Introduction

N-acetylcysteine is thought to regulate glutamate neurotransmission in the brain, and also acts as a potential anti-oxidant. It increases the amount of extracellular glutamate by enhancing the activity of the cystine/ glutamate transporter.

There are a number of other drugs that are sometimes used to treat OCD that act on glutamate. These include: Memantine; Riluzole, D-cycloserine; and lamotrigine. Summaries of these other drugs will hopefully follow in time.

The possible mechanism of action is unknown, but there is evidence that glutamate is involved in development of the symptoms of obsessive-compulsive disorder (OCD).[1-3] Of course, glutamate is the main 'excitatory' neurotransmitter in the brain, so it is likely to be involved in all neural processes to some extent.

Parts of the brain that are likely to be involved in the development of OCD (such as the striatum, parts of the basal ganglia, and some of the cortico-striatral-thalamo-cortical circuits) have large amounts of excitatory (i.e. glutamatergic) input relating to information about movements and sensory integration. It is possible that this large amount of glutamatergic input puts these parts of the brain at risk of becoming dysregulated, with overstimulation of extra-synaptic glutamate receptors.

Methods

This is not a systematic review, but is based around a review of what information is available. It is intended to provide an overview of what the evidence would support in terms of treatment. Only randomised, controlled studies (RCTs) have been included.

Outcome data (intervention vs control) were extracted and entered into ‘forest plots’ showing the outcomes from each study, along with the combined effect of all studies combined. These forest plots were drawn using the MS Excel files from Exploratory Software for Confidence Intervals, a resource developed alongside a book by Geoff Cumming. Intention-to-treat outcomes were extracted where available.

In one study,[4] data had to be extracted using WebPlotDigitizer.[5]

Results

Six RCTs of N-Acetylcysteine have been included.[4, 6-10] A summary of these trials is given below in Table 1. The studies are sorted by year (earliest first). You can download this summary in MS Excel format here.

Four studies were in adults, whilst two studies were in patients under the age of 18 years.

Table 1:

Study ID	Place conducted	No. of participants	Population	Duration (weeks)	Intervention vs Control	Baseline Y-BOCS (mean ± SD)	Age ± SD	Other current treatment	Previous failed treatment	Primary outcome
Afshar, 2012	Iran	48	Adult	12	N-acetylcysteine (up to 2400mg/day) vs placebo	27.7 ± 5.5	30.9 ± 5.0	SRI	12 weeks of SSRI or Clomipramine	Y-BOCS
Sarris, 2015	Australia	44	Adult	16	N-Acetylecystine (3000mg/day) vs placebo	26.6 ± 5.7	37 (range 18-68)	70% were taking medication; 57% taking SSRIs	No treatment, or stable medication	Y-BOCS
Paydary, 2016	Iran	44	Adult	10	N-Acetylcystine (2000mg/day) vs placebo	27.0 ± 4.4	33.7 ± 11.3	Fluvoxamine 200mg/day	None for 6 weeks prior to study	Y-BOCS
Costa, 2017	Brazil	40	Adult	16	N-Acetylcysteine (3000mg/day) vs placebo	25.2 ± 3.9	38.0 ± 10.8	Stable dose of SRI	Failure to respond to at least 1 adeuqate drug treatment (Clomipramine or SSRI)	Y-BOCS
Ghanizadeh, 2017	Iran	34	Child & Adolescent	10	N-Acetylcysteine (2400mg/day) vs placebo	21.0 ± 8.2	16.5 ± 2.9	SRI	At least a previous trial of an SSRI	Y-BOCS
Li, 2020	USA	11	Child & Adolescent	12	N-Acetylcysteine (2700mg/day) vs placebo	21.4 ± 4.7	13.4 ± 3.4	Unspecified amount on SRI	None specified	CY-BOCS

 

Forest plot of outcomes

Forest plots, showing the estimated results from each study along with the overall results, are shown below. Groups have been defined by whether they were in adults or children/ adolescents.

Overall, there was a slight positive effect for NAC vs placebo, but the effect was very much less in adult vs adolescent populations. Excluding the two studies in adolescents resulted in a non-significant overall effect for NAC.

It should be recognised that 3/4 of the adult studies were not statistically significant. Removing the single positive study (Afshar et al, 2012) removes any effect for NAC.

Conclusions

If N-Acetylcysteine (NAC) has an effect, it is likely to be small and only evident in adolescents. There is no convincing effect for NAC in adults.

The observation that the first trial conducted (in 2012) is positive, whilst successive trials (2015-2020) are negative, is commonly seen in science.

The majority of studies included individuals who were not especially severe. The non-weighted average baseline Y-BOCS across all studies was 24.8, and in adult populations only it was 26.6. This is broadly similar to most other trials of psychological/ drug treatment for OCD.

