Glutathione
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Endogenous tripeptide (Glu-Cys-Gly) and master intracellular antioxidant; widely used in functional medicine via IV, oral, and liposomal delivery alongside peptide therapy protocols.
Quick Facts
| Property | Value |
|---|---|
| Also Known As | GSH, L-glutathione, gamma-glutamylcysteinylglycine, reduced glutathione |
| Category | Anti-Aging / Functional Medicine |
| Sequence | gamma-L-Glutamyl-L-cysteinyl-glycine (tripeptide with gamma-peptide bond) |
| Molecular Weight | ~307.3 Da |
| Molecular Formula | C₁₀H₁₇N₃O₆S |
| PubChem CID | 124886 |
| Administration | IV, Oral, Liposomal, Nebulized, Topical, Suppository |
| Typical Dose Range | Oral: 250-1000 mg/day; Liposomal: 500-1000 mg/day; IV: 600-2400 mg per session |
| Half-Life | ~2-3 hours (plasma); intracellular GSH has longer functional persistence |
| Storage | Room temperature (stable); protect from light; reduced (GSH) form preferred over oxidized (GSSG) |
| FDA Status | Not FDA-approved as a drug; sold as a dietary supplement (GRAS). IV glutathione is an off-label compounded preparation |
| WADA Status | Not prohibited |
Mechanism of Action
Glutathione is the most abundant low-molecular-weight thiol in mammalian cells, present at intracellular concentrations of 1-10 mM. It is synthesized endogenously in a two-step process: (1) gamma-glutamylcysteine synthetase (GCL) ligates glutamate and cysteine, then (2) glutathione synthetase adds glycine. Cysteine availability is the rate-limiting factor for synthesis.
Antioxidant defense: Glutathione's thiol group on its cysteine residue directly scavenges reactive oxygen species (ROS) and reactive nitrogen species (RNS). In the process, reduced glutathione (GSH) is oxidized to glutathione disulfide (GSSG). Glutathione reductase regenerates GSH from GSSG using NADPH. The GSH/GSSG ratio (normally >100:1 in cytoplasm) is a key indicator of cellular redox status.
Detoxification: Glutathione S-transferases (GSTs) conjugate GSH to electrophilic toxins, drugs, and xenobiotics, rendering them water-soluble for excretion. This Phase II detoxification pathway handles heavy metals (mercury, lead, arsenic), acetaminophen metabolites (NAPQI), carcinogens, and endogenous waste products.
Vitamin regeneration: GSH regenerates oxidized vitamins C and E back to their active reduced forms, maintaining the antioxidant network. This makes glutathione a "master antioxidant" that supports other antioxidant systems.
Immune function: GSH is critical for lymphocyte proliferation, NK cell activity, and T-cell function. Intracellular GSH levels in immune cells directly affect their antimicrobial capacity. RCT data show oral GSH supplementation increases NK cell cytotoxicity by up to 200-400% (PMID-24791752, PMID-28853742).
Age-related decline: Intracellular GSH levels decline with aging (estimated 10-15% per decade after age 45), contributing to increased oxidative damage, reduced immune function, and accelerated cellular senescence. This decline provides the rationale for GSH supplementation in anti-aging protocols.
