of SSRI/SNRI discontinuation versus continuation prior to psilocybin is urgently required.

BACKGROUND: Reference to an intrinsic healing mechanism or an inner healer is commonplace amongst psychedelic drug-using cultures. The inner healer refers to the belief that psychedelic compounds, plants or concoctions have an intrinsically regenerative action on the mind and brain, analogous to intrinsic healing mechanisms within the physical body, for example, after sickness or injury. AIMS: Here, we sought to test and critique this idea by devising a single subjective rating item pertaining to perceived inner healing effects. METHODS: The item was issued to 59 patients after a single high (25 mg, n = 30) or placebo (1 mg, n = 29) dose of psilocybin in a double-blind randomised controlled trial of psilocybin for depression. RESULTS: Inner healer scores were higher after the high versus placebo dose of psilocybin (t = 3.88, p

RationaleTreatments 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.ObjectivesWe aimed to explore potential interactions between psilocybin and SSRIs by characterizing peoples' real-world experiences using psilocybin mushrooms and SSRIs together.MethodsWe 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.Results8% 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.ConclusionsPsilocybin'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.

Do psychedelics affect sexual functioning postacutely? Anecdotal and qualitative evidence suggests they do, but this has never been formally tested. While sexual functioning and satisfaction are generally regarded as an important aspect of human wellbeing, sexual dysfunction is a common symptom of mental health disorders. It is also a common side effect of selective serotonin reuptake inhibitors (SSRIs), a first line treatment for depression. The aim of the present paper was to investigate the post-acute effects of psychedelics on self-reported sexual functioning, combining data from two independent studies, one large and naturalistic and the other a smaller but controlled clinical trial. Naturalistic use of psychedelics was associated with improvements in several facets of sexual functioning and satisfaction, including improved pleasure and communication during sex, satisfaction with ones partner and physical appearance. Convergent results were found in a controlled trial of psilocybin therapy versus an SSRI, escitalopram, for depression. In this trial, patients treated with psilocybin reported positive changes in sexual functioning after treatment, while patients treated with escitalopram did not. Despite focusing on different populations and settings, this is the first research study to quantitively investigate the effects of psychedelics on sexual functioning. Results imply a potential positive effect on post-acute sexual functioning and highlight the need for more research on this.

Psilocybin, a serotonergic psychedelic, is being increasingly researched in clinical studies for the treatment of psychiatric disorders. The relatively lengthy duration of oral psilocybins acute effects (4-6 h) may have pragmatic and cost-effectiveness limitations. Here, we explored the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT), a closely related, but faster-acting psychedelic intervention, on mental health outcomes in healthy volunteers. Data is reported from two separate analyses: (1) A comparison of mental health-related variables 1 week after 7, 14, 18, and 20 mg of IV DMT versus IV saline placebo (n = 13) and, (2) A prospective dataset assessing effects before versus 2 weeks after 20 mg of IV DMT (n = 17). Mental health outcomes included measures of depression severity (QIDS-SR16), trait anxiety (STAI-T), Neuroticism (NEO-FFI), wellbeing (WHO-5), meaning in life (MLQ), optimism (LOT-R), and gratitude (GQ-6). In both the prospective and placebo-controlled datasets, significant improvements in scores of depression were found 1-2 weeks after DMT administration. Significant reductions in trait Neuroticism were only found for the placebo-controlled sample. Finally, changes in depression and trait anxiety correlated with acute peak experiences (assessed via Oceanic Boundlessness). While the use of two separate cohorts in pooled analysis limits the generalizability of these correlational findings, these results suggest that DMT may reduce depressive symptomatology by inducing peak experiences. The short half-life of IV DMT and its potential for flexible dosing via controlled infusions makes it an appealing candidate for psychedelic medicine. Further research in clinical samples is needed to corroborate the therapeutic potential of DMT.

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.

BACKGROUND: Chronic pain is a leading cause of disability worldwide. Fibromyalgia is a particularly debilitating form of widespread chronic pain. Fibromyalgia remains poorly understood, and treatment options are limited or moderately effective at best. Here, we present a protocol for a mechanistic study investigating the effects of psychedelic-assisted-therapy in a fibromyalgia population. The principal focus of this trial is the central mechanism(s) of psilocybin-therapy i.e., in the brain and on associated mental schemata, primarily captured by electroencephalography (EEG) recordings of the acute psychedelic state, plus pre and post Magnetic Resonance Imaging (MRI). METHODS: Twenty participants with fibromyalgia will complete 8 study visits over 8 weeks. This will include two dosing sessions where participants will receive psilocybin at least once, with doses varying up to 25mg. Our primary outcomes are 1) Lempel-Ziv complexity (LZc) recorded acutely using EEG, and the 2) the (Brief Experiential Avoidance Questionnaire (BEAQ) measured at baseline and primary endpoint. Secondary outcomes will aim to capture broad aspects of the pain experience and related features through neuroimaging, self-report measures, behavioural paradigms, and qualitative interviews. Pain Symptomatology will be measured using the Brief Pain Inventory Interference Subscale (BPI-IS), physical and mental health-related function will be measured using the 36-Item Short Form Health Survey (SF-36). Further neurobiological investigations will include functional MRI (fMRI) and diffusion tensor imaging (changes from baseline to primary endpoint), and acute changes in pre- vs post-acute spontaneous brain activity - plus event-related potential functional plasticity markers, captured via EEG. DISCUSSION: The results of this study will provide valuable insight into the brain mechanisms involved in the action of psilocybin-therapy for fibromyalgia with potential implications for the therapeutic action of psychedelic-therapy more broadly. It will also deliver essential data to inform the design of a potential subsequent RCT.

