This review (2017) examines studies on psilocybin-assisted therapy to treat psychiatric disorders related to depression, anxiety, and substance abuse. In contrast to conventional paradigms, psilocybin-assisted therapy consists of only a few six-hour medication therapy sessions that may significantly improve symptoms and help patients achieve response or remission within weeks with support from integrative psychotherapy sessions.
Review: Recent research suggests that functional connectivity changes may be involved in the pathophysiology of psychiatric disorders. Hyperconnectivity in the default mode network has been associated with psychopathology, but psychedelic serotonin agonists like psilocybin may profoundly disrupt these dysfunctional neural network circuits and provide a novel treatment for psychiatric disorders. We have reviewed the current literature to investigate the efficacy and safety of psilocybin-assisted therapy for the treatment of psychiatric disorders. There were seven clinical trials that investigated psilocybin-assisted therapy as a treatment for psychiatric disorders related to anxiety, depression, and substance use. All trials demonstrated reductions in psychiatric rating scale scores or increased response and remission rates. There were large effect sizes related to improved depression and anxiety symptoms. Psilocybin may also potentially reduce alcohol or tobacco use and increase abstinence rates in addiction, but the benefits of these two trials were less clear due to open-label study designs without statistical analysis. Psilocybin-assisted therapy efficacy and safety appear promising, but more robust clinical trials will be required to support FDA approval and identify the potential role in clinical psychiatry.
Interest in serotonergic psychedelics has resurged in recent years as neuroimaging and neuroscience advances offer new ways to study brain circuits implicated in psychiatric disorders. The authors describe a context in which default mode network (DMN) hyperconnectivity, particularly involving subgenual and pregenual cingulate regions, has been linked to depressive rumination and illness duration, and they note that diverse rapid-acting interventions (for example, electroconvulsive therapy, ketamine, transcranial magnetic stimulation) may share effects on dysfunctional network dynamics. Psilocybin, a classic 5-HT agonist, is proposed as both a probe of brain function and a potential therapeutic agent capable of disrupting pathological network hubs and enabling healthier reconnection patterns after the acute drug effect subsides. This review aims to synthesize the pharmacokinetic and pharmacodynamic properties of psilocybin together with the clinical trial evidence available through 31 December 2016 for psilocybin-assisted therapy in psychiatric indications related to anxiety, depression, and substance use. Thomas and colleagues therefore set out to evaluate efficacy signals, safety issues, and gaps in the current evidence base to inform whether further robust clinical trials are warranted.
Papers cited by this study that are also in Blossom
Tracy, D., Baumeister, D., Barnes, G. et al. · Therapeutic Advances in Psychopharmacology (2014)
Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A. et al. · Journal of Psychopharmacology (2015)
Carhart-Harris, R. L., Bolstridge, M., Rucker, J. et al. · Lancet Psychiatry (2016)
Carhart-Harris, R. L., Erritzoe, D., Williams, T. et al. · PNAS (2012)
The authors performed a targeted literature review using PubMed. For clinical evidence they searched for articles classified as "Clinical Trial" on the topic of "psilocybin and psychiatry" up to 31 December 2016. Additional PubMed searches using the terms "psilocybin," "pharmacokinetics," and "pharmacodynamics" were used to assemble background information about the drug's behaviour and mechanism. The extracted text does not report further details such as additional databases searched, formal eligibility criteria, or a PRISMA-style flow diagram. No formal meta-analytic methods, risk-of-bias assessment approach, or quantitative pooling strategy are described in the extracted text. Instead, the review summarises pharmacokinetic and pharmacodynamic findings from human and in vitro studies and narratively reports results from seven clinical trials addressing anxiety, depression, obsessive-compulsive disorder (OCD), alcohol dependence, and tobacco addiction. Where available, the authors report primary outcomes, effect sizes, correlations with subjective experience measures, and adverse events as presented in the original trials.
