Glutathione
L-Glutathione, reduced (GSH)
Endogenous thiol tripeptide (glutamate-cysteine-glycine) and the principal intracellular antioxidant, also the conjugation substrate that phase II detoxification runs on. It is used in three channels whose evidence bases are very different. Oral and liposomal capsules have real randomized data, and it is mixed: Richie 2015 raised body stores over 6 months, Allen 2011 found no change in oxidative stress markers over 4 weeks. Clinic intravenous push has one randomized human trial, in Parkinson's disease, where it was well tolerated but produced no significant difference from placebo (Hauser 2009). Subcutaneous and intramuscular self-injection, which is what most operators actually run, has no controlled trial at any dose. Most global consumer demand is cosmetic: glutathione is the dominant skin-lightening agent in parts of Asia, and the injectable form is the one regulators have acted on. Sonthalia 2016 records that adverse effects from intravenous glutathione led the Philippine FDA to issue a public warning against its use for skin lightening.
At a glance
- Half-life
- ~14 min Plasma half-life of exogenous glutathione is about 14 minutes (Aebi 1991, 10 healthy volunteers, 2 g per square meter intravenously). Volume of distribution was 176 mL/kg, close to extracellular water, which is consistent with a molecule that stays outside cells. The functional effect outlasts the plasma curve because what persists is the cysteine that was delivered, not the tripeptide.
- Routes
- SubQ · IM · Oral · IV
- Vial sizes
- 200 mg · 600 mg · 1200 mg · 2000 mg
- Evidence base
- 6 studies 5 human · 1 review
Mechanism
Glutathione is the reducing substrate for glutathione peroxidase, which neutralizes peroxides, and for glutathione S-transferase, which conjugates electrophiles and xenobiotics for excretion. It regenerates oxidized vitamins C and E, and the GSH to GSSG ratio is the standard readout of cellular redox state. The antimelanogenic effect runs through direct and indirect tyrosinase inhibition plus a shift from eumelanin to pheomelanin synthesis, which is why it lightens skin. Delivery is the whole argument. Oral glutathione meets gamma-glutamyl transpeptidase in gut and liver, and for years was assumed to be fully hydrolyzed before absorption; Richie 2015 disproved the strong version of that claim. Parenteral glutathione bypasses gut hydrolysis but is cleared from plasma in minutes (Aebi 1991 measured a 14 minute half-life), and even then cells do not import the intact tripeptide: the infusion works by delivering cysteine equivalents, and intracellular glutathione is resynthesized from them.
Dosing
Any amounts shown here are reported from published studies only. 5 of 6 catalogued studies involved human subjects. COMPOUND does not publish its own dosing guidance.
Where a study reports an amount, it appears in that study's entry below, attributed to the source.
Published evidence
-
Human RCT 2015
Randomized controlled trial of oral glutathione supplementation on body stores of glutathione
n=54 non-smoking adults, 6-month double-blind placebo-controlled trial of 250 or 1000 mg/day oral GSH. At 6 months the high-dose arm raised glutathione 30-35% in erythrocytes, plasma and lymphocytes and 260% in buccal cells; the low-dose arm raised blood and erythrocyte levels 17% and 29%. Natural killer cytotoxicity more than doubled versus placebo at 3 months. Levels returned to baseline after a 1-month washout. First demonstration that oral glutathione raises body stores.
-
Human RCT 2011
Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers
n=40 healthy adults, randomized double-blind placebo-controlled, 500 mg oral GSH twice daily for 4 weeks. No change in urinary F2-isoprostanes or 8-OHdG, and no change in erythrocyte reduced, oxidized or ratio glutathione measures. A clean negative result at 4 weeks; the contrast with Richie 2015 is duration rather than contradiction.
