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02. Exploring the Evidence of N-Acetyl-Cysteine (NAC) for Mood Disorders

Published on November 1, 2023 Certification expiration date: November 1, 2026

David Mischoulon, M.D., Ph.D.

Professor of Psychiatry - Harvard Medical School

Key Points

NAC promotes the synthesis of glutathione-stimulating hormone (GSH).
GSH reduces oxidative stress and protects brain cells.
NAC has potential applications in unipolar depression and bipolar disorder.
NAC may have benefits in children.

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Slides and Transcript

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The first agent that we will talk about today is N-acetylcysteine or NAC which is often used for the treatment of mood disorders.

Exploring the Evidence of N-Acetyl-Cysteine (NAC) for Mood Disorders Slide 1 of 12

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NAC is a natural compound that functions primarily by increasing the synthesis of glutathione in the body and this helps to reduce oxidative stress in the mitochondrial electron transport chain.

References:

Bradlow, R. C., Berk, M., Kalivas, P. W., Back, S. E., & Kanaan, R. A. (2022). The potential of N-acetyl-L-Cysteine (NAC) in the treatment of psychiatric disorders. CNS Drugs, 36(5), 451-482.

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Slide 3 of 12

In addition to reducing oxidative stress, NAC and glutathione may help to protect brain cells from damage that may occur through oxidation or other pathological processes. It has been suggested that some of its mood stabilizing effects may be similar to those that you see with lithium or valproic acid which are common mood stabilizers.

References:

Bradlow, R. C., Berk, M., Kalivas, P. W., Back, S. E., & Kanaan, R. A. (2022). The potential of N-acetyl-L-Cysteine (NAC) in the treatment of psychiatric disorders. CNS Drugs, 36(5), 451-482.

Exploring the Evidence of N-Acetyl-Cysteine (NAC) for Mood Disorders Slide 3 of 12

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Now, let’s discuss some of the clinical trial-based evidence for NAC in various psychiatric conditions. In major depressive disorder, there are currently two published randomized clinical trials. The first one by Berk and colleagues came out in 2014. They recruited 269 patients with depression, treated them for 12 weeks at a dose of 2000 mg a day and they found significant clinical improvement in various scales measuring depression.

References:

Bradlow, R. C., Berk, M., Kalivas, P. W., Back, S. E., & Kanaan, R. A. (2022). The potential of N-acetyl-L-Cysteine (NAC) in the treatment of psychiatric disorders. CNS Drugs, 36(5), 451-482.

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Slide 5 of 12

The second study was by Porcu and colleagues published in 2018. This study was smaller with only 67 patients. They followed the patients for 12 weeks at a dose of 1800 mg a day. In this study, they found a significant improvement in the CGI, Clinical Global Improvement Scale, only in individuals who had C-reactive protein levels higher than 3 as opposed to those who had levels of less than 3.

References:

Porcu, M., Urbano, M. R., Verri, W. A., Barbosa, D. S., Baracat, M., Vargas, H. O., Machado, R. C., Pescim, R. R., & Nunes, S. O. (2018). Effects of adjunctive N-acetylcysteine on depressive symptoms: Modulation by baseline high-sensitivity C-reactive protein. Psychiatry Research, 263, 268-274.

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C-reactive protein is a measure of inflammatory activity and this suggests that NAC might be more effective in people with higher inflammatory activity but this remains to be worked out in more detail.

References:

Bradlow, R. C., Berk, M., Kalivas, P. W., Back, S. E., & Kanaan, R. A. (2022). The potential of N-acetyl-L-Cysteine (NAC) in the treatment of psychiatric disorders. CNS Drugs, 36(5), 451-482.

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Slide 7 of 12

Next, what do we know about NAC as a treatment for bipolar disorder? There are seven randomized clinical trials published. They typically included patients with bipolar disorder type 1, the manic type and bipolar disorder type 2, the hypomanic type. Collectively, these studies followed patients for anywhere from 12 to 24 weeks and the samples varied from relatively small at 17 to as large as 181 patients and doses ran between 1000 to 3000 mg a day.

References:

Bradlow, R. C., Berk, M., Kalivas, P. W., Back, S. E., & Kanaan, R. A. (2022). The potential of N-acetyl-L-Cysteine (NAC) in the treatment of psychiatric disorders. CNS Drugs, 36(5), 451-482.

Exploring the Evidence of N-Acetyl-Cysteine (NAC) for Mood Disorders Slide 7 of 12

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The results overall were mixed and again the patients with higher levels of C-reactive protein seemed to do better. Again, the degree of inflammation may impact on the efficacy of this treatment both for unipolar and bipolar disorder.

References:

Bradlow, R. C., Berk, M., Kalivas, P. W., Back, S. E., & Kanaan, R. A. (2022). The potential of N-acetyl-L-Cysteine (NAC) in the treatment of psychiatric disorders. CNS Drugs, 36(5), 451-482.

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Slide 9 of 12

Next, what about evidence in children? There is a study by Wozniak and colleagues published in 2022 in which they tried NAC in children with bipolar disorder. The sample size was 24 so this was essentially a small pilot study. This was an open label trial, meaning that no placebo was used. And the children ages 5 to 17 with bipolar spectrum disorder were treated for 12 weeks. 53% of the patients completed the study and it was found that they had a significant reduction in various mood scales such as the Young Mania Rating Scale, the Hamilton Depression Scale, for example. And about 54% demonstrated an anti-manic response. So it seems that NAC can help to reduce mania. 62% experienced an anti-depressive response. So this suggests that NAC can work both to prevent mania and depression in children.

References:

Wozniak, J., DiSalvo, M., Farrell, A., Vaudreuil, C., Uchida, M., Ceranoglu, T. A., Joshi, G., Cook, E., Faraone, S. V., & Biederman, J. (2022). Findings from a pilot open-label trial of N-acetylcysteine for the treatment of pediatric mania and hypomania. BMC Psychiatry, 22(1).

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I’ll summarize with these key points. N-acetylcysteine is a natural agent that functions as a mitochondrial modulator by promoting the synthesis of glutathione stimulating hormone or GSH. The production of GSH reduces oxidative stress and protects brain cells.

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Slide 11 of 12

NAC has potential applications in mood disorders including unipolar depression and bipolar disorder and may have benefits in children.

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Next Section

03. Evidence for NAC in Other Psychiatric Disorders

Learning Objectives:

After completing this activity, the learner will be able to:

Evaluate the evidence-based applications and benefits of natural medication in psychiatric treatments.
Analyze the potential risks and side effects of using natural medication in psychiatric treatments.
Identify potential combinations of natural remedies and acquire strategies to optimize their use in psychiatric care.

Original Release Date: November 1, 2023

Review and Re-release Date: March 1, 2024

Expiration Date: November 1, 2026

Expert: David Mischoulon, M.D.

Medical Editor: Paz Badía, M.D.

Relevant Financial Disclosures:

David Mischoulon declares the following interests:

- Nordic Naturals: Received research support (medication and placebo for a study)

- heckel medizintechnik GmbH: Received research support (Whole Body Hyperthermia device for research study)

- MGH Clinical Trials Network and Institute (CTNI): Received salary support

All of the relevant financial relationships listed above have been mitigated by Medical Academy and the Psychopharmacology Institute.

None of the others faculty, planners, and reviewers for this educational activity have relevant financial relationships to disclose during the last 24 months with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

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