Pharmacokinetics: Psilocybin is rapidly dephosphorylated to the active metabolite psilocin in the intestinal mucosa. The extracted text reports evidence of a first-pass effect, detectable plasma psilocin within 20–90 minutes after oral dosing, and a bioavailability estimate of about 52.7% after 10–20 mg oral psilocybin. Reported terminal elimination half-lives for psilocin are heterogeneous: about 74 minutes after intravenous psilocybin administration in one study and 135–163 minutes after oral dosing in other studies. Psilocin undergoes glucuronidation (notably via UGT1A10 in the gut and UGT1A9 in liver) and is partly renally excreted; urine levels typically fall below the lower limit of quantitation within 24 hours. Pharmacodynamics: The psychological and physiological effects of psilocybin are attributed primarily to agonism at the 5-HT2A receptor, with reported binding affinity (Ki) of approximately 6 nM for 5-HT2A versus lower affinity at 5-HT1A (Ki ≈ 190 nM). Antagonism with ketanserin attenuated subjective effects on standard altered-states questionnaires and cognitive/physiological measures, supporting a 5-HT2A-mediated mechanism. The review notes high cortical expression of 5-HT2A receptors on deep-layer pyramidal neurons and discusses proposed downstream signalling (PLC/PKC and PLA2 pathways), potential effects on thalamic gating and cortical oscillatory power, and peripheral 5-HT2A-mediated vascular effects—hence routine cardiovascular monitoring in trials. Cancer-related anxiety and depression trials: Seven clinical trials are summarised overall; among them, three randomised, double-blind crossover trials in patients with cancer-related anxiety or depression are described. A 12-participant crossover trial compared 0.2 mg/kg psilocybin with niacin placebo and reported reductions in Beck Depression Inventory (BDI) scores at six months (mean Δ≈−9, p = 0.03) and reductions in trait anxiety at one and three months. A 29-participant crossover (0.3 mg/kg vs niacin) found significant improvements across multiple scales at seven weeks post-dose 1 with large Cohen's d values (for example HAD-T Δ≈7, d = 1.36, p ≤ 0.001) and higher response/remission rates for those receiving psilocybin first (BDI response 83% vs 14%, p ≤ 0.01; BDI remission ~80% vs ~15%, p ≤ 0.01). A larger 51-participant double-blind crossover comparing high-dose (22–30 mg/70 kg) with low-dose (1–3 mg/70 kg) found substantially greater response and remission rates at five weeks for the high-dose-first group (GRID-HAMD-17 response 92% vs 32%, p < 0.001; HAM-A response 76% vs 24%, p < 0.001), with effects largely sustained at six months. Treatment‑resistant depression and other disorders: An open-label pilot in 12 participants with treatment-resistant major depressive disorder reported large reductions on the Quick Inventory of Depressive Symptoms (QIDS mean baseline 19.2, mean Δ at 1 week −11.8; Hedges' g = 3.1) and on BDI, HAM-D and STAI-T at one week and up to three months. An open-label, dose-escalation OCD study (n = 9) reported a significant main effect of time on Yale-Brown Obsessive-Compulsive Scale scores (p = 0.046) and mean YBOCS reductions 24 hours after dosing (p = 0.028), though durability was not systematically assessed. Open-label alcohol dependence (n = 10) and tobacco addiction (n = 15 completers) proof-of-concept studies reported clinically meaningful decreases in heavy drinking days (mean baseline ~35% reduced to ~9% during weeks 1–8 post-dose; mean difference −26.0, 95% CI −8.7 to −43.2) and high smoking abstinence at six months (80% biologically supported point prevalence abstinence) respectively; both studies noted correlations between greater intensity of subjective psychedelic experience (HRS, 5D-ASC, MEQ) and better outcomes. Safety and adverse events: Across trials the most common acute adverse reactions were transient elevations in systolic and diastolic blood pressure and heart rate, transient anxiety or fear during sessions, headaches, nausea, and occasional transient psychotic-like symptoms. Reported peak mean SBP values during sessions ranged into the 130–150 mm Hg range with some individuals experiencing episodic SBP > 160 mm Hg. Adverse psychological reactions typically resolved by session end and were managed with psychological support. The review notes that many trials included preparatory and supportive psychotherapy, complicating attribution of benefit to the pharmacological agent alone.
Thomas and colleagues interpret the collected evidence as promising but preliminary. They highlight large effect sizes reported in several small trials—sometimes Hedges' g > 2—and suggest that the limited number of psilocybin-assisted therapy sessions is a distinctive treatment model compared with daily pharmacotherapy. The authors emphasise that benefits in some studies were durable for months after only a few dosing sessions, and they note a consistent correlation across studies between intensity of mystical- or peak-type subjective experience and magnitude of clinical improvement. At the same time, the review stresses important limitations and uncertainties. Considerable heterogeneity existed across the small trials in patient populations (different DSM-IV diagnoses, cancer-related comorbidity), study designs (open-label vs double-blind crossover; active vs niacin or low-dose controls), dosing regimens, concomitant psychotherapy, and timing of outcome measurement. The authors point out that no trial isolated psilocybin without supportive psychotherapy, making it unclear how much clinical benefit is attributable to the drug itself versus the psychotherapeutic context. They also note that some positive findings came from open-label designs without statistical controls, limiting causal inference. In terms of safety, the researchers characterise the profile as favourable for short-term, limited exposure: most adverse events were transient cardiovascular or psychological reactions occurring during sessions and resolving thereafter. Nevertheless, the authors recommend continued monitoring and standardised safety procedures in future trials. They conclude that larger, methodologically consistent randomised trials are required to replicate findings, determine optimal psychotherapy–drug combinations, clarify mechanisms linking subjective experience to outcomes, and support regulatory decisions; ongoing larger trials in alcohol and tobacco use disorders are cited as examples of this next step.
Psilocybin, a 5-HT2A agonist, shows preliminary evidence of efficacy for conditions related to anxiety, depression, and substance use when administered within a structured psychotherapy-supported model that typically involves a few prolonged dosing sessions. The reviewed trials indicate rapid and sometimes durable improvements on clinician-rated and self-report symptom scales, with a safety profile dominated by transient cardiovascular and psychological effects during sessions. The authors conclude that further well‑controlled, adequately powered clinical trials with standardised methods are necessary to establish whether psilocybin-assisted therapy is sufficiently safe and effective to enter mainstream psychiatric practice and to support regulatory approval.
