Obsessive-compulsive disorder (OCD) is a highly prevalent and disabling neuro-psychiatric condition for which currently available treatments are insufficiently effective and alternatives merit priority attention. Psilocybin may represent a safe and effective avenue for treatment of individuals affected by this condition. In this chapter we briefly introduce OCD symptoms, epidemiology, as well as relevant hypotheses on the mechanism of disease that may inform treatment interventions. We briefly describe currently available treatments, mechanisms of action, and efficacy limitations, as preamble to the potential use of psilocybin and perhaps similar compounds in the treatment of OCD and related conditions. Although much is reviewed throughout this book about the mechanisms of action of psychedelic agents, a focused discussion of psilocybin effects as they pertain to OCD is also included. Our experience with incidental observation, prospective research, and current explorations of psilocybin in OCD are also described.
Obsessive Compulsive Disorder (OCD) is a chronic neuropsychiatric condition, characterized by obsessions and compulsions, which usually impairs the daily activities of the suffering individual. It has a lifetime prevalence of 2–3%. The first-line treatment is not effective in around 41–43% of patients. There are case reports in the scientific literature showing improvement in OCD symptoms after the consumption of psilocybin-containing mushrooms. One report included the case of a treatment-resistant OCD patient who showed long-term reduction of symptoms after the consumption of psilocybin-containing mushrooms.
1.2 Hypothesized Mechanisms of Disease
OCD is a heterogenous condition with proposed clinical subtypes, some of which have been associated with biological, psychological, developmental, and environmental risk factors, and with distinct course of disease and treatment response. It is safe to assume that no single mechanism of disease explains OCD, and the complexity of the OCD phenotype may explain at least in part the variability of findings from pharmacological, psychotherapeutic, imaging, genetic, epidemiologic, and other study approaches.
1.3 Psychological Theories
Traditional psychoanalytic theories postulate that obsessional neurosis, a term that preceded the modern OCD diagnosis, results from unresolved fixations or regressions to primitive stages of psychosexual development, specifically the “Anal Phase.” In the anal phase, aggressive and sexual impulses conflict with a rigid superego and certain ego defenses that attempt to keep such impulses out of consciousness, as they are unacceptable to personal imperatives as conscience and cultural development occur. More recent formulations informed by object relations theory focus on the development of a fragmented or ambivalent self. Patients feel threatened by thoughts that they are bad, imperfect, unreliable, uncontrollable, or immoral, and are unable to integrate these attributions into a coherent self-image. Cognitive Behavioral Theories have supported the development of current psychological best practices for OCD. Learning theory maintains that a neutral event stimulus (i.e., perception, thought) comes to elicit fear when it is repeatedly presented together with an event that causes pain/distress (obsession formation). Subsequently, escape or avoidance behaviors (i.e., compulsions) are developed and maintained to reduce the anxiety. OCD has been characterized by the following erroneous cognitions:
- Assigning a high probability of danger to situations that are relatively safe;
- Exaggerating the severity of anticipated negative outcomes;
- Assuming dangerous qualities of an event or object in the absence of evidence of safety.
Traditional analytical and modern cognitive-behavioral formulations overlap in that they emphasize contradictory and poorly integrated attributions of self and other. Regardless of the particular psychodynamic formulation, obsessions and compulsions can serve the function to keep patients’ attention away from longstanding conflicts, some of which may be brought to awareness during the psilocybin experience, and which may be an important target for the support and integration that occurs in the context of psilocybin sessions.
1.4 Biological Theories
It is known that OCD is heritable, with estimates from twin studies that 27–65% of the variance in symptoms may be attributable to genetic variance. OCD also runs in families, and it is observed four times more frequently in relatives of people with OCD than in the general population. Certain subtypes of OCD are clearly more heritable, including early onset OCD, and the heterogeneity of ascertainment methods used in studies may explain the variability of results. Several neurotransmitters, neurohormones, and immunological alterations have been proposed as explanations for symptom generation, and treatment response, including specific elements of the serotoninergic, glutamatergic, GABAergic, and dopaminergic systems. Molecular genetic studies suggest a higher representation of certain genes related to serotonin function in patients with OCD, particularly the serotonin transporter and the serotonin 2a receptor gene. Furthermore, the role of glutamate in OCD neurobiology and pathophysiology is also well supported, although treatments involving this neurochemical are in need of further research.