BackgroundClinical trials using psilocybin therapy to treat anorexia nervosa (AN) are currently underway. The safety and tolerability of psilocybin is of utmost importance in individuals with AN who may present unique medical vulnerabilities. The purpose of this review is to describe how the common physiologic adverse effects of psilocybin may impact medical complications experienced by individuals with AN in clinical trials of psilocybin therapy.Main bodyThe physiologic underpinnings of common adverse effects following psilocybin administration are described, including tachycardia, hypertension, electrocardiogram changes, nausea, headache, and lightheadedness. These anticipated physiologic changes are described in relation to the common medical correlates seen in individuals with AN. Risk mitigation strategies for each adverse effect are proposed.ConclusionEarly evidence suggests that psilocybin therapy is well-tolerated in individuals with AN. Understanding the unique medical complications of AN, and how they may be impacted by common physiologic adverse effects of psilocybin administration, leads to tailored risk mitigation strategies to enhance safety and tolerability of this novel intervention.

BACKGROUND: Psilocybin Therapy (PT) is being increasingly studied as a psychiatric intervention. Personality relates to mental health and can be used to probe the nature of PTs therapeutic action. METHODS: In a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, over a core 6-week trial period. Five-Factor model personality domains, Big Five Aspect Scale Openness aspects, Absorption, and Impulsivity were measured at Baseline, Week 6, and Month 6 follow-up. RESULTS: PT was associated with decreases in neuroticism (B = -0.63), introversion (B = -0.38), disagreeableness (B = -0.47), impulsivity (B = -0.40), and increases in absorption (B = 0.32), conscientiousness (B = 0.30), and openness (B = 0.23) at week 6, with neuroticism (B = -0.47) and disagreeableness (B = -0.41) remaining decreased at month 6. Escitalopram Treatment (ET) was associated with decreases in neuroticism (B = -0.38), disagreeableness (B = -0.26), impulsivity (B = -0.35), and increases in openness (B = 0.28) at week 6, with neuroticism (B = -0.46) remaining decreased at month 6. No significant between-condition differences were observed. CONCLUSIONS: Personality changes across both conditions were in a direction consistent with improved mental health. With the possible exception of trait absorption, there were no compelling between-condition differences warranting conclusions regarding a selective action of PT (v. ET) on personality; however, post-ET changes in personality were significantly moderated by pre-trial positive expectancy for escitalopram, whereas expectancy did not moderate response to PT.

Studies of psychedelic-assisted therapy with LSD, psilocybin, MDMA, and related substances show clinical promise but inadequately assess side effects. Measuring side effects is challenging because they are not always easily differentiated from treatment effects or disease symptoms and show high heterogeneity, variable duration and impact, and sensitivity to context. A systematic questionnaire describing important characteristics of side effects of psychedelics and MDMA would greatly improve on previous methods. We aimed to create a standardized tool for recording clinically relevant side effects of psychedelics and MDMA, including their severity, duration, impact, and treatment-relatedness. We constructed the Swiss Psychedelic Side Effects Inventory (SPSI) based on insights from previous research. It was pilot tested in 145 participants from three studies. Structured feedback from an expert panel was used to improve validity and feasibility. The final SPSI contains 32 side effects and standardized follow-up questions about their severity, impact, treatment-relatedness, and duration. It is compatible with any study design and can be administered as an interview or self-report at any timepoint after treatment with psychedelics or MDMA. The SPSI omits relatively unimportant side effects for brevity's sake, though space for additional symptoms is given. Future studies are needed to confirm its validity in different contexts. The SPSI is available in English and German for collecting systematic data on side effects from psychedelics and MDMA. This information is vital for improving clinical decisions, informed consent, and patient safety. • Psychedelics and MDMA can cause a unique profile of side effects which are not well-captured by the methods used in previous studies. • Psychedelic side effects vary in their severity, duration, and subjective impact. • Using previous studies, pilot data, and expert feedback, we developed the Swiss Psychedelic Side Effects Inventory (SPSI). • The SPSI contains 32 side effects and assesses their severity, impact, duration, and treatment-relatedness. • The SPSI can be used at any timepoint after psychedelic administration in any study of psychedelics or MDMA. [ABSTRACT FROM AUTHOR]

Despite psychedelic microdosing being a growing practice, the research on the topic is still in its infancy. While several studies have described the characteristics, motivations and practices of microdosers, the differences between individuals that only microdose and those that use both micro and macrodoses of psychedelics remain unexplored. In an online survey, we collected data of 6193 psychedelic consumers of which 2488 were microdosers of up to 11 different classical and atypical psychedelics. In comparison to respondents that use both microdoses and macrodoses, exclusive microdosers were older in age (46.4 vs. 42.0 years), had a larger proportion of females (68.4% vs. 44.7%), were non-Caucasian (25.4% vs. 14.7%), urban residents (43.9% vs. 38.5%), and had a lower average lifetime use of non-psychedelic substances (3.8 vs. 4.7 substances). Most consumers (52.5%) microdosed psychedelics multiple times a month, commonly using psilocybin (74.5%), LSD (34.4%), and ketamine (15.8%), with most users (64.6%) not testing their substances. The most common reason for microdosing was improving general wellbeing (73.0%), and psychedelics were used for treating several physical and mental health conditions. Additional analyses examined spending habits of consumers. This study adds to the growing literature on the naturalistic use of psychedelic microdosers. [ABSTRACT FROM AUTHOR]

