The Neurochemical Etiology of Obsessive-Compulsive Disorder: A Review
Psychiatrist, author, advocate.
August 22, 2026
Abstract
Obsessive-compulsive disorder affects 2–3% of the population and remains, for 25–40% of patients, resistant to first-line exposure and response prevention (ERP) and serotonin reuptake inhibitors (SRIs) (Goodman et al., American Journal of Psychiatry, 2021). Although the disorder has historically been framed as a serotonergic illness, the modern consensus is that OCD arises from dysregulation across multiple neurotransmitter systems converging on the cortico-striato-thalamo-cortical (CSTC) circuit. This review surveys the serotonergic, dopaminergic, noradrenergic, glutamatergic, GABAergic, and emerging endocannabinoid and glial hypotheses, and argues that no single-transmitter deficit model is adequate.
The circuit framework
Contemporary models locate OCD not in a single region but in dysfunction of parallel, segregated CSTC loops (Goodman et al., American Journal of Psychiatry, 2021). Functional imaging with PET and fMRI consistently shows hyperactivity in the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and caudate nucleus in the symptomatic state, and this hyperactivity tends to normalize with successful pharmacotherapy, ERP, deep brain stimulation, neurosurgical lesioning, and transcranial magnetic stimulation (Goodman et al., American Journal of Psychiatry, 2021). A widely held mechanistic account holds that excessive tone in the "direct" (net excitatory) pathway relative to the "indirect" (net inhibitory) pathway biases the individual toward selecting, and failing to inhibit, repetitive behavioral sequences (Goodman et al., American Journal of Psychiatry, 2021). Each neurochemical hypothesis below best describes dysregulation at a different node or connection within this shared circuit (Dougherty et al., JAMA Psychiatry, 2018).
The serotonergic hypothesis
The serotonin hypothesis originated in serendipity rather than pathophysiology: the 1975 observation that clomipramine, a potent serotonin transporter inhibitor, unlike other tricyclics, benefited OCD, followed by trials showing SSRIs were superior to the noradrenergic agent desipramine (Goodman et al., American Journal of Psychiatry, 2021). Critically, the preferential efficacy of SRIs has not translated into demonstrated serotonergic abnormalities. Acute tryptophan depletion does not worsen obsessions in SRI responders; pharmacologic challenge studies have been equivocal; and augmentation with serotonergic agents such as buspirone, tryptophan, and ondansetron has largely failed in controlled trials (Goodman et al., American Journal of Psychiatry, 2021).
Molecular imaging offers partial support. A 2025 systematic review and meta-analysis of unmedicated patients found lower serotonin transporter (SERT) binding potential in the brainstem, midbrain, and thalamus/hypothalamus, providing evidence of a 5-HT system dysfunction while acknowledging the mechanism remains elusive (Pastre et al., Psychiatry and Clinical Neurosciences, 2025). The prevailing interpretation is that potent SRIs act through an intact serotonergic system to compensate for dysfunction in a functionally coupled circuit — dampening hyperactive orbitofrontal-subcortical activity — rather than correcting a primary serotonin deficit (Goodman et al., American Journal of Psychiatry, 2021). As Pittenger summarizes, SRIs are effective, but the evidence does not support a simple serotonin-deficit model (Pittenger, Annual Review of Clinical Psychology, 2026).
The dopaminergic and noradrenergic hypotheses
Dopamine has emerged as a robust contributor. PET and SPECT studies demonstrate increased striatal dopamine transporter density and decreased striatal D1 and D2/D3 receptor binding, patterns suggestive of striatal dopaminergic hyperactivity (Dougherty et al., JAMA Psychiatry, 2018). A 2026 scoping review of 19 studies found consistent dopaminergic dysfunction across CSTC structures, with altered receptor availability in the dorsal striatum, ventral striatum, and ACC linked to cognitive rigidity, emotional dysregulation, and compulsive behavior — and noted that both hyperdopaminergic and hypodopaminergic states may influence symptoms (Mota et al., Journal of Psychiatric Research, 2026). Preclinical work refines the picture: substantia nigra dopamine neurons bidirectionally gate OCD-like grooming, with a striatal D1 pathway promoting it and an orbitofrontal D2 pathway suppressing it (Xue et al., Proceedings of the National Academy of Sciences, 2022).
Clinically, this hypothesis is validated indirectly by the fact that dopamine-modulating antipsychotics — particularly the high-affinity D2 antagonist risperidone and the partial agonist aripiprazole — constitute the augmentation strategy with the most empirical support after SRIs, though only about one-third of treatment-refractory patients respond (Dougherty et al., JAMA Psychiatry, 2018; Goodman et al., American Journal of Psychiatry, 2021). Importantly, the therapeutic signal is for dopamine antagonism, not agonism. The noradrenergic system, by contrast, has weaker support: the historical inferiority of the noradrenergic reuptake inhibitor desipramine to serotonergic agents argues against a primary noradrenergic mechanism, and no controlled evidence supports noradrenergic agonists for compulsivity (Goodman et al., American Journal of Psychiatry, 2021).
The glutamatergic and GABAergic hypotheses
The glutamatergic hypothesis has gained the most traction as a candidate primary mechanism. Support comes from imaging, genomics, cerebrospinal fluid biochemistry, and animal models of aberrant grooming (Goodman et al., American Journal of Psychiatry, 2021). Early magnetic resonance spectroscopy studies found elevated glutamate/glutamine (Glx) in the caudate of pediatric patients that appeared to normalize with paroxetine, though replication has been inconsistent (Dougherty et al., JAMA Psychiatry, 2018). More recent 7-Tesla spectroscopy links supplementary motor area glutamate to compulsivity and shows elevated glutamate with reduced GABA in the ACC of OCD patients, implicating an excitatory/inhibitory imbalance underlying habitual control (Biria et al., Nature Communications, 2023).
