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.