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]

Psilocybin is gaining popularity as research shows potential benefits to those with anxiety, depression, and other mental health conditions. Individuals with risk factors for psychosis are typically excluded from such studies, limiting the empiric research of the risks and benefits in vulnerable populations. In the real-world setting, many individuals who seek treatment with psilocybin will have comorbid psychiatric conditions and other factors that predispose them to psychosis. We report a case of a patient with multiple predisposing risk factors, including a history of depression, personality disorder traits, and cannabis use, who experienced a psychotic episode with catatonic features and suicidality after several months of heavy psilocybin use. A review of similar previously published case reports demonstrates a pattern of psilocybin-induced psychosis occurring primarily in individuals with predisposing factors who have consumed either high or repeated doses of the drug. This case report furthers this pattern, which serves as both a warning that psilocybin use is not without risks and reassurance for researchers using much lower doses to treat mental illness. [ABSTRACT FROM AUTHOR]

Substance use disorder (SUD) is common in psychiatric patients and has a negative impact on health and well-being. However, SUD often goes untreated, and there is a need for psychiatrists, of all specialties, to address this pervasive clinical problem. In this review, the authors' goal is to provide a resource that describes treatments for SUD, using neuroscience as a framework. They discuss the effect of pharmacotherapy on craving, intoxication, and withdrawal and its ability to interrupt the cycle of substance use in SUD. The neuroscience of stress is reviewed, including medications targeting neurotransmitter systems activated by alarm and fear. Neuroplasticity and promising treatments that use this mechanism, including ketamine, psilocybin, and transcranial magnetic stimulation (TMS), are discussed. The authors conclude by listing resources and practice guidelines for physicians interested in learning more about treatments for SUD. [ABSTRACT FROM AUTHOR]

• Psilocybin has shown promise for the treatment of psychiatric disorders. • Psilocybin was administered following extinction of cocaine self-administration. • Psilocybin had no effect on reinstatement in mice or rats. There are currently no pharmacological treatments for cocaine use disorder. Recently there has been a great deal of interest in the potential of psychedelic drugs such as psilocybin to treat psychiatric disorders. Human studies have indicated that a single administration of psilocybin can have long-lasting effects. Few preclinical studies have examined a role for psilocybin in addiction models. The goal of the current study was to determine whether psilocybin would enhance extinction following cocaine self-administration in male and female mice and rats and thus result in an attenuation of cue-induced drug-seeking. In experiments in mice, 16 female and 19 male mice underwent 8d of cocaine self-administration (0.5 mg/kg/infusion) and extinction training. Immediately following extinction trials, mice were injected with vehicle or 1.0 mg/kg psilocybin. Following the conclusion of extinction training, mice were tested for cue-induced reinstatement. In experiments in rats, 24 female and 23 male rats underwent 15d of cocaine self-administration (0.8 mg/kg/infusion) and extinction training. Immediately following extinction trials, rats were injected with vehicle, 1.0 mg/kg psilocybin, or 2.5 mg/kg psilocybin. Following the conclusion of extinction training, rats were tested for cue-induced reinstatement. Psilocybin administered following extinction trials had no effect, as both female and male mice and rats demonstrated significant cue-induced reinstatement. These data suggest that psilocybin is ineffective at altering cocaine-seeking behavior in the paradigm and doses used in the current study. It remains to be seen whether treatment with psilocybin under different conditions may be useful in the long-standing goal of finding pharmacotherapies to treat CUD. [ABSTRACT FROM AUTHOR]

The recreational use of psilocybin or psilocin-containing products, a chemical found naturally in certain mushroom species, is on the rise across the United States. Several cases of serious clinical effects related to mushroom-containing products have recently been reported to the Food and Drug Administration (FDA). The emergence of these new products and their health consequences are not yet well understood. This case series aims to characterize exposures to mushroom-containing chocolate products, including patient characteristics, clinical effects, treatment(s), and clinical outcome severity, reported to a poison center network. This was a retrospective case series conducted in patients exposed to mushroom-containing chocolate products across three poison centers between January 2023 to August 2024. Patients were identified via a database search of ToxSentry®. Patients were included if they were exposed to a mushroom-containing chocolate product. Patients were excluded if they ingested an unrelated product or if there was insufficient information documented within ToxSentry®. The primary endpoint was to describe clinical outcome severity after exposure to mushroom-containing chocolate products. A query of ToxSentry® identified 164 cases; 36 cases met study criteria. The median age of patients in this case series was 17 years old. For most patients (23, 64 %), the reason for the exposure was intentional, with 20 reporting intentional abuse or misuse of the product. Common clinical effects reported included mental status changes (26, 76 %), paranoia/hallucinations (10, 28 %), dysrhythmias (7, 19 %) and gastrointestinal discomfort (6, 17 %). There was one report of seizure. Most clinical effects lasted between 3 and 24 h after ingestion (29, 81 %). Intravenous fluids (18, 50 %) and benzodiazepines (7, 19 %) were the most common treatments given. No fatalities were reported. While most patients in this series experienced minor clinical effects, some developed serious effects after ingestion of a mushroom-containing chocolate product. Findings from this study further characterize the limited patient demographics, clinical effects, and outcomes published thus far. Further characterization in a larger cohort of patients could expand on our initial findings and is needed to better identify factors that may influence clinical outcomes. [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]

