Deciphering psilocybin: Cytotoxicity, anti-inflammatory effects, and mechanistic insights.

A decade of clinical research has indicated psilocybin's effectiveness in treating various neuropsychiatric disorders, such as depression and substance abuse. The correlation between increased pro-inflammatory cytokines and the severity of neuropsychiatric symptoms, along with the known anti-inflammatory potential of some psychedelics, suggests an immunomodulatory role for psilocybin. This study aims to understand the mechanism of action of psilocybin by investigating the cytotoxic and immunomodulatory effects of psilocybin and psilocin on both resting and LPS-activated RAW 264.7 murine macrophages. The study evaluated the cytotoxicity of psilocybin and psilocin using an LDH assay across various doses and assessed their impact on cytokine production in RAW 264.7 cells, measuring cytokine expression via ELISA. Different doses, including those above and below the LC50, were used in both pre-treatment and post-treatment approaches. The LDH assay revealed that psilocybin is almost twice as cytotoxic as psilocin, with an LC50 of 12 ng/ml and 28 ng/ml, respectively. In resting macrophages, both psilocybin and psilocin triggered significant release of TNF- α after 4 h, with the lowest doses inducing higher levels of the cytokine than the highest doses. IL-10 expression in resting cells was only triggered by the highest dose of psilocin in the 4-hour incubation group. In LPS-stimulated cells, psilocin reduced TNF- α levels more than psilocybin in pre-treatment and post-treatment, with no significant effects on IL-10 in pre-treatment. Psilocin, but not psilocybin, induced a significant increase of IL-10 in post-treatment, leading to the conclusion that psilocin, but not psilocybin, exerts anti-inflammatory effects on classically activated macrophages.

Effect of a single psilocybin treatment on Fos protein expression in male rat brain.

Psilocybin has received attention as a treatment for depression, stress disorders and drug and alcohol addiction. To help determine the mechanisms underlying its therapeutic effects, here we examined acute effects of a range of behaviourally relevant psilocybin doses (0.1-3 mg/kg SC) on regional expression of Fos, the protein product of the immediate early gene, c-fos in brain areas involved in stress, reward and motivation in male rats. We also determined the cellular phenotypes activated by psilocybin, in a co-labeling analysis with NeuN, a marker of mature neurons, or Olig1, a marker of oligodendrocytes. In adult male Sprague-Dawley rats, psilocybin increased Fos expression dose dependently in several brain regions, including the frontal cortex, nucleus accumbens, central and basolateral amygdala and locus coeruleus. These effects were most marked in the central amygdala. Double labeling experiments showed that Fos was expressed in both neurons and oligodendrocytes. These results extend previous research by determining Fos expression in multiple brain areas at a wider psilocybin dose range, and the cellular phenotypes expressing Fos. The data also highlight the amygdala, especially the central nucleus, a key brain region involved in emotional processing and learning and interconnected with other brain areas involved in stress, reward and addiction, as a potentially important locus for the therapeutic effects of psilocybin. Overall, the present findings suggest that the central amygdala may be an important site through which the initial brain activation induced by psilocybin is translated into neuroplastic changes, locally and in other regions that underlie its extended therapeutic effects.

Intravenous psilocybin attenuates mechanical hypersensitivity in a rat model of chronic pain.

There is a renewed interest in psychedelic drugs as potential therapeutic agents for the treatment of psychiatric disorders. In particular, psilocybin has shown promise for the treatment of refractory depression1 and major depressive disorder2, and has also been explored as a treatment for tobacco and alcohol abuse3,4. However, despite suggestive evidence5,6, there has been no systematic study to investigate the effectiveness of psilocybin in attenuating indices of chronic pain. To address this gap, we investigated the effect of psilocybin on mechanical hypersensitivity and thermal hyperalgesia in a well-established rat model of formalin-induced, centralized chronic pain7,8 and demonstrate that a single intravenous bolus administration of psilocybin can attenuate mechanical hypersensitivity for 28 days.

Psilocybin-assisted therapy for depression: A systematic review and meta-analysis.