It has been suggested that the psychedelic compound lysergic diethylamide (LSD) may have been one catalyst for ushering in the modern era of molecular psychiatry during the early 1950s since, roughly a decade after Albert Hoffman discovered LSD, other researchers first recognized the chemically similar endogenous neurotransmitter serotonin. Interest in these psychedelic compounds has been recently renewed for investigating the therapeutic potential of serotonin (5-HT) agonists, like psilocybin, and also learning more about brain activity with these compounds. Advances in neuroimaging technology have enabled a more robust investigation of the human brain than was possible in the 1950s, when the first edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM) was published and the earliest psychiatric medications received FDA approval. These advances in technology have prompted the National Institute of Mental Health (NIMH) to propose the Research Domain Criteria (RDoC) project research initiative in 2009, which provided a framework for new ways of studying mental disorders that may eventually inform a more objective diagnostic paradigm than the current nosology of symptom clusters from the DSM. This RDoC framework consists of a matrix specifying functional constructs characterized in aggregate by the genes, molecules, and circuits used to measure human behavior. In one line of research inquiry consistent with the RDoC framework,has formulated a unifying triple network model of psychopathology and suggested that depression may be characterized by enhanced functional connectivity with other nodes of the default mode network (DMN) for pregenual and subgenual-cingulate cortex (SCC), along with adjoining ventromedial prefrontal cortex. The DMN connectivity in one neuroimaging study was defined by posterior-cingulate cortex (PCC) connectivity, which was stronger for SCC in major depressive disorder (MDD) patients than healthy controls (p < 0.05). The subjective scores on the Rumination Response Styles (RRS) inventory were also positively correlated with SCC-PCC connectivity (r = 0.68, p < 0.001) and researchers concluded that DMN hyperconnectivity could potentially explain the excessive ruminating thoughts of depressed patients. Interestingly, SCC functional connectivity in the DMN has also been positively correlated with duration of the current depressive episode (r = 0.49, p = 0.014)). This emerging evidence may necessitate a paradigm shift in how we understand psychiatric disorders and may offer new explanations for why such disparate treatment modalities like electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), ketamine infusion, and psilocybin-assisted therapy all rapidly reduce depression symptoms. More recently, there have been a series of neuroimaging studies specifically investigating the effects of psilocybin on functional connectivity networks in the brain. A recent review evaluating these psychedelic neuroimaging studies speculated on psilocybin's possible mechanism of action for treating psychiatric disorders: "following psychedelic-induced disintegration within local networks, as well as increased global interconnectivity, connections responsible for psychiatric-disorder-associated hub failures are disrupted and broken by the emergence of strong, topologically long-range functional connections. Then, as the effect of the drug wears off, networks can reconnect in 'healthy' ways, in the absence of the pathological driving forces(s) that originally led to a hub failure and disease". The purpose of this article is to review the pharmacokinetics, pharmacodynamics, and clinical evidence for psilocybin-assisted therapy as a novel treatment approach for psychiatric disorders related to anxiety, depression, and substance use.
We reviewed the available literature in order to investigate the potential role of psilocybin-assisted therapy for treating psychiatric disorders. A PubMed search was performed for "Clinical Trial" articles on the topic of "psilocybin and psychiatry" published through December 31, 2016. We also performed a PubMed search on the topics of "psilocybin," "pharmacokinetics," and "pharmacodynamics" to provide background drug information about this novel therapeutic agent with emerging clinical evidence.
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is a substituted indolealkylamine from the tryptamine group of compounds. Psilocybin was shown to rapidly dephosphorylate to an active metabolite, psilocin, by alkaline phosphatase and nonspecific esterase in the intestinal mucosa. There may be a first-pass effect with psilocybin based on the very low psilocin levels at the time to peak plasma concentration (tmax) and relatively higher levels of the inactive metabolite 4-hydroxy-indole-3-acetic acid (4HIAA). It remains unknown if any specific cytochrome P450 enzymes catalyze the formation of psilocybin metabolites, since human studies of pharmacokinetic parameters are limited. Psilocin was also found to be glucuronidated by UDP-glucuronosyltransferases (UGTs) into psilocin glucuronide, with the greatest activity from UGT1A10 in the small intestine and then UGT1A9 in the liver. Psilocin was shown to be renally excreted, partially in the form of psilocin glucuronide, and the lower limit of quantitation for psilocin in urine samples (10 μg/L) was usually reached 24 hours after ingestion. Psilocybin administered intravenously (IV) demonstrated a psilocin mean terminal elimination half-life (t 1/2β ) of 74 minutes, but psilocin's half-life was 163 minutes when psilocybin was given by mouth (PO), which suggests that there may be a dose-dependent effect on metabolism. Another study measuring PO psilocybin pharmacokinetic parameters demonstrated a similar psilocin half-life (t 1/2 ) of 135 minutes, elimination constant (k e ) of 0.307/h, and absorption constant (k a ) of 1.307/h). Psilocin's bioavailability is estimated to be 52.7% after PO psilocybin administration (10-20 mg), with plasma levels detectable 20 to 90 minutes after ingestion (tmax = 85-180 min) and perceptible psychological effects at psilocin plasma levels ranging from 4 to 6 ng/ml.
