Supplement evidence
N-Acetylcysteine (NAC)
The psychiatric trials, by condition, and where the pooled estimates land.
What Its Legal Status Actually Means
Read this before anything below it. Legal to sell is not the same fact as reviewed, verified, or approved.
No NAC product is approved for any psychiatric indication. NAC is an FDA-approved prescription drug for two things that have nothing to do with psychiatry: intravenous acetylcysteine (Acetadote) is approved to prevent or lessen liver injury after a potentially hepatotoxic acetaminophen ingestion, and inhaled/oral acetylcysteine solution is approved as a mucolytic for thick or inspissated airway secretions in conditions such as cystic fibrosis, bronchiectasis and chronic bronchopulmonary disease. Neither label mentions depression, OCD, trichotillomania or addiction. Because NAC was approved as a drug before it was marketed as a supplement, the FDA has concluded that NAC is legally excluded from the definition of a dietary supplement; in a final guidance issued in August 2022 the agency said it intends to exercise enforcement discretion — that is, not to act against otherwise-lawful NAC supplements — while it completes rulemaking or resolves the citizen petitions on the question. So the capsules on the shelf are sold under an explicit regulatory forbearance rather than under a settled legal category.
Quoted whole from the 2026-08-18 study harvest. Not summarized, not shortened.
What the Research Shows
5 records from the 2026-08-18 harvest, each checked against PubMed and Europe PMC on that date. How a study was designed, how many people were in it, and who paid for it are printed above what it found, because those three facts decide how much the finding is worth.
Study 1 · 2016
- Meta-analysis of randomized trials
- 574 participants
- Reputable journal
- Funding not established
moderate61/100Reasonable evidence with real limitations.
Read this first: Two of the five authors — Berk and Dean — are investigators on trials included in the pooled estimate, so this is not an independent synthesis of other people's work, and Berk's disclosures elsewhere in this literature record consultancy to Bioadvantex, a company commercialising NAC. The search ended in November 2014 and so predates the larger negative bipolar trial listed below. No funding statement was readable, so funding is UNKNOWN.
Of 38 studies examined, five double-blind placebo-controlled trials met inclusion, giving 574 participants (291 NAC, 283 placebo) followed for 12-24 weeks across mixed diagnoses — two bipolar, one major depression, one trichotillomania, one heavy smoking. NAC improved depressive symptoms with a standardised mean difference of 0.37 (95% CI 0.19 to 0.55, P<0.001) and improved global functioning, with no change in quality of life and only minor adverse events (OR 1.61, 95% CI 1.01 to 2.59). An SMD of 0.37 is a small-to-moderate effect drawn from five heterogeneous trials in five different populations.
How this record was checked
PubMed record 27137430 fetched via NCBI efetch 2026-08-18; title, all five authors, journal (J Clin Psychiatry 2016;77(4):e457-e466), year, DOI, the 38-studies-screened to 5-included selection, N=574 (291 NAC, 283 placebo), the 12-24 week follow-up range, SMD 0.37 (95% CI 0.19-0.55), and the adverse-event OR confirmed from the abstract. Europe PMC core record checked 2026-08-18: no PMC full text, no grant list, no funding statement, so funding is UNKNOWN and conflicts false. Berk's Bioadvantex consultancy was read directly in the competing-interests section of PMC6346513 on 2026-08-18.
Study 2 · 2014
- Randomized trial
- 252 participants
- Reputable journal
- Funding not established
- Preregistered
moderate60/100Reasonable evidence with real limitations.
Read this first: The positive signals appeared at week 16, after treatment had been discontinued at week 12, and in secondary outcomes and a severity subgroup — the classic shape of findings that do not replicate. The trial is from the research group that has published most of the positive NAC literature, and its senior author's disclosures elsewhere record consultancy to Bioadvantex, a NAC commercialiser, hence independent false. No funding or disclosure statement was readable for this paper.
252 people in a current episode of major depression added NAC or placebo to their usual treatment for 12 weeks. The trial missed its primary endpoint: the group-by-visit interaction on the Montgomery-Asberg Depression Rating Scale was not significant (P=.067) and the groups did not separate at week 12 (P=.265). Some secondary measures favoured NAC — functioning at week 12, and response, remission and symptom scores at week 16, four weeks after treatment stopped — and NAC caused more gastrointestinal and musculoskeletal adverse events. The authors' own summary is that, being negative at the week 12 endpoint, the study "provides only limited support" for NAC in depression.
How this record was checked
PubMed record 25004186 fetched via NCBI efetch 2026-08-18; title, authors, journal (J Clin Psychiatry 2014;75(6):628-636), year, DOI, N=252, the 12-week treatment with follow-up to 16 weeks, the non-significant primary interaction (P=.067) and week-12 comparison (P=.265), and the registration ACTRN12607000134426 (hence preregistered true) confirmed from the abstract. Europe PMC core record fetched 2026-08-18 lists only a bare "Medical Research Council" grant entry with no funding statement and no PMC full text, so funding is recorded UNKNOWN and conflicts false.
