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We present a case of takotsubo cardiomyopathy following recreational ingestion of Psilocybe semilanceata (known as ‘magic mushrooms’). The patient presented with respiratory distress and pulmonary oedema responding to standard medical measures. Investigations included: echocardiogram, cardiac MRI and angiogram. Based on our search, we suggest this is only the second recognised case in the published literature.

Psychedelic therapy shows promise for Major Depressive Disorder, especially when treatment-resistant, as well as life-threatening illness distress. The objective of this systematic review, inclusive of meta-analysis, is to examine recent clinical research on the therapeutic effects of classic psychedelics on depressive symptoms.Fourteen psychedelic therapy studies, utilising psilocybin, ayahuasca, or LSD, were systematically reviewed. For the meta-analysis, standardised mean differences were calculated for seven randomised controlled trials.The systematic review indicated significant short- and long-term reduction of depressive symptoms in all conditions studied after administration of psilocybin, ayahuasca, or LSD, with psychological support. In the meta-analysis, symptom reduction was significantly indicated in three timepoints out of four, including 1-day, 1-week, and 3-5 weeks, supporting the results of the systematic review, with the exception of the 6-8 weeks follow-up point which was less conclusive.The absence of required data for 2 studies necessitated the less precise use of graphical extraction and imputation. The small sample size in all but one study negatively affected the statistical power. None of the studies had long-term follow-up without also utilising the cross-over method, which did not allow for long-term results to be included in the meta-review.This review indicates an association between psychedelic therapy and significant reduction of depressive symptoms at several time points. However, the small number of studies, and low sample sizes, calls for careful interpretation of results. This suggests the need for more randomised clinical trials of psychedelic therapy, with larger and more diverse samples.

Psychedelics and related compounds have shown efficacy for the treatment of a variety of conditions that are prevalent among older adults, including mood disorders, the psychological distress associated with a serious medical illness, post-traumatic stress disorder (PTSD), and prolonged grief disorder. Psychedelics also have properties that could help provide therapeutic benefits for patients with dementing disorders, as well as promoting personal growth among healthy older adults. This article focuses on psilocybin, a classic psychedelic, and MDMA, a substituted amphetamine with properties similar to classic psychedelics. Both act on the 5HT

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

BACKGROUND: Psilocybin is being studied for use in treatment-resistant depression.METHODS: In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits).RESULTS: A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; PCONCLUSIONS: In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).

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

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

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

Microdosing—the intermittent ingestion of minute, sub-hallucinogenic amounts of psychedelic substances, repeatedly and over time—has become a widespread, albeit largely understudied, phenomenon. Regulations around using psychedelics at any dose—micro, mini, macro, or mega—pose all sorts of difficulties for those who wish to systematically study the effects of Schedule I drugs, especially in the United States. Microdosers commonly claim that taking a sub-hallucinogenic (pre-hallucinogenic or sub-perceptual) dose improves higher brain functions, including creativity, productivity, and mood. If true, these results would provide an important experimental edge in distinguishing psychosocial effects (e.g. caused by expectation) from those related to the active psychedelic ingredient. In this critical integrative synthesis, we explore the psychobiological science of dose amounts and how it informs microdosing with classical psychedelics (e.g. lysergic acid diethylamide [LSD] and psilocybin) to highlight and fuel research into questions (e.g. in cognitive neuroscience, consciousness studies, and metacognition). We sketch the hurdle-laden regulatory landscape and the procedures that shroud research with Schedule I drugs. Finally, we offer some future directions relevant to both scholars and clinicians in the social and behavioral sciences as well as in mental health and neurological science.

Psychedelic-assisted psychotherapy holds great promise in the treatment of mental health disorders. Research into 5-hydroxytryptamine 2A receptor (5-HT

Classic psychedelics, such as LSD, psilocybin, and the DMT-containing beverage ayahuasca, show some potential to treat depression, anxiety, and addiction. Importantly, clinical improvements can last for months or years after treatment. It has been theorized that these long-term improvements arise because psychedelics rapidly and lastingly stimulate neuroplasticity. The focus of this review is on answering specific questions about the effects of psychedelics on neuroplasticity. Firstly, we review the evidence that psychedelics promote neuroplasticity and examine the cellular and molecular mechanisms behind the effects of different psychedelics on different aspects of neuroplasticity, including dendritogenesis, synaptogenesis, neurogenesis, and expression of plasticity-related genes (e.g., brain-derived neurotrophic factor and immediate early genes). We then examine where in the brain psychedelics promote neuroplasticity, particularly discussing the prefrontal cortex and hippocampus. We also examine what doses are required to produce this effect (e.g., hallucinogenic doses vs. “microdoses”), and how long purported changes in neuroplasticity last. Finally, we discuss the likely consequences of psychedelics’ effects on neuroplasticity for both patients and healthy people, and we identify important research questions that would further scientific understanding of psychedelics’ effects on neuroplasticity and its potential clinical applications.

A recent paper in

Background and Objectives: PolDrugs is the largest Polish naturalistic nationwide survey to present basic demographic and epidemiological data that could potentially prevent harm from illicit substances intake in drugs users. The most recent results were presented in 2021. The goal of this year’s edition was to re-present the above data and compare it to the previous edition’s data to identify and describe the differences. Materials and Methods: The survey included original questions about basic demographics, substance use, and psychiatric treatment. The survey was administered via the Google Forms platform and promoted via social media. The data was collected from 1117 respondents. Results: People of all ages use a variety of psychoactive substances in many situations. The three most commonly used drugs are marijuana, 3,4-methylenedioxymethamphetamine, and hallucinogenic mushrooms. The most common reason for seeking professional medical help was amphetamine use. A total of 41.7 percent of respondents were receiving psychiatric treatment. The three most common psychiatric diagnoses among the respondents were depressive disorders, anxiety disorders, and ADHD. Conclusions: Key findings include increases in the use of psilocybin and DMT, increases in the use of heated tobacco products, and a near doubling in the percentage of individuals receiving psychiatric help in the past two years. These issues are discussed in the discussion section of this paper, which also addresses the limitations to the article.

