N-Acetylcysteine (NAC) in Psychiatry: A Review of the Rationale and Evidence

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Why NAC?

N-acetylcysteine (NAC), a derivative of the amino acid cysteine is widely known and utilized as an antidote for acetaminophen (paracetamol) overdose and as a mucolytic agent (to help break up mucus secretions) to manage respiratory conditions.  However, over the past two decades, this compound has become a subject of investigation in neuropsychiatry and much speculation and promotion by companies selling supplements.

This shift is based on a its hypothetical ability to influence complex processes in the central nervous system (CNS), including oxidative stress, neurotransmission (communication between neurons), and neuroinflammation. These mechanisms are hypothesized to play a role in the development of a wide array of psychiatric illnesses.  NAC is low-cost, and generally well-tolerated (if increased slowly) which makes it highly attractive as a potential medicine.

I discuss the neurobiological mechanisms that reportedly justify NAC’s use, incorporating evidence from animal models that provided the basis for human trials. Next, I evaluate the clinical evidence in adult psychiatric disorders, followed by NACs efficacy and safety in pediatric populations. Because more and more parents are using NAC as an alternative to FDA approved medications, I will provide a focused discussion on the specific evidence for NAC in relation to common childhood disorders including autism spectrum disorder (ASD), anxiety disorders, and attention-deficit/hyperactivity disorder (ADHD).


Rationale for NAC’s Use in Psychiatry

The theoretical foundation for NAC's use in psychiatry rests on three interconnected mechanisms of action: replenishing the body's primary antioxidant, modulating the brain's principal excitatory neurotransmitter system, and reducing neuroinflammatory stress.


The Antioxidant Pathway: Glutathione Synthesis

The most well-understood function of NAC is its role as a precursor to the amino acid L-cysteine.  L-cysteine is necessary for the synthesis of glutathione (glutathione), which is an abundant endogenous antioxidant in the human body.

The brain is vulnerable to oxidative stress—an imbalance between the production of reactive oxygen species (ROS) and the body's ability to counteract them.  A growing body of evidence has implicated oxidative stress in the development of numerous psychiatric disorders, including depression, anxiety disorders, schizophrenia, and bipolar disorder.

NAC may improve the entire antioxidant defense system. Glial cells in the brain, particularly astrocytes, maintain much higher concentrations of glutathione than neurons and are essential for supporting the neurons’ antioxidant capacity. Astrocytes release glutathione precursors, including cysteine, into the extracellular space for neuronal uptake.  Oral NAC administration effectively bypasses the normal rate-limiting step of glutathione synthesis, thereby replenishing and supporting this critical glial-neuronal protective system.  In addition to this precursor role, NAC has been shown to scavenge certain oxidants directly, such as the hydroxyl radical.


The Glutamatergic Pathway

NAC has the ability to modulate glutamatergic neurotransmission affecting either directly or indirectly most of the brain's activity.  NAC achieves this by interacting with something called the cystine-glutamate antiporter (a transporter that trades cystine for glutamate) which is predominantly located on astrocytes.

The mechanism is reported to ultimately "rebalance" glutamate levels rather than simply blocking them.  In the end, it can help reduce the firing of neurons that are over-active.

  1. First, oral administration of NAC increases systemic levels of cysteine.

  2. Cysteine is oxidized in the extracellular space to its dimer, cystine.

  3. The astrocytic antiporter system then transports this extracellular cystine into the astrocyte. In exchange, it transports intracellular glutamate out of the astrocyte and into the non-synaptic extracellular space.

  4. This small additional release of glutamate stimulates inhibitory glutamate receptors on presynaptic neurons.

  5. The activation of these inhibitory autoreceptors reduces the release of glutamate, particularly in "hyper-glutamatergic" states.

This dampening function is the rationale for investigating NAC in disorders characterized by glutamate dysregulation (i.e. too much excitability in the brain), such as addiction, compulsive disorders (e.g., OCD), and anxiety. It is a slow-acting modulator and so NAC's effects are hypothesized to take weeks or months to become apparent.


The Anti-inflammatory and Neurotrophic Pathways

The antioxidant and glutamatergic pathways are further supported by NAC's effects on inflammation and neurotrophic factors. NAC has been shown to modulate inflammatory pathways by reducing the production of pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). This action is linked with its antioxidant properties, as oxidative stress and inflammation are mutually reinforcing processes.  Given the evidence implicating neuroinflammation in the pathophysiology of depression, schizophrenia, and cognitive decline, this mechanism provides another potential therapeutic target.

