Glutathione | Supplementopedia

Overview

Glutathione (GSH) is a tripeptide composed of glutamate, cysteine, and glycine that exists primarily in its reduced (thiol) form within cells. It functions as the body’s master antioxidant, maintaining redox balance, detoxifying reactive species, and supporting enzymatic processes essential for health.

Benefits

Oxidative‑stress reduction: Clinical trials show oral or intravenous GSH lowers biomarkers of oxidative damage (e.g., malondialdehyde) and improves antioxidant capacity (Ferric‑reducing ability of plasma).
Detoxification & liver support: Supplementation increases hepatic glutathione S‑transferase activity, aiding clearance of xenobiotics, acetaminophen, and heavy metals.
Immune modulation: Elevated GSH improves T‑cell proliferation and NK‑cell activity, reducing infection rates in elderly and post‑operative patients.
Cognitive function: Higher brain GSH correlates with better memory scores; supplementation modestly improves executive function in mild cognitive impairment.
Physical performance & recovery: Athletes receiving 500–1000 mg/day report reduced muscle fatigue and faster post‑exercise recovery, linked to attenuated lipid peroxidation.
Metabolic health: GSH supplementation improves insulin sensitivity and reduces HbA1c in type‑2 diabetes, likely via reduction of oxidative stress in pancreatic β‑cells.
Skin health: Topical and oral GSH increase melanin‑inhibiting activity, leading to reduced hyper‑pigmentation and improved skin elasticity.

How It Works

Redox buffer: Glutathione operates chiefly as a redox buffer. The cysteine thiol (–SH) donates electrons to neutralize reactive oxygen/nitrogen species, forming oxidized glutathione (GSSG).
Recycling: Glutathione reductase recycles GSSG back to GSH using NADPH, sustaining intracellular redox potential (E_h ≈ −240 mV).
Co-factor: GSH serves as a co‑factor for glutathione peroxidases (GPx) that reduce hydrogen peroxide and lipid peroxides, and for glutathione‑S‑transferases (GST) that conjugate electrophilic toxins via a thiol‑mediated nucleophilic attack, making them water‑soluble.
Mitochondrial Protection: In mitochondria, GSH protects mitochondrial DNA, preserves membrane integrity, and regulates apoptosis through the glutathione‑dependent peroxidase/thioredoxin network.
Enzyme/Transcription Factor Preservation: By maintaining a reduced environment, GSH preserves the function of enzymes, receptors, and transcription factors (e.g., NF‑κB, Nrf2) that orchestrate inflammation, detoxification, and cellular survival pathways.

Dosage

Oral capsules/tablets: 250 – 500 mg once daily is typical for antioxidant support; 500 – 1000 mg split into two doses (morning/evening) is used for metabolic or immune benefits.
Liposomal or sublingual forms: 200 – 400 mg per dose, taken on an empty stomach for improved absorption; repeat 2–3 ×  daily if higher plasma levels are required.
Intravenous (clinical settings): 2 – 5 g per infusion, administered 2–3 times weekly for acute liver injury, chemotherapy‑induced toxicities, or severe oxidative stress.
Special considerations: Athletes may cycle 500 mg pre‑exercise and 500 mg post‑exercise; diabetics often start at 250 mg to assess tolerance. Food can modestly reduce oral bio‑availability, so many clinicians advise taking GSH 30 min before meals.

Safety & Side Effects

Glutathione is generally well‑tolerated.
Mild adverse effects: Mild adverse effects (≤ 5 % of users) include abdominal cramping, nausea, or a mild “metallic” taste.
High dose effects: High oral doses (> 2 g/day) may cause gastrointestinal upset.
Intravenous administration: Intravenous administration can lead to transient flushing, hypotension, or rare allergic reactions; monitoring is advised in patients with asthma or severe cardiac disease.
Contraindications: Contraindications include known hypersensitivity to GSH or its excipients.
Drug interactions: GSH may diminish the efficacy of certain chemotherapeutics (e.g., cisplatin) by enhancing detoxification, and can interfere with the action of some antibiotics (e.g., quinolones) that rely on oxidative mechanisms.
Pregnancy/Lactation/Pediatric Use: Pregnant or lactating women should use only under medical supervision; pediatric use is limited to specific clinical indications.

Chemistry

Glutathione (reduced) is a tripeptide: γ‑L‑glutamyl‑L‑cysteinyl‑glycine.

Molecular formula: C₁₀H₁₇N₃O₆S (M ≈ 307.32 g mol⁻¹)
IUPAC name: (2S)-2‑Amino‑4‑[(2‑S‑[[(2‑S‑[[(2‑S‑{(2‑amino‑2‑carboxyethyl)‑(2‑sulfo‑1‑yl)‑2‑hydroxy‑1‑carboxy‑ethyl]‑amino)‑2‑hydroxy‑2‑methyl‑propane‑1‑yl]‑amino]‑2‑hydroxy‑3‑oxopropyl]‑amino]‑butanoic acid (commonly given as γ‑L‑glutamyl‑L‑cysteinyl‑glycine).
Key structural features: a γ‑peptide bond linking glutamate’s γ‑carboxyl to cysteine’s amino group; a free thiol on cysteine (the active antioxidant moiety); and a C‑terminal glycine, which facilitates transport across cellular membranes via the peptide transporter PEPT1/2.
Water Solubility: The molecule is highly water-soluble (pKa ≈ 9.2 for the thiol) and exists in a dynamic equilibrium between reduced (GSH) and oxidized (GSSG) forms.

Sources & Quality

Natural glutathione is harvested from yeast (Saccharomyces cerevisiae) and bacterial cultures (e.g., Bacillus subtilis) using fermentation, followed by purification via ion‑exchange and crystallization.
Reduced glutathione: Commercial supplements often use reduced glutathione produced by controlled microbial fermentation, which yields a high‑purity (> 98 %) product.
Synthetic GSH: An alternative is synthetic GSH, chemically assembled from the three amino acids under controlled conditions; however, the fermentation method is preferred for its lower impurity profile and better stereospecificity.
Bioavailability Enhancement: For oral supplements, many manufacturers employ liposomal encapsulation or sublingual buccal delivery to enhance bio‑availability.
Quality Considerations: Quality considerations include verification of the reduced (GSH) to oxidized (GSSG) ratio (< 5 % GSSG), absence of heavy metals, and compliance with pharmacopeial standards (USP, EP). Third‑party testing (e.g., NSF, USP) is recommended to ensure potency and purity.