Evidence Trace, complete trial record
In plain terms
In plain terms: NAC (N-Acetyl Cysteine) shows early signals in human research but the evidence is limited -- small trials, surrogate endpoints, or not yet independently replicated. It is an emerging area, not yet a proven one.
NAC (N-Acetyl Cysteine)
C
Limited: small, mixed or unreplicated trials
The endpoint this grade is based on: Validated scale scored by a clinician blinded to treatment, Symptoms in schizophrenia as an adjunct to antipsychotics, about 2 g/day (C, mixed); COPD exacerbation rate at 600 mg twice daily in moderate to severe disease (C, mixed and dose-dependent); ovulation in clomiphene-resistant polycystic ovary syndrome as an adjuvant, on one trial (C). Glutathione precursor, antioxidant defense, liver protection and insulin sensitivity in healthy adults have no randomized trial with a clinical or functional endpoint on this record and carry no letter.
The evidence as the record states it
Schizophrenia. Berk et al. (Biol Psychiatry, 2008; PMID 18436195): 140 patients with chronic schizophrenia, 1 g twice daily for 24 weeks added to antipsychotics; PANSS total, negative and general scores improved more than placebo. Yolland et al. (Aust N Z J Psychiatry, 2020; PMID 31826654): meta-analysis of 7 randomized trials, 440 patients; PANSS negative and total scores improved only after 24 weeks of treatment, and the working memory domain of cognition improved. Zhang et al. (Hum Psychopharmacol, 2024; PMID 37712506): meta-analysis of 8 trials, 594 patients; no difference from placebo on any PANSS score at or beyond 24 weeks. Neill et al. (Schizophr Bull, 2022; PMID 35857752): 84 clozapine-resistant patients, 2 g/day for a year, publicly funded; no effect on negative symptoms, cognition or quality of life. Conus et al. (Schizophr Bull, 2018; PMID 29462456): 63 early-psychosis patients, 2.7 g/day for 6 months; no change in symptoms, processing speed improved. COPD exacerbations. Zheng et al. (Lancet Respir Med, 2014; PMID 24621680), PANTHEON: 1,006 Chinese patients with moderate to severe COPD, 600 mg twice daily for a year; exacerbations 1.16 against 1.49 per patient-year (risk ratio 0.78); the full report states funding by the maker of the studied product. Tse et al. (Chest, 2013; PMID 23348146), HIACE: 120 patients, 600 mg twice daily for a year; exacerbations 0.96 against 1.71 per year. Decramer et al. (Lancet, 2005; PMID 15866309), BRONCUS: 523 patients, 600 mg once daily for 3 years; no effect on lung function decline or exacerbations. Zhou et al. (Nat Commun, 2024; PMID 39349461): 968 patients with mild to moderate COPD, 600 mg twice daily for 2 years, no commercial funding; exacerbation rate not significantly lower (0.65 against 0.72 per patient-year, relative risk 0.90, 95% CI 0.80 to 1.02) and lung function unchanged. Polycystic ovary syndrome. Rizk et al. (Fertil Steril, 2005; PMID 15705376): 150 women with clomiphene-resistant PCOS, 1.2 g/day added to clomiphene; ovulation 49.3 against 1.3 percent and pregnancy 21.3 against 0 percent. Combination. Kumar et al. (J Gerontol A Biol Sci Med Sci, 2023; PMID 35975308) studied GlyNAC, the glycine plus N-acetylcysteine combination, in 24 older adults; it cannot carry a grade for NAC alone and is graded under its own entry. Grade C: mixed randomized evidence in each graded use.
PMID 31826654 PMID 35975308 PMID 37712506 PMID 35857752 PMID 29462456 PMID 18436195 PMID 24621680 PMID 23348146 PMID 15866309 PMID 39349461 PMID 15705376
Evidence by specific use
Symptoms in schizophrenia, as an adjunct to antipsychotic treatment
Grade C
Mixed. The original 140-patient trial found PANSS scores improved over 24 weeks (Berk et al., 2008; PMID 18436195), and a 7-trial meta-analysis found negative and total symptoms improved only after 24 weeks (Yolland et al., 2020; PMID 31826654). A later 8-trial meta-analysis found no PANSS difference at any time point (Zhang et al., 2024; PMID 37712506), the one-year trial in clozapine-resistant patients was null (Neill et al., 2022; PMID 35857752), and the early-psychosis trial was null on symptoms with processing speed improved (Conus et al., 2018; PMID 29462456). PANSS is a clinician-rated scale in double-blind trials. Mixed randomized evidence is C.
PMID 18436195 PMID 31826654 PMID 37712506 PMID 35857752 PMID 29462456
COPD exacerbation rate at 600 mg twice daily in moderate to severe COPD
Grade C
Mixed and dose-dependent. Two Chinese trials at 600 mg twice daily reduced exacerbations: PANTHEON, 1,006 patients, risk ratio 0.78 (Zheng et al., 2014; PMID 24621680), whose full report states funding by the maker of the studied product, and HIACE, 120 patients (Tse et al., 2013; PMID 23348146). Two trials were null: BRONCUS at 600 mg once daily over 3 years (Decramer et al., 2005; PMID 15866309) and a 968-patient non-commercial trial at 600 mg twice daily in mild to moderate COPD, relative risk 0.90 with an interval crossing 1 (Zhou et al., 2024; PMID 39349461). Exacerbations are clinical events. Positive trials in moderate to severe disease against null trials at a lower dose and in milder disease: mixed, C. Re-adjudicated by the editor in October 2026 and kept at C. Within the use as written, 600 mg twice daily in moderate to severe disease, PANTHEON is positive on its primary endpoint, but HIACE found fewer exacerbations as a secondary endpoint in 120 patients, with a manufacturer's employee among its authors. The one trial at this dose with no commercial funding (Zhou et al., 2024; PMID 39349461) came from the PANTHEON group itself and was null in patients with lung function of 50 percent predicted and above, which overlaps the moderate band where PANTHEON found its effect strongest.
PMID 24621680 PMID 23348146 PMID 15866309 PMID 39349461
Ovulation and pregnancy in clomiphene-resistant polycystic ovary syndrome, NAC added to clomiphene
Grade C
Rizk et al. (Fertil Steril, 2005; PMID 15705376): double-blind placebo-controlled trial, 150 women; ovulation 49.3 against 1.3 percent and pregnancy 21.3 against 0 percent with NAC added to clomiphene. The one trial this record cites for the use; later trials and pooled analyses of NAC in PCOS were not reviewed in this pass, so the row is graded on the single cited trial, C.
PMID 15705376
Why Grade C and not Grade B
Grade C reflects early or limited human evidence -- small trials, surrogate endpoints, or preliminary findings not yet independently replicated. The evidence points in a promising direction but does not yet meet the standard for Grade B. A single well-powered, independently replicated trial with a meaningful endpoint would move this to Grade B or higher.
What would move this grade
A well-powered randomized trial with an objective, clinically meaningful primary endpoint and at least one independent replication would support Grade B or higher.
How to track whether this is working
For the graded uses, the measure the trials used: the PANSS or a clinician symptom scale over 24 weeks in schizophrenia; exacerbation count over a year in COPD. Glutathione levels, liver enzymes and inflammatory markers are mechanism readouts, not graded endpoints.