The aim of this review was to determine the effect of psilocybin on depressive symptoms in patients diagnosed with life-threatening illnesses or major depressive disorder. Systematic searches were conducted to search for randomized clinical trials and open-label trials that evaluated depression symptoms after psilocybin therapy. Data was pooled using a random-effects model. The primary outcome was the standardized mean difference (SMD) in depression severity, determined by calculating the change in depression ratings from baseline to the primary endpoint in the psilocybin arm versus the control arm. The literature search yielded 1734 studies, and 13 studies (n = 686) were included in either qualitative and/or quantitative analyses. The meta-analysis included 9 studies (pooled n = 596) and yielded a large effect size in favour of psilocybin (SMD = -0.78; p<0.001). Risk ratios for response and remission were large and significant in favour of psilocybin. A review of open-label trials showed robust decreases in depressive symptoms following psilocybin administration. These findings provide preliminary evidence for antidepressant efficacy with psilocybin-assisted psychotherapy, however, further studies are needed to evaluate safety and efficacy and to optimize treatment protocols.

Psychedelics, With a Focus on Psilocybin: Issues for the Clinician.

There has been a burgeoning interest in psychedelics among the public, state legislatures, psychiatrists and other clinical providers, and within the research community. Increasing numbers of studies evaluating psychedelics for depression, anxiety, posttraumatic stress disorder, and substance use disorders have been conducted or are underway. While discussing psychedelics in general, the focus of this paper is on psilocybin and its mechanism, how it exerts a psychedelic effect, dosing, and a review of the treatment studies of psilocybin, which were primarily for treatment-resistant depression and cancer-related anxiety. Future directions and potential limitations of studying and regulating psilocybin and other psychedelics are also discussed.

UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice.

The effects of context on the subjective experience of serotonergic psychedelics have not been fully examined in human neuroimaging studies, partly due to limitations of the imaging environment. Here, we administered saline or psilocybin to mice in their home cage or an enriched environment, immunofluorescently-labeled brain-wide c-Fos, and imaged iDISCO+ cleared tissue with light sheet fluorescence microscopy (LSFM) to examine the impact of environmental context on psilocybin-elicited neural activity at cellular resolution. Voxel-wise analysis of c-Fos-immunofluorescence revealed clusters of neural activity associated with main effects of context and psilocybin-treatment, which were validated with c-Fos+ cell density measurements. Psilocybin increased c-Fos expression in subregions of the neocortex, caudoputamen, central amygdala, and parasubthalamic nucleus while it decreased c-Fos in the hypothalamus, cortical amygdala, striatum, and pallidum in a predominantly context-independent manner. To gauge feasibility of future mechanistic studies on ensembles activated by psilocybin, we confirmed activity- and Cre-dependent genetic labeling in a subset of these neurons using TRAP2+/-;Ai14+ mice. Network analyses treating each psilocybin-sensitive cluster as a node indicated that psilocybin disrupted co-activity between highly correlated regions, reduced brain modularity, and dramatically attenuated intermodular co-activity. Overall, our results indicate that main effects of context and psilocybin were robust, widespread, and reorganized network architecture, whereas context×psilocybin interactions were surprisingly sparse.

The Effect of Combined Treatment of Psilocybin and Eugenol on Lipopolysaccharide-Induced Brain Inflammation in Mice.