Psychedelics, including ketamine, 3,4-Methyl enedioxy methamphetamine (MDMA), and psilocybin, have gained attention for their potential therapeutic role in mental health treatment. While recreational use is prohibited in Canada, medicinal exemptions can be granted. There are several psychedelic clinics in Ontario, Canada, promoting the use of psychedelics for a variety of medical indications. Our objective was to identify the indications for which psychedelics are being prescribed in Ontario clinics and assess the quality of evidence used to support these claims. Internet searches were conducted using Google and Bing to identify psychedelic clinics in Ontario. Inclusion criteria was as follow: clinics were physically located in Ontario, had a functioning website link, and demonstrated involvement of a licensed physician or nurse practitioner. Identified clinics were evaluated for their claims of effectiveness, the quality of evidence used to support these claims, and statements on psychedelic-related harms. The cited studies were appraised for quality using Oxford Centre for Evidence-Based Medicine Levels of Evidence, "level 5" being the lowest quality and "level 1" being the highest quality. Out of 200 search results, 10 psychedelic clinic websites met our inclusion criteria. These clinics advertised psychedelics for 47 medical conditions, most commonly for depression. Only 2 out of 10 clinics described potential risks associated with psychedelic use. There were 29 studies cited by these websites, majority coming from "level 4" evidence consisting of case-series and case-control studies. Overall, the cited evidence quality was low to moderate. Psychedelic clinics in Ontario promote a wide range of medical indications for psychedelics using primarily low to moderate "level 4" evidence. There is limited information shared on the potential adverse effects of psychedelics. Our study emphasizes the importance of using transparent and high-quality evidence by clinics and clinicians to ensure safe and effective use of psychedelics in mental health treatments. [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]

\nPlain Language SummaryResults from clinical trials show that serotonergic psychedelics have efficacy in treating psychiatric disorders, where currently approved pharmacotherapies are inadequate. Developing psychedelic medicines, however, comes with unique challenges, such as tempering heightened anxiety associated with the psychedelic experience. We conceived a new strategy to potentially mitigate psychedelic effects with defined electromagnetic signals (ES). We recorded the electromagnetic fields emitted by the serotonin 2 receptor (5-HT2R) agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) and converted them to a playable WAV file. We then exposed the DOI WAV ES to mice to assess its effects on the DOI-elicited, 5-HT2AR dependent head-twitch response (HTR). The DOI WAV signal significantly attenuated the HTR in mice elicited by 0.1 and 0.3 mg/kg subcutaneous DOI (p < 0.05 and p < 0.01, respectively). A scrambled WAV signal did not affect the DOI-elicited HTR, suggesting specificity of the DOI WAV signal. These results provide evidence that defined ES could modulate the psychoactive effects of serotonergic psychedelics. We discuss putative explanations for the distinct effects of the DOI WAV signal in the context of previous studies that demonstrate ES’s efficacy for treating other conditions, including pain and cancer.Numerous clinical studies demonstrate that psychedelic drugs can treat psychiatric disorders. A challenge with psychedelic drugs is that they can elicit distressing experiences, which require psychological support in some patients. Recent developments have allowed for the recording of the electromagnetic shell or field of molecules in solution. These electromagnetic signals (ES) can be emitted (as a magnetic field) to emulate the effects of the recorded drug. By using ES, we have the potential to manage or mitigate the negative effects of a drug, simply by turning off the magnetic field. The main target of serotonergic psychedelic drugs is the serotonin receptor, 5-HT2A. A reliable and well-studied drug used in psychedelic research is (±)-2,5-dimethoxy-4-iodoamphetamine (DOI). DOI binds and activates the 5-HT2A receptor. DOI is known to elicit head twitching in mice (called the head-twitch response or HTR) that is indicative of 5-HT2A receptor activation. A recording of DOI was played to evaluate its effect on the head-twitch response in mice. Here we report that the DOI WAV signal decreased the head-twitch response observed after treating mice with the DOI drug. The effects were measurable, reproducible and demonstrated the ability of the DOI recording to dampen the head-twitch response. This WAV recording has the potential to interfere with the unwanted effects of psychedelics, making their use safer. [ABSTRACT FROM AUTHOR]

As clinical trials for psychedelics move into phase III in the USA, Europe must address its lag in integrating professional education around psychedelic-assisted therapy (PAT) and supporting psychedelic drug research. This paper evaluates the necessary frameworks for implementing PAT in Germany, emphasizing the nation's potential leadership role within the European Union. With Australia having already approved MDMA and psilocybin for mental health indications, the Ukrainian government exploring MDMA treatment for war-related PTSD, and initial clinical trials involving MDMA and LSD with patients in Switzerland which restarted the restricted medical use of these substances around 2014, the medical authorization of psychedelics in these countries establishes precedent showcasing both the promise and challenges of researching and implementing PAT in nations where the substances were formally scheduled as illicit substances. Key challenges include establishing rigorous standards for practitioner training, accessibility, and defining regulatory oversight. This paper focuses on the development of robust infrastructure in Germany, which will support the roll out of PAT, and details ethical considerations, training protocols, and governmental roles in the formulation of treatment frameworks. This approach aims not only to guide Germany in adopting PAT but also to influence broader European policy, ensuring that patients receive ethically sound and proficient care. The findings suggest pathways for Europe to reclaim its historical lead in psychiatric and therapeutic innovation. [ABSTRACT FROM AUTHOR]

