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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

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.

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

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.

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.

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.

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.

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.

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.

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.

3.1. A topic of significant and rapidly growing interest in the public is the phenomenon of “microdosing”. Microdosing refers to consumption of a ‘subthreshold’ dose of a psychedelic substance, most commonly LSD or psilocybin. These doses involve only minimal noticeable changes in conscious experience. Early research indicates that microdosing is low risk and may have benefits for mental health and cognitive performance. To date, there have been only a small number of studies investigating the neurobiological effects of microdosing and the fundamental mechanisms involved. The proposed study will use a self-blinding design to investigate neurological, biological, and behavioral differences between microdosing and placebo conditions. These data will allow for substantial progress in our understanding of what microdosing does in the brain, and potentially elucidate neurobiological correlates of psychological effects.

A U.S. Special Operations Command (SOCOM) funded study completed in 2017 found that U.S. special operations forces (SOF) have a 30% higher suicide rate than the U.S. military average. Nearly half of the twenty-nine suicide cases explored in the psychological autopsy study had a diagnosed mental health disorder. These findings underscore how suicide, and its contributing factors, are a growing threat to the health of the force and combat readiness across SOCOM. This thesis examined psychedelic-assisted therapy as a component of an overall holistic approach to addressing mental health conditions and combatting suicide across SOCOM. We reviewed two emerging psychedelic treatments for ameliorating mood and trauma-based mental health disorders, comparing them to two in-use novel therapies. Notwithstanding limits to existing data, our review found that psychedelic-assisted therapies show potential in three critical ways. There is a rapid and sustained decrease in disorder-related symptoms, exhibited efficacy in treatment-resistant cases, and minimal adverse events when administered in a controlled environment. Alone, no single weapon or piece of technology has ever won a war, and in a similar fashion, successful mental health treatment models for suicide prevention strategies require a multi-faceted approach. While psychedelic therapies are not a panacea for the mental health crisis within the military, they carry emended potential to be another tool for treatment and recovery. Major, United States Army Major, United States Army Major, United States Army Approved for public release. Distribution is unlimited.

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.

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 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.

Treatment of major depressive disorder (MDD) including treatment-resistant depression (TRD) remains a major unmet need. Although there are several classes of dissimilar antidepressant drugs approved for MDD, the current drugs have either limited efficacy or are associated with undesirable side effects and withdrawal symptoms. The efficacy and side effects of antidepressant drugs are mainly attributed to their actions on different monoamine neurotransmitters (serotonin, norepinephrine, and dopamine). Development of new antidepressants with novel targets beyond the monoamine pathways may fill the unmet need in treatment of MDD and TRD. The recent approval of intranasal Esketamine (glutamatergic agent) in conjunction with an oral antidepressant for the treatment of adult TRD patients was the first step toward expanding beyond the monoamine targets. Several other glutamatergic (AXS-05, REL-1017, AV-101, SLS-002, AGN24175, and PCN-101) and GABAergic (brexanolone, zuranolone, and ganaxolone) drugs are currently in different stages of clinical development for MDD, TRD and other indications. The renaissance of psychedelic drugs and the emergence of preliminary positive clinical trial results with psilocybin, Ayahuasca, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and lysergic acid diethylamide (LSD) may pave the way towards establishing this class of drugs as effective therapies for MDD, TRD and other neuropsychiatric disorders. Going beyond the monoamine targets appears to be an effective strategy to develop novel antidepressant drugs with superior efficacy, safety, and tolerability for the improved treatment of MDD and TRD.

Treatments for addressing psychiatric mental health issues in vulnerable patients with cancer are established. Yet, many patients persist with unrelenting psychological difficulties despite intervention. There is growing interest in the role of psilocybin-assisted psychotherapy for managing treatment-resistant mental health challenges in patients with cancer. Psilocybin is a naturally occurring compound derived from certain mushroom species that can induce entheogenic experiences or an altered state of consciousness. Reed's Self-Transcendence Theory provides a holistic lens to examine existential concerns and mental health in individuals who perceive their illness as potentially life threatening, such as those with cancer. This scoping literature review used Arksey and O’Malley's template to evaluate research examining psilocybin-assisted psychotherapy for patients with cancer. Eight articles met inclusion/exclusion criteria (four quantitative, two mixed methods, and two qualitative). Review findings indicated that the majority of patient experiences were positive, centering on themes of death acceptance, reflection, and broadened spirituality. Although psilocybin-assisted psychotherapy is in early stages of clinical testing, it thus shows promise for carefully screened patients with cancer who have persistent existential suffering. It will be critical for investigators to tailor this emerging intervention to select patients and for clinicians to be engaged in assessment of outcomes and efficacy.

Using data from the National Survey on Drug Use and Health (2005–2014), weighted to be representative of the US adult population, the present study investigated the association between lifetime classic psychedelic use and hypertension in the past year among adults in the United States. The results showed that respondents who reported having used a classic psychedelic at least once in their lifetime had significantly lower odds of hypertension in the past year after adjusting for several potential confounders (adjusted odds ratio, 0.86 [0.81–0.91]; P P =0.0001). Though these associations are novel, rigorous randomized controlled trials are warranted to investigate potential causal pathways of classic psychedelics on blood pressure.