Inflammation is an organism's biological defense mechanism. Acute and chronic inflammation of the body triggers the production of pro- and anti-inflammatory pathways that can affect the content of cytokines in the brain and thus cause brain inflammation. Disorders such as depression and posttraumatic stress disorder (PTSD) are often associated with elevated inflammation. Recently, positive and promising clinical results of psilocybin for the treatment of depression and PTSD were reported. Thus, we decided to test whether psilocybin alone or in combination with eugenol, an anti-inflammatory and antioxidant agent, would prevent the increase in or decrease the content of cytokines in the brain of C57BL/6J mice injected with lipopolysaccharides (LPS). Two experiments were performed, one with pre-treatment of mice through gavage with psilocybin (0.88 mg/kg), eugenol (17.6 mg/kg), or combinations of psilocybin and eugenol (1:10, 1:20, or 1:50), followed by intraperitoneal injection of LPS, and the second, post-treatment, with initial injection with LPS, followed by treatment with psilocybin, eugenol, or their combination. Brain tissues were collected, and cytokines were analyzed by qRT-PCR, Western blot, and ELISA. Data were analyzed with a one-way ANOVA followed by Tukey's post hoc test or with multiple unpaired t-tests. LPS upregulated mRNA expression of COX-2, TNF-α, IL-1ß, and IL-6. All pre-treatments decreased the expression of COX-2 and TNF-α, with psilocybin alone and in 1:50 combination, with eugenol being the most effective. In the post-treatment, all combinations of psilocybin and eugenol were effective in reducing inflammation, with the 1:50 ratio displaying the most prominent results in reducing the mRNA content of tested cytokines. Western blot analysis confirmed the effect on COX-2 and IL-1ß proteins. Finally, the ELISA showed that post-treatment with psilocybin + eugenol (1:50) demonstrated the best results, decreasing the expression of multiple markers including IL-6 and IL-8. This demonstrates the anti-inflammatory effects of a combination of psilocybin and eugenol in the brain of animals with systemically induced inflammation.

Experiences of psilocybin treatment for clinical conditions: A qualitative meta-synthesis.

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

Psychedelics for Patients With Cancer: A Comprehensive Literature Review.

OBJECTIVE: To assess the role of psychedelics in the treatment of anxiety or depression among patients with cancer. DATA SOURCES: PubMed search from inception to March 11, 2022, using the terms anxiety, depression, psychedelics, psilocybin, lysergic acid, methylenedioxymethamphetamine, or ayahuasca. STUDY SELECTION AND DATA EXTRACTION: Studies assessing patients with cancer receiving psychedelics for the treatment of anxiety or depression. DATA SYNTHESIS: Five unique randomized, double-blind, placebo-controlled trials were conducted. Significant reductions were found in 2 trials with 2 anxiety scales (State-Trait Anxiety Inventory-State, State-Trait Anxiety Inventory-Trait) and in 1 trial with 2 additional anxiety scales (Hamilton Rating Scale-Anxiety, Hospital Anxiety and Depression Scale-Anxiety). Significant reductions were found in 2 trials in 2 depression scales (Hospital Anxiety and Depression Scale-Depression, Beck Depression Inventory) and in 1 trial with an additional depression scale (Hamilton Rating Scale-Depression). Two studies assessed for clinically relevant reductions in anxiety and depression scores, and they occurred much more commonly in psychedelic-treated patients than those given placebo. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: There is a new potential option for treating patients with anxiety and depression along with cancer, which is important given the generally lackluster benefits with traditional antidepressants. Only a few sessions may also provide benefits extending out for 6 to 12 months and possibly beyond that. However, the studies were small, had many methodological limitations, and there were increases in blood pressure and heart rate. CONCLUSIONS: Psychedelics have a unique mechanism of action that might be well suited for treating anxiety and depression associated with cancer. This offers new promise for patients who are not being sufficiently treated with current antianxiety or antidepressant medications.

Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin.

Psilocybin is a psychedelic with therapeutic potential. While there is growing evidence that psilocybin exerts its beneficial effects through enhancing neural plasticity, the exact brain regions involved are not completely understood. Determining the impact of psilocybin on plasticity-related gene expression throughout the brain can broaden our understanding of the neural circuits involved in psychedelic-evoked neural plasticity. In this study, whole-brain serial two-photon microscopy and light sheet microscopy were employed to map the expression of the immediate early gene, c-Fos, in male and female mice. The drug-induced c-Fos expression following psilocybin administration was compared to that of subanesthetic ketamine and saline control. Psilocybin and ketamine produced acutely comparable elevations in c-Fos expression in numerous brain regions, including anterior cingulate cortex, locus coeruleus, primary visual cortex, central and basolateral amygdala, medial and lateral habenula, and claustrum. Select regions exhibited drug-preferential differences, such as dorsal raphe and insular cortex for psilocybin and the CA1 subfield of hippocampus for ketamine. To gain insights into the contributions of receptors and cell types, the c-Fos expression maps were related to brain-wide in situ hybridization data. The transcript analyses showed that the endogenous levels of Grin2a and Grin2b predict whether a cortical region is sensitive to drug-evoked neural plasticity for both ketamine and psilocybin. Collectively, the systematic mapping approach produced an unbiased list of brain regions impacted by psilocybin and ketamine. The data are a resource that highlights previously underappreciated regions for future investigations. Furthermore, the robust relationships between drug-evoked c-Fos expression and endogenous transcript distributions suggest glutamatergic receptors as a potential convergent target for how psilocybin and ketamine produce their rapid-acting and long-lasting therapeutic effects.