Most classic psychedelics, including psilocybin, are non-selective serotonin agonists with psychoactive effects related to agonism of the 5-hydroxytryptamine 2A (5-HT 2A ) receptor subtype). Psilocin binds with the highest affinity to 5-HT 2A (Ki = 6 nM) and to a lesser extent 5-HT 1A (Ki = 190 nM), with relatively lower affinity for other serotonin receptors). Agonism of the 5-HT 2A receptor stimulates phospholipase C (PLC) via G q/11 , which leads to downstream activation of protein kinase C (PKC) and an increased release of Ca 2+ from intracellular stores. Another independent 5-HT 2A receptor activation signaling pathway stimulates phospholipase A 2 (PLA 2 ), which can hydrolyze phospholipids and produce free arachidonic acid). Psilocybin's psychological effects have been attributed to the 5-HT 2A receptor, since the 5-HT 2A antagonist ketanserin has reversed psilocybin-induced effects, such as enhanced positive mood and attenuated recognition of negative facial expression. Ketanserin also reduced psilocybin-induced subjective psychological effects like oceanic boundlessness (⊿ ~700 points) and visionary restructuralization (⊿ ~500 points) as measured by the 5-Dimensions Altered States of Consciousness (5D-ASC) 94-item questionnaire self-rating scale (p < 0.0002), along with decreasing psilocybininduced mean error rates in the conflict condition of the Stroop test (~4 vs. ~2 errors, p < 0.0001). Pretreatment with ketanserin also prevented the psilocybin-induced reductions in the acoustic startle response measured by prepulse inhibition (PPI) at short lead intervals (p < 0.008). These studies provide compelling evidence that psilocybin's psychological effects are mediated primarily by agonism at the 5-HT 2A receptor subtype. This 5-HT 2A receptor agonism may be especially significant in the cerebral cortex, since in vitro light microscopic autoradiography has demonstrated exceptionally high concentrations of 5-HT 2A receptors localized over layer III and V pyramidal neurons of several cortical areas in postmortem brain tissue. The activation of the 5-HT 2A receptors in the reticular nucleus may inhibit thalamic filtering of information via GABAergic projections, potentially allowing cortical areas to receive more sensory information passing through). Dynamic causal modeling has also demonstrated that deep-layer pyramidal cell excitation could provide a net effect of feedback inhibition, which would be consistent with the decreased brain activity and oscillatory power shown on magnetic encephalography (MEG) after psilocybin administration. In addition to high 5-HT 2A receptor expression in the cortex, there are also 5-HT 2A receptors in the periphery, where agonism has been associated with contraction of vascular smooth muscle and platelet aggregation). Due to the potential risk of cardiovascular adverse reactions, psilocybin clinical trials have frequently monitored cardiac vital signs for safety. In one landmark clinical trial evaluating psilocybin-occasioned mystical-type experiences, psilocybin demonstrated doseand time-related effects on cardiac vital signs with a higher mean systolic blood pressure (SBP Δ20.5 mm Hg), diastolic BP (DBP Δ11.3 mm Hg), and heart rate (HR Δ8.2 bpm) than placebo (p < 0.05) in the highest dose condition (30 mg/70 kg), which were transient and normalized six hours post-dose. Clinical trials for cancer-related anxiety and depressive disordersconducted the first double-blind, placebo-controlled, crossover study of 12 participants with advanced-stage cancer and reactive anxiety, which was defined by a DSM-IV diagnosis of acute stress disorder, generalized anxiety disorder (GAD), anxiety disorder due to cancer, or adjustment disorder with anxiety. Participants met with study staff for a preparatory session to discuss expectations and goals of the two experimental sessions. During each of the two six-hour experimental sessions, separated by several weeks, participants were given either a dose of psilocybin (0.2 mg/ kg) or niacin placebo (250 mg), along with psychological support. During the second experimental session, each participant was given the opposite treatment they were randomized to in the first session and followed for six months. The main outcomes were cardiac safety (SBP, DBP, HR) and subjective experience (5D-ASC) during the sessions, followed by Beck Depression Inventory (BDI), Profile of Mood States (POMS), and State-Trait Anxiety Inventory (STAI) efficacy measures at monthly intervals for six months after the second experimental session. Participants wore a Holter cardiac monitor for 24 hours, which started at admission and included the entire experimental dose session. Mean BDI after psilocybin was lower than baseline after six months (~Δ9 points, p = 0.03), while mean STAI trait anxiety score was lower than baseline after one month (~Δ7, p = 0.001) and three months (~Δ6, p = 0.03). Mean POMS was not significantly different than mean