BACKGROUND: COMP360 is a proprietary, synthetic formulation of psilocybin being developed for treatment-resistant depression (TRD), a burdensome, life-threatening illness with high global impact. Here, we expand upon the previous report of primary outcomes from a phase 2 study of COMP360 in individuals with TRD-the largest randomised controlled clinical trial of psilocybin-to discuss findings of the exploratory efficacy endpoints.METHODS: In this phase 2, double-blind trial, 233 participants with TRD were randomised to receive a single dose of psilocybin 25 mg, 10 mg, or 1 mg (control), administered alongside psychological support from trained therapists. Efficacy measures assessed patient-reported depression severity, anxiety, positive and negative affect, functioning and associated disability, quality of life, and cognitive function.RESULTS: At Week 3, psilocybin 25 mg, compared with 1 mg, was associated with greater improvements from Baseline total scores in all measures. The 10 mg dose produced smaller effects across these measures.LIMITATIONS: Interpretation of this trial is limited by the absence of an active comparator and the possibility of functional unblinding in participants who received a low dose of psilocybin.CONCLUSIONS: Three weeks after dosing, psilocybin 25 mg and, to a lesser degree, 10 mg improved measures of patient-reported depression severity, anxiety, affect, and functioning. These results extend the primary findings from the largest randomised clinical trial of psilocybin for TRD to examine other outcomes that are of importance to patients.

The serotonergic classical psychedelics include compounds that primarily activate the brain’s serotonin 2 A receptor (5-HT2AR), such as LSD, psilocybin, and DMT (ayahuasca). The acute effects of these compounds are well-known as are their ability to increase the emotional state both in healthy people and in those with neuropsychiatric disorders. In particular psilocybin, the psychoactive constituent in “magic mushrooms”, has shown great potential for treatment of anxiety and depression. A unique and compelling feature of psychedelics is that intake of just a single psychedelic dose is associated with long-lasting effects. This includes effects on personality, e.g., higher openness, and amelioration of depressive symptoms. This review focuses on these stunning effects and summarizes our current knowledge on which behavioral, biochemical, neuroimaging, and electrophysiological data support that the intriguing effects of psychedelics on the human brain and mind are based on neural plasticity. The review also points to so far understudied areas and suggests research questions to be addressed in future studies which potentially can help to understand the intriguing long-term effects after intake of a single (or a few) psychedelic doses.

People affected by serious illness usually experience suffering in its various dimensions, not only in the physical but also in the psychosocial and spiritual aspects. The interest in psychedelic-assisted therapies as a potential new therapeutic modality has increased since evidence suggests a significant impact of their use on the outcomes of patients with serious illness.To systematically review the available evidence on the effects of psychedelic-assisted therapies for symptom control in patients diagnosed with serious illness.The protocol of this systematic review has been prepared according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. This review included randomized and non-randomized controlled trials published in peer-reviewed scientific journals. A comprehensive search for studies was carried out in the main scientific databases, including Web of Science, Scopus, Cochrane Library, PsycINFO, PubMed, CINAHL, and EMBASE. There were no limitations regarding the year or language of publication.The sample was composed of 20 studies. The results suggest positive effects of psychedelic-assisted therapies for symptom control in patients diagnosed with serious illness, with considerable safety of use. Most studies have been conducted with lysergic acid diethylamide, psilocybin, and N,N-dipropyltryptamine in cancer patients. The adverse effects reported were of physical and/or psychological nature and of mild to moderate intensity, transient, and self-resolutive.The evaluated evidence suggests positive effects of psychedelic-assisted therapies for symptom control in patients diagnosed with serious illness, especially regarding symptoms of psychological and spiritual nature.

Logic Space, as described in the Geometry of Logic (Emmerson, 2023), allows us to generate a virtual logic-based vector space for notating and analyzing chemical compounds and their correlate behaviors within virtual neural nets. Interestingly, we find that the golden ratio is a relevant aspect in the digital harmonies of psilocybin.

Classic psychedelic molecules, such as lysergic acid (LSD), psilocybin (the active ingredient of “magic mushrooms”), and N,N-Dimethyltryptamine (DMT) are 5-hydroxytryptamine 2A (5-HT2A) receptor agonists that can alter perception, mood and cognition (Nichols, 2016). Over the last 10-15 years, new scientific evidence has emerged on the therapeutic potential of psychedelic compounds in patients with depression, anxiety and post-traumatic stress disorder (Carhart-Harris, 2016; Griffiths, 2016; Grob, 2011; Ross, 2016; dos Santos, 2016; Thomas, 2017). In the same period, a novel use paradigm of psychedelics has also emerged, called ‘microdosing’, which is the regular usage of psychedelic drugs at sub-perceptual doses (Fadiman 2011). A considerable number of experience reports claims that microdosing can improve psychological well-being and cognitive functioning (Experience reports 1-3; Fadiman, 2011; Waldman, 2017). However, more rigorous research has failed to demonstrate an effect of microdosing on psychological outcomes while controlling for placebo effects and blind-breaking. We propose a laboratory-based study to investigate the effects of psychedelic microdosing on cognitive performance, biological and genetic indices relevant to neural plasticity, immune functioning, and mental and physical health symptoms. Our study has an observational design with the addition of an innovative self-blinding procedure that allows self-experimenters to implement their own placebo control. Participants will be allocated 1:1 to the microdosing (MD) or placebo (PL) condition. The primary objectives of the study are to test whether psychedelic microdosing has an effect beyond placebo on cognitive function, neurophysiology, and mental health domains (e.g., depression or anxiety). The strength of this study design is (1) the substantial expected sample size (up to 80 participants) relative to what is typically feasible in a clinical study at lower cost, while also controlling for expectations/placebo effects that are likely to bias other observational studies; (2) our focus on a unique cohort of microdose users who are self-medicating mental health problems, bearing greater relevance to clinical applications of microdosing; and (3) the ability to probe more deeply into biological/genetic changes that may accompany psychological and cognitive improvements.