Psilocybin-assisted therapy improves psycho-social-spiritual well-being in cancer patients.

BACKGROUND: While psychedelics have been shown to improve psycho-spiritual well-being, the underlying elements of this change are not well-characterized. The NIH-HEALS posits that psycho-social-spiritual change occurs through the factors of Connection, Reflection & Introspection, and Trust & Acceptance. This study aimed to evaluate the changes in NIH-HEALS scores in a cancer population with major depressive disorder undergoing psilocybin-assisted therapy. METHODS: In this Phase II, single-center, open label trial, 30 cancer patients with major depressive disorder received a fixed dose of 25 mg of psilocybin. Participants underwent group preparation sessions, simultaneous psilocybin treatment administered in adjacent rooms, and group integration sessions, along with individual care. The NIH-HEALS, a self-administered, 35-item measure of psycho-social spiritual healing was completed at baseline and post-treatment at day 1, week 1, week 3, and week 8 following psilocybin therapy. RESULTS: NIH-HEALS scores, representing psycho-social-spiritual wellbeing, improved in response to psilocybin treatment (p < 0.001). All three factors of the NIH-HEALS (Connection, Reflection & Introspection, and Trust & Acceptance) demonstrated positive change by 12.7 %, 7.7 %, and 22.4 %, respectively. These effects were apparent at all study time points and were sustained up to the last study interval at 8 weeks (p < 0.001). LIMITATIONS: The study lacks a control group, relies on a self-report measure, and uses a relatively small sample size with limited diversity that restricts generalizability. CONCLUSIONS: Findings suggest that psilocybin-assisted therapy facilitates psycho-social-spiritual growth as measured by the NIH-HEALS and its three factors. This supports the factors of Connection, Reflection & Introspection, and Trust & Acceptance as underlying elements for psycho-social-spiritual healing in cancer patients, and validates the use of the NIH-HEALS within psychedelic research.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Report: Serotonergic Psychedelic Treatments for Major Depressive Disorder.

OBJECTIVE: Serotonergic psychedelics are re-emerging as potential novel treatments for several psychiatric disorders including major depressive disorder. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence and provide a consensus recommendation for the clinical use of psychedelic treatments for major depressive disorder. METHODS: A systematic review was conducted to identify contemporary clinical trials of serotonergic psychedelics for the treatment of major depressive disorder and cancer-related depression. Studies published between January 1990 and July 2021 were identified using combinations of search terms, inspection of bibliographies and review of other psychedelic reviews and consensus statements. The levels of evidence for efficacy were graded according to the Canadian Network for Mood and Anxiety Treatments criteria. RESULTS: Only psilocybin and ayahuasca have contemporary clinical trials evaluating antidepressant effects. Two pilot studies showed preliminary positive effects of single-dose ayahuasca for treatment-resistant depression (Level 3 evidence). Small randomized controlled trials of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy and safety to an active comparator (escitalopram with supportive psychotherapy) in major depressive disorder, with additional randomized controlled trials showing efficacy specifically in cancer-related depression (Level 3 evidence). There was only one open-label trial of psilocybin in treatment-resistant unipolar depression (Level 4 evidence). Small sample sizes and functional unblinding were major limitations in all studies. Adverse events associated with psychedelics, including psychological (e.g., psychotomimetic effects) and physical (e.g., nausea, emesis and headaches) effects, were generally transient. CONCLUSIONS: There is currently only low-level evidence to support the efficacy and safety of psychedelics for major depressive disorder. In Canada, as of 2022, psilocybin remains an experimental option that is only available through clinical trials or the special access program. As such, Canadian Network for Mood and Anxiety Treatments considers psilocybin an experimental treatment and recommends its use primarily within clinical trials, or, less commonly, through the special access program in rare, special circumstances.