In general, tolerability of N-Acetylcysteine was good. In most studies, there were no significant differences between the NAC group and the placebo group. The most common adverse effects include: nausea; changes in bowel habit; and headache. Most side effects tend to be mild and few studies had high numbers of drop-outs. It often has an unpleasant smell that can make it difficult to take.

N-Acetylcysteine can be found in health-food shops and is typically around £8-10 for 30 capsules at a dose of 600mg. This means that in order to get up to the typical doses used in the studies, 30 capsules will last you about one week.

Overall, it is likely to be safe for most adults but it is unlikely to have a clinically-significant benefit; particularly in those with more severe symptoms and those who have not responded to at least one or two previous treatments. However, some people may wish to try it given its ‘health food’ status and its good tolerability.

References

1. KARIUKI-NYUTHE C, GOMEZ-MANCILLA B, STEIN DJ. Obsessive compulsive disorder and the glutamatergic system. Current Opinion in Psychiatry. 2014; 27(1): 32-37. https://doi.org/10.1097/YCO.0000000000000017

2. PITTENGER C, BLOCH MH, WILLIAMS K. Glutamate abnormalities in obsessive compulsive disorder: neurobiology, pathophysiology, and treatment. Pharmacology & Therapeutics. 2011; 132(3): 314-332. https://doi.org/10.1016/j.pharmthera.2011.09.006

3. VLCEK P, POLAK J, BRUNOVSKY M, HORACEK J. Role of Glutamatergic System in Obsessive-Compulsive Disorder with Possible Therapeutic Implications. Pharmacopsychiatry. 2018; 51(6): 229-242. https://doi.org/10.1055/s-0043-118665

4. PAYDARY K, AKAMALOO A, AHMADIPOUR A, PISHGAR F, EMAMZADEHFARD S, AKHONDZADEH S. N-acetylcysteine augmentation therapy for moderate-to-severe obsessive-compulsive disorder: randomized, double-blind, placebo-controlled trial. Journal of Clinical Pharmacy and Therapeutics. 2016; 41(2): 214-219. https://doi.org/10.1111/jcpt.12370

5. WebPlotDigitizer [Computer Program] (2020). Version 4.3 for Microsoft Windows. Pacifica, California, USA: Automeris LLC. https://automeris.io/WebPlotDigitizer.

6. AFSHAR H, ROOHAFZA H, MOHAMMAD-BEIGI H, HAGHIGHI M, JAHANGARD L, SHOKOUH P, SADEGHI M, HAFEZIAN H. N-Acetylcysteine Add-On Treatment in Refractory Obsessive-Compulsive Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial. Journal of Clinical Psychopharmacology. 2012; 32(6): 797-803. http://dx.doi.org/10.1097/JCP.0b013e318272677d

7. COSTA DLC, DINIZ JB, REQUENA G, JOAQUIM MA, PITTENGER C, BLOCH MH, MIGUEL EC, SHAVITT RG. Randomized, Double-Blind, Placebo-Controlled Trial of N-Acetylcysteine Augmentation for Treatment-Resistant Obsessive-Compulsive Disorder. Journal of Clinical Psychiatry. 2017; 78(7): e766-e773. https://doi.org/10.4088/JCP.16m11101

8. GHANIZADEH A, MOHAMMADI MR, BAHRAINI S, KESHAVARZI Z, FIROOZABADI A, ALAVI SHOSHTARI A. Efficacy of N-Acetylcysteine Augmentation on Obsessive Compulsive Disorder: A Multicenter Randomized Double Blind Placebo Controlled Clinical Trial. Iranian Journal of Psychiatry. 2017; 12(2): 134-141. https://www.ncbi.nlm.nih.gov/pubmed/28659986

9. LI F, WELLING MC, JOHNSON JA, COUGHLIN C, MULQUEEN J, JAKUBOVSKI E, COURY S, LANDEROS-WEISENBERGER A, BLOCH MH. N-Acetylcysteine for Pediatric Obsessive-Compulsive Disorder: A Small Pilot Study. Journal of Child and Adolescent Psychopharmacology. 2020; 30(1): 32-37. https://doi.org/10.1089/cap.2019.0041

10. SARRIS J, OLIVER G, CAMFIELD DA, DEAN OM, DOWLING N, SMITH DJ, MURPHY J, MENON R, BERK M, BLAIR-WEST S, NG CH. N-Acetyl Cysteine (NAC) in the Treatment of Obsessive-Compulsive Disorder: A 16-Week, Double-Blind, Randomised, Placebo-Controlled Study. CNS Drugs. 2015; 29(9): 801-809. https://doi.org/10.1007/s40263-015-0272-9

---

Last Updated on 22 October 2023 by David Christmas