The serotonergic system, however, is among the most broadly supported given the seemingly selective pharmacological response to serotonin acting agents, the reports of serotonin related changes in the central nervous system, and other alterations in peripheral markers of serotonin function in OCD patients. Intriguingly, laboratory-induced reductions in brain serotonin availability in patients recovered from OCD do not lead to a worsening of obsessive-compulsive symptoms. In contrast, specific blockade of serotonin subtype-2 receptors (5HT2) in patients recently improved and receiving treatment with serotonin enhancing medications causes an acute return of OCD symptoms. Furthermore, 5HT2 blockers used in practice such as atypical neuroleptics and mirtazapine appear to be beneficial in the treatment of OCD. These findings suggest that response to OCD is not only related to activity at a specific receptor, but rather the complex postsynaptic functional and structural changes that may involve the function of various neurochemicals and/or regions and circuits.
1.5 Brain Basis of OCD
Data from animal models as well as functional and structural human brain imaging studies point to the involvement of parallel and partially-segregated circuits that play a role in initiation and termination of thoughts and behaviors. The so-called Cortico-Striato-Thalamo-Cortical (CSTC) circuit refers to interconnectivity of the orbitofrontal cortex, the caudate nucleus, and the thalamus, however a larger number of regions frequently interacting with CSTC have been implicated in OCD. Interestingly, specific-symptom dimensions of OCD appear to be associated with findings in different brain regions, further supporting the heterogeneity of OCD.
The proposed OCD cortico-striatal hyperactivity leads to a persistently high error signal, ultimately resulting in its characteristic psychopathology, including irrational fears or obsessions, or that an action was not completed correctly according to a set of internal unattainable rules, triggering repetitive, compensatory behaviors (i.e., compulsions). An index of this error signal is larger in OCD patients, its magnitude relates to the continuum of OCD symptom severity.
1.6 OCD Treatments
Modern treatment guidelines support the use of Cognitive Behavioral Therapy (CBT) for OCD with emphasis on the value of Exposure and Response Prevention (ERP), and/or pharmacotherapy with serotonin reuptake inhibitor medications.
The U.S. Food and Drug Administration (FDA) has approved a small number of agents to treat this disorder. They are all potent serotonin reuptake inhibitors that lead to an increase in serotonin function and include:
- Clomipramine (Anafranil®),
- Fluoxetine (Prozac®),
- Fluvoxamine (Luvox®),
- Sertraline (Zoloft®),
- Paroxetine (Paxil®)
In spite of their established efficacy, a number of shortcomings limit their ability to improve a patient’s function. For example, in spite of OCD medications being frequently prescribed at higher doses and for longer periods than for other disorders, only about half of the patients receiving adequate treatment-trials will reach a satisfactory response, while most patients that do improve only have a one third to one half decrease in severity ratings. Their residual symptoms continue to cause dysfunction and increase vulnerability to complications and exacerbations.
Drugs such as desipramine and bupropion, which may act primarily by enhancing function of norepinephrine and/or dopamine, have been found to be ineffective at treating OCD. The apparent selectivity of treatment response to medication that acts on the serotonin system, and the finding that serotonin blockers cause a relapse of OCD symptoms further justifies pursuing options related to serotonin actions in this population.
CBT has been the mainstay of non-analytic therapy and a first-choice treatment for OCD. CBT comprises two components: cognitive reappraisal of distorted beliefs and a behavioral intervention to prevent symptom engagement. The treatment of choice for OCD is ERP, which involves gradual and prolonged exposure to fear-provoking stimuli combined with instructions to abstain from the compulsive behavior. The integration of ERP with cognitive components, such as the discussion of feared consequences and other dysfunctional beliefs, can enhance the acceptability and effectiveness of ERP, particularly for patients with limited insight or those that may find exposure treatments difficult to tolerate.
Treatment Strategies for Poor Responders
Although both pharmacotherapy and psychotherapy can be useful alone, the most effective outcomes typically occur through a combination of these treatment forms (pharmacology and CBT). When these treatments fail due to intolerance or lack of benefit after adequate trials of evidence supported first line interventions, an increasingly complex series of alternatives is possible, often with the goal of diminishing symptom severity rather than anticipating symptom remission. These include: alternative drug trials, augmentations and combination strategies, and the use of repeated transcranial magnetic stimulation (TMS), electroshock treatment, deep brain stimulation (DBS) in the anterior cingulate cortex and other targets, and surgical ablation such as cingulotomy and other lesion-based treatments.
Surgical options may be tried only after other avenues have been exhausted in highly treatment-resistant cases. Given that a significant portion of individuals remain symptomatic and impaired in spite of escalation of treatment strategies with increasing associated morbidity and decreased likelihood of benefit, identifying new options for treatments of patients with severe and treatment resistant OCD has become a high priority.