-
Human RCT 2009
Randomized, double-blind, pilot evaluation of intravenous glutathione in Parkinson's disease
n=21 Parkinson's patients randomized to 1400 mg intravenous glutathione or placebo three times a week for 4 weeks. Well tolerated with no withdrawals for adverse events and adverse events similar between groups. No significant UPDRS difference: ADL plus motor scores improved 2.8 units more on glutathione (p=0.32) then worsened 3.5 units more over the following 8 weeks (p=0.54). The only randomized human trial of intravenous glutathione.
-
Human pilot 2018
Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function
n=12 healthy adults, 1-month open pilot of liposomal GSH at 500 or 1000 mg/day. Glutathione rose within 1 week, peaking at 2 weeks at 40% in whole blood and 100% in PBMCs. Plasma 8-isoprostane fell 35%, natural killer cytotoxicity rose up to 400% and lymphocyte proliferation up to 60%. No difference between doses, though the sample was too small to resolve one. Industry-funded and uncontrolled.
-
Human pilot 1991
High-dose intravenous glutathione in man. Pharmacokinetics and effects on cyst(e)ine in plasma and urine
n=10 healthy volunteers, 2 g per square meter infused intravenously. Plasma total glutathione rose from 17.5 to 823 micromol/L, elimination half-life 14.1 plus or minus 9.2 min, volume of distribution 176 mL/kg. Plasma cysteine rose 13-fold while total cyst(e)ine fell, indicating cellular uptake of cysteine rather than of intact glutathione. Urinary glutathione excretion rose 300-fold. The reference human PK for parenteral glutathione.
-
Review 2016
Glutathione as a skin whitening agent: Facts, myths, evidence and controversies
Review of glutathione as a systemic skin-lightening agent. Three randomized controlled trials support the effect and safety of topical and oral glutathione. Intravenous glutathione injection is popular but has no evidence of efficacy, and adverse effects from it led the Philippine FDA to issue a public warning condemning its use for off-label indications such as skin lightening. Duration, longevity of effect and maintenance remain unanswered.
Reported side effects
- Sulfur odor and taste
- Very common Mild · A thiol smell on the breath, skin and urine is the normal signature of a sulfur-containing compound and is not a sign of contamination.
- Injection site reaction
- Common Mild · Stinging, redness and transient welts at subcutaneous sites. More pronounced with the larger volumes the higher-strength vials require.
- GI upset
- Occasional Mild · Bloating, loose stool and nausea on the oral route. Dose dependence has not been formally characterized for glutathione.
- Skin lightening
- Common Mild · The antimelanogenic effect is the point for cosmetic users and an unwanted effect for everyone else. Weschawalit 2017 measured a reduced melanin index in a 12-week randomized placebo-controlled trial of oral glutathione. Depigmentation can be patchy rather than uniform.
- Injectable form is unstudied and regulator-flagged
- Unknown Serious · No controlled trial has tested subcutaneous or intramuscular glutathione. Sonthalia 2016 reports that adverse effects from intravenous glutathione led the Philippine FDA to issue a public warning condemning its use for off-label indications such as skin lightening, and concludes there is no evidence supporting the efficacy of intravenous glutathione injections. Sterility of the product and of the technique is the dominant practical risk on this route.
Interactions
-
NAD+ Caution
Two unrelated mechanisms often infused together in the same clinic visit. There is no interaction data for the combination and no trial of either agent by that route.
Reconstitution and storage
Injectable glutathione ships either as a lyophilized powder or as a ready solution. A 600 mg lyophilized vial reconstituted with 3 mL bacteriostatic water gives 200 mg per mL, so 10 units on an insulin syringe holds 20 mg. Reconstituted glutathione oxidizes on contact with air faster than a peptide does; a solution that has gone cloudy or dark has oxidized to GSSG and is no longer the reduced form.
Lyophilized: refrigerate, protect from light. Reconstituted: 2-8C, use quickly, and keep the vial full rather than half empty since headspace oxygen drives oxidation. Oral capsules: room temperature, dry, sealed; liposomal preparations usually specify refrigeration after opening.