Psilocybin-Assisted Therapy : A Review of a Novel Treatment for Psychiatric Disorders, Kelan Thomas et al., 2017

Psilocybin-Assisted Therapy : A Review of a Novel Treatment for Psychiatric Disorders

Kelan Thomas, Pharm.D., M.S., Benjamin Malcolm, Pharm.D., M.P.H., and Dan Lastra, B.S.

Journal of Psychoactive Drugs, 2017

Doi : 10.1080/02791072.2017.1320734



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 psycho-pathology, 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.

Keywords : Anxiety; depression; psilocybin; psychedelic; substance use


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 (Nichols 2004). 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 (Nichols 2016).

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 (Cuthbert 2015). This RDoC framework consists of a matrix specifying functional constructs characterized in aggregate by the genes, molecules, and circuits used to measure human behavior (Cuthbert 2015). In one line of research inquiry consistent with the RDoC framework,Menon (2011) has formulated a unifying triple network model of psycho-pathology 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 (vmPFC). The DMN connectivity in one neuro-imaging 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) (Berman et al. 2010). 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 (Berman et al. 2010). 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) (Greicius et al. 2007).

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 neuro-imaging studies specifically investigating the effects of psilocybin on functional connectivity networks in the brain (Carhart-Harris et al. 2012; Muthukumaraswamy et al. 2013; Roseman et al. 2014). 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” (Nichols, Johnson, and Nichols 2017). 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.