Study 3 · 2019
- Randomized trial
- 181 participants
- Reputable journal
- Mixed funding
- Preregistered
- Declared conflicts of interest
moderate66/100Reasonable evidence with real limitations.
Read this first: A clean null on the primary outcome, with post-discontinuation secondary signals that the authors themselves flag as needing explanation. Study medications and placebos were supplied by commercial nutraceutical companies (Nutrition Care, BioCeuticals and Catalent, Australia) alongside public NHMRC and CRC funding, hence MIXED; the senior author's disclosed consultancy to Bioadvantex, a NAC commercialiser, is why independence is marked false. A published erratum (BMC Med 2019;17(1):35) applies.
181 people with bipolar disorder and current depressive symptoms were randomised for 16 weeks to NAC 2,000 mg/day, NAC plus a combination of other mitochondrial nutraceuticals, or placebo, added to usual treatment. Among the 148 with post-randomisation data there were no between-group differences on any clinical or functioning measure — the primary MADRS outcome included. Some measures favoured the combination arm at a week-20 visit after treatment had been discontinued. Gastrointestinal symptoms were significantly more common on NAC than placebo. The authors describe the results as "overall negative".
How this record was checked
PubMed record 30678686 fetched via NCBI efetch 2026-08-18; title, authors, journal (BMC Med 2019;17(1):18), year, DOI, N=181 randomised (59 NAC, 61 combination, 61 placebo) with 148 analysed, the 16-week design, the null primary outcome, and the registration ACTRN12612000830897 (hence preregistered true) confirmed from the abstract. Europe PMC core record fetched 2026-08-18 lists NHMRC project grant APP1026307 and the CRC for Mental Health. PMC full text PMC6346513 read 2026-08-18: the Funding section confirms those grants and states "Study medications and blinded placebos were supplied by Nutrition Care, Catalent and BioCeuticals, Australia" (hence MIXED), and the Competing interests section (hence conflicts true) records that MB "served as a consultant to ... Bioadvantex" among others.
Study 4 · 2009
- Randomized trial
- 50 participants
- Top-tier journal
- Funding not established
- Preregistered
moderate66/100Reasonable evidence with real limitations.
Read this first: One trial, 50 people, one site, and a very large effect — the combination that most often fails to replicate, and in this case did fail to replicate in children four years later. No funding or disclosure statement could be read (the journal page returned HTTP 403 on 2026-08-18), so funding is UNKNOWN, conflicts false, and independence left null.
50 adults with trichotillomania (45 women, 5 men, mean age 34) received NAC 1,200-2,400 mg/day or placebo for 12 weeks. NAC produced significantly greater reductions in hair-pulling on the Massachusetts General Hospital Hair Pulling Scale (P<.001) and the Psychiatric Institute Trichotillomania Scale (P=.001), with 56% "much or very much improved" versus 16% on placebo — a 40-percentage-point absolute difference. Benefit did not appear until about week 9. No adverse events were reported in the NAC group. This single 50-person trial is the origin of NAC's reputation for compulsive behaviours; read it together with the failed replication below.
How this record was checked
PubMed record 19581567 fetched via NCBI efetch 2026-08-18; title, all three authors, journal (Arch Gen Psychiatry 2009;66(7):756-763), year, DOI, N=50 (45 women, 5 men, mean age 34.3), the 1,200-2,400 mg/day dose range, the 12-week design, the 56% versus 16% much-improved rates, and the registration NCT00354770 (hence preregistered true) confirmed from the abstract. Europe PMC core record checked 2026-08-18: no grant list, no funding statement, no PMC full text; a direct fetch of the JAMA Network article page on 2026-08-18 returned HTTP 403, so funding remains UNKNOWN.
Study 5 · 2013
- Randomized trial
- 39 participants
- Reputable journal
- Independently funded
- Preregistered
- Declared conflicts of interest
strong84/100Well-supported by good-quality research.
Read this first: A 39-person trial has limited power, and the authors discuss whether the frequent study visits and psychoeducation inflated the placebo response — so this is a failed replication rather than proof that NAC does nothing in children. It is included precisely because the positive adult trial is usually cited without it.
39 children and adolescents aged 8-17 with trichotillomania were randomised to NAC or matching placebo for 12 weeks. There was no significant difference on any primary or secondary outcome: 25% of the NAC group were judged responders versus 21% on placebo, and both groups improved with time regardless of assignment. The authors, who included the first author of the positive adult trial, state plainly that the finding "stands in contrast" to that trial and conclude that children with trichotillomania should be referred for behavioural therapy before any medication is started.
How this record was checked
PubMed record 23452680 fetched via NCBI efetch 2026-08-18; title, all five authors, journal (J Am Acad Child Adolesc Psychiatry 2013;52(3):231-240), year, DOI, N=39, ages 8-17, the 12-week design, and the 25% versus 21% responder rates confirmed from the abstract. PMC full text PMC3745012 read 2026-08-18: funded by NIMH and NCRR grants (including K08MH081190, K23 MH091240, R25 MH077823, T32MH018268-26, UL1RR024139) with additional funding from the Trichotillomania Learning Center, a patient advocacy organisation and not a NAC manufacturer, hence funding INDEPENDENT; the page carries a full per-author Disclosure section (hence conflicts true) and the registration NCT00993265 (hence preregistered true).
