Despite its prevalence—affecting approximately 2-3% of the global population—no OCD-specific drugs exist. Current medications, while helpful to some patients, provide moderate efficacy at best and primarily serve to mask symptoms rather than address the underlying pattern of anxiety, circular thinking, and compulsions.

However, around 40% of patients fail to respond to available pharmacotherapy. This can be attributed to the intricate nature of OCD; it is more accurately characterised as a multifaceted, fluctuating constellation of behaviours that worsen themselves when left to free-run, rather than a static disease.

From a biological standpoint, OCD symptoms correlate with specific changes in brain function. The condition is most closely associated with an abnormally hyperactive cortico-striato-thalamo-cortical (CSTC) circuit, which can be observed through fMRI. But directly targeting areas within the CSTC loop through non-invasive repetitive transcranial magnetic stimulation (rTMS) shows promising, yet inconclusive, results.

Underpinning this ambiguity is the question of causality: does the abnormal firing of neurons within the CSTC circuitry spark the initial onset of OCD symptoms, making it a root cause?

Or, are the root causes of OCD more psychological, and is the CSTC loop's overactivity just a biological by-product of months or years of stress and compulsions? After all, chronic conditions alter the brain’s cytoarchitecture and structure, and an OCD diagnosis is rarely transient; one longitudinal study found 49% of participants to still have clinically diagnosable symptoms 10–20 years after their integration into the study.

OCD symptoms gain momentum over time

The debilitating symptoms of OCD, namely the heightened anxiety levels and incessant obsessions and compulsions, can amplify when left unchecked because the habitual execution of compulsions further entrenches the fears that trigger them.

This paradox is explained by how the brain’s anxiety circuitry works. Performing compulsions confirms to the amygdala, which encodes and sustains the brain's fear memories and receives contextual cues from the cortex and hippocampus, that the fears are a real and relevant threat. On the other hand, when OCD patients are exposed to their triggers while refraining from all compulsive behaviours, it sends a contrary message to the brain. This prompts the brain to re-evaluate stimuli linked with these triggers—whether sounds, noises, or physical sensations—as harmless and insignificant.

This is the essence of exposure response prevention (ERP), a form of cognitive-behavioral therapy (CBT) designed to desensitise individuals to their feared themes, situations, and triggers. It encourages the medial prefrontal cortex to strengthen its inhibitory connections with the amygdala, which suppress the specific fear memory traces related to the patient’s worries. This is how the brain ‘extinguishes’ a specific fear, in OCD patients and healthy people alike: by forming neural pathways that selectively inhibit the memories related to it. This is an active form of learning, rather than a passive ‘forgetting’, requiring the individual to receive sufficient contextual and sensory cues from the environment that frame their previous fears in a new, neutral, or positive light.

ERP: neutralising patients’ nuanced, multilayered triggers

ERP is considered the most effective treatment for OCD, with 50–60% of patients showing clinically significant improvements. However, it can be challenging for clinicians to practice ERP effectively, as the sufferer's real core fears have to be identified. These encapsulate not just the outcome they fear related to their theme (e.g., contamination, imprisonment, or the risk of harming others), but also the negative emotional state they believe this outcome will subject them to (e.g., intolerable anxiety, isolation, or grief).

Effective ERP involves mental exposures as well as real-life ones, as OCD has a strong meta-component where individuals fear and ruminate over their own thoughts about their theme, rather than just the theme itself (e.g., "What do these disturbing thoughts say about me?"). Many OCD patients take this a step further, also questioning their thoughts about their OCD-related thoughts (e.g., "Why am I spending so much time thinking about OCD?"), making OCD an infinite regress of recursive fears to tackle, both in one’s mind and in real life.

However, despite this ability to incrementally edge towards facing real-life triggers, ERP can involve a perceived high barrier of entry; whether exposures are imaginal, conducted in virtual reality settings, or done in the real world, many sufferers struggle to accept knowing they have to face their worst fears.

This is where pharmacotherapy stands out as a helpful aid. Although ERP-style interventions are what directly desensitise the fear circuitry and unravel the OCD pattern, effective medication can streamline this necessary desensitisation journey. Mechanistically, they can do so by softening either the affective (emotion/anxiety/mood-related) or cognitive (attentional/learning/understanding/decision-making and memory-related) factors that fuel the OCD pattern.

