Dear Editor,
Obsessive-compulsive disorder (OCD) is a debilitating psychiatric condition characterized by persistent, intrusive thoughts (obsessions) and repetitive behaviors or mental acts (compulsions). Current first-line treatments include selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy (CBT).1 However, a significant portion of patients remains refractory to these treatments, necessitating the exploration of alternative therapeutic strategies.
N-acetylcysteine (NAC) is a derivative of the amino acid cysteine and acts as a precursor to the antioxidant glutathione. It’s hypothesized that NAC may regulate glutamate transmission in the brain, with dysregulation in this system being implicated in the pathophysiology of OCD.2
The glutamatergic system, the primary excitatory neurotransmitter system in the human brain, is crucial for neuroplasticity, learning, and memory—processes that may be disrupted in OCD. Research has uncovered several glutamatergic abnormalities in individuals with OCD. One significant finding is the altered levels of glutamate observed in specific brain regions, such as the orbitofrontal cortex and the basal ganglia.3,4 These areas are critical for behavior and emotion regulation, and their dysregulation may contribute to OCD symptoms. The regulation of glutamate homeostasis presents a multifaceted challenge, as glutammate has the capability to diffuse beyond the confines of the synaptic cleft. While the stimulation of NMDA receptors located postsynaptically facilitates the conveyance of information, synaptic plasticity, and trophic effects on neuronal cells, the triggering of NMDA receptors situated outside the synapse inhibits these functions and may precipitate excitotoxicity, resulting in neuronal damage and apoptosis.5 Beyond glutamate levels, the transport of glutamate also appears to be affected in OCD. Glutamate transporters, which are responsible for clearing glutamate from the synaptic space to prevent excitotoxicity, may function abnormally in OCD, leading to an imbalance in excitatory signaling.6 Additionally, alterations in N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and intracelllar signaling pathwats modulated by glutamate, have been implicated in OCD, further supporting the notion of glutamatergic dysregulation.2,6
Thus, the potential role of glutamatergic abnormalities has opened new avenues for treating OCD, particularly for patients who do not respond to conventional treatments. Drugs targeting the glutamatergic system, such as memantine, an NMDA receptor antagonist, and NAC, are being investigated, offering hope for more effective interventions.7 NAC is characterized by its antioxidative, hepatoprotective, and mucolytic properties. It donates a cysteine unit that is integral to the synthesis of glutathione. Cysteine that is not utilized in this process crosses the blood-brain barrier, facilitated by sodium-dependent transport pathways. Once within the central nervous system, it is transformed into cystine.8 This cystine subsequently gets exchanged with glutamate through a cystine-glutamate antiporter, leading to the activation of metabotropic glutamate receptors mGLuR2/3. This cascade of biochemical reactions culminates in the suppression of glutamate release at synaptic junctions and the rebalancing of extracellular glutamate concentrations.9
In addition to its effects on the glutamatergic system, NAC has been found to modulate dopamine release and reduce the formation of inflammatory cytokines. These properties, along with the reduction of oxidative stress and the re-establishment of glutamatergic balance, would lead to an increase in growth factors, such as brain-derived neurotrophic factor (BDNF), and the regulation of neuronal cell death through B-cell lymphoma 2 (Bcl-2) expression.2
NAC potential efficacy as an adjunctive treatment in OCD has been explored. Some randomized controlled trials (RCTs) have reported significant reductions in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores at dosages of 2,000-3,000 mg per day.10-12 These pivotal studies have been excellent in investigating this therapeutic possibility. However, the rationale behind the dosages used in those studies is not clear. There is a need for further research with various dosages, including higher ones, and over longer periods, which are often necessary to observe improvements in various psychiatric disorders, including this one.
Notably, NAC has proved to be safe even in high dosages. Potential and very rare side effects with the oral administration include gastrointestinal disturbances and hypersensitivity reactions such as anaphylactic shock, anaphylactic/anaphylactoid reactions, bronchospasm, angioedema, rash, and itching.9 These side effects might not be attributable to NAC itself, but rather to other excipients in the formulations, such as sodium benzoate, parahydroxybenzoates, sorbitol, aspartame, Sunset Yellow FCF (E110), lactose, and propylene glycol. Furthermore, the pharmaceutical forms available on the market typically contain 200-600 mg of NAC, and the presence of these excipients restricts their use at higher doses needed to reach therapeutic levels for OCD.13
In conclusion, it’s worth underlying that despite the compelling evidence associating glutamatergic abnormalities with OCD, the relationship is complex and not fully understood. OCD likely emerges from a multifaceted interplay of factors, encompassing neurochemical imbalances, genetic predispositions, environmental triggers, and psychological influences. However, the use of N-acetylcysteine may prove to be not only effective but also safe. More rigorous, large-scale trials are needed. The empirical or off-label use is limited by the absence of medicinal formulations with the correct dosage specifically for OCD treatment.