baseline score at any time point during the six months. Psilocybin increased cardiac vital signs during the session between 1-5 hours after psilocybin administration that peaked at two hours, when HR and SBP were greater than placebo, while DBP was not: mean HR 81.5 vs. 70.4 bpm (p < 0.007); mean SBP 138.9 vs. 117.0 mm Hg (p < 0.01); mean DBP 75.9 vs. 69.6 mm Hg.also conducted a double-blind, placebo-controlled, crossover study of 29 participants with cancer-related anxiety and depression. The majority met DSM-IV criteria for an adjustment disorder with anxiety (n = 26), while the rest (n = 3) met criteria for GAD. Participants met with study staff for three twohour preparatory sessions to discuss expectations and goals of the experimental sessions. During each of the two six-hour experimental sessions, separated by seven weeks, participants were either given a dose of psilocybin (0.3 mg/kg) or niacin placebo (250 mg), along with psychological support. During the second experimental session, each participant was given the opposite treatment they were randomized to in the first session and followed for another 6.5 months. The primary outcomes of cancer-related anxiety and depression improvements and response/remission were measured by self-reported STAI for anxiety, along with Hospital Anxiety Depression Scale (HADS) and BDI for depression, using the following rating subscales: STAI-State (STAI-S), STAI-Trait (STAI-T), HADS Anxiety (HAD-A), HADS Depression (HAD-D), HADS Total (HAD-T), and BDI. These primary outcome variables were measured pre-crossover at baseline, one day pre-dose 1, oneday post-dose 1, two weeks post-dose 1, six weeks postdose 1, and seven weeks post-dose 1. After seven weeks post-dose 1, participants first receiving psilocybin had lower mean scores on all six rating subscales than the participants receiving niacin first (p < 0.05). The difference in mean HAD-T scores between groups at seven weeks post-dose was ~Δ7, which demonstrated the largest effect size of the primary outcomes, represented by Cohen's d = 1.36 (p ≤ 0.001). The other seven weeks post-dose 1 estimated differences in mean scores between groups, with corresponding Cohen's d values and p-values as follows: STAI-T ~Δ10, d = 1.29, p ≤ 0.001; STAI-S ~Δ12, d = 1.18, p ≤ 0.01; HAD-A ~Δ3, d = 1.07, p ≤ 0.01; HAD-D ~Δ3, d = 0.98, p ≤ 0.01; HAD-T ~Δ7, d = 1.36, p ≤ 0.001; BDI ~Δ6, d = 0.82, p < 0.05. The depression response was defined by a ≥ 50% reduction in score, while remission was defined by a ≥ 50% reduction plus HAD-D ≤ 7 or BDI ≤ 12. The following depression response or remission rates at seven weeks post-dose 1 were higher for participants first receiving psilocybin than the niacin placebo: response rates by HAD-A (58% vs. 14%, p ≤ 0.01), HAD-T (~70% vs. ~20%, p ≤ 0.01), and BDI (83% vs. 14%, p ≤ 0.01), along with remission rates by BDI (~80% vs. ~15%, p ≤ 0.01). The subjective effects of the psilocybin sessions, measured by the Mystical Experience Questionnaire (MEQ) total score, were also positively correlated with the magnitude of score change for the following primary outcomes: STAI-T, r = 0.40, p = 0.04; STAI-S, r = 0.42, p = 0.03; HAD-T, r = 0.49, p = 0.009; HAD-A, r = 0.46, p = 0.01. The most common adverse events related to psilocybin were elevations in BP and HR (76%), headaches (28%), transient anxiety (17%), nausea (14%), and transient psychotic-like symptoms (7%)). The mean SBP peaked at ~142 mm Hg, 180 minutes after psilocybin administration, but was higher than the niacin placebo at time points between 60 to 300 minutes post-dose (p ≤ 0.01). The mean DBP peaked at ~82 mm Hg, 180 minutes after psilocybin administration, but was higher than the niacin placebo at time points between 60 to 240 minutes post-dose (p < 0.05). The mean heart rate was relatively consistent at ~70 bpm after psilocybin administration, but was higher than the niacin placebo at time points between 90 to 120 minutes post-dose (p < 0.05), primarily due to heart rate reductions from baseline with the niacin placebo.conducted a randomized, double-blind, crossover study of 51 cancer participants with life-threatening diagnoses and symptoms of depression and/or anxiety. The participants with a life-threatening cancer diagnosis also met DSM-IV criteria for chronic adjustment disorder with anxiety (n = 11), chronic adjustment disorder with mixed anxiety and depressed mood (n = 11), GAD (n = 5), dysthymic disorder (n = 5), MDD (n = 14), comorbid GAD with MDD (n = 5), or GAD with dysthymic disorder (n = 1). Participants met with study staff for two or more preparatory sessions to discuss expectations and goals of the two experimental sessions. During each of the two approximately six-hour experimental sessions, separated by approximately five weeks, participants were given either high-dose psilocybin (22 or 30 mg/70 kg) or low-dose psilocybin (1 or 3 mg/70 kg), along with psychological support. During the second