OCD, Psychedelics, and Cannabinoids: New Evidence

Amidst the resurgence in psychedelics research, a new study evaluated the potential of psychedelics like psilocybin, as well as cannabinoids, to treat obsessive-compulsive disorder. Investigators found potential in psilocybin, but no strong evidence supporting cannabinoids as treatment. Psychiatric Times discussed findings and implications of these treatments with key investigators.

Psychiatric Times: Can you review the data and findings from your paper “New treatments for OCD? Evidence for cannabinoids and psychedelics”?

Michael von Ameringen, MD: The etiology of obsessive-compulsive disorder (OCD) is complex and appears to involve multiple biological pathways. Imbalances in central serotonin, dopamine, and glutamate activities are widely thought to play a causative role. Despite strong evidence supporting first-line OCD pharmacotherapies, approximately 40 to 60% of OCD patients remain partially responsive or nonresponsive and are considered treatment resistant (TR). Although a range of agents have been examined in TR-OCD, there is no gold standard, indicating a need to broaden our clinical armamentarium. Cannabis has been used for centuries in many cultures for both medicinal and recreational purposes, and modern clinical interest in these agents has recently reemerged. The current evidence for the use of cannabinoids in OCD is very small and includes survey-based, self-report studies with very few controlled trials. Additionally, after a long hiatus from psychiatric research, psychedelics have reemerged as agents of interest within the past decade. A comprehensive scoping review of the OCD literature including published and grey literature was conducted and detailed in this paper.

The current evidence associated with cannabinoids, psilocybin, lysergic acid diethylamide (LSD), N,N-Dimethyltryptamine (N,N-DMT), and methylenedioxyphenethylamine (MDMA) in the treatment of OCD is detailed. Much of the current evidence examining cannabinoids and psychedelics in OCD is from cross-sectional surveys and case reports, as well as some small clinical trials. There is a shortage of well-controlled, methodologically rigorous randomized controlled trials (RCTs) to properly test the efficacy of cannabinoids or psychedelics in OCD and related disorders. However, the current evidence appears to indicate a lack of evidence supporting the use of either synthetic or natural cannabinoids to treat OCD, but a stronger signal for the use of psilocybin in TR-OCD.

PT: How does OCD function neurologically in the brain, and what systems are implicated?

von Ameringen: The most consistently implicated neural system is the cortico-striato-thalamo-cortical (CSTC) circuit, particularly involving the orbitofrontal cortex, anterior cingulate cortex, striatum (notably the caudate), and thalamus. Functional neuroimaging studies demonstrate hyperactivity within this loop, leading to persistent error and threat signaling and impaired inhibitory control. Clinically, this manifests as intrusive obsessions that feel urgent and distressing, along with compulsive behaviors that are difficult to suppress despite preserved insight. A core neurophysiological feature of OCD is exaggerated error monitoring and threat detection. Electrophysiological and imaging studies show heightened anterior cingulate activity and increased error-related neural responses, even in the absence of objective mistakes. This hyperresponsivity is thought to underlie pathological doubt, inflated responsibility, and intolerance of uncertainty. Notably, these abnormalities may persist after symptomatic improvement, suggesting a trait-like vulnerability rather than a purely state-dependent phenomenon.

Neurotransmitter systems modulate these circuit abnormalities. Serotonergic dysfunction is implicated indirectly through the robust efficacy of high-dose selective serotonin reuptake inhibitors (SSRIs), likely via downstream effects on cortical–striatal connectivity and neuroplasticity rather than simple monoamine deficiency. Dopaminergic involvement, particularly within basal ganglia circuits, is supported by overlap with tic disorders and the benefit of antipsychotic augmentation in treatment-refractory cases. Increasing evidence also points to glutamatergic dysregulation within frontostriatal networks, reinforcing OCD as a disorder of excitatory–inhibitory imbalance. Structurally, OCD is associated with subtle and heterogeneous alterations in frontostriatal regions and their white-matter connections rather than focal lesions. Importantly, both pharmacotherapy and exposure-based cognitive behavioral therapy are associated with normalization of functional activity within these circuits, supporting a model of OCD as a circuit-based disorder that is responsive to experience-dependent neuroplastic change.

PT: How are cannabinoids and psychedelics theorized to function in treating OCD?

von Ameringen: Cannabinoids (eg, THC) interact with CB1 receptors, which are prevalent in OCD-related brain regions such as the basal ganglia and amygdala, and activate the endocannabinoid system (ECS). CB1 receptor activation modulates GABA and glutamate signaling (also implicated in OCD) and can influence gene transcription, synaptic function, and cell migration. Cannabinoid signaling in the ECS may therefore affect OCD-related functioning

Psychedelics modulate neural circuits involved in compulsive behavior, anxiety regulation, and affective processing—core domains disrupted in OCD. Psychedelics may promote neuroplasticity, enhance cognitive flexibility and reduce the rigidity of maladaptive thought patterns through activation of 5-HT2A receptors and downstream signaling pathways.

PT: What effect does psilocybin have on the brain in relation to treatment-resistant OCD?

von Ameringen: Psychedelics suppress the default mode network (DMN), a brain network associated with self-referential thinking and ruminations (both heightened in OCD). By disrupting the hyperconnectivity within the DMN and CSTC loop, psychedelics may loosen the rigidity characteristic of OCD, allowing for greater cognitive flexibility and altered behavioral responses. Serotonergic psychedelics may promote neuroplasticity through activation of 5-HT2A receptors, which increases brain-derived neurotrophic factor levels and engages the mTOR signaling pathway (facilitates synaptogenesis and dendritic remodeling).

PT: How do you see your findings impacting practicing psychiatrists?

von Ameringen: In terms of the use of cannabinoids, there is a complete lack of evidence to support their use in OCD, and clinicians should not be using these in clinical practice to treat OCD. With respect to the psychedelics, particularly psilocybin, there are encouraging signals from the small-scale studies that have been done thus far. Although encouraging, there really is not enough high-level evidence to use the psychedelics for the treatment of OCD at this point.

PT: What do you hope the future of OCD treatment research looks like?

von Ameringen: Larger randomized controlled trials of longer duration and follow-up are needed. These RCTs should include an active control in samples who are ideally naïve to psychedelics.

PT: Thank you!