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]

AbstractBackgroundMethodsResultsConclusionsCurrently, there are great hopes for psychedelic substances in treating psychiatric conditions and improving well-being. These substances are illegal in many countries, and we lack knowledge of how conflicting discourses shape psychedelic use in naturalistic settings. This study explores how psilocybin use is made meaningful by participants and staff at a retreat including psychedelic ceremonies aimed at personal growth.Ethnographic fieldwork was conducted at a psychedelic retreat with participants from Sweden. The material was organized using Zinberg’s model of drug, set, and setting. Theoretical work related to comparisons was utilized to elucidate how psilocybin use was distinguished from other illicit drug use.The participants’ desires to be fundamentally transformed, combined with the staff’s staging of the setting as a haven primed the participants to approach psilocybin as an inherently benevolent substance. Positive experiences during the ceremonies were attributed to the substance, and negative experiences to personal shortcomings.The staff and participants combined different discourses to define the meaning of psilocybin, all of which condemned using it for purely recreational purposes. The psilocybin use at the retreat was considered an improvement and wholly unrelated to illegal drug use, dissociating this practice from such use to establish legitimate transgression. [ABSTRACT FROM AUTHOR]

Psychedelic therapies are an emerging class of treatments in psychiatry with great potential, however relatively little is known about their interactions with other commonly used psychiatric medications. As psychedelic therapies become more widespread and move closer to the clinic, they likely will need to be integrated into existing treatment models which may include one or more traditional pharmacological therapies, meaning an awareness of potential drug-drug interactions will become vital. This commentary outlines some of the issues surrounding the study of drug-drug interactions of this type, provides a summary of some of the relevant key results to date, and charts a way forward which relies crucially on multimodal neuroimaging investigations. Studies in humans which combine Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI), plus ancillary measures, are likely to provide the most comprehensive assessment of drug-drug interactions involving psychedelics and the relevant effects at multiple levels of the drug response (molecular, functional, and clinical). [ABSTRACT FROM AUTHOR]

Background: Psilocybin is a psychedelic 5HT2A receptor agonist found in "magic mushrooms". Recent studies have indicated that 5HT2A agonists, such as dimethyltryptamine, given before middle cerebral artery occlusion (MCAo), improve staircase behavior, increased BDNF expression, and reduce brain infarction in stroke rats. The objective of this study is to determine the protective effect of psilocybin in cellular and animal models of stroke. Methods: Adult male and timed-pregnant Sprague-Dawley rats were used for this study. The neural protective effects of psilocybin were determined in primary rat cortical neurons and adult rats. Rats were subjected to a 60-min middle cerebral artery occlusion. Brain tissues were collected for histological and qRTPCR analysis. Results: Psilocybin reduced glutamate-mediated neuronal loss in rat primary cortical neuronal cultures. Psilocybin-mediated protection in culture was antagonized by the BDNF inhibitor ANA12. Pretreatment with psilocybin reduced brain infarction and neurological deficits in stroke rats. Early post-treatment with psilocybin improved locomotor behavior, upregulated the expression of MAP2 and synaptophysin, and down-regulated the expression of IBA1 in the stroke brain. ANA12 significantly attenuated psilocybin-mediated reduction in brain infarction and improvements in locomotor behavior. Conclusions: Psilocybin reduced brain infarction and improved locomotor behavior in stroke rats; the protective mechanisms involve regulating BDNF expression. Our data support a novel therapeutic approach of psilocybin in stroke. Highlights: Psilocybin reduced glutamate-mediated neuronal loss in primary cortical neuronal cultures. ANA12 reduced psilocybin-mediated protection in culture. Psilocybin reduced brain infarction, reduced neurological deficits, and increased locomotor behavior in stroke rats. Psilocybin enhanced the expression of MAP2 and synaptophysin, and down-regulated IBA1 in the stroke rat brain. [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]

Objectives: The purpose of this systematic review of randomized controlled trials (RCTs) was to evaluate the effectiveness, safety, and tolerability of psilocybin in adult patients with major depressive disorder (MDD). Methods: A systematic search (up to September 14, 2023) was conducted for RCTs that examined the efficacy, safety, and tolerability of psilocybin in physically healthy adult patients with MDD. Three independent researchers extracted data from publications where the primary outcome was a change in depressive symptoms, and key secondary outcomes were changes in anxiety symptoms and suicidal ideation, discontinuation rates for any reason, and adverse drug reactions (ADRs). Results: Five RCTs with 472 adult patients with MDD on psilocybin (n = 274) and controls (n = 198) were included. Two of the five RCTs (40%) reported mixed results, while the other three (60%) found that psilocybin had a beneficial effect on MDD treatment. Four RCTs (80%) assessing the anxiolytic effects of psilocybin for treating MDD found that psilocybin was significantly more effective than the control group in improving anxiety symptoms. Psilocybin was more effective than the control group in improving suicidal ideation in one out of five RCTs. Discontinuation rates were similar for any reason between the psilocybin group (2-13%) and the control group (4-21%) (P > 0.05). Four RCTs (80%) reported ADRs in detail. The most common ADR in both groups was headache. Conclusion: Psilocybin was effective in improving depressive symptoms in over half of the included studies and reduced anxiety symptoms in patients with MDD. The long-term efficacy and safety of psilocybin for MDD treatment needs to be further investigated in large RCTs. [ABSTRACT FROM AUTHOR]