Furthermore, these actions appear to promote cell survival and the synthesis of neurotrophic factors (molecules that promote neurons to be produced or to grow new connections). The preclinical data for this is encouraging. For example, in a rat neurodevelopmental model of schizophrenia, administration of NAC was found to increase the expression of Brain-Derived Neurotrophic Factor (BDNF) mRNA and levels in the prefrontal cortex. Also adding NAC appeared to allow for a reduction in the dose of an antipsychotic medication well below what was normally required to improve the rat’s behaviors.  However, humans are not rats.


Translational Gaps

The multi-target mechanisms of action for NAC provide a rationale for its investigation in psychiatry. However, a disconnect often emerges when translating these foundational mechanisms from preclinical models to human patients.

This is best illustrated by the "mechanism versus biomarker" problem. As noted, rat studies show an ability of NAC to modulate neurotrophic factors, such as increasing BDNF in the prefrontal cortex of rats. However, a clinical trial of NAC added to traditional treatments for for depression in humans reported no significant changes in serum levels of BDNF, IL-6, or C-reactive protein (CRP).

This discrepancy highlights a critical translational gap that complicates the field. It suggests several possibilities:

  1. Serum biomarkers (like serum BDNF) may be poor proxies for the specific, localized changes occurring within brain structures like the prefrontal cortex.

  2. The therapeutic mechanism in human depression may be different from that in any animal model, relying more heavily on the glutamatergic pathway rather than the BDNF or inflammatory pathways.

  3. The human clinical trials may be underpowered (to few subjects) or too short to detect these biological changes, even if the behavioral changes are apparent.

This gap between the "bench" and the "bedside" underscores the complexity of studying things like NAC and may explain the heterogeneous results seen in human clinical trials, which will be discussed in Section III.


Evidence from Animal Models

Below are a few of the many animal models that test whether NAC's ability to modulate glutamate, boost glutathione, and reduce inflammation may produce meaningful, measurable changes in behaviors analogous to human psychiatric disorders. The results from animal studies such as these provide the primary justification for human clinical trials.

The evidence for NAC in preclinical models of addiction and compulsivity is among the strongest, directly supporting the glutamatergic hypothesis.


  • Compulsive Behaviors (OCD/Grooming): Studies such as one in a mouse model of OCD that measured repetitive, compulsive-like behaviors (such as excessive burying), found that NAC decrease burying behavior in a dose-dependent manner that was not due to sedation (it did not affect general locomotor activity.)


Preclinical data for anxiety and depression similarly support "mechanism-to-behavior" links.

  • Anxiety: NAC has shown consistent anxiolytic properties across a wide battery of standard behavioral tasks. It has been found to reduce anxiety-like behaviors in the open field test, the light/dark box, the hole-board, and social interaction models in mice and rats. In zebrafish, a 7-day treatment with NAC successfully reversed both the behavioral and physiological effects of 14 days of chronic stress.


  • Depression: A particularly elegant study using transgenic mice modeling Huntington's Disease (HD) provided a direct link between mechanism and depressive behavior. These mice exhibited both glutamate dyshomeostasis and depressive-like behaviors. The administration of NAC successfully rescued both the depressive-like behavior and the underlying glutamate homeostasis. This study provides direct support for a glutamate-based hypothesis of depression (in mice).


Translational Implications

Numerous studies in the preclinical literature report positive behavioral effects after administering NAC. Across diverse animal models (from cocaine-seeking in rats and compulsive marble-burying in mice to depressive-like behavior in transgenic mice and chronic stress in zebrafish) NAC demonstrated improvements in behaviors. This kind of signal encourages widespread investigation in humans. More importantly, these animal studies do more than simply show "NAC helps." They provide support for the proposed mechanism leading to the behavior.


Evidence in Human Adults

The transition from the preclinical models to the complex reality of human clinical trials reveals a common theme: the data becomes "mixed" and "inconclusive".  While NAC's strong safety profile, low cost, and mechanistic rationale make it an ideal candidate for adjunctive psychiatric treatment, the clinical evidence is heterogeneous and contradictory. 

Some researchers suggest this is an artifact of flawed trial design. Many studies are criticized for being underpowered (having too few participants) and, perhaps, being "too brief". Given NAC's potentially slow, modulatory mechanism, trials lasting only a few weeks may be insufficient to capture its true therapeutic effect, potentially leading to false-negative results. However, this criticism doesn’t prove that longer, larger trials will confirm NACs potential.