Drugs in focus: SSRIs, the classic OCD intervention

Before the 1990s, clomipramine, a tricyclic antidepressant, was the go-to pharmaceutical treatment for OCD. Its therapeutic benefits were largely credited to its ability to enhance serotonin and dopamine signaling across various brain regions involved in OCD, by blocking their reuptake. However, since the early 2000s, selective serotonin reuptake inhibitors (SSRIs) like fluoxetine, fluvoxamine, and sertraline have supplanted it as the gold-standard treatment. As with clomipramine, SSRIs primarily act on the serotonin transporter (SERT), inhibiting it so it can’t clear away serotonin from the synaptic cleft. This leads to overall enhanced serotonin levels in this area between neurons, allowing serotonin to act freely on its various receptors.

The brain houses seven classes of serotonin receptors: 5HT1-7. These are G protein-coupled receptors, which are embedded in the surfaces of cells, where they transmit signals from the extracellular environment to the intercellular environment. OCD involves dysfunctional serotonergic signaling at the 5-HT2A, 5-HT2B, 5-HT2C, and possibly 5HT1A and 5HT1B serotonin receptors. These receptors are all present in the prefrontal cortex, regulating mood, cognition, stress responses, decision-making, perception, and reward processing—all of which are altered in OCD, a condition extending far beyond just anxiety.

However, SSRIs work as a relatively blunt instrument, generally increasing the levels of serotonin available in synapses across the entire brain rather than targeting any of these highlighted receptors. Does this approach work? While SSRIs can reduce the severity of OCD symptoms by 40–60% in adults and children alike, over 40% of patients do not record an adequate response to them. Their indirect mode of action notoriously also leads to side effects such as lethargy, weight gain, and apathy, which are minimal in fortunate individuals but exaggerated in some.

Drugs in focus: combining treatments when SSRIs fall short

In certain circumstances, other medications, mainly clomipramine, antipsychotics, or mood stabilizers, are given alongside SSRIs. Augmentation with antipsychotic medication is widely favored, as 30–50% of OCD patients who do not respond to SSRIs find notable relief from symptoms through supplementary antipsychotic therapy. Aripiprazole, risperidone, and olanzapine demonstrate the greatest effectiveness in this regard.

This underscores the necessity of broadening our understanding beyond serotonin mechanisms when considering OCD. Classic antipsychotic drugs like chlorpromazine and haloperidol chiefly operate by subduing dopamine activity within the brain, achieved through the blockade of the D2 receptor. They are antagonists of the D2 receptor, occupying it and preventing endogenous dopamine from binding to it. However, newer 'atypical' antipsychotics like risperidone and aripiprazole have more nuanced modes of action, with both acting on the serotonin system and aripiprazole enhancing signaling at D2 receptors, instead of attenuating it.

The runner-up in popularity for augmenting SSRI therapy in OCD is lamotrigine, originally designed to control epilepsy and stabilise mood in those with bipolar disorder. It has been noted to show reasonable efficacy in tandem with an SSRI, with one study reported a 67.23% reduction in OCD obsessions and compulsions (scored together) at the end of 16 weeks of adjunctive lamotrigine alongside an SSRI. However, lamotrigine is not suitable for all patients; its possible side effects include dizziness, headaches, drowsiness, nausea, vomiting, and life-threatening skin rashes requiring hospitalisation.

OCD involves an imbalance between brain excitation and inhibition

Unlike antipsychotics, lamotrigine's primary mode of action is the inhibition of voltage-gated sodium channels, which suppresses neuronal firing. The key role of these sodium channels is in generating and propagating neuronal action potentials. Consequently, they affect the release of the neurotransmitter glutamate, the brain's main excitatory neurotransmitter.

Glutamate triggers neuronal firing, while GABA, the brain's main inhibitory neurotransmitter, suppresses it. Imbalances in glutamatergic signalling have been observed in all psychiatric disorders, including OCD. Fresh insights from a study held by University College London identified a peculiar imbalance between glutamate and GABA levels in the frontal regions of the brain—specifically within the anterior cingulate cortex (ACC)—among a sample of 31 individuals diagnosed with OCD.