experimental session, each participant was given the opposite treatment they were randomized to in the first session. The primary outcomes of depression and anxiety response and remission were measured by the GRID-Hamilton Depression Rating Scale (GRID-HAMD-17) and the structured interview guide for the Hamilton Anxiety Rating Scale (HAM-A assessed with SIGH-A). The depression or anxiety response was defined by a ≥ 50% reduction in score, while remission was defined by a ≥ 50% reduction plus GRID-HAMD-17 or HAM-A ≤ 7, respectively. These primary outcome variables were measured at baseline, five weeks post-session 1, five weeks post-session 2, and six months after baseline. Secondary outcome rating scales measured included the BDI, HAD-T, HAD-D, HAD-A, HAM-A, and STAI-T, among others. The GRID-HAMD-17 response rates (92% vs. 32%, p < 0.001), HAM-A response rates (76% vs. 24%, p < 0.001), GRID-HAMD-17 remission rates (60% vs. 16%, p < 0.01), and HAM-A remission rates (52% vs. 12%, p < 0.01) were all higher for participants receiving high-dose psilocybin first than low-dose psilocybin first at five weeks post-session 1). After a six-month follow-up, the response and remission rates were sustained, as demonstrated by a nonsignificant difference between post-session 1 vs. six months in the high-dose first group or between post-session 2 vs. six months in the low-dose first group on these outcomes. The rating scales reductions in mean scores for participants receiving the high-dose first, were greater than participants receiving low-dose first, were as follows: GRID-HAMD-17 Δ8.2 (p < 0.001), BDI Δ5.9 (p < 0.01), HAD-D Δ2.1 (p < 0.05), HAM-A Δ8.2 (p < 0.001), and STAI-T Δ5.8 (p < 0.05). The subjective effects of the psilocybin sessions, measured by MEQ total score, were also correlated with a reduction in scores on the HAM-A (r = -0.59, p < 0.0001) and HAD-D (r = -0.36, p < 0.01) rating scales. Adverse events appeared to be more frequent in the high-dose vs. low-dose psilocybin sessions, with more participants experiencing episodes of transient elevated SBP (> 160 mm Hg: 34% vs. 17%), elevated DBP (> 100 mm Hg: 13% vs. 2%), nausea/vomiting (15% vs. 0%), physical discomfort (21% vs. 8%), anxiety (26% vs. 15%), psychological discomfort (32% vs. 12%), and paranoid ideation (2% vs. 0%), but these transient episodic events were not statistically tested for any differences.
Carhart-Harris et al. () conducted an open-label pilot study of 12 participants with moderate to severe MDD who already failed adequate trials (> 6 weeks) with at least two antidepressants. An initial four-hour preparatory psychotherapy session was completed prior to the first dose of psilocybin. During the first treatment session, a low dose of psilocybin (10 mg) was administered along with psychological support. One week after the low-dose safety session, each participant completed a high-dose (25 mg) session and was followed for assessments at several time points: one week, two weeks, three weeks, five weeks, and three months. The primary outcome was the difference in the Quick Inventory of Depressive Symptoms (QIDS) scores from baseline to one week after the high-dose session, but other rating scales measured included the BDI, HAM-D, STAI-T, among others. The mean baseline QIDS was 19.2, while the mean difference after one week was -11.8 (95% CI: -9.15 to -14.35; Hedges' g = 3.1) and after three months was -9.2 (95% CI: -5.69 to -12.71; Hedges' g = 2). The mean differences on other rating scales after one week were as follows: BDI -25.0 (95% CI: -20.1 to -29.9; Hedges' g = 3.2), HAM-D -14.0 (95% CI: -9.6 to -18.4; Hedges' g = 2.4), STAI-T -29.5 (95% CI: -22.03 to -36.97; Hedges' g = 2.7). Adverse events reported during the psilocybin sessions included transient anxiety (100%), confusion or thought disorder (75%), nausea (33%), headache (33%), and paranoia (8%). Clinical trial for obsessive-compulsive disorderconducted an open-label, doseescalation study with nine participants diagnosed with obsessive-compulsive disorder (OCD) who failed an adequate trial (> 12 weeks) with at least one serotonin reuptake inhibitor. Participants received up to four doses of psilocybin with at least a week between sessions. Doses were administered in an escalating fashion (0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg) with the exception of a very-low-dose session of 0.025 mg/kg, which was given in random sequence any time after the first 0.1 mg/kg dose. The Yale Brown Obsessive-Compulsive Scale (YBOCS) and a visual analog scale (VAS) for overall OCD symptom severity were administered prior to psilocybin ingestion and at 4, 8, and 24 hours after ingestion. A Hallucinogen Rating Scale (HRS) was also administered once, eight hours after ingestion. A repeated measures ANOVA was used to analyze efficacy with YBOCS values, which demonstrated a significant main effect of time (p = 0.046), although there was no effect of dose or interaction