A Few Examples of Conflicting Supportive Evidence

  • Obsessive-Compulsive Disorder (OCD): This is sometimes reported as the most promising area for NAC. A 2020 systematic review and meta-analysis identified NAC as a "promising agent". This was reinforced by a 2024 systematic review and meta-analysis of six randomized controlled trials (RCTs) involving 195 patients. This analysis concluded that adjunctive NAC "may serve as an effective adjunct" for adults with moderate-to-severe OCD.  However,  NAC was found to be significantly effective only when used for a duration of 5 to 8 weeks, but showed no significant effect for durations shorter than 4 weeks or longer than 12 weeks, which makes it effectively useless in clinical practice.


  • Substance Use Disorders (SUDs): The evidence for SUDs is highly contradictory. A narrative review from 2020 suggests NAC is helpful across a wide range of substance use disorders, both for cravings and for withdrawal symptoms. One 2017 meta-analysis found a very large and significant effect size (Hedges' G = 0.94) for craving reduction.  However, more recent 2024 meta-analyses stated that while NAC seems to reduce cravings, the "evidence is weak". The true efficacy of NAC for SUDs is highly uncertain.


  • Schizophrenia: There is limited evidence that adjunctive NAC is effective for a specific symptom cluster in schizophrenia. NAC may provide a beneficial effect for the negative symptoms of schizophrenia (e.g., anhedonia, avolition, which are notoriously difficult to treat with standard antipsychotics) along with evidence that it may improve cognitive deficits in working memory.  This evidence is preliminary.


  • Bipolar Disorder & Major Depressive Disorder (MDD): This is another conflicted and confusing area of NAC research. A 2018 meta-analysis found NAC was not effective for depressive or manic symptoms. A 2021 review of meta-analyses for MDD and bipolar depression concluded that NAC augmentation had no good evidence for effect in either. A 2024 meta-analysis found that adjunctive NAC may ameliorate depressive symptoms in patients with depression and bipolar but the evidence is weak at best.



Summary of Human Adult Evidence

The one thing these conflicting meta-analyses can agree on is that there needs to be far better studies before anything conclusive can be stated.  This leaves clinicians with no clear, evidence-based recommendation for or against the use of NAC in mood disorders.  One of the primary apologetic arguments for this is that NAC is a slow-acting modulator, not an acute treatment. This implies that trials of relatively short duration may be false negatives.  They may have been stopped before NAC's slow homeostatic effects on glutamate and inflammation could manifest behaviorally.  There is however, no good evidence that this is the case, especially in OCD, where NAC was shown to be apparently effective between 5-8 weeks, but not after 12 weeks.


Evidence in Pediatric Humans

There is significant interest in N-acetylcysteine for pediatric psychiatric disorders, particularly for use in school-age and preschool children. This interest is driven by a desire for perceived safer options or to postpone the use of medication. The current FDA-approved medications for behavioral dysregulation in children, such as atypical antipsychotics, carry a burden of potential side effects, including metabolic syndrome, significant weight gain, and tardive dyskinesia. NAC, with its high safety profile, is being explored as a potential alternative or adjunctive agent.


Efficacy in Autism Spectrum Disorder (ASD)

ASD is the best-studied pediatric indication for NAC. The evidence here is nuanced and points toward efficacy for specific symptoms, but not the core disorder.

  • Positive Findings: Case studies suggest some patients with ASD would benefit from NAC, especially for irritability and aggression. A small 2020 systematic review and meta-analysis of four RCTs suggest that NAC reduces symptoms of irritability and hyperactivity as measured by the Aberrant Behavior Checklist (ABC).

  • Negative Findings: The evidence appears consistent that NAC does not treat the "core" symptoms of autism. A scoping review and a six month 2016 RCT both found no significant improvement in the primary outcomes of communication, social interaction, or repetitive behaviors.

The clinical utility of NAC in ASD is therefore very specific (and not yet strong). It is unlikely effective for the core diagnostic symptoms, but has demonstrated potential efficacy for irritability and aggression making it a potential alternative or adjunctive treatment to antipsychotics for managing these behaviors.


Efficacy in Pediatric-Onset Bipolar Disorder

The evidence for pediatric bipolar disorder can at best suggest more studies be conducted. An open-label trial with no comparison group and high drop out rate studied NAC in 24 children and adolescents aged 5–17 years with bipolar spectrum disorders. The 12-week trial found significant improvements in both manic and depressive symptoms. Specifically, 54% of participants had an anti-manic response (defined as >30%reduction in Young Mania Rating Scale (YMRS) scores), and 62% had an anti-depressive response (defined as >30% reduction in Hamilton Depression Rating Scale (HDRS) scores).  The high drop-out rate suggests a large selection bias (those getting better were more likely to stay while those not getting better left) and the fact that there was no comparison group means that, honestly, nothing can be said about the efficacy of NAC.