The emerging novel therapeutic psilocybin produces psychedelic effects via engagement of cerebral serotonergic targets by psilocin (active metabolite). The serotonin 2A receptor critically mediates these effects by altering distributed neural processes that manifest as increased entropy, reduced functional connectivity (FC) within discrete brain networks (i.e., reduced integrity) and increased FC between networks (i.e., reduced segregation). Reduced integrity of the default mode network (DMN) is proposed to play a particularly prominent role in psychedelic phenomenology, including perceived ego-dissolution. Here, we investigate the effects of a psychoactive peroral dose of psilocybin (0.2-0.3 mg/kg) on plasma psilocin level (PPL), subjective drug intensity (SDI) and their association in fifteen healthy individuals. We further evaluate associations between these measures and resting-state FC, measured with functional magnetic resonance imaging, acquired over the course of five hours after psilocybin administration. We show that PPL and SDI correlate negatively with measures of network integrity (including DMN) and segregation, both spatially constrained and unconstrained. We also find that the executive control network and dorsal attention network desegregate, increasing connectivity with other networks and throughout the brain as a function of PPL and SDI. These findings provide direct evidence that psilocin critically shapes the time course and magnitude of changes in the cerebral functional architecture and subjective experience following psilocybin administration. Our findings provide novel insight into the neurobiological mechanisms underlying profound perceptual experiences evoked by this emerging transnosological therapeutic and implicate the expression of network integrity and segregation in the psychedelic experience and consciousness.

Psychologists are a vital component of mental health treatment and their perceptions of psychedelic-assisted therapy are critical for future implementation. This cross-sectional quasi-experimental electronic survey study explored the attitudes about psychedelics used in treatment among 366 clinical psychologists in the United States. Participants expressed cautiously favorable attitudes toward therapeutic psychedelic experiences but indicated concern about possible psychiatric and neurocognitive risks. Most participants indicated that they lack an understanding of the full range of effects of psychedelics, would need to seek out additional consultation, and endorsed positive beliefs in the potential of psychedelic treatment and the need for further research. Overall, this research identified the need to increase education and training about psychedelics for psychologists in order to help increase knowledge and reduce stigma about psychedelic therapies.

Background: Psilocybin is a serotonin type 2A (5-HT2A) receptor agonist and naturally occurring psychedelic. 5-HT2A receptor density is known to be associated with body mass index (BMI), however, the impact of this on psilocybin therapy has not been explored. While body weight-adjusted dosing is widely used, this imposes a practical and financial strain on the scalability of psychedelic therapy. This gap between evidence and practice is caused by the absence of studies clarifying the relationship between BMI, the acute psychedelic experience and long-term psychological outcomes. Method: Data were pooled across three studies using a fixed 25 mg dose of psilocybin delivered in a therapeutic context to assess whether BMI predicts characteristics of the acute experience and changes in well-being 2 weeks later. Supplementing frequentist analysis with Bayes Factors has enabled for conclusions to be drawn regarding the null hypothesis. Results: Results support the null hypothesis that BMI does not predict overall intensity of the altered state, mystical experiences, perceptual changes or emotional breakthroughs during the acute experience. There was weak evidence for greater ‘dread of ego dissolution’ in participants with lower BMI, however, further analysis suggested BMI did not meaningfully add to the combination of the other covariates (age, sex and study). While mystical-type experiences and emotional breakthroughs were strong predictors of improvements in well-being, BMI was not. Conclusions: These findings have important implications for our understanding of pharmacological and extra-pharmacological contributors to psychedelic-assisted therapy and for the standardization of a fixed therapeutic dose in psychedelic-assisted therapy.

Following a decades long period of investigational dormancy, there is renewed interest in employing psychedelics as psychiatric treatments. The academic journals, institutions, and countries that have helped sustain clinical psychedelic research and the evolution of the literature on clinical studies of psychedelics have only recently begun to be investigated. To expand upon this work, we conducted a bibliometric analysis of clinical studies of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT), ayahuasca, dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), ibogaine, mescaline, 3,4-methylenedioxymethamphetamine (MDMA), and psilocybin published from 1965-2021. Our search revealed 394 relevant articles. After a lull from the 1970s-1990s, publications in this area have resurged. Studies most frequently focused on MDMA (49%), LSD (19%), psilocybin (18%), and ayahuasca (7%). A subanalysis of studies from 1965 to 2009 ("Older cohort") compared to 2010-2021 ("Recent cohort") revealed that the Recent cohort had a higher proportion of studies investigating psychedelics' therapeutic applications and a lower proportion of studies investigating the effects of psychedelics on people using them in non-research settings. Compared to the Older cohort, psilocybin studies increased proportionally in the Recent cohort, while DMT and mescaline studies decreased. Network analyses of inter-country collaborations suggested that psychedelic researchers in the United Kingdom have the most diverse international collaborations.