BackgroundPsychedelic-assisted therapy [e.g., with lysergic acid diethylamide (LSD)] has shown promising results as treatment for substance use disorders (SUDs). Previous systematic reviews assessing the efficacy of psilocybin in SUDs only included clinical trials conducted in the last 25 years, but they may have missed clinical trials assessing the efficacy of psilocybin that were conducted before the 1980s, given much research has been done with psychedelics in the mid-20th century. In this systematic review, we specifically assessed the efficacy of psilocybin in patients with a SUD or non-substance-related disorder with no publication date restrictions in our search strategy.MethodsA systematic literature search was performed according to Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines from the earliest published manuscript up to September 2, 2022, in seven electronic databases, including clinical trials in patients with a SUD or non-substance-related disorder evaluating the efficacy of psilocybin.ResultsA total of four studies (six articles, of which two articles were long-term follow-up results from the same trial) were included in this systematic review. Psilocybin-assisted therapy was administered to n = 151 patients in a dose ranging from 6 to 40 mg. Three studies focused on alcohol use disorder, and one study on tobacco use disorder. In a pilot study (n = 10), the percentage of heavy drinking days decreased significantly between baseline and weeks 5–12 (mean difference of 26.0, 95% CI = 8.7–43.2, p = 0.008). In another single-arm study (n = 31), 32% (10/31) became completely abstinent from alcohol (mean duration of follow-up 6 years). In a double-blind, placebo-controlled randomized controlled trial (RCT, n = 95), the percentage of heavy drinking days during the 32-week double-blind period was significantly lower for psilocybin compared to placebo (mean difference of 13.9, 95% CI = 3.0–24.7, p = 0.01). In a pilot study (n = 15), the 7-day point prevalence of smoking abstinence at 26 weeks was 80% (12/15), and at 52 weeks 67% (10/15).ConclusionOnly one RCT and three small clinical trials were identified assessing the efficacy of psilocybin combined with some form of psychotherapy in patients with alcohol and tobacco use disorder. All four clinical trials indicated a beneficial effect of psilocybin-assisted therapy on SUD symptoms. Larger RCTs in patients with SUDs need to evaluate whether psilocybin-assisted therapy is effective in patients with SUD.

Psilocybin is a psychoactive molecule derived from tryptamine precursors that is present in some mushrooms, especially those belonging to the Psilocybe genus. Its pharmacologically active metabolite, produced by dephosphorylation, is psilocin, which can cross the blood-brain barrier. It is believed that the psychedelic effects of psilocin result from its partial agonistic activities on 5-HT2A receptors, the main receptor subtype among serotonin G-protein-coupled receptors (GPCRs). Psilocin also binds to a number of other subtypes of these receptors, but the effects it has on these receptors have not been fully explored yet. Psilocybin has been studied for its potential use in treating anxiety, depression, and disorders caused by addictive substances when administered in concentrations sufficient to produce psychedelic effects. The pharmacological potential of psilocybin is without the risks of potential addiction or overdose compared to other psychoactive drugs such as cocaine, alcohol, methamphetamine, and others. Due to the increasing worldwide trend of addiction, overdose, and suicidal deaths, it is necessary to seek new therapeutic alternatives. However, it is also necessary to assess various contraindications that may limit the possibility of using psilocybin as a pharmacological therapy....

Background: Past research reports a positive relationship between experience with classic serotonergic psychedelics and nature relatedness (NR). However, these studies typically do not distinguish between different psychedelic compounds, which have a unique psychopharmacology and may be used in specific contexts and with different intentions. Likewise, it is not clear whether these findings can be attributed to substance use per se or unrelated variables that differentiate psychedelic users from nonusers. Aims: The present study was designed to determine the relative degree to which lifetime experience with different psychedelic substances is predictive of self-reported NR among psychedelic-experienced users. Methods: We conducted a combined reanalysis of five independent datasets ( N = 3817). Using standard and regularized regression analyses, we tested the relationship between degree of experience with various psychedelic substances (binary and continuous) and NR, both within a subsample of psychedelic-experienced participants as well as the complete sample including psychedelic-naïve participants. Results/Outcomes: Among people experienced with psychedelics, only past use of psilocybin (versus LSD, mescaline, Salvia divinorum, ketamine, and ibogaine) was a reliable predictor of NR and its subdimensions. Weaker, less reliable results were obtained for the pharmacologically similar N,N-dimethyltryptamine (DMT). Results replicate when including psychedelic-naïve participants. In addition, among people exclusively experience with psilocybin, use frequency positively predicted NR. Conclusions/Interpretation: Results suggest that experience with psilocybin is the only reliable (and strongest) predictor of NR. Future research should focus on psilocybin when investigating effects of psychedelic on NR and determine whether pharmacological attributes or differences in user expectations/use settings are responsible for this observation.