This group was characterised by elevated glutamate concentrations, potentially indicating a state of hyperactivity within this region. In contrast, levels of GABA were found to be diminished. Ultimately, this results in a compromised equilibrium between these critical neurotransmitters within the ACC and the adjacent supplementary motor area SMA. Lamotrigine's effectiveness may stem from its corrective action, restoring the balance between brain excitation and inhibition. However, lamotrigine is only used in treatment-resistant OCD patients, due to its risky side effects profile.

Advancing OCD treatment: the quest for innovative pharmaceuticals

Evidently, it's a mistake to describe OCD as the result of a single faulty neurotransmitter system. No psychiatric condition can be classified so reductively, with growing bodies of evidence recognising the limited nature of the serotonin theory of depression and indicating the role of other neurotransmitters, too, as well as factors like inflammation and mitochondrial dysfunction.

However, few psychiatric conditions can be improved, albeit moderately, by as wide a range of drugs as OCD. To further illustrate this, it seems that stimulants can paradoxically ameliorate OCD symptoms. One study found caffeine to relieve obsessions and compulsions when given alongside SSRIs , and in investigations by Koran et al., (2009), both caffeine and dextroamphetamine proved capable of significantly improving treatment-resistant patients’ symptoms. This challenges the long-standing notion that stimulants increase anxiety in susceptible people.

Why do stimulants seem to calm obsessions and compulsions?

Nicotine is a unique stimulant, acting primarily on acetylcholine, a neurotransmitter that plays a crucial role in learning and memory, attention, motor control, and bodily functions like heart rate and digestion. Nicotine is an agonist (activator) of the nicotinic acetylcholine receptors in the brain, named after it. Evolution has refined these neurotransmitter-gated ion channels to convert chemical signals into electrical signals extremely quickly. By stimulating nicotinic receptors embedded in neurons, nicotine upregulates the release of dopamine and norepinephrine, leading to increased alertness, improved mood, and enhanced cognitive function.

A meta-analysis examined nicotine's effects in severe, treatment-resistant OCD, concluding that it yielded significant improvements in reducing intrusive thoughts and compulsions. Its addictive nature and the physiological dependence associated with it probably render it an unsustainable treatment, but this bolsters the notion that OCD is sustained by cognitive deficits reflective of a failure of the cortex to modulate subcortical regions.

Nicotine’s ability to enhance attention, working memory, episodic memory, and fine motor skills is attributed to its effects on the prefrontal cortex and basal ganglia, which caffeine and amphetamine also act on30. Unsurprisingly, these are key parts of the OCD-implicated CSTC circuit. Stimulants may assuage OCD symptoms by engaging cognitive functions geared towards goal-oriented thinking, diverting individuals from their more habitual, reflexive OCD-related thought patterns.

N-Acetyl cysteine (NAC): lesser-known compound that decreases oxidative stress and inflammation

A particularly unconventional substance that has been found to improve OCD symptoms is NAC, derived from the amino acid L-cysteine (which is found in high-protein foods including chicken, turkey, legumes, and eggs). A meta-analysis assessing five studies found that in four of them, NAC elicited significant shifts in symptoms when taken alongside a pharmaceutical medication. While it is known to modulate glutamate and dopamine signalling, its impact on OCD symptoms may stem from its more general role in decreasing oxidative stress and inflammation in the brain.

Multiple lines of evidence indicate that oxidative stress might contribute to the pathophysiology of OCD. Studies have reported increased levels of markers of oxidative stress in individuals with OCD compared to healthy controls, such as lipid peroxidation products, and decreased levels of antioxidants.

NAC doesn’t target oxidative stress directly; the body converts NAC into L-cysteine, which then becomes glutathione, a powerful antioxidant that helps protect neurons from oxidative stress. Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defence mechanisms. ROS, such as superoxide radicals and hydrogen peroxide, are highly reactive molecules that can damage cellular components, including lipids, proteins, and DNA. The brain is particularly vulnerable to oxidative stress due to its high oxygen consumption, high lipid content, and relatively low levels of antioxidants compared to other organs.

Inflammation, characterised by the activation of the immune system and the release of pro-inflammatory cytokines, is closely intertwined with oxidative stress. In the brain, microglial cells are the primary mediators of the immune response and play a crucial role in regulating neuroinflammation.