1.7 Background of Psilocybin in OCD
Psilocybin, LSD, and mescaline are known to bind to a large number of receptors, transporters, and other proteins; however, they are extremely potent agonists at 5-HT1A, 5-HT2A, and 5-HT2C receptors and their binding potency to these receptors is correlated with their human potency as hallucinogens. It is possible that involvement of other sites of action may explain the acute improvement in symptoms described in the published case reports, however it is likely that interactions with 5-HT1A, 5-HT2A, and 5-HT2C receptors may be an important component of anti-OCD drug action. SSRIs lead to increases in activation of postsynaptic 5-HT1A, and chronic downregulation of 5-HT2A. Additionally, the observations that administration of the non-selective 5-HT antagonists metergoline or ritanserin exacerbates OCD symptoms in patients recently remitted with SSRI treatment add complexity to the interpretation of a receptor specific effect.
Important questions arise from the reports above, including: why are the anti-obsessional effects so immediate with psilocybin, while potent serotonin enhancing agents like clomipramine and the SSRIs take weeks to months to show beneficial responses? Why do some 5HT2 blockers actually help treat OCD symptoms (atypical neuroleptic medications, mirtazapine), while experimental 5HT2 blockers ritanserin, ketanserin, and MDL-100,907 do not cause any effect?
Advances in our understanding of OCD, psychedelic mechanisms, and brain circuitry in the last two decades suggest a more complex mechanism may be in play than initially proposed, involving a variety of postsynaptic effects, interactions with other neurochemical systems, and brain circuits in the anti-obsessional response. Considering specific receptors within the serotonergic system, researchers have proposed that serotonin neurotransmission enhances two distinct adaptive responses to adversity, in which postsynaptic 5-HT1A signaling mediates passive coping characterized by stress moderation (SSRI treatments), whereas 5-HT2A signaling facilitated by psychedelics mediates active coping and further enhances plasticity. In terms of interactions with other neurochemical systems, knockout mice who do not express the metabotropic glutamate receptor-2 (mGluR2) also fail to have the cellular and behavioral responses to LSD similar to 5-HT2A knockouts, suggesting that the interaction of mGluR2 and 5-HT2A is necessary for certain neuro-behavioral effects to take place.
Successful treatments, both pharmacological and psychological therapies, show a normalization of CSTC circuits in patients with OCD, indicating that a disruption of the CSTC circuits might be a good target for the treatment of OCD with psychedelics. Patients with OCD show higher functional connectivity and ventral striatal activity in sensorimotor and ventral cognitive circuits, while at the same time showing lower functional connectivity followed by disinhibition of dorsal striatal circuits.
The 5-HT2A agonism of psychedelics is thought to disrupt the CSTC circuits. It has been proposed that this disruption lessens the sensory input filtering of the thalamus, thus allowing an increase of information in the cortex.
1.7 Psilocybin Efficacy
Providing another perspective on its potential therapeutic benefits, a single dose of psilocybin has been associated with a change in neocortical 5-HT2A receptor binding followed by long-term increased mindfulness. Furthermore, it has been shown that 5-HT2A signaling can enhance neural plasticity and low-level learning as well as extinction learning which is a key component of ERP and CBTs in OCD.
Psychedelics may also prompt neuroplasticity within the DMN. With the assumption that the DMN is controlling how information is integrated, it can be reasoned that incongruent or dissonant information deriving from perceptual anomalies and ambiguities will be dismissed by existing narratives, which in the case of OCD can be described as rigid and overlearned thought patterns and beliefs. Psychedelics are thought to interfere with this restrictive process. Excessive self-referential cognitive activity that is characteristic for OCD can be loosened by disrupting and “resetting” the DMN, allowing a healthier engagement with the patients’ environment, by disengaging rigid top-down information processing patterns.
Thus multiple levels of analysis prompt optimism about the use of psychedelics to disrupt rigid patterns, both neural and psychological, in OCD. Independent of what level of analysis one prefers to describe the potential mechanism of action, there is sufficient support for the psychedelic class of drug as a tool to rapidly reduce OCD symptoms with the clinical benefit lasting significantly more than the subjective effects of the drug paving the way for important explorations of therapeutic potential.
When administered in a supportive clinical environment, psilocybin is tolerated well and leads to a transient reduction of OCD symptoms. Psychedelic substances like psilocybin hold promise as a future treatment option for a broad spectrum of mental disorders, and in particular for individuals with disorders that include the transdiagnostic symptoms of rigid and repetitive negative thinking, and the inability to inhibit unhelpful and unwanted behaviors.
Preliminary data suggest that psilocybin may be an important agent to pursue as we explore alternative treatment options for OCD. Moreover, the current research base concerning brain chemistry and network function in OCD and how patients respond to the administration of psychedelics further motivates the promise of using psychedelics as a part of an intervention package for those with treatment-resistant OCD.