Can N-acetylcysteine (NAC) cause fatigue?

From the Guidelines

N-acetylcysteine (NAC) does not have a significant association with causing fatigue, as the majority of studies have reported it to be well tolerated with no difference in adverse events between NAC and placebo groups. The studies examined, including those by Hansen et al, Pela et al, and Zheng et al 1, focused on the efficacy of NAC in reducing exacerbations of COPD and did not specifically investigate fatigue as a side effect. However, they did report on the tolerability and adverse effects of NAC, with no significant difference in adverse events between the NAC and placebo groups.

Some key points to consider:

• The study by Zheng et al 1 was the largest to date, with 1,006 patients, and found that NAC was well tolerated with no difference in adverse events between the NAC and placebo groups.
• The incidence of adverse effects attributed to the study drug did not differ between the NAC and placebo groups in any of the studies examined 1.
• While fatigue may be a potential side effect of many medications and supplements, the current evidence does not suggest a significant association between NAC and fatigue 1.
• If fatigue is experienced while taking NAC, it may be related to individual factors or other medications, and consulting with a healthcare provider is recommended to determine the best course of action.

From the FDA Drug Label

ADVERSE REACTIONS Adverse effects have included stomatitis, nausea, vomiting, fever, rhinorrhea, drowsiness, clamminess, chest tightness, and bronchoconstriction. The FDA drug label does not answer the question.

From the Research

N-acetylcysteine (NAC) and Fatigue

• The relationship between N-acetylcysteine (NAC) and fatigue is complex and has been studied in various contexts, including exercise performance and disease management 2, 3, 4.
• A study on the effects of oral NAC on fatigue, critical power, and W' in exercising humans found that NAC increased time to fatigue at 80% of peak power output, but not at higher work rates 2.
• Another study on the performance and side effects of NAC supplementation found that the mean increase in performance was 0.29%, but the difference in the odds ratio of side effects on NAC compared with placebo was 1.11, suggesting a potential increase in side effects with higher doses of NAC 3.
• A randomized, double-blind, placebo-controlled trial on SLE patients found that NAC reduced disease activity, including fatigue, by blocking mammalian target of rapamycin in T cells 4.
• However, there is no direct evidence to suggest that NAC causes fatigue, and its effects on fatigue may depend on the context, dosage, and individual response 2, 3, 4.

Side Effects of NAC

• The side effects of NAC have been studied in various contexts, including exercise performance and disease management 5, 3, 4.
• A study on the effect of NAC on metabolic profile in metabolic syndrome patients found that NAC decreased HOMA-IR, hsCRP, and systolic BP, but increased HDL and nitrite levels 5.
• A systematic review of clinical trials on NAC in psychiatry and neurology found that NAC treatment appears to be safe and tolerable, but further well-designed, larger controlled trials are needed to confirm its efficacy and safety in specific disorders 6.
• The most common side effect of NAC reported in the studies is nausea, particularly at higher doses 3, 4.