What are N-Acetylcysteine (NAC) supplements?

What is N-Acetylcysteine (NAC)?

N-Acetylcysteine (NAC) is a medication and dietary supplement that serves as a precursor to the amino acid L-cysteine and functions primarily as an antioxidant by increasing glutathione production in the body. 1

Chemical Structure and Formulation

• NAC is the N-acetyl derivative of the naturally-occurring amino acid L-cysteine, with the molecular formula C5H9NO3S and a molecular weight of 163.2 1
• It appears as a white crystalline powder and is available as a sterile solution containing 20% (200 mg/mL) acetylcysteine 1
• The compound is naturally found in onions and has been used as a pharmaceutical agent since the 1960s 2

Primary Mechanisms of Action

• Antioxidant Function: NAC acts as an excellent source of sulfhydryl (SH) groups and is converted into metabolites that stimulate glutathione (GSH) synthesis, the body's most crucial biothiol responsible for cellular redox balance 3, 4
• Direct Free Radical Scavenging: Beyond increasing glutathione, NAC directly scavenges free radicals, especially oxygen radicals 3, 5
• Anti-inflammatory Effects: NAC reduces levels of tumor necrosis factor-alpha (TNF-α) and interleukins (IL-6 and IL-1β) by suppressing nuclear factor kappa B (NF-κB) activity 4
• Glutamatergic Modulation: Through cysteine's role as a modulator of the glutamatergic system, NAC influences the reward-reinforcement pathway 6

FDA-Approved Medical Uses

• Acetaminophen Overdose Antidote: NAC is FDA-approved and listed on the WHO Model List of Essential Medicines as the primary antidote to prevent or lessen hepatic injury following acetaminophen overdose 1, 2

• Treatment must be initiated as soon as possible after overdose and within 24 hours of ingestion 1

• The American College of Emergency Physicians recommends NAC for known or suspected acute acetaminophen overdose with serum levels in the risk zones on the Rumack-Matthew nomogram 7

• Mucolytic Agent: NAC is approved for inhalation as a mucolytic agent in various respiratory illnesses, where it softens tenacious mucous secretions 1, 5

Established Clinical Applications Beyond FDA Approval

• Acetaminophen-Associated Acute Liver Failure: The American Gastroenterological Association strongly recommends NAC for all patients with acetaminophen-associated acute liver failure, demonstrating mortality reduction (relative risk 0.65,95% CI 0.43-0.99) 8, 9

• NAC reduces mortality in hepatic failure from 80% to 52% when administered regardless of time since ingestion 8, 7

• Non-Acetaminophen Acute Liver Failure: NAC improves transplant-free survival (41% versus 30%, OR 1.61,95% CI 1.11-2.34) and overall survival (76% versus 59%, OR 2.30,95% CI 1.54-3.45) in non-acetaminophen acute liver failure 9, 10

• The American Gastroenterological Association recommends considering NAC in non-acetaminophen acute liver failure, especially when the cause is indeterminate 8, 9

Dosing Regimens

• Oral Administration: 140 mg/kg loading dose followed by 70 mg/kg every 4 hours for 17 doses (18 total doses) 7, 9
• Intravenous Administration: 150 mg/kg loading dose over 15 minutes, followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours 7, 9

Dietary Supplement and Investigational Uses

• NAC is widely used in food supplements and cosmetics, with projections showing continued market growth 2
• Investigational uses include conditions characterized by oxidative stress: HIV infection, cancer, heart disease, cigarette smoking, and heavy metal poisoning 3
• Psychiatric applications are being explored for disorders related to oxidative stress (schizophrenia, bipolar disorder) and impulsive/compulsive symptoms (trichotillomania, pathological gambling, substance misuse) 6

Safety Profile

• NAC has a well-established safety profile with uncommon toxicity dependent on route of administration and dosage 4
• The overall incidence of adverse effects is low: nausea/vomiting <5%, skin rash <5%, and bronchospasm 1-2% 9, 10
• It is considered a safe substance, though clinical trial results for various applications remain controversial or incomplete 2

Common Pitfalls

• Despite NAC's abundant use and therapeutic potential in experimental studies, its effectiveness in clinical trials for many pathological conditions beyond acetaminophen overdose remains limited and requires further investigation 4
• The dosages, pharmacological strategies (monotherapy versus augmentation), and long-term risks for psychiatric and other non-approved uses are not fully established 6