A potential role for psilocybin in the treatment of obsessive-compulsive disorder

A comprehensive (2020) review of psilocybin in the treatment for OCD. The current research is limited in scope (one trial), but points towards possible mechanisms and effectiveness.

Abstract

“The recent revivification of interest in the therapeutic use of psychedelics has had a particular focus on mood disorders and addiction, although there is reason to think these drugs may be effective more widely. After outlining pertinent aspects of psilocybin and obsessive-compulsive disorder (OCD), the current review summarizes the evidence indicating that there may be a role for psilocybin in the treatment of OCD, as well as highlighting a range of potential therapeutic mechanisms that reflect the action of psilocybin on brain function. Although the current evidence is limited, that multiple signals point in directions consistent with treatment potential, alongside the psychological and physiological safety of clinically administered psilocybin, support the expansion of research, both in animal models and in further randomized controlled trials, to properly investigate this potential.”

Author: Edward Jacobs

Summary

Psilocybin may be effective in the treatment of obsessive-compulsive disorder, and the current evidence supports the expansion of research into this potential use.

INTRODUCTION

The last decade has witnessed a resurgence of interest in serotonergic psychedelics for the treatment of a range of psychopathologies. This review discusses the potential use of psilocybin for patients with Obsessive-Compulsive Disorder.

Background

Psilocybin is a naturally occurring psychoactive compound found in the sclerotia and fruiting bodies of approximately 200 mushroom species worldwide. It has been in Schedule I of the United Nations Single Convention on Psychotropic Substances since 1971.

Pharmacology & neurobiology of psilocybin

Psilocybin, a tryptamine alkaloid, was first isolated from the Psilocybe mexicana in 1957, and synthesized the following year by the discoverer of LSD, chemist Albert Hofmann. It shows notable affinity for the serotonin 5-HT1A, 5-HT2A, and 5-HT2C sub-types.

Characteristic use and effects of psilocybin

After oral administration of 10 – 20 mg of psilocybin, peak plasma levels of psilocin are reached after approximately 105 minutes. Typical effects include dramatic changes to cognition and perception, as well as distortions to perception of self, time, and space, often accompanied by heightened affect.

Psilocybin effects increase monotonically with dose, and a typical recreational dose is 10 to 50 mg. However, the natural variability of psilocybin content and other psychoactive alkaloids means that users risk some inaccuracies in their dosing.

Magic mushrooms have a negative image associated with mental ill-health, but two recent large scale retrospective population studies failed to find any evidence of an association. In fact, they were associated with lower likelihood of impaired mental health and suicidality following psychedelic use.

Clinical efficacy

Although 40,000 patients were treated with psychedelics in the 1950s and 1960s, most of the research from that period does not stand up to modern standards of descriptive, methodological, or analytical rigor.

Currently, the best-explored indication for psilocybin is in the treatment of anxiety and depression secondary to cancer, or terminal diagnoses. Patients wore eyeshades and listened to music, and received light-touch, supportive, and largely non-directive contributions from therapists.

Psilocybin produces rapid and enduring decreases in anxiety and depression, as well as significant improvements in demoralization, hopelessness, and attitudes towards death. These effects are accompanied by significant persisting effects on positive attitudes about life and self, as well as improved relationships.

In an open-label trial of psilocybin, patients with treatment-resistant depression showed some reduction in depression severity 1 week after the high-dose session, with clinically significant reductions sustained by most patients for 3 – 5 weeks.

In open-label studies of psilocybin in substance use disorders, two or three doses of psilocybin embedded within a CBT-based smoking cessation therapy course led to significantly higher levels of biologically-verified smoking abstinence at 12-months.

Burden of OCD

OCD is a complex condition characterized by anxiety-laden intrusive thoughts, images, or urges, and repetitive behaviors that only temporarily reduce that anxiety. Both behavioral and pharmacotherapies have high nonresponse rates.

Pathophysiology of OCD

Studies have shown inconsistent results with single monoamine-targeted treatments for OCD, and inconclusive evidence from pharmacologic challenge studies. These findings indicate a biological heterogeneity of OCD phenotype, and may indicate a functionally coupled system underlying the neurobiology of OCD.

