Overview
Glutathione (GSH) is the most abundant endogenous antioxidant in the body, playing a critical role in neutralizing reactive oxygen species (ROS), maintaining cellular redox balance, and supporting immune function [2][1]. It is synthesized intracellularly from three amino acids—cysteine, glycine, and glutamate—and is particularly concentrated in the liver, lungs, and brain. GSH participates in detoxification, mitochondrial integrity, immune regulation, and post-translational modification of proteins via glutathionylation, influencing processes such as apoptosis, inflammation, and neural signaling [1][7]. Depletion of GSH is associated with oxidative stress-related conditions including liver disease, cystic fibrosis, and psychiatric disorders [7][4]. While oral GSH supplementation increases blood GSH levels in healthy adults [2], its bioavailability is limited by intestinal degradation; thus, precursors like N-acetylcysteine (NAC) may be more effective for boosting intracellular GSH [6]. Notably, in critically ill patients with COVID-19, intravenous NAC improved oxygenation, likely through enhancing GSH-dependent antioxidant defenses [6]. However, inhaled GSH did not improve lung function in cystic fibrosis patients over 6 months [3], and GSH's role in cancer is complex, with evidence suggesting it supports tumor initiation but may become redundant in advanced stages [5].
Dosage Guide
Therapeutic Doses
For treatment of specific conditions
Special Forms
Alternative forms for specific needs
Improved oral bioavailability compared to standard oral glutathione
Precursor to cysteine; more effective than oral GSH for increasing intracellular glutathione
Clinical Notes
- Oral glutathione has limited bioavailability due to degradation by γ-glutamyltransferase in the gut.
- NAC is often preferred over oral GSH for boosting intracellular glutathione, especially in liver disease and respiratory conditions.
- High-dose antioxidant supplementation, including glutathione, may interfere with cancer therapies; caution in active malignancy [5].
- IV NAC is generally safe but can cause anaphylactoid reactions in rare cases; monitoring recommended.
- Inhaled glutathione is not recommended for cystic fibrosis due to lack of efficacy in clinical trials.
Research
Glutathionylation is a key post-translational regulatory mechanism affecting apoptosis, immune function, and metabolic processes.
Oral glutathione at 250 or 1,000 mg/day significantly increased blood glutathione levels in healthy adults over 6 months.
Inhaled glutathione (646 mg twice daily) did not improve FEV1 in cystic fibrosis patients over 6 months.
Low brain glutathione is linked to stress-related psychiatric disorders; enhancing GSH may have therapeutic potential.
Glutathione synthesis is required for cancer initiation, but becomes dispensable in later stages due to compensatory pathways.
IV N-acetylcysteine improved oxygenation in critically ill COVID-19 patients, likely via glutathione synthesis.
Glutathione deficiency is a hallmark of alcoholic and non-alcoholic liver diseases; restoration may support liver function.