Background: The emergence of New Psychoactive Substances (NPS), including synthetic psilocybin, has raised concern among health experts due to the numerous health and socioeconomic consequences. The current trend is shifting to the hazardous use of synthetic psilocybin in vaping, and little is known about the prevalence of use, specifically among amphetamine-type stimulants (ATS) users. Methods: Interviewer-administered questionnaires were conducted in drug detention centers between March and October 2022. The study was conducted using ASSIST 3.0 and obtained information on the respondents' socio-demographic characteristics and clinical profiles. N = 355 ATS users were enrolled in this study. Results: The results show a high prevalence of psilocybin vaping among ATS users (182/355, 53.1%). Most of the respondents were males (85.1%) and unmarried (69.3%), with a mean age of 29.2 (SD = 7.3). Across all respondents, five factors were associated with psilocybin vaping: tobacco smoking, aOR =5.790 (95% CI: 1.723, 8.183); cannabis uses, aOR= 9.152 (95% CI: 2.693, 10.396); and alcohol use, aOR= 3.137 (95% CI: 1.461, 5.817). Respondents of the Malay race had higher odds of being involved in psilocybin vaping compared to other races, with aOR= 1.638 (0.043, 2.459). Meanwhile, a reduction in age by 1.9 will increase the likelihood of involvement in psilocybin vaping with aOR = 1.897 (95% CI: 0.857, 1.938). Conclusion: Psilocybin in vaping is growing among ATS users and across all populations. Unfortunately, knowledge regarding the long-term effects on health is limited. Further studies should highlight the harmful effects of psilocybin and the potential risk of psilocybin vaping among the younger population. [ABSTRACT FROM AUTHOR]

Background: In recent years, both meditation and psychedelics have attracted rapidly increasing scientific interest. While the current state of evidence suggests the promising potential of psychedelics, such as psilocybin, to enhance meditative training, it remains equivocal whether these effects are specifically bound to psilocybin or if other classical psychedelics might show synergistic effects with meditation practice. One particularly promising candidate is N,N -dimethyltryptamine (DMT), an active ingredient of ayahuasca. Aim: This study aims to investigate the effect of the psychedelic substance DMT, combined with the monoamine oxidase inhibitor harmine (DMT-harmine), on meditative states, compared to meditation with a placebo. Method: Forty experienced meditators (18 females and 22 males) participated in a double-blind, placebo-controlled study over a 3-day meditation retreat, receiving either placebo or DMT-harmine. Participants' levels of mindfulness, compassion, insight, and transcendence were assessed before, during, and after the meditation group retreat, using psychometric questionnaires. Results: Compared to meditation with a placebo, meditators who received DMT and harmine self-attributed greater levels of mystical-type experiences, non-dual awareness, and emotional breakthrough during the acute substance effects and, when corrected for baseline differences, greater psychological insight 1 day later. Mindfulness and compassion were not significantly different in the DMT-harmine group compared to placebo. At 1-month follow-up, the meditators who received DMT and harmine rated their experience as significantly more personally meaningful, spiritually significant, and well-being-enhancing than the meditators who received placebo. Conclusion: Investigating the impact of DMT-harmine on meditators in a naturalistic mindfulness group retreat, this placebo-controlled study highlights the specific effects of psychedelics during meditation. Trial registration: ClinicalTrials.gov identifier NCT05780216. [ABSTRACT FROM AUTHOR]

Background: Psychedelic-assisted therapy (PAT) is permitted in Switzerland under its limited medical use program. Data from patients in this program represent a unique opportunity to analyze the real-world practice of PAT. Aims: This study compared the subjective effects of lysergic acid diethylamide (LSD) and psilocybin between patients undergoing PAT and healthy volunteers. For the patients, it also investigated the relationship between antidepressant effects and six measures of acute drug effects. Methods: We compared data on acute psychedelic drug effects between 28 PAT patients with data from 28 healthy participants who participated in a randomized, double-blind crossover trial. All participants received varying doses of psilocybin and LSD. Subjective effects were assessed on an hourly basis during the acute drug effects, and the Mystical Experience Questionnaire (MEQ) was completed retrospectively. For patients, depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). Results: Ratings of overall drug effect and mystical experience were similar across groups. Compared with healthy controls, patients reported lower ratings of ego dissolution. Patients showed a significant decrease in MADRS scores, and the greatest predictor of antidepressant outcome was relaxation during the PAT session. We did not observe a relationship between mystical-type experiences and antidepressant effects. Most patients experienced mild adverse effects which resolved within 48 h. Conclusion: PAT reduced depressive symptoms in this heterogeneous patient group. Patients may experience more challenging psychedelic effects and reduced ego dissolution. Hourly assessment of drug effects may predict clinical outcomes better than retrospectively assessed mystical experiences, and the impact of relaxation during PAT should be investigated further. [ABSTRACT FROM AUTHOR]