The dopamine and serotonin systems interact in the basal ganglia, which is consistently implicated in OCD. Damage to this area is known to produce OCD symptoms. Functional neuroimaging of OCD patients typically reveals increased activation in the orbitofrontal cortex and anterior cingulate cortex, which are connected to the basal ganglia via cortico-striatal-thalamo-cortical (CSTC) circuitry. This increased activation leads to a positive feedback loop between the OFC and ACC and the thalamus.

OCD patients experience aversive emotional responses to stimuli, including fear, disgust, and anxiety. These affective responses are subserved by hyperactivity in the amygdala.

Research supporting psilocybin’s use in treating OCD

Although there are few clinical trials investigating the antiobsessional effect of psilocybin, a number of user reports on the internet and one critically acclaimed stand-up comedy show attest to its efficacy.

In a rodent model of OCD, psilocybin and Psilocybe argentipes reduced marble burying without reducing general locomotor activity, but the study is beset with interpretive challenges. Furthermore, the test shows poor predictive validity because it is also responsive to anxiolytic drugs with no anti-compulsive activity.

Several case studies have reported that patients with OCD and similar diagnoses have experienced relief from symptoms with self-administration of serotonergic psychedelics including Psilocybe mushrooms. Unfortunately, none of these reports include lab-based analyses of the drugs in question.

Nine patients with moderate-to-severe symptoms of OCD received three escalating doses of psilocybin, each separated by at least a week, and experienced marked relief from symptoms in one or more psilocybin sessions. Two-thirds of patients maintained a 50% decrease in YBOCS score at 24 hours for at least one session.

In this study, patients were not provided with formal adjunct therapy in advance of and after treatment. This might have been beneficial, as it has been suggested that longer therapist-patient contact before drug sessions increases the probability of a peak experience. In four patients with OCD, a very low dose of psilocybin produced substantial relief from symptoms. This may be explained by an expectancy-driven placebo effect.

Possible psychedelic mechanisms of action in OCD

The acute action of psychedelics may cause perceptual distortions and the manifestation of otherwise unconscious psychic material, while their longer-lasting effects may act like a ‘reset button’, restoring normal functioning of the CSTC circuitry after an acute disruption.

A neurobiological account of obsessional activity in OCD emphasizes the role of dysfunctional activity in the DMN, which is associated with self-referential cognitive processing. Psilocybin may ease an overly strong, top-down filtering bias, thereby re-establishing normal responsiveness towards the environment.

Successful treatment for OCD may be cast in part as restorations to cognitive flexibility, which is mediated by the OFC and its connectivity to the wider CSTC loop.

The evidence for the role of 5-HT2A receptor binding in the attenuation of deficiencies related to OCD is mixed, with the largest and most homogenous samples failing to replicate early indications of increased binding in OCD patients relative to controls or increased binding within patients correlating to symptom severity.

Future research directions

Psilocybin’s legal status and stigma inhibit research into its potential role in OCD. The best-resourced and most determined scientists are able to pursue research, but entry costs to all psychedelic research are so high, that animal studies trail behind clinical research.

While psilocybin has not been directly compared to SSRIs for treating OCD, wider contextual factors favor its further investigation, including the participation of patients with comorbid disorders.

The Arizona lab that completed the original clinical study is now running an expanded, placebo-controlled trial with psilocybin. However, the trial is not embedded within a wider psychotherapeutic program, and more research is needed before a proper understanding is secured.

The UK government has funded some psilocybin research, but removing the excessive restrictions surrounding legitimate uses of psilocybin would vastly reduce the financial and bureaucratic hindrances associated with research.

CONCLUSION

OCD and its management remain a global healthcare problem. Psilocybin, a safe alternative drug, has been demonstrated to be both physiologically and psychologically safe, and has very low dependence potential.

Preclinical evidence and a single controlled trial point towards a possible treatment effect from psilocybin. However, political inertia and excessive restrictions impede systematic investigation of psilocybin as a treatment for OCD.