of dose and time). The combined baseline mean YBOCS scores, when stratified by dose groups, ranged from 18.3 to 24.1, were reduced 24 hours after psilocybin administration, and then ranged from 10.7 to 11.3 (p = 0.028). Durability of response was not studied formally, but two participants reported symptomatic improvement lasting most of the week and one participant achieved long-term remission measured after six months. The only adverse reaction reported was mild and transient hypertension in one participant, with BP peaking at 142/105 mm Hg four hours after administration. Clinical trial for alcohol dependenceconducted an open-label proof of concept study in 10 participants who met DSM-IV criteria for alcohol dependence, drank heavily (females ≥ 4/day, males ≥ 5/day) at least two of the past 30 days, and were concerned about their drinking. Weekly psychotherapy was provided over 12 weeks, with four sessions prior to the first psilocybin session, four between the psilocybin sessions, and four after the second psilocybin session. Psychotherapy sessions consisted of three preparatory sessions, seven motivational enhancement therapy sessions, and two debriefing sessions. Psilocybin was administered at a dose of 0.3 mg/ kg during the first session and 0.4 mg/kg during the second session, with the exception of one participant who received 0.3 mg/kg for both sessions. The primary outcome to determine response was the difference in percent heavy drinking days, assessed by the Time-Line Follow-Back procedure, in participants at baseline (during 12 weeks prior to enrollment) and during weeks 5 to 12 (one to eight weeks after first psilocybin session) of the study. Participants were also followed up at 36 weeks and completed an Addiction Research Inventory (ARCI) after each psilocybin session. Acute effects of psilocybin were captured using self-report scales by participants seven hours after ingestion, including intensity subscales of the HRS, 5D-ASC questionnaire, and MEQ. The mean percent heavy drinking days was ~35% at baseline, which decreased between one to eight weeks after the first psilocybin session to ~9% (mean difference = -26.0, 95% CI -8.7 to -43.2). Reductions in heavy drinking were not present during the four weeks prior to the first psilocybin session, but the reductions one to eight weeks after the psilocybin session persisted for 32 weeks. Intensity of subjective psilocybin experiences varied greatly and was negatively correlated with percent of heavy drinking days, which demonstrated that a greater intensity of subjective effects on HRS intensity subscale (r = -0.76, p = 0.017), 5D-ASC (r = -0.89, p = 0.001), and MEQ (r = -0.85, p = 0.004) was correlated with less heavy drinking days. Psilocybin also produced transient increases in BP between 30 to 180 minutes after ingestion and peaked at ~150/90. Other treatmentrelated adverse events included mild headache (50%), emesis (10%), diarrhea (10%), and insomnia (10%).
Johnson et al. () conducted an open-label pilot study to assess the feasibility of a psilocybin-based intervention for treating tobacco addiction in 15 participants who completed the trial. All participants smoked at least 10 cigarettes per day, had multiple past quit attempts and a present desire to quit smoking. A 15-week smoking cessation protocol was followed with psilocybin sessions at weeks 5, 7, and 13 along with weekly cognitive behavioral therapy (CBT) sessions for smoking cessation during the weeks psilocybin was not administered. Each participant set a target quit date coinciding with the first psilocybin session during week 5 of the study. Participants received 20 mg/70 kg (0.29 mg/kg) at week 5 and optionally increased to 30 mg/70 kg (0.43 mg/kg) during weeks 7 and 13. Participants were instructed to abstain from other medications for smoking cessation during the study period, although one participant reported use of nicotine lozenges. The primary outcome of remission was self-reported, biologically supported, seven-day point prevalence abstinence at six months. Acute effects of psilocybin were measured using the States of Consciousness Questionnaire (SOCQ) and post-session headache interview. There were 12 (80%) who were abstinent after six months and 10 (67%) who were abstinent after 12 months. Three of the 12 who were abstinent reported self-corrected relapses in the period between the psilocybin session and the six-month follow up. Psilocybin appeared to increase peak BP and HR over baseline readings 1.5 to 2.5 hours after ingestion: mean SBP 153 vs. 125 mm Hg; DBP 87 vs. 71 mm Hg; and HR 87 vs. 68 bpm; but these differences were not statistically tested. The SOCQ revealed that 40% of participants experienced strong or extreme ratings of fear, fear of insanity, or feeling trapped at some time during the moderate or high-dose psilocybin sessions, but these were managed with interpersonal support and had resolved by the end of the session.