The aim of this systematic review is to present the current literature on the therapeutic potential of the classic psychedelic compound psilocybin for depressive disorders and the neurocognitive mechanisms involved recorded with functional magnetic resonance imaging (fMRI). A comprehensive literature search was conducted in the electronic databases Web of Science, Scopus and Medline EBSCO using a Boolean search string containing the keywords psilocybin, depression, fMRI, MRI and PET. Our inclusion criteria require original neuroimaging research articles published in scientific peer-reviewed journals involving participants diagnosed with depression receiving psilocybin in conjunction with psychological support. Five articles were identified including a total of 104 participants with depression and 75 who received treatment, resulting in significant reduction of depressive symptoms associated with observable changes in neural activity. Specifically reduced cerebral blood flow (CBF) in amygdala, decreased brain modularity along with functional changes in default mode network (DMN), executive network (EN), salience network (SN), decrease in functional connectivity (FC) between ventromedial prefrontal cortex (vmPFC) to amygdala and increased amygdala reactivity to fearful faces. Limitations of our systematic review include a currently limited amount of articles published and thus lack of control groups in most studies. The current evidence indicates that the therapeutic potential of psilocybin-assisted therapy may provide fast acting and efficient amelioration of depressive symptoms and the effects may be mediated by neurocognitive changes acute and post-treatment. The preliminary results warrants further research in order to optimize treatment and establish safety and efficacy long term.

This dissertation has taken an interdisciplinary approach to investigate and give insights into psilocybin’s neurobiological underpinnings. Psilocybin is a naturally occurring serotonergic psychedelic and is the main ingredient in hallucinogenic mushrooms. Research has demonstratedthat psilocybin profoundly activates the serotonin (5-hydroxytryptamine) 2A (5-HT2A) receptors. Upon activation of these receptors in the brain, psilocybin induces profound perceptual changes such as hallucinations and illusions, altering one’s self-perception, bodily image and mood.There is a growing interest in psilocybin’s therapeutic utility, focusing on psychiatric disorders, such as treatment-resistant depression. Despite psilocybin’s therapeutic potential, the underlying neurobiological mechanisms of psilocybin remain elusive. Therefore, this dissertation aimed to understand and delineate the acute dose-dependent effects of psilocybin on an epigenetic, neurobiological and cognitive level.

The need to identify effective therapies for the treatment of psychiatric disorders is a particularly important issue in modern societies. In addition, difficulties in finding new drugs have led pharmacologists to review and re-evaluate some past molecules, including psychedelics. For several years there has been growing interest among psychotherapists in psilocybin or lysergic acid diethylamide for the treatment of obsessive-compulsive disorder, of depression, or of post-traumatic stress disorder, although results are not always clear and definitive. In fact, the mechanisms of action of psychedelics are not yet fully understood and some molecular aspects have yet to be well defined. Thus, this review aims to summarize the ethnobotanical uses of the best-known psychedelic plants and the pharmacological mechanisms of the main active ingredients they contain. Furthermore, an up-to-date overview of structural and computational studies performed to evaluate the affinity and binding modes to biologically relevant receptors of ibogaine, mescaline, N,N-dimethyltryptamine, psilocin, and lysergic acid diethylamide is presented. Finally, the most recent clinical studies evaluating the efficacy of psychedelic molecules in some psychiatric disorders are discussed and compared with drugs already used in therapy.

In "retreat_ap2eg_overall_preregistration.pdf", a registration of the overall project is given, including all hypotheses of all study components and information shared between them. The preregistration follows the template at https://osf.io/preprints/metaarxiv/epgjd/ and includes the sections "Study Information", "Design Plan" and "Sample Plan". The sections "Variables" and "Analysis Plan" are omitted here, but will be specified for each study component seperately in their individual preregistration documents.

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

This is a scoping review of the administration Methodologies of Psilocybin for Depression, Persons Aged over 18 years old.

RATIONALE & OBJECTIVES: ±3,4-Methylenedioxymethamphetamine (MDMA) and psilocybin are currently moving through the US Food and Drug Administration’s phased drug development process for psychiatric treatment indications: posttraumatic stress disorder and depression, respectively. The current standard of care for these disorders involves treatment with psychiatric medications (e.g., selective serotonin reuptake inhibitors), so it will be important to understand drug-drug interactions between MDMA or psilocybin and psychiatric medications. METHODS: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we queried the MEDLINE database via PubMed for publications of human studies in English spanning between the first synthesis of psilocybin (1958) and December 2020. We used 163 search terms containing 22 psychiatric medication classes, 135 specific psychiatric medications, and 6 terms describing MDMA or psilocybin. RESULTS: Forty publications were included in our systematic review: 26 reporting outcomes from randomized controlled studies with healthy adults, 3 epidemiologic studies, and 11 case reports. Publications of studies describe interactions between MDMA (N = 24) or psilocybin (N = 5) and medications from several psychiatric drug classes: adrenergic agents, antipsychotics, anxiolytics, mood stabilizers, NMDA antagonists, psychostimulants, and several classes of antidepressants. We focus our results on pharmacodynamic, physiological, and subjective outcomes of drug-drug interactions. CONCLUSIONS: As MDMA and psilocybin continue to move through the FDA drug development process, this systematic review offers a compilation of existing research on psychiatric drug-drug interactions with MDMA or psilocybin.