Classic Psychedelics in Addiction Treatment: The Case for Psilocybin in Tobacco Smoking Cessation.

This manuscript reviews research suggesting that classic psychedelics (5-HT2A receptor agonists) are effective in treating addictions including tobacco use disorder. I review historical research from the 1950s to 1970s suggesting that classic psychedelics are associated with addiction recovery across pharmacologically distinct drugs of addiction. I then review anthropological reports about ceremonial use of classic psychedelics and epidemiological studies that are consistent with anti-addiction efficacy. I review modern research using psilocybin in the treatment of alcohol use disorder and tobacco use disorder. Both lines of research show high success rates in preliminary studies. General anti-addiction efficacy across a variety of classes of addictive drugs is consistent with the notion that the persisting positive behavior change prompted by psychedelic therapy is due to amplification of psychotherapeutic processes. Future research should examine classic psychedelic treatment of additional substance use disorders including for opioids, cocaine, methamphetamine, and cannabis, and other disorders broadly characterized as addictions (e.g., obesity, problem gambling, hypersexual disorder). Future research should also explore addiction treatments with other classic psychedelics including LSD, mescaline, DMT, 5-MeO-DMT, and yet-to-be-discovered compounds. Experimental research is also needed to test different protocols for the delivery of classic psychedelic therapy for addictions. Given the staggering society costs of substance use disorders, including the mortality caused by tobacco smoking, it is critical that public funding be made available for scientists to follow up on promising early findings of classic psychedelics in addiction treatment. The costs and risks of not conducting such research are too great.

Human behavioral pharmacology of psychedelics.

The past decade has witnessed a rapid growth of research on the basic science and clinical understanding of psychedelics. This chapter provides an overview of the human behavioral pharmacology of psychedelics focusing on three prototypic classic psychedelics-psilocybin, lysergic acid diethylamide (LSD), and dimethyltryptamine (DMT). A brief historical overview of the classic psychedelics and naming and drug classification is first specified. Next, special considerations in the conduct of human behavioral pharmacology work with psychedelics is described including the role of set and setting, mystical experience measurement, the use of effective blinding and placebos, and the abuse liability of psychedelics. Following, a description of the subjective, physiological, and clinical effects of psilocybin, LSD, and DMT is provided. This body of work clearly documents a unique and complex collection of subjective effects following psychedelic use, both during acute drug administration and as related to long-term behavior change following use. Clinical research demonstrates potential therapeutic utility with early phase clinical trials showing positive and enduring effects in many difficult-to-treat conditions including treatment-resistant depression, alcohol use disorder, and cigarette smoking. Future work in this newly reemerged field is needed to reveal mechanisms of behavior change in psychedelic drug action. Behavioral pharmacology is ultimately well served to provide this direction answering questions at the intersection of environment and pharmacology.

Psychedelics and Hallucinogens in Psychiatry: Finding New Pharmacological Targets.

BACKGROUND: The therapeutic options for neurobehavioral disorders are still limited, and in many cases, they lack a satisfactory balance between efficacy and side effects. OBJECTIVES: This work aims to review current evidence regarding the potential contribution of psychedelics and hallucinogens to the discovery of new drugs for treating different psychiatric disorders. DISCUSSION: Ayahuasca/N,N-dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and psilocybin have evidence supporting their use in depression, and psilocybin and ayahuasca have also shown good results in treatment-resistant depression. In randomized controlled trials (RCTs) conducted with anxious patients, there were symptomatic improvements with psilocybin and LSD. Psilocybin diminished Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores in a small obsessive- compulsive disorder (OCD) sample. The evidence is less robust regarding substance use disorders, but it suggests a possible role for LSD and psilocybin in alcohol use disorders and for psilocybin in tobacco addiction. In a clinical setting, these substances seem to be safe and well-tolerated. Their mechanisms of action are not fully elucidated, but there seems to be a preponderant role of 5-hydroxytryptamine (5HT) 2A agonism, as well as connectivity changes within the default mode network (DMN) and amygdala and some other molecular modifications. CONCLUSION: The studies underlying the conclusions have small samples and are heterogeneous in their methods. However, the results suggest that the use of psychedelics and hallucinogens could be considered in some disorders. More studies are needed to reinforce their evidence as potential new drugs.

