Glutathione
Common Name(s): Gamma-L-Glutamyl-L-cysteinylglycine, Glutathione, GSH
Medically reviewed by Drugs.com. Last updated on Jul 14, 2023.
Clinical Overview
Use
Glutathione supplementation has been evaluated in clinical trials in various formulations (eg, oral, intravenous [IV], topical, intranasal, nebulized) for its effects on HIV, Parkinson disease, Alzheimer disease, autism, cystic fibrosis, and cardiovascular diseases, among other conditions. N-acetylcysteine, as the precursor to glutathione, has demonstrated efficacy in raising glutathione levels and is frequently chosen for this purpose.
Dosing
Glutathione has been evaluated in clinical trials in various formulations, including oral, IV, topical, intranasal, and nebulized. The oral formulation has shown mixed results, with some data suggesting it does not increase RBC glutathione and other data showing efficacy. Liposomal formulations of glutathione may confer better effects, but further research is needed. N-acetylcysteine, as the precursor to glutathione, has demonstrated efficacy in raising glutathione levels. Cystic fibrosis: In a clinical trial of children with cystic fibrosis, oral reduced glutathione 65 mg/kg/day (divided into 3 doses per day at mealtimes) was administered for 6 months. Parkinson disease: A small clinical study used IV glutathione at a dosage of 1,400 mg 3 times per week for 4 weeks.
Contraindications
Contraindications have not been identified.
Pregnancy/Lactation
Information regarding safety and efficacy in pregnancy and lactation is lacking.
Interactions
Acetaminophen in high doses is known to deplete glutathione, especially in the liver.
Adverse Reactions
Increased flatulence and loose stools, flushing, and weight gain were reported in one study. A case report shows reversible, severe hepatic injury related to use of IV glutathione, and inhaled glutathione may exacerbate asthma.
Toxicology
Glutathione has received "generally recognized as safe" (GRAS) status from the US Food and Drug Administration (FDA) for use in food products.
Source
Glutathione is a tripeptide that can be synthesized in all cells of the body from its constituent amino acids L-cysteine, L-glutamic acid, and glycine. It is found in lower concentrations in plasma and extracellular fluid, except in bile where concentrations are higher. Lower levels are found in the brain; this is considered a protective mechanism because glutathione precursor molecules may be toxic in high concentrations.Rae 2017, Smeyne 2013 The synthesis of glutathione varies according to tissue type, and levels are affected by pregnancy, exercise, and nutritional status, with diurnal variation also reported.Ballatori 2009, Forman 2009, Wu 2004
Whey protein is used as a dietary supplement for cysteine, which is one of the substrates for glutathione synthesis.Bumrungpert 2018
History
The substance known today as glutathione was discovered in 1888 under a microscope by the French researcher J. de Rey-Pailhade. In the early 1920s, its structures and metabolism were described by the