Rationale Ketamine and psilocybin belong to the rapid-acting antidepressants but they also produce psychotomimetic effects including timing distortion. It is currently debatable whether these are essential for their therapeutic actions. As depressed patients report that the “time is dragging,” we hypothesized that ketamine and psilocybin-like compounds may produce an opposite effect, i.e., time underestimation, purportedly contributing to their therapeutic properties. Objectives Timing was tested following administration of (R)- and (S)-ketamine, and psilocybin, psilocin, and norpsilocin in the discrete-trial temporal discrimination task (TDT) in male rats. Timing related to premature responses, and cognitive and unspecific effects of compounds were tested in the 5-choice serial reaction time task (5-CSRTT) in the standard 1-s, and “easier” 2-s stimulus duration conditions, as well as in the vITI variant promoting impulsive responses. Results (S)-ketamine (15 but not 3.75 or 7.5 mg/kg) shifted psychometric curve to the right in TDT and reduced premature responses in 5-CSRTT, suggesting expected time underestimation, but it also decreased the accuracy of temporal discrimination and increased response and reward latencies, decreased correct responses, and increased incorrect responses. While (R)-ketamine did not affect timing and produced no unspecific actions, it reduced incorrect responses in TDT and increased accuracy in 5-CSRTT, suggesting pro-cognitive effects. Psilocin and psilocybin produced mainly unspecific effects in both tasks, while norpsilocin showed no effects. Conclusions Time underestimation produced by (S)-ketamine could be associated with its antidepressant effects; however, it was accompanied with severe behavioral disruption. We also hypothesize that behavioral disruption produced by psychedelics objectively reflects their psychotomimetic-like actions.

Background: Many benefits and some harms associated with psychedelic use could be attributable to these drugs’ acceptance/avoidance-promoting effects and corresponding changes in psychological flexibility. Underlying psychological mechanisms are insufficiently understood. Aim: The purpose of this study was the validation of a psychological model of acceptance/avoidance-promoting psychedelic experiences, which included the development of a theory-based self-report instrument: the Acceptance/Avoidance-Promoting Experiences Questionnaire (APEQ). Its two main scales, acceptance-related experience (ACE) and avoidance-related experience (AVE), represent the theorized model’s core constructs. We aimed to test the model’s central assumptions of complementarity (ACE and AVE may occur alternatingly but not simultaneously, and are therefore empirically independent), intertwinedness (subaspects within ACE and AVE are mutually contingent and therefore highly inter-correlated), context-dependence (ACE and AVE depend on context factors) and interaction (longer-term outcomes depend on the interplay between ACE and AVE). Method: A bilingual retrospective online survey including 997 English- and 836 German-speaking participants. Each participant reported on one psychedelic experience occasioned by lysergic acid diethylamide (LSD), psilocybin, mescaline, or ayahuasca. Results: Whereas ACE and AVE were found to be relatively independent aspects of participants’ reported psychedelic experiences (complementarity), their subaspects were mostly distinguishable but strongly correlated among each other (intertwinedness). Therapeutic, escapist, and hedonic use motives were differentially associated with ACE and AVE (context-dependence), which were in turn associated with retrospective changes in psychological flexibility following participants’ reported experiences. The positive association between ACE and increased psychological flexibility was significantly moderated by AVE (interaction). Conclusion: These results provide an initial validation of the APEQ and its underlying theoretical model, suggesting the two can help clarify the psychological mechanisms of psychedelic-induced benefits and harms. Both should be further investigated in prospective-longitudinal and clinical studies.

Introduction: As their name suggests, ‘psychedelic’ (mind-revealing) compounds are thought to catalyse processes of psychological insight; however, few satisfactory scales exist to sample this. This study sought to develop a new scale to measure psychological insight after a psychedelic experience: the Psychological Insight Scale (PIS). Methods: The PIS is a six- to seven-item questionnaire that enquires about psychological insight after a psychedelic experience (PIS-6) and accompanied behavioural changes (PIS item 7). In total, 886 participants took part in a study in which the PIS and other questionnaires were completed in a prospective fashion in relation to a planned psychedelic experience. For validation purposes, data from 279 participants were analysed from a non-specific ‘global psychedelic survey’ study. Results: Principal components analysis of PIS scores revealed a principal component explaining 73.57% of the variance, which displayed high internal consistency at multiple timepoints throughout the study (average Cronbach’s α = 0.94). Criterion validity was confirmed using the global psychedelic survey study, and convergent validity was confirmed via the Therapeutic-Realizations Scale. Furthermore, PIS scores significantly mediated the relationship between emotional breakthrough and long-term well-being. Conclusion: The PIS is complementary to current subjective measures used in psychedelic studies, most of which are completed in relation to the acute experience. Insight – as measured by the PIS – was found to be a key mediator of long-term psychological outcomes following a psychedelic experience. Future research may investigate how insight varies throughout a psychedelic process, its underlying neurobiology and how it impacts behaviour and mental health.

Psilocybin is a psychoactive alkaloid that is produced naturally by approximately 200 species of mushrooms. The potential medical use of this molecule for the treatment of mental illness is gaining renewed momentum. As demand grows and clinical trials progress, appropriate methods for producing a quality pharmaceutical product are needed. This review highlights the methods currently available, such as the prominent synthetic method and its biosynthetic alternatives, as well as others on the near horizon. This article further seeks to discuss the rapid and evolving nature of the psilocybin industry in the 21st century.