Background: Non-ordinary states of consciousness induced by psychedelics can be accompanied by so-called "peak experiences," characterized at the emotional level by their intensity and positive valence. These experiences are strong predictors of positive outcomes following psychedelic-assisted therapy, and it is therefore important to better understand their biology. Despite growing evidence that the autonomic nervous system (ANS) plays an important role in mediating emotional experiences, its involvement in the psychedelic experience is poorly understood. The aim of this study was to investigate to what extent changes in the relative influence of the sympathetic (SNS) and parasympathetic nervous systems (PNS) over cardiac activity may reflect the subjective experience induced by the short-acting psychedelic N,N-Dimethyltryptamine (DMT). Methods: We derived measures of SNS and PNS activity from the electrocardiograms of 17 participants (11 males, mean age = 33.8 years, SD = 8.3) while they received either DMT or placebo. Results: Results show that the joint influence of SNS and PNS ("sympathovagal coactivation") over cardiac activity was positively related to participants' ratings of "Spiritual Experience" and "Insightfulness" during the DMT experience, while also being related to improved well-being scores 2 weeks after the session. In addition, we found that the state of balance between the two ANS branches ("sympathovagal balance") before DMT injection predicted scores of "Insightfulness" during the DMT experience, as well as subsequent sympathovagal coactivation. Conclusion: These findings demonstrate the involvement of the ANS in psychedelic-induced peak experiences and may pave the way to the development of biofeedback-based tools to enhance psychedelic therapy. [ABSTRACT FROM AUTHOR]

Background: The applications of psilocybin, derived from 'magic mushrooms,' are vast, including a burgeoning practice known as microdosing, which refers to the administration of sub-hallucinogenic doses of psychedelic substances to obtain benefits without experiencing significant cognitive and perceptual distortion. However, current research is fairly new with several limitations and gaps that hinder adequate conclusions on its efficacy. Aims: This semi-structured review aimed to identify and highlight research gaps in the field of psilocybin microdosing for future research. Methods: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses based strategy was employed, utilizing a chain of keywords and key phrases across multiple databases, augmented by a cross-sectional Google search for relevant grey literature in the form of the top 10 search results. A total of 40 studies and 8 unique websites were identified, summarized and tabulated into four distinct categories, namely non-clinical, clinical, observational and anecdotal evidence. Results: The majority of available evidence originates from observational studies, while non-clinical and clinical study findings remain comparatively sparse and inconsistent. Web-based findings were consistent with current research findings. Key research gaps were highlighted: the imperative for more randomized placebo-controlled trials, exploration of dose-response ranges, psychological and personality testing of participants, utilization of active placebos, greater diversity in study populations, an increase in psilocybin-exclusive microdosing studies and the refinement of animal models. Conclusion: Definitive conclusions regarding the efficacy of psilocybin microdosing remain elusive, emphasizing the need for further study. Numerous research gaps necessitate consideration for future investigations. [ABSTRACT FROM AUTHOR]

Background: Psychedelic drugs have been of interest in medicine since the early 1950s. There has recently been a resurgence of interest in psychedelics. Aims: The objective of this study is to determine the extent of the available literature on psilocybin for medical indications including the designs used, study characteristics, indications studied, doses, and authors' conclusions. We identify areas for further study where there are research gaps. Methods: We conducted a systematic scoping review of clinical indications for psilocybin, encompassing psychiatric and medical conditions. We systematically searched Medline and Embase using keywords related to psilocybin. We reviewed titles and texts in duplicate using Covidence software. We extracted data individually in duplicate using Covidence software and a senior reviewer resolved all author conflicts. We analyzed data descriptively. Results: We included 193 published and 80 ongoing studies. Thirty-seven percent of included studies were systematic reviews. Only 12% of included studies were randomized controlled trials. The median number of participants was 22 with a median of 18 participants who had taken psilocybin. Thirty-eight percent of studies reported at least one potential conflict of interest. The most common indication was depression (28%). Also commonly studied were substance use (14%), mental health in life-threatening illness (9%), headaches (6%), depression and anxiety (6%), obsessive-compulsive disorder (3%), and anxiety disorders (3%). Conclusions: Most studies involving the administration of psilocybin have small sample sizes and the most common focus has been psychiatric disorders. There is a need for high-quality randomized trials on psilocybin and to expand consideration to other promising indications, such as chronic pain. [ABSTRACT FROM AUTHOR]