New clinical evidence for psilocybin-assisted therapy in psychiatry has emerged during the past decade, represented by seven studies with a combined total of 135 participants (Table). The large effect sizes (Hedges' g > 2) demonstrated in some of these small studies warrant more robust clinical trials to ascertain psilocybin's efficacy for specific psychiatric indications. This novel treatment approach with limited psilocybin therapy sessions would be remarkably different from the current treatment paradigm of daily medication. However, there is some precedent for using alternative treatment modalities with limited sessions when depressed patients fail antidepressants, such as ketamine infusion, ECT, or TMS. One important distinction from these other session-based treatments would be that the benefits of psilocybin-assisted therapy may only require a few dosing sessions and the effects appear to persist longer than other treatment options. Another distinction is the use of psychotherapy before, during, and after the psilocybin sessions. While these studies demonstrated that psilocybin-assisted psychotherapy improved symptoms more than psychotherapy alone, it is unclear what clinical benefit (if any) would be derived from psilocybin alone, since there were no experimental conditions omitting supportive psychotherapy. A psilocybin-alone experimental condition may have been deemed unethical, sincesuggested that previous research had already documented that more preparation and interpersonal Preliminary evidence also suggests that the subjective experience during the psilocybin-assisted therapy session may be important, given the positive correlation between mystical-type experiences and improved clinical outcomes). However, further research is needed to determine how subjective effects and clinical responses are related to psilocybin, psychotherapy, or the optimal synergistic combination of both. Psilocybin-assisted therapy for depression symptoms seems to have the strongest clinical evidence thus far, with four studies demonstrating clinically significant reductions on rating scale scores and often with subsequently higher response or remission rates. In these studies, reductions on the BDI, HAD-D, HAM-D, and QIDS have ranged from ~3-25 points, while response/remission rates (defined by the BDI, HAD-T, and HAMD-17 scores) have been ~3-6fold higher after psilocybin sessions. Psilocybin also has compelling evidence for anxiety symptoms, with four studies demonstrating significant reductions on rating scale scores and often accompanied by higher response or remission rates. In these studies, reductions on the HAD-A, HAM-A, Y-BOCS, and STAI-T have ranged from ~6-30 points, while response/remission rates (defined by the HAD-A and HAM-A scores) have been ~3-4fold higher after psilocybin sessions. The potential to treat substance use disorders has relatively weaker clinical evidence, but promising results from open-label proof-of-concept trials have prompted researchers to launch larger randomized controlled trials recruiting for target enrollments of 180 participants with alcohol use disorder (NCT02061293) and 50 participants with tobacco use disorder (NCT01943994). The safety profile for psilocybin also appears favorable, especially given the short-term exposure required for only a few sessions. The most commonly reported adverse drug reactions were transient hypertension (in some cases BP > 160/100) and psychological reactions (anxiety or fear) that appeared to resolve by the end of the experimental sessions. Despite the large effect sizes and favorable safety profile demonstrated in these small clinical trials, it is important to recognize that there was substantial heterogeneity in the populations enrolled, due to different DSM-IV diagnoses and comorbidities (cancer), along with different study designs and timelines for measuring endpoints. If psilocybin-assisted therapy will eventually become a therapeutic option in clinical psychiatry, future trials must employ consistent methodology to expand and replicate this emerging evidence base.
The psychedelic 5-HT 2A agonist, psilocybin, is beginning to demonstrate potential for treating psychiatric disorders related to anxiety, depression, and substance use. Psilocybin-assisted therapy is a new investigational psychiatric treatment paradigm characterized by only a few six-hour medication therapy sessions with psychological support. These psilocybin sessions, supported by several weeks of integrative psychotherapy sessions, may significantly improve symptom scores and help patients achieve response or remission within weeks, which could persist for many months after taking psilocybin. Additional studies are required to determine if psilocybin will be deemed safe and effective enough to gain FDA approval. While psilocybin's clinical utility still remains uncertain, it should be investigated further to determine if this novel treatment paradigm has the potential to dramatically improve outcomes in patients with psychiatric disorders.
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Griffiths, R. R., Johnson, M. W. · Journal of Psychopharmacology (2016)
Griffiths, R. R., Richards, W. A., Mccann, U. et al. · Journal of Psychopharmacology (2006)
Grob, C. S., Danforth, A. L., Chopra, G. S. et al. · JAMA Psychiatry (2011)
Johnson, M. W., Garcia-Romeu, A., Cosimano, M. P. et al. · Journal of Psychopharmacology (2014)
Johnson, M. W., Garcia-Romeu, A., Griffiths, R. R. · The American Journal of Drug and Alcohol Abuse (2016)
Kometer, M., Schmidt, A., Bachmann, R. et al. · Biological Psychiatry (2012)
Lebedev, A. V., L€ Ovd En, M., Rosenthal, G. et al. · Human Brain Mapping (2015)
Moreno, F. A., Wiegand, C. B., Taitano, E. K. et al. · Journal of Clinical Psychiatry (2006)
Muthukumaraswamy, S. D., Carhart-Harris, R. L., Moran, R. J. et al. · Journal of Neuroscience (2013)
Nichols, D. E. · Pharmacology and Therapeutics (2004)
Nichols, D. E. · Pharmacological Reviews (2016)
Nichols, C. D., Nichols, D. E., Johnson, M. W. · Clinical Pharmacology and Therapeutics (2016)
Passie, T., Seifert, J., Schneider, U. et al. · Addiction Biology (2002)
Quednow, B. B., Kometer, M., Geyer, M. A. et al. · Neuropsychopharmacology (2011)
Roseman, L., Leech, R., Feilding, A. et al. · Frontiers in Human Neuroscience (2014)
Ross, S., Bossis, A. P., Guss, J. et al. · Journal of Psychopharmacology (2016)
Tylš, F., Páleníček, T., Horacek, J. · European Neuropsychopharmacology (2013)
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