The Risks
Nobody checks this purchase the way a prescription is checked. No prescriber reviews it against the rest of what you take, no pharmacist screens the interaction, and no regulator confirms the dose in the capsule before it is sold. That is why this section sits here at full length rather than as a footnote.
What the paragraph below covers:
- Stomach and gut
Oral NAC at the doses used in psychiatric trials — typically 1,200-2,400 mg/day, up to 2,000-3,000 mg/day — is generally benign, and this is one of the few supplements where "well tolerated" is backed by placebo-controlled adverse-event data. The consistent finding is more gastrointestinal complaints than placebo: nausea, heartburn, diarrhoea, abdominal discomfort. In a 252-person depression trial the NAC group had significantly more gastrointestinal and musculoskeletal adverse events than placebo, and in a 181-person bipolar depression trial gastrointestinal symptoms were significantly more common on NAC. NAC smells and tastes strongly of sulphur, which is the most common reason people stop. The serious anaphylactoid reactions associated with NAC occur with the intravenous antidote given rapidly in hospital, not with oral capsules. The most important caveat is not toxicity: in the one condition where NAC produced a large positive trial — trichotillomania in adults — the replication in children failed outright, and those investigators concluded that children should be referred for habit-reversal behavioural therapy before any drug is tried.
What Is Not Known
The boundaries of the section above, in the harvest’s own words. What it excluded, why, and where it looked and found nothing. An absence of evidence is not evidence of absence, and it is not evidence of benefit either.
What Was Left Out, and Why
Quoted from the harvest, where these notes sat above the study list rather than after it. Where a note says “below” it means the studies in the section above.
- Deepmala et al. 2015, "Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review" (Neurosci Biobehav Rev, PMID 25957927), was fetched and verified but is excluded as a study record: it is a broad favourable narrative-style synthesis across dozens of unrelated conditions, one of its co-authors is affiliated with BioAdvantex Pharma Inc. (a company commercialising NAC), and its condition-level claims are better served here by the trial-level evidence, including the nulls. Flagged so the reader knows the most-cited pro-NAC review exists and who is on it.
- Rosenblat 2016 (Bipolar Disord, PMID 26990051) excluded: it pools NAC with NSAIDs, omega-3 and pioglitazone as "anti-inflammatory agents", so its effect size is not a NAC result (the NAC contribution was 76 participants).
- Individual NAC trials in schizophrenia, autism, cocaine and cannabis use disorder are out of scope for a mental-health-supplement record focused on mood and compulsive behaviour.
The Retraction Check
PubMed efetch records for all five PMIDs inspected 2026-08-18 for "Retraction in" flags; none present. Berk 2019 (30678686) carries an "Erratum in" (BMC Med 2019;17(1):35), which is a correction, not a retraction.
Questions for a Prescriber or Pharmacist
This page does not tell anyone to take N-Acetylcysteine (NAC) or to avoid it. It is not able to: it does not know what else you take, what you have tried, or what you are treating. These are the questions each study above raises, written to be asked out loud.
- The NAC evidence pools people with bipolar disorder, depression, hair-pulling and smoking into one number — is there any trial in a population that actually looks like me?
- The largest NAC trial in depression missed its main endpoint — before I try it, what would we agree counts as it working, and when would we stop?
- NAC did not beat placebo for bipolar depression in a properly sized trial — is there anything about my situation that would make it worth trying anyway?
- For hair-pulling or skin-picking, how does NAC compare with habit-reversal therapy, which has evidence in both adults and children?
- NAC worked in adults with hair-pulling but not in children — if this is for my child, what does the evidence actually support us doing first?
And the one to ask at the counter, whatever the answers above turn out to be: given everything I am already taking, what would you want to know about N-Acetylcysteine (NAC) before I put it in the same body?
Where This Page Comes From
Transcribed from the study-harvest-2026-08-18 record for nac, built into this page by scripts/supplement-ingest.mjs on 2026-09-07. Nothing here is fetched at page load, and nothing here was written by a model without a citation behind it.
| Source file | study-harvest/2026-08-18/nac.yaml |
|---|---|
| Source repo | REPTechnologies/avalo-backend |
| SHA-256 | 1aa63a6193f04e5e855704bff34e7dd2a2b8795e95a17d4fec007549881f7a58 |
| Also searched as | N-acetylcysteine, NAC, N-acetyl-L-cysteine, acetylcysteine, Acetadote, Mucomyst |
The Other Substances
- 5-HTP
- Ashwagandha
- Cannabidiol (CBD)
- Cannabis and THC
- Creatine
- Kratom
- L-Theanine
- Magnesium
- Melatonin
- Methylene Blue
- Microdosing
- Omega-3
- Phenibut
- SAMe
- St John’s Wort
- Valerian
Do any supplements actually work? asks the question across all of them. The full library has the medication records, the funding investigations, and the glossary.