Background: Psychedelic substances reliably induce marked altered states of consciousness (ASC), which may be important for lasting effects and clinical outcomes of psychedelic intervention. Several instruments are available to measure the acute psychedelic experience, of which the Five Dimensional Altered States of Consciousness Questionnaire (5D-ASC) is commonly used. The questionnaire can be scored and analyzed as having five dimensions or 11 subscales, but the two have not been evaluated with comparable factor analysis methods. Methods: The Danish translation of the 5D-ASC was completed by one sample of healthy volunteers receiving psilocybin in a laboratory setting (N = 47) and one sample of recreative users5D-ASC of psychedelics (N = 550), who reported retrospectively through an online survey based on their most recent experience with psilocybin. We calculated internal consistency measures of Cronbach's alpha and McDonald's omega, conducted a confirmatory factor analysis of the previously suggested factor structures, and tested for possible associations between the 5D-ASC total scores and dose, setting, and intention. For the 11 subscales, we reported omega-sem (composite reliability) using the parameters of the fitted confirmatory factor analyses model. Results: Confirmatory factor analysis showed that the 11 subscales had a good fit to data and showed a better fit compared to the originally proposed five-dimensional solution and good internal consistencies. We further found that the 5D-ASC total scores correlated positively with the dose in the recreative sample. We found no correlations between 5D-ASC total scores and intention or setting. Discussion: We find the Danish 5D-ASC to be a valid tool for measuring ASC among Danish-speaking individuals. [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]

Objective: Despite rapid advances in psychedelic sciences and the increasing number of countries legalizing psychedelics for the treatment of mental illnesses, the attitudes, knowledge and readiness of both mental health consumers and the general population remain largely unknown. Methods: A cross-sectional survey was conducted among Australians, targeting individuals with mental illness as potential mental health service users. A sub-sample of individuals free of mental illness was also surveyed to assess attitudes in the general population. Participants completed the Attitudes on Psychedelics Questionnaire, the Basic Knowledge of Psychedelics Test and a questionnaire by Corrigan et al. to capture attitudes toward psychedelic therapy by mental health service users. Results: Of the 502 respondents, 64.5% self-identified as having a mental illness. A significant proportion favored legalizing psychedelics for medical use (43%) and were open to their use (52.4%), yet fewer viewed their effects positively (24%) or considered them safe (33%). Most participants reported to be psychedelic naive (61%). Participants with mental illness had significantly more experience with psychedelics than participant free of mental illness (44.1% vs 29.7%). Experience, perceived knowledge and actual knowledge significantly predicted attitudes toward legalization, effects, risks and openness to psychedelics. Conclusions: While a large proportion of Australians are in favor of legalizing psychedelics for medical purposes, concerns about safety remain. People with self-identified mental illness, those with previous recreational psychedelic experience and those with greater knowledge of psychedelics were more likely to have positive attitudes toward psychedelics and psychedelic-assisted therapy. [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]

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]

Psychedelic medicine is currently being evaluated for numerous mental health indications, and there is significant interest in applying these models of care to eating disorders (EDs) given the limited efficacy of available treatment models, especially for those living with anorexia nervosa. Preliminary findings across a number of studies suggest promise. In this commentary, researchers with experience in psychedelics and EDs present a rationale and considerations for the application of psychedelic medicine, including psychedelic-assisted therapy (PAT) for EDs. These contributions are informed by those with lived experience as well as the authors' experiences in the field. By addressing underlying psychological and transpersonal factors and improving treatment engagement, psychedelic medicine, though not without risks, may offer a valuable adjunct to existing treatments, enhancing overall outcomes for some living with an ED. This commentary also aims to provide a multi-dimensional perspective to inform the field, including with respect to the etiology of these illnesses, as psychedelic medicine becomes more accessible in naturalistic, research and clinical settings. [ABSTRACT FROM AUTHOR]

There are profound methodological challenges facing microdosing research. One way we can address some of these methodological issues is by understanding how psilocybin microdosing fits in the broader existential context of people’s lives. We recruited participants who underwent psilocybin microdosing on their own and consented to being monitored for harm mitigation purposes. We combined momentary ecological assessment and detailed retrospective interviews. Participants reported loosening of mental structures (i.e., less intense strength of thoughts, tangential stream of consciousness), increased salience of external stimuli (varyingly associated with greater interest in otherwise mundane activities, as well as sensory overload), an increase in flexible cognition, a decrease in stable cognition, and various ego-dystonic contents. Highly structured environments were conducive to positive appraisal of experiences and vice versa. Momentary ecological assessment and retrospective interviews yielded differing accounts of microdosing experience. We relate our findings to stable and flexible cognition, as well as the notion of salience. We point out the necessity for systematic mixed methods studies to better characterize the lived experience of taking low doses of psilocybin. [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]

Psychedelic-assisted therapy (PAT) has shown preliminary efficacy for psychiatric and physical health conditions. Although some people report naturalistic psychedelic use with so-called “underground” practitioners, little is known about PAT that occurs outside of controlled clinical settings or perspectives of these practitioners. We conducted an anonymous online survey of individuals who reported providing psychedelic support services (e.g. trip sitting and/or preparatory/follow-up psychotherapy) in naturalistic settings. We investigated demographics, including education and licensing, details about services provided, and reported client outcomes. Among 107 participants, 40.2% held a full or in-progress license and 44.9% had not obtained a relevant graduate degree. Almost all participants reported pre-screening clients before treatment, offering preparation, integration, and trip-sitting services, and most employed a range of therapeutic modalities, centering primarily on non-directive approaches. Participants reported that clients most commonly consumed psilocybin, and treated numerous conditions, primarily aligning with indications targeted in psychedelic clinical research. Perceptions of clients’ symptom changes were largely positive, although a small proportion reported worsened personality disorder symptoms. Further research delineating client and practitioner perspectives of naturalistic PAT services is warranted, and such work may shed light on the benefits and risks specific to naturalistic PAT as well as inform best practices for practitioners. [ABSTRACT FROM AUTHOR]