Other Pediatric Conditions

  • Trichotillomania (TTM): A 12-week, double-blind, placebo-controlled trial from 2009 with 50 children (45 females) aged 8–17 years found a significant difference between NAC (1200–2400 mg/day) and placebo in reducing the severity of hair-pulling after 12 weeks. However, a similar trial from 2014 including 39 children aged 8 to 17 years found no significant difference between NAC and placebo using the same dosing.


  • Tourette Syndrome: An RCT from 2016 found no significant difference between NAC and placebo in reducing tics.


Safety and Tolerability in Children

Across the pediatric literature, NAC is consistently described as "safe" and "well-tolerated".  No serious adverse events have been consistently reported; the most common adverse events were gastrointestinal. These included nausea, vomiting, and diarrhea. This finding has practical implications for clinical use, as GI distress can lead to non-adherence in pediatric populations.


Summary of Pediatric Evidence

The evidence in pediatric populations is as inconclusive as that in adult populations.  NAC likely should not be thought of as treating any particular disorder, but as a possible symptom modulator (in the future). In autism, NAC does not "treat autism" (i.e., the core symptoms of social/communication deficits and repetitive behaviors). Instead, it may treat the trans-diagnostic symptoms of irritability and hyperactivity (but the evidence is still weak). NAC as a potential adjunctive agent for behavioral dysregulation across multiple disorders, rather than a primary, disorder-modifying drug.  However, there is no high quality evidence for its use in any disorder or for any symptom.


NAC and Anxiety Disorders

A Possible Mechanism: Oxidative Stress and Glutamate in Anxiety

The rationale for using NAC in anxiety disorders stems from the fact that anxiety is understood to be multifactorial, involving many of the same pathways NAC modulates. There is an established link between chronic emotional stress and cellular oxidative stress. Furthermore, glutamatergic dysfunction is implicated in the pathophysiology of anxiety disorders. NAC is considered a "multitarget agent" that can simultaneously address all of these domains: it provides antioxidant support, attenuates neuroinflammation, and, most importantly, modulates glutamatergic dysfunction.


Children Aren’t Adults; Neither Are They Rats

The evidence for NAC in anxiety does not translate from the theory.

  • Preclinical Data: The preclinical evidence is highly suggestive of anxiolytic effects.  In multiple animal models (open field, light/dark box), NAC demonstrates presumed anxiolytic properties.

  • Direct Clinical Evidence (GAD): In sharp contrast, the direct clinical evidence for NAC in Generalized Anxiety Disorder (GAD) is almost non-existent if studies of OCD are excluded. A 2019 review of multitarget anxiolytics found no studies of NAC specifically in anxiety disorders.

  • Indirect Clinical Evidence (OCD): Given this lack of direct evidence, the entire clinical case for using NAC in anxiety disorders is currently built by extrapolating from the limited clinical evidence in from conditions such as Obsessive-Compulsive Disorder (OCD).


The takeaway is the "evidence by proxy" dilemma. Currently, there is no robust, direct, evidence-base for recommending NAC as a treatment for Generalized Anxiety Disorder or any other anxiety disorder in either adults or children. The entire case rests on a three-legged stool of "proxy" evidence:

  1. Preclinical (animal) anxiolytic data.

  2. Relevant multimarket mechanistic rationale.

  3. Suggestive clinical (adult) data in OCD as an adjunct.

While NAC is a logical and promising candidate for GAD, it cannot be considered an "evidence-based" treatment for this specific indication at this time. Its use is hypothesized to work based on its very limited success in a mechanistically-similar disorder, and it awaits validation in dedicated, high-quality RCTs.


NAC and ADHD

The Neurobiological Rationale: Dopamine, Glutamate, and Oxidative Stress

The theoretical basis for using NAC in ADHD is the same for other disorders. The pathogenesis of ADHD is linked to dysregulation of the dopamine and glutamate neurotransmitter systems, as well as evidence of increased oxidative stress. NAC has the potential to modulate all of these pathways.

NAC has been shown to modulate the dopamine system, possibly by protecting dopamine transporters from oxidative damage and by facilitating striatal dopamine release via its activity at glutamate receptors. Additionally its anti-inflammatory and antioxidant properties have been proposed to treat ADHD.