Dose effect of psilocybin on primary and secondary depression: a preliminary systematic review and meta-analysis.

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<0.001). As psilocybin dose increases within a certain range, the antidepressive effect declines and then increases, with 30-35 mg/70 kg achieving the optimal therapeutic effect. Subgroup analysis suggested that the antidepressive effect of psilocybin was extremely significant at a relatively high dose (30-35mg/70kg: Hedges' g=3.059, 95%CI=[2.269, 3.849], p<0.001), long-term (>1month: Hedges' g=1.123, 95%CI=[0.861, 1.385], p<0.001) and when used in primary depression patients (Hedges' g=2.190, 95%CI=[1.423, 2.957], p<0.001). 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.

Psychedelics and health behaviour change.

Healthful behaviours such as maintaining a balanced diet, being physically active and refraining from smoking have major impacts on the risk of developing cancer, diabetes, cardiovascular diseases and other serious conditions. The burden of the so-called 'lifestyle diseases'-in personal suffering, premature mortality and public health costs-is considerable. Consequently, interventions designed to promote healthy behaviours are increasingly being studied, e.g., using psychobiological models of behavioural regulation and change. In this article, we explore the notion that psychedelic substances such as psilocybin could be used to assist in promoting positive lifestyle change conducive to good overall health. Psilocybin has a low toxicity, is non-addictive and has been shown to predict favourable changes in patients with depression, anxiety and other conditions marked by rigid behavioural patterns, including substance (mis)use. While it is still early days for modern psychedelic science, research is advancing fast and results are promising. Here we describe psychedelics' proposed mechanisms of action and research findings pertinent to health behaviour change science, hoping to generate discussion and new research hypotheses linking the two areas. Therapeutic models including psychedelic experiences and common behaviour change methods (e.g., Cognitive Behaviour Therapy, Motivational Interviewing) are already being tested for addiction and eating disorders. We believe this research may soon be extended to help promote improved diet, exercise, nature exposure and also mindfulness or stress reduction practices, all of which can contribute to physical and psychological health and well-being.

The Therapeutic Potential of Psilocybin.

The psychedelic effects of some plants and fungi have been known and deliberately exploited by humans for thousands of years. Fungi, particularly mushrooms, are the principal source of naturally occurring psychedelics. The mushroom extract, psilocybin has historically been used as a psychedelic agent for religious and spiritual ceremonies, as well as a therapeutic option for neuropsychiatric conditions. Psychedelic use was largely associated with the "hippie" counterculture movement, which, in turn, resulted in a growing, and still lingering, negative stigmatization for psychedelics. As a result, in 1970, the U.S. government rescheduled psychedelics as Schedule 1 drugs, ultimately ending scientific research on psychedelics. This prohibition on psychedelic drug research significantly delayed advances in medical knowledge on the therapeutic uses of agents such as psilocybin. A 2004 pilot study from the University of California, Los Angeles, exploring the potential of psilocybin treatment in patients with advanced-stage cancer managed to reignite interest and significantly renewed efforts in psilocybin research, heralding a new age in exploration for psychedelic therapy. Since then, significant advances have been made in characterizing the chemical properties of psilocybin as well as its therapeutic uses. This review will explore the potential of psilocybin in the treatment of neuropsychiatry-related conditions, examining recent advances as well as current research. This is not a systematic review.

Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin.