Background Previous studies have shown that psilocybin has antidepressant effects. In the current study, we aim to explore the dose effects of psilocybin on primary (major depression patients) and secondary depression (depressed cancer patients). Methods Published studies concerning psilocybin for depression were retrieved. In accordance with PRISMA guidelines, 6 databases (PubMed, Embase, Web of Science, Cochrane Library, Clinicaltrials.gov 2.3 and WanFang database) were searched for research studies published or still in progress from inception to 30 November, 2020, with language restricted to English and Chinese. Hedges’ g of Beck Depression Inventory (BDI) score changes was calculated as the primary outcome. Results 7 articles were finally included, with a total of 136 participants. In terms of efficacy, Hedges’ g was 1.289 (95%CI=[1.020, 1.558], heterogeneity I2=50.995%, p 1month: Hedges’ g=1.123, 95%CI=[0.861, 1.385], p Limitations Only a small number of studies can be identified of variable quality, thus our conclusions remain preliminary. Conclusions Our preliminary results have shown that psilocybin exerts a rapid effect in reducing depressive symptom on primary and secondary depression. The optimal dose of psilocybin may be 30-35mg/70kg or higher; future clinical trials are warranted for further evaluation on its effect.

Background:Psilocybin, a psychoactive serotonin receptor partial agonist, has been reported to acutely reduce clinical symptoms of depressive disorders. Psilocybin’s effects on cognitive function have not been widely or systematically studied.Aim:The aim of this study was to explore the safety of simultaneous administration of psilocybin to healthy participants in the largest randomised controlled trial of psilocybin to date. Primary and secondary endpoints assessed the short- and longer-term change in cognitive functioning, as assessed by a Cambridge Neuropsychological Test Automated Battery (CANTAB) Panel, and emotional processing scales. Safety was assessed via endpoints which included cognitive function, assessed by CANTAB global composite score, and treatment-emergent adverse event (TEAE) monitoring.Methods:In this phase 1, randomised, double-blind, placebo-controlled study, healthy participants ( n = 89; mean age 36.1 years; 41 females, 48 males) were randomised to receive a single oral dose of 10 or 25 mg psilocybin, or placebo, administered simultaneously to up to six participants, with one-to-one psychological support – each participant having an assigned, dedicated therapist available throughout the session.Results:In total, 511 TEAEs were reported, with a median duration of 1.0 day; 67% of all TEAEs started and resolved on the day of administration. There were no serious TEAEs, and none led to study withdrawal. There were no clinically relevant between-group differences in CANTAB global composite score, CANTAB cognitive domain scores, or emotional processing scale scores.Conclusions:These results indicate that 10 mg and 25 mg doses of psilocybin were generally well tolerated when given to up to six participants simultaneously and did not have any detrimental short- or long-term effects on cognitive functioning or emotional processing.Clinical Trial Registration:EudraCT ( https://www.clinicaltrialsregister.eu/ ) number: 2018-000978-30.

Introduction: Psychedelic drugs were used quite extensively before their prohibition in 1968 which delayed research. However, since the 1990s, studies on the potential therapeutic benefits of psychedelics have rapidly increased. Areas covered: This systematic review provides an overview of the clinical effects of psilocybin in the treatment of a variety of mental disorders. Only (randomized) clinical trials were selected. A total of 11 studies (15 publications) were selected, including seven randomized controlled trials (eight publications) and four single arm open-label studies (seven publications). In total, 488 patients were included in the selected studies: 333 patients treated with psilocybin and 155 patients treated with (active) placebo. In nine studies, psychotherapeutic support was provided as an integral part of the psilocybin treatment. The findings of these studies collectively show that psilocybin has a positive benefit–risk balance in the treatment of various mental disorders with an immediate and prolonged effect following 1–3 doses of psilocybin and a few (serious) adverse events. Expert opinion: Psilocybin–mostly combined with psychotherapy or psychotherapeutic support–shows a promise as a treatment for various (treatment-resistant) mental disorders. Larger double-blind RCTs with objective (long-term) outcomes are needed to confirm these findings before standard clinical use of psilocybin can be considered.

Psychedelics are increasingly being recognized for their potential to treat a wide range of brain disorders including depression, post-traumatic stress disorder (PTSD), and substance use disorder. Their broad therapeutic potential might result from an ability to rescue cortical atrophy common to many neuropsychiatric and neurodegenerative diseases by impacting neurotrophic factor gene expression, activating neuronal growth and survival mechanisms, and modulating the immune system. While the therapeutic potential of psychedelics has not yet been extended to neurodegenerative disorders, we provide evidence suggesting that approaches based on psychedelic science might prove useful for treating these diseases. The primary target of psychedelics, the 5-HT(2A) receptor, plays key roles in cortical neuron health and is dysregulated in Alzheimer’s disease. Moreover, evidence suggests that psychedelics and related compounds could prove useful for treating the behavioral and psychological symptoms of dementia (BPSD). While more research is needed to probe the effects of psychedelics in models of neurodegenerative diseases, the robust effects of these compounds on structural and functional neuroplasticity and inflammation clearly warrant further investigation.

A confluence of factors has renewed interest in the scientific understanding and translational potential of psychedelic drugs such as lysergic acid diethylamide (LSD), mescaline, and psilocybin: the desire for additional approaches to mental health care, incremental progress in basic and clinical research, and the reconsideration and relaxation of existing drug policies. With the United States Food and Drug Administration's designation of psilocybin as a "Breakthrough Therapy" for treatment-resistant depression, a new path has been forged for the conveyance of psychedelics to the clinic. Essential to the further development of such applications, however, is a clearer understanding of how these drugs exert their effects at the molecular level. Here we review the current knowledge regarding the molecular details of psychedelic drug actions and suggest that these discoveries can facilitate new insights into their hallucinogenic and therapeutic mechanisms.

