What is the safe dose of glutathione (GSH) for oral and intravenous supplementation?

Safe Dosing of Glutathione

For oral glutathione supplementation, doses of 250-500 mg/day have been studied and appear safe for up to 12 weeks, though systemic bioavailability is negligible; for intravenous administration, N-acetylcysteine (a glutathione precursor) at 20-50 mg/kg/day is the evidence-based alternative recommended in clinical guidelines. 1

Oral Glutathione Dosing

Established Oral Doses

• 250 mg/day of reduced glutathione (GSH) or oxidized glutathione (GSSG) has been studied for 12 weeks in healthy subjects with good tolerability 2
• 500 mg/day (in two divided doses) has been evaluated for 4 weeks in clinical trials without serious adverse effects 3
• 300 mg/day has been studied for 4 months in patients with nonalcoholic fatty liver disease with acceptable safety 4
• 500 mg L-Cystine combined with 250 mg L-Glutathione daily for 12 weeks demonstrated safety in a controlled trial 5

Critical Limitation of Oral Administration

• Oral glutathione has negligible systemic bioavailability due to hydrolysis by intestinal and hepatic gamma-glutamyltransferase 6
• A single 3-gram oral dose (0.15 mmol/kg) failed to increase plasma glutathione, cysteine, or glutamate concentrations in healthy volunteers 6
• This means oral glutathione is not effective for raising circulating glutathione levels despite being safe at studied doses 6

Intravenous/Parenteral Administration

N-Acetylcysteine as Glutathione Precursor

• 20-50 mg/kg/day of N-acetylcysteine (NAC) is the guideline-recommended dose for increasing blood glutathione levels in pediatric parenteral nutrition 1, 7
• NAC is preferred over direct glutathione administration because it serves as a precursor that cells can use to synthesize glutathione 7

Glutamine (Not Glutathione) Parenteral Dosing

Important distinction: Guidelines address glutamine (an amino acid precursor to glutathione), not glutathione itself:

• 0.2-0.4 g/kg/day of L-glutamine (or 0.3-0.6 g/kg/day alanyl-glutamine dipeptide) for ICU patients requiring parenteral nutrition 7
• 0.35-0.6 g/kg/day for surgical patients or hematopoietic stem cell transplant patients 8

Critical Safety Warnings for Parenteral Use

• High-dose glutamine is contraindicated in critically ill patients with multi-organ failure due to increased mortality risk 8
• Avoid in acute kidney injury or chronic kidney disease with kidney failure 8
• No standardized pharmaceutical-grade glutathione formulations exist for subcutaneous use 1
• Subcutaneous administration carries unknown risks including injection site reactions, tissue irritation, abscess formation, and unpredictable absorption 1

Route-Specific Recommendations

When Oral Supplementation is Considered

• For cosmetic skin lightening purposes: 250-500 mg/day for up to 12 weeks appears safe, though efficacy is modest 2, 3
• Recognize that oral glutathione will not meaningfully increase systemic glutathione levels 6

When Parenteral Supplementation is Needed

• Use N-acetylcysteine 20-50 mg/kg/day rather than direct glutathione administration 1
• Reserve glutamine supplementation (0.35-0.6 g/kg/day) for specific indications: HSCT patients, surgical patients on exclusive parenteral nutrition 8
• Never use subcutaneous route due to lack of safety data and appropriate formulations 1

Common Pitfalls to Avoid

• Do not confuse glutathione with glutamine—they are different compounds with different indications 7, 8
• Do not expect oral glutathione to raise systemic levels—it is extensively metabolized before absorption 6
• Do not use glutathione for taxane-induced peripheral neuropathy—a large trial of 185 patients showed no benefit 1
• Do not recommend glutathione therapy for cystic fibrosis patients—no supporting data exists 1, 8
• Avoid high-dose parenteral glutamine in multi-organ failure—associated with increased mortality 8