Key Research Areas
- Oral bioavailability — RCT demonstrated oral GSH effectively increases body stores at 250-1000 mg/day (PMID-24791752)
- Liposomal delivery — Faster onset of GSH elevation and immune enhancement vs standard oral (PMID-28853742)
- Diabetes and oxidative stress — RCT showed improved HbA1c and reduced oxidative damage in elderly T2D (PMID-35624890)
- Immune enhancement — NK cell cytotoxicity increases with GSH supplementation
- Skin lightening — Evidence for melanin reduction (controversial; safety concerns with IV route)
- Neurodegenerative disease — GSH depletion in Parkinson's substantia nigra; supplementation under investigation
Evidence Level Summary
| Evidence Type | Count | Notes |
|---|---|---|
| Human RCTs | Several | Oral supplementation, T2D, skin lightening |
| Systematic reviews | 1+ | Skin lightening applications |
| Human observational | Many | GSH levels in disease states |
| Animal in vivo | Extensive | Detoxification, neuroprotection |
| In vitro | Extensive | Antioxidant mechanism, immune cell biology |
Clinical Applications
- Anti-Aging — Master antioxidant, declines with age
- Immune Support — NK cell and T-cell function enhancement
- Type 2 Diabetes — Oxidative stress reduction, HbA1c improvement
- Neuroprotection — GSH depletion in neurodegenerative disease
Protocols Using This Peptide
- Anti-Aging Daily Protocol — Antioxidant support component
- Longevity Stack Protocol — GSH as foundational antioxidant
Ageless Peps Products
- AP-Glutathione-Vial — Glutathione Vial, $65, retail (draft status)
Dosing Reference
Supplementation Dosing Ranges
| Route | Dose Range | Frequency | Duration | Source |
|---|---|---|---|---|
| Oral (standard) | 250-1000 mg | Daily | 3-6+ months | PMID-24791752 |
| Oral (liposomal) | 500-1000 mg | Daily | 1+ months | PMID-28853742 |
| IV push | 600-2400 mg | 1-3x/week | Variable (clinic-dependent) | Off-label clinical practice |
| Nebulized | 600 mg | 1-2x/day | Variable | Off-label (respiratory) |
| Suppository | 200-500 mg | Daily | Variable | Alternative to oral/IV |
Cycling
Not typically cycled — used as ongoing daily supplementation. IV sessions may be periodic (weekly/biweekly) as part of clinical detoxification or wellness protocols.
Contraindications & Safety
- Contraindications: Known allergy to glutathione (rare); caution with IV use in patients with asthma (theoretical sulfite sensitivity)
- Common side effects: Oral: generally well-tolerated; occasional GI discomfort. IV: rare anaphylaxis, headache, flushing
- Drug interactions: May reduce efficacy of chemotherapy drugs that depend on oxidative mechanisms (cisplatin, doxorubicin — theoretical); may enhance acetaminophen detoxification
- Pregnancy/nursing: Endogenous molecule; supplementation generally considered safe but limited formal study
- Special populations: IV glutathione lacks standardized dosing protocols; quality of compounded IV preparations varies
Synergistic Combinations
- NAD+ + Glutathione — Both decline with age; complementary cellular maintenance (NAD+ for energy/sirtuins, GSH for redox/detox)
- SS-31 + Glutathione — Mitochondrial protection (SS-31 targets cardiolipin, GSH scavenges mitochondrial ROS)
- Glutathione + N-acetylcysteine (NAC) — NAC provides cysteine for endogenous GSH synthesis
- Glutathione + Vitamin C — GSH regenerates oxidized vitamin C; synergistic antioxidant network
Related Research
| PMID | Title | Year | Study Type |
|---|---|---|---|
| 24791752 | Oral Glutathione Supplementation RCT: Body Stores | 2015 | RCT |
| 28853742 | Liposomal Glutathione: GSH and Immune Markers | 2018 | Open-Label Pilot |
| 35624890 | GSH Supplementation in Elderly T2D: RCT | 2022 | RCT |
References
- PMID-24791752 — Richie et al., Oral GSH RCT, Eur J Nutr 2015
- PMID-28853742 — Sinha et al., Liposomal GSH pilot, Eur J Clin Nutr 2018
- PMID-35624890 — Sekhar, GSH in T2D RCT, Antioxidants 2022
Related
Note: Glutathione is not a traditional peptide therapeutic but is widely used in functional medicine alongside peptide therapy protocols. It is the most abundant endogenous tripeptide and serves as the master intracellular antioxidant. This vault entry provides the scientific context for its use in integrative clinical practice.
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