Dysregulated neuroinflammatory processes have been implicated in various psychiatric disorders, including OCD. One study observed that OCD patients’ monocytes released higher levels of the proinflammatory cytokines GM-CSF, IL-1β, IL-6, IL-8, and TNF-α compared to controls, with medicated OCD patients exhibiting ‘intermediate’ levels of these markers (between unmedicated patients and healthy controls). Another study reported inflammation specifically in the relevant CSTC circuit. However, these results are not consistently seen, potentially because other factors like diet, exercise, and sleep are strongly immunomodulatory (and, hence, represent confounders).

Although NAC is well-tolerated at the doses that help OCD patients, more research needs to be done to ensure that its effects—immunomodulatory, neurotransmission-related, and beyond—don't catalyze any unwanted effects in the long term.

Could psilocybin-assisted therapy help OCD patients?

Clearly, OCD is complex to treat pharmacologically—at least in a way that promises significant benefits. Various chemical compounds, each targeting different neurotransmitters and pathological brain processes, provide only partial relief, and a significant subset of patients do not respond to the established pharmaceutical treatments even when coupled with therapy. The demand for a pioneering treatment approach capable of addressing the multifaceted nature of OCD symptoms persists.

Initial findings imply that psilocybin, a naturally occurring psychedelic compound, could potentially become a novel auxiliary tool for therapy in the future. A small 2006 proof-of-concept study conducted by Moreno and colleagues at the University of Arizona administered four doses of psilocybin to treatment-resistant OCD patients in a controlled environment.

Subjects were required to have experienced at least one ‘treatment failure’, characterised by a lack of significant improvement despite receiving a satisfactory treatment duration with an SSRI for a minimum of 12 weeks. The administered doses ranged from a very low, sub-perceptual dose considered a ‘microdose’, to a high dose capable of eliciting overt perceptual effects. Vital signs and OCD symptoms were measured 1, 4, 8, and 24 hours following each of the four doses.

All nine participants registered noteworthy reductions in their obsessions and compulsions following the administration of at least one of the doses. Encouragingly, the study also reported no consequential adverse effects related to the compound. Neither a correlation between observed symptom improvement and dose, nor an association between the reduction in symptoms and the reported psychedelic intensity was established, making a compelling case for the efficacy of low doses and relatively mild experiences – which many patients may prefer.

How might psilocybin mechanistically target OCD symptoms?

Psilocybin is renowned for its psychoactive characteristics that chiefly originate from its strong affinity for serotonin 5-HT2A receptors, densely expressed in the prefrontal cortex. This receptor is instrumental in governing affective states, cognitive processes, and perceptual experiences, and it’s one of the serotonin receptors most robustly linked to OCD.

The interaction between psilocybin and 5-HT2A receptors in the prefrontal cortex modulates the default mode network (DMN), a network of brain regions, including the medial prefrontal cortex, that are most active during introspection and daydreaming. The DMN is acutely involved in our perception of ourselves and others. Psychedelic compounds like psilocybin attenuate DMN activity, temporarily reducing the propensity of the brain towards self-related thinking and assessments whilst enhancing its engagement with external information.

Evidence also suggests that psilocybin increases neuroplasticity, allowing these altered network dynamics to leave a long-lasting mark. Neuroplasticity refers to the brain's ability to form new neuronal pathways by strengthening the firing of neurons across synapses. Psilocybin raises levels of the brain-derived neurotrophic factor (BDNF), which enhances long-term potential, the main mechanism underpinning neuroplasticity (and the mechanism by which both conscious and implicit learning relies on).

More research needs to be done before the psychological shifts that psychedelic therapy can catalyse should be precisely mapped to this molecular mechanism. However, in major depressive disorder (another condition involving cognitive rigidity and entrenched, pessimistic thought patterns), increased serum BDNF levels correlate with successful recovery to the extent that it can be considered a biomarker for successful treatment.

Much of the established therapeutic potential of psilocybin likely owes itself to this plasticity enhancement. This is particularly relevant to OCD, a condition involving high degrees of cognitive rigidity, low confidence and overvalued negative beliefs, and a skewed balance between habits and compulsions and goal-oriented thinking. These cognitive features of OCD may all be improved by a low, well-tolerated dose of psilocybin, facilitating faster learning from ERP exposures and making them more bearable.