BACKGROUND: Psilocybin is a serotonergic psychedelic found in "magic mushrooms" with a putative therapeutic potential for treatment-resistant depression, anxiety, obsessive-compulsive disorder, and addiction. In rodents, psilocybin acutely induces plasticity-related immediate early genes in cortical tissue; however, studies into the effects on subcortical regions, of different doses, and the subsequent translation of corresponding proteins are lacking. METHODS: We examined the acute effects of a single administration of psilocybin (0.5-20 mg/kg) on the expression of selected genes in the prefrontal cortex and hippocampus. In total, 46 target genes and eight reference genes were assessed using real-time quantitative polymerase chain reaction. Corresponding protein levels of the three most commonly regulated genes were assessed using Western blotting. RESULTS: In the prefrontal cortex, psilocybin increased the expression of Cebpb, c-Fos, Dups1, Fosb, Junb, Iκß-α, Nr4a1, P11, Psd95, and Sgk1, and decreased the expression of Clk1. In the hippocampus, psilocybin strongly increased the expression of Arrdc2, Dusp1, Iκß-α, and Sgk1 in a dose-dependent manner, and decreased the expression of Arc, Clk1, Egr2, and Ptgs2. Protein levels of Sgk1, Dusp1, and Iκß-α showed only partial agreement with transcriptional patterns, stressing the importance of assessing downstream translation when investigating rapid gene responses. CONCLUSION: The present study demonstrates that psilocybin rapidly induces gene expression related to neuroplasticity, biased towards the prefrontal cortex, compared to the hippocampus. Our findings provide further evidence for the rapid plasticity-promoting effects of psilocybin.

Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial.

Importance: Major depressive disorder (MDD) is a substantial public health burden, but current treatments have limited effectiveness and adherence. Recent evidence suggests that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression. Objective: To investigate the effect of psilocybin therapy in patients with MDD. Design, Setting, and Participants: This randomized, waiting list-controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. Adults aged 21 to 75 years with an MDD diagnosis, not currently using antidepressant medications, and without histories of psychotic disorder, serious suicide attempt, or hospitalization were eligible to participate. Enrollment occurred between August 2017 and April 2019, and the 4-week primary outcome assessments were completed in July 2019. A total of 27 participants were randomized to an immediate treatment condition group (n = 15) or delayed treatment condition group (waiting list control condition; n = 12). Data analysis was conducted from July 1, 2019, to July 31, 2020, and included participants who completed the intervention (evaluable population). Interventions: Two psilocybin sessions (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg) were given (administered in opaque gelatin capsules with approximately 100 mL of water) in the context of supportive psychotherapy (approximately 11 hours). Participants were randomized to begin treatment immediately or after an 8-week delay. Main Outcomes and Measures: The primary outcome, depression severity was assessed with the GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at baseline (score of ≥17 required for enrollment) and weeks 5 and 8 after enrollment for the delayed treatment group, which corresponded to weeks 1 and 4 after the intervention for the immediate treatment group. Secondary outcomes included the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR). Results: Of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 postsession assessments. This population had a mean (SD) age of 39.8 (12.2) years, was composed of 16 women (67%), and had a mean (SD) baseline GRID-HAMD score of 22.8 (3.9). The mean (SD) GRID-HAMD scores at weeks 1 and 4 (8.0 [7.1] and 8.5 [5.7]) in the immediate treatment group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed treatment group. The effect sizes were large at week 5 (Cohen d = 2.5; 95% CI, 1.4-3.5; P < .001) and week 8 (Cohen d = 2.6; 95% CI, 1.5-3.7; P < .001). The QIDS-SR documented a rapid decrease in mean (SD) depression score from baseline to day 1 after session 1 (16.7 [3.5] vs 6.3 [4.4]; Cohen d = 2.6; 95% CI, 1.8-3.5; P < .001), which remained statistically significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d = 2.3; 95% CI, 1.5-3.0; P < .001). In the overall sample, 17 participants (71%) at week 1 and 17 (71%) at week 4 had a clinically significant response to the intervention (≥50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (≤7 GRID-HAMD score). Conclusions and Relevance: Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression. Trial Registration: ClinicalTrials.gov Identifier: NCT03181529.