B. The Limited Clinical Evidence: Extrapolating from Other Populations

Similar to GAD, the direct clinical evidence for NAC in "typical" ADHD is virtually non-existent. The entire case is built indirectly, from symptom-level data and studies in other populations.

  • Direct Evidence (Typical ADHD): I uncovered no published RCTs of NAC for typical ADHD in either children or adults.

  • Indirect Evidence (SLE Adults): A paper promoting the use of antioxidants like NAC for ADHD report a single study (R. F. van Vollenhoven et al.) investigated NAC in adults with Systemic Lupus Erythematosus (SLE). This study found that NAC (at 2.4–4.8 g/day) did significantly reduce ADHD symptoms, as measured by the ADHD Self-Report Scale (ASRS). However, the study population was not psychiatric, did not confirm childhood onset of symptoms, and therefore is poorly suggestive of possible benefit to children with ADHD.

  • Indirect Evidence (ASD Children - Symptom Data): This is probably the most relevant piece of data for ADHD. NAC has been shown (but not confirmed) to reduce hyperactivity scores on the Aberrant Behavior Checklist.  Given the high symptomatic overlap between ASD and ADHD, this finding provides the strongest rationale for dedicated trials in ADHD, which have not been done.


There is no direct clinical evidence to support the use of NAC for typical ADHD. The entire case rests on a very weak "indirect evidence" model:

  1. A plausible neurobiological rationale.

  2. A single, positive study in a non-psychiatric adult population (SLE) that cannot be generalized.

  3. A weak signal for a single trans-diagnostic symptom (hyperactivity) in a related pediatric disorder (ASD).

The finding that NAC reduces hyperactivity in children with ASD  suggests (but does not prove) its most promising application may not be as a "treatment for ADHD," but rather as an adjunctive, trans-diagnostic treatment for behavioral dysregulation (hyperactivity, irritability) in pediatric populations, regardless of their primary diagnosis.


A Disconnect Between Promise and Proof

N-acetylcysteine’s use in psychiatric disorders paints a consistent narrative of translational disconnect. It possesses a reportedly powerful, multi-target mechanism of action—modulating glutamate, boosting glutathione, and reducing inflammation—that is directly relevant to the pathophysiology of many psychiatric disorders. This mechanism appeared to translate into consistent positive effects in a wide range of preclinical animal models, from addiction to anxiety.

However, this preclinical promise failed to consistently translate to human clinical trials. The clinical literature is best described as mixed, inconclusive, and weak. While there are promising signals in specific areas (e.g., OCD, schizophrenia-negative-symptoms), there is not high quality confirmation of this and it contrasts with inconsistent findings in meta-analyses in major mood disorders and a near-total lack of direct evidence for GAD and ADHD.

The conclusion across virtually all reviews is the need for "larger, well-designed trials" and these trials would likely have the best chance of being found effective if continued for many months instead of weeks.  Dedicated, high-quality, long-duration RCTs are necessary for GAD and typical ADHD to move beyond the current "evidence by proxy." In pediatric research, future studies may focus on "trans-diagnostic" effects (irritability, hyperactivity) and investigate formulations or delivery methods that mitigate the high rate of GI side effects to improve adherence and allow for a true test of efficacy.


Resources

  • General Reviews and Mechanisms of Action (NAC in Psychiatry/Neurology)











  • The neuroprotective effects of N-acetylcysteine in psychiatric and neurodegenerative disorders: From modulation of glutamatergic transmission to restoration of synaptic plasticity - PubMed, https://pubmed.ncbi.nlm.nih.gov/40414419/



  • Oxidative Stress, Inflammation, and BDNF Mechanisms









  • Substance Use and Addiction/Craving









  • Obsessive-Compulsive and Related Disorders (OCD, Trichotillomania)






  • Depression and Bipolar Disorder





  • Autism Spectrum Disorder (ASD) and Childhood Disorders












  • Other Conditions (Huntington's, Anxiety, ADHD)







By: T. Ryan O’Leary, MD

The author(s) may use Ai Large Language Models to assist with the content creation. The content is edited and fact checked by the author based on their expertise. All content should be considered the opinion of the author and not that of any civil or government agency for which they may work or contract. None of the content should be considered personal medical advice and all readers should consult with their physician for personal medical advice.

PDF Version: https://drive.google.com/file/d/1Xaro5osKe2LihZ7DjOtLs1r6R-fe4sM1/view 

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