Glutamate-modulating agents have therefore been tested extensively. Riluzole, memantine, and N-acetylcysteine have shown benefit in a subset of patients in small trials, though pivotal RCTs of riluzole did not meet primary endpoints and the memantine literature has been questioned for methodological weaknesses (Goodman et al., American Journal of Psychiatry, 2021). Ketamine, an NMDA antagonist, produced rapid symptom reduction in a small placebo-controlled crossover trial, and its acute increase in medial prefrontal GABA correlated with symptom improvement, one of the few direct lines of evidence implicating GABAergic deficiency (Dougherty et al., JAMA Psychiatry, 2018). GABAergic dysfunction, marked by reduced medial prefrontal and orbitofrontal cortical GABA, remains comparatively understudied (Dougherty et al., JAMA Psychiatry, 2018).
Emerging models: endocannabinoid and glial
Newer hypotheses extend beyond classical neurotransmitters. Preclinical data consistently show that enhancing endocannabinoid system (ECS) activity attenuates compulsive and habitual behaviors while inhibiting it exacerbates them, and human samples show downregulation of ECS synthetic enzymes and receptors, raising the possibility that deficient endocannabinoid signaling modulates frontostriatal circuitry (Idd et al., Neuroscience and Biobehavioral Reviews, 2026; Bellia et al., Translational Psychiatry, 2024). Clinical evidence for cannabinoids, however, remains limited to case reports and small uncontrolled studies, and a recent scoping review found the current data do not support cannabinoids for OCD, with a somewhat stronger signal for psilocybin in treatment-resistant disease (Van Ameringen et al., Journal of Psychiatric Research, 2025). Separately, a glial-centric model reframes OCD as a disorder of neuro-glial dysfunction, positing that astrocytes, critical regulators of glutamate and GABA homeostasis and dopamine metabolism, shape excitatory/inhibitory balance and perseverative behavior (Gonzalez and Bezzi, Journal of Neurochemistry, 2025).
An integrated view
The convergent conclusion across authorities is that OCD reflects an array of neurochemical abnormalities producing a common endpoint: overactive CSTC circuitry characterized by striatal dopaminergic and glutamatergic hyperactivity (Dougherty et al., JAMA Psychiatry, 2018). One integrative account holds that this hyperactive state may arise from primary abnormalities in glutamate-related genes and/or be secondary to diminished midbrain and prefrontal serotonergic tone, since serotonergic raphe projections normally inhibit striatal dopamine and, via 5-HT2A receptors on prefrontal GABA interneurons, restrain striatal glutamatergic drive (Dougherty et al., JAMA Psychiatry, 2018). This helps reconcile why serotonergic, dopaminergic, and glutamatergic interventions can each help distinct subsets of patients.
The clinical implication is that OCD is not "only a serotonin problem." A nonreductionist, circuit-based framework that integrates multiple transmitter systems and increasingly, glial and genetic contributions offers the most coherent account of pathophysiology and the strongest rationale for developing and matching treatments to biologically defined subgroups (Pittenger, Annual Review of Clinical Psychology, 2026; Goodman et al., American Journal of Psychiatry, 2021).
Works Cited
Bellia, Fabio, et al. "Selective Alterations of Endocannabinoid System Genes in Obsessive-Compulsive Disorder." Translational Psychiatry, 2024.
Biria, Marjan, et al. "Cortical Glutamate and GABA Are Related to Compulsive Behaviour in Individuals with Obsessive Compulsive Disorder and Healthy Controls." Nature Communications, 2023.
Dougherty, Darin D., Brian P. Brennan, S. Evelyn Stewart, et al. "Neuroscientifically Informed Formulation and Treatment Planning for Patients With Obsessive-Compulsive Disorder: A Review." JAMA Psychiatry, 2018.
Gonzalez, Laura, and Paola Bezzi. "Astrocyte Dysfunctions in Obsessive Compulsive Disorder: Rethinking Neurobiology and Therapeutic Targets." Journal of Neurochemistry, 2025.
Goodman, Wayne K., Eric A. Storch, and Sameer A. Sheth. "Harmonizing the Neurobiology and Treatment of Obsessive-Compulsive Disorder." American Journal of Psychiatry, 2021.
Idd, Halima, et al. "The Endocannabinoid System in Obsessive-Compulsive Disorder: A Scoping Review." Neuroscience and Biobehavioral Reviews, 2026.
Mota, Pedro, Maria Picó-Pérez, and Pedro Morgado. "Mapping Dopamine's Role in Obsessive-Compulsive Disorder: A Scoping Review of Neural Circuits, Brain Regions, and Behavioral Implications." Journal of Psychiatric Research, 2026.
Pastre, Marc, et al. "Serotonergic Underpinnings of Obsessive-Compulsive Disorder: A Systematic Review and Meta-Analysis of Neuroimaging Findings." Psychiatry and Clinical Neurosciences, 2025.
Pittenger, Christopher. "Biological Mechanisms and Treatment of Obsessive-Compulsive Disorder." Annual Review of Clinical Psychology, 2026.
Van Ameringen, Michael, et al. "New Treatments for OCD? Evidence for Cannabinoids and Psychedelics." Journal of Psychiatric Research, 2025.
Xue, Jia, et al. "Midbrain Dopamine Neurons Arbiter OCD-like Behavior." Proceedings of the National Academy of Sciences, 2022.