This systematized review sought to fill a gap in psilocybin research by investigating the structure and format of psilocybin-assisted psychotherapy (PAP), with a focus on the counseling components of the treatment.A systematized review of PAP was conducted by using the PubMed and PsycInfo databases to search for peer-reviewed studies of human clinical trials, published within the past 25 years, in which psilocybin was administered with psychological support in a clinical setting.Eleven articles matched the criteria necessary for inclusion in this review. PAP was found to consist of three stages: pretreatment sessions to prepare participants for psilocybin, treatment sessions in which psilocybin was administered, and posttreatment sessions to integrate the experience with daily life. Conventional psychotherapy was primarily seen in the pre- and posttreatment sessions. Psychotherapies included in PAP differed among studies, but most often included music therapy and a nondirective supportive approach to treatment.This systematized review found important commonalities among clinical trials of PAP published within the past 25 years and revealed key differences among studies in psychotherapy's incorporation into PAP. Additional research is needed to identify the unique effect of psychotherapy in PAP.

Background: Terminally ill patients may experience existential distress, depression, or anxiety, limiting quality of life in the final stage. Existing psychotherapeutic or pharmacological interventions have (time) limited efficacy. Psychedelic treatment may be a safe and effective alternative treatment option. Aim: Systematically review studies on psychedelic treatment with and without psychotherapy for existential distress, depression, and anxiety in terminally ill patients. Methods: Medline, PsycINFO, and Embase were searched for original-data studies on the treatment of depression, anxiety, and existential distress with classical or a-typical psychedelics in patients with a terminal illness, using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: A total of 1850 records were screened, and 33 articles were included in this review: 14 studies on classical psychedelics (DPT, LSD, and psilocybin) and 19 studies on atypical psychedelics (MDMA and ketamine). Results of early pre-post studies are promising but have serious methodological flaws. Recent (controlled) trials with LSD, psilocybin, ketamine, and MDMA are of higher methodological quality and indicate positive effects on existential and spiritual well-being, quality of life, acceptance, and reduction of anxiety and depression with few adverse and no serious adverse effects. Conclusions: Both classical and a-typical psychedelics are promising treatment options in patients with terminal illness. To draw final conclusions on effectiveness and safety of psychedelics, we need larger high-quality studies for classical psychedelics and MDMA. Ketamine studies should pay more attention to existential dimensions of well-being and the psychotherapeutic context of the treatment.

Can the use of psychedelic drugs induce lasting changes in metaphysical beliefs? While it is popularly believed that they can, this question has never been formally tested. Here we exploited a large sample derived from prospective online surveying to determine whether and how beliefs concerning the nature of reality, consciousness, and free-will, change after psychedelic use. Results revealed significant shifts away from ‘physicalist’ or ‘materialist’ views, and towards panpsychism and fatalism, post use. With the exception of fatalism, these changes endured for at least 6 months, and were positively correlated with the extent of past psychedelic-use and improved mental-health outcomes. Path modelling suggested that the belief-shifts were moderated by impressionability at baseline and mediated by perceived emotional synchrony with others during the psychedelic experience. The observed belief-shifts post-psychedelic-use were consolidated by data from an independent controlled clinical trial. Together, these findings imply that psychedelic-use may causally influence metaphysical beliefs—shifting them away from ‘hard materialism’. We discuss whether these apparent effects are contextually independent.

This article proposes alternative understandings of certain structuralist informed (Diagnostic and Statistical Manual of Mental Disorders - DSM-IIIrd to 5th Eds.) configurations of mental disorders. Life’s negative discourses and the mind’s captive responses present a “general theory of mental suffering” which phenomena are classified as modernist, DSM mental disorders, such as addictions, depression, and obsessive-compulsive disorders. Recent research has indicated that the psychedelic drug, psilocybin, has produced safe and effective outcomes for these mental suffering states. In this context, the article draws on the concept of brain plasticity order, firstly, to identify the means for a person to move away from subjection of life’s negative, dominant discourses that “capture” the brain, and then to intentionally move towards more acceptable, preferred, ethical subjectivities. These explanations, using the phenomenon of depression, provide the foundation for further proposals that an innovative form of narrative therapy could be a safe, effective and meaningful approach for persons in relationship with other similar ways of mental suffering, such as, anxiety, addiction, obsessive-compulsive disorder, and anorexia nervosa.

Objective To systematically examine the effectiveness and tolerability of psilocybin for treating end-of-life anxiety symptoms.Methods The Medline, Embase, CENTRAL, and PsycINFO databases were searched up to November 25, 2020. We enrolled clinical trials investigating psilocybin for treating end-of-life anxiety symptoms. Meta-analysis was conducted using random-effects model.Results Overall, five studies were included, revealing that psilocybin was superior to the placebo in treating state anxiety at 1 day (Hedges’ g, -0.70; 95% confidence interval, -1.01 to -0.39) and 2 weeks (-1.03; -1.47 to -0.60) after treatment. Psilocybin was more effective than placebo in treating trait anxiety at 1 day (-0.71; -1.15 to -0.26), 2 weeks (-1.08; -1.80 to -0.36), and 6 months (-0.84; -1.37 to -0.30) after treatment. Psilocybin was associated with transient elevation in systolic (19.00; 13.58–24.41 mm Hg) and diastolic (8.66; 5.18–12.15 mm Hg) blood pressure compared with placebo. The differences between psilocybin and placebo groups with regard to allcause discontinuation, serious adverse events, and heart rates were nonsignificant.Conclusion Psilocybin-assisted therapy could ameliorate end-of-life anxiety symptoms without serious adverse events. Because of the small sample sizes of the included studies and high heterogeneity on long-term outcomes, future randomized controlled trials with large sample sizes are needed.

The studies of psychedelics, especially psychedelic tryptamines like psilocybin, are rapidly gaining interest in neuroscience research. Much of this interest stems from recent clinical studies demonstrating that they have a unique ability to improve the debilitating symptoms of major depressive disorder (MDD) long-term after only a single treatment. Indeed, the Food and Drug Administration (FDA) has recently designated two Phase III clinical trials studying the ability of psilocybin to treat forms of MDD with "Breakthrough Therapy" status. If successful, the use of psychedelics to treat psychiatric diseases like depression would be revolutionary. As more evidence appears in the scientific literature to support their use in psychiatry to treat MDD on and substance use disorders (SUD), recent studies with rodents revealed that their therapeutic effects might extend beyond treating MDD and SUD. For example, psychedelics may have efficacy in the treatment and prevention of brain injury and neurodegenerative diseases such as Alzheimer's Disease. Preclinical work has highlighted psychedelics' ability to induce neuroplasticity and synaptogenesis, and neural progenitor cell proliferation. Psychedelics may also act as immunomodulators by reducing levels of proinflammatory biomarkers, including IL-1β, IL-6, and tumor necrosis factor-α (TNF-α). Their exact molecular mechanisms, and induction of cellular interactions, especially between neural and glial cells, leading to therapeutic efficacy, remain to be determined. In this review, we discuss recent findings and information on how psychedelics may act therapeutically on cells within the central nervous system (CNS) during brain injuries and neurodegenerative diseases.

Emerging evidence from randomized, double-blind, placebo-controlled clinical trials suggests psychedelic compounds such as 3,4-methylenedioxymethamphetamine (MDMA), psilocybin, and lysergic acid diethylamide (LSD), when administered as an adjunct to psychotherapy, that is, psychedelic-assisted psychotherapy (PAP), may be beneficial for treating substance use disorders, posttraumatic stress disorder (PTSD), depression, anxiety, and other psychiatric conditions. Previous ethnopsychopharmacological research has identified ethnoracial differences in the metabolism, safety, and efficacy of psychotropic drugs, yet no studies have directly investigated the impact of ethnoracially based differences in psychedelic drug pharmacology. Although there is an extensive global history of psychedelic use among peoples of various cultures, ethnicities, and intersectional identities, psychedelic research has been conducted almost exclusively on White populations in North America and Western Europe. The failure to include Black, Indigenous, and People of Color (BIPOC) in psychedelic research trials neglects the ethnic, racial, and cultural factors that may impact individual responses to PAP and thereby prevents generalizability of findings. This article investigates the impact of biological and social factors related to culture, ethnicity, and race on pharmacological responses to PAP, as well as clinical outcomes. The limitations of ethnopsychopharmacology are discussed, and the authors present expected cultural, clinical, and public health benefits of expanding funding for this area. This work will draw attention to the unique and individualized needs of ethnoracially diverse clients in therapeutic settings and is intended to inform future PAP trials. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Psilocybin, a drug most commonly recognized as a recreational psychedelic, is quickly gaining attention as a promising therapy for an expanding range of neurological conditions, including depression, anxiety, and addiction. This growing interest has led to many recent advancements in psilocybin synthesis strategies, including multiple in vivo fermentation-based approaches catalyzed by recombinant microorganisms. In this work, we show that psilocybin can be produced in biologically relevant quantities using a recombinant E. coli strain in a homebrew style environment. In less than 2 days, we successfully produced approximately 300 mg/L of psilocybin under simple conditions with easily sourced equipment and supplies. This finding raises the question of how this new technology should be regulated as to not facilitate clandestine biosynthesis efforts, while still enabling advancements in psilocybin synthesis technology for pharmaceutical applications. Here, we present our homebrew results, and suggestions on how to address the regulatory concerns accompanying this new technology.

Psilocybin is a psychotropic molecule that is a partial agonist of serotonin 2A receptors and is the main psychoactive compound in hallucinogenic mushrooms. After the observation in 1953 in Mexico of ritual practices involving ingestion of such mushrooms, psilocybin was chemically characterized and synthesized in 1958 thanks to the collaboration between the Museum national d’Histoire naturelle in France and the Sandoz pharmaceutical laboratories in Switzerland. The interest of this substance in psychiatric therapy was then evaluated for the first time at the Sainte-Anne Hospital in Paris, by the team of Professor Jean Delay. Among the patients who received this substance was a 35-year-old woman who was hospitalized for compulsive manifestations emblematic of anorexia nervosa and who experienced an immediate and lasting improvement. The original 1959 article (published in the Annales de la Societe Medico-Psychologique) gives details of the patient's family background, biography and clinical examination. It then outlines the observations after two injections of psilocybin four days apart, in particular the autobiographical verbal statements that allowed the patient to understand the psychogenesis of her illness. After a long hiatus, psilocybin is once again the subject of medical research, with clinical trials now underway assessing psilocybin in the treatment of anorexia nervosa ( NCT04505189 ; NCT04052568 ; NCT04661514 ) and this 1959 case study, is the first known demonstration of the safety and efficacy of psilocybin treatment of anorexia nervosa. This case study thus provides an interesting insight into possible therapeutic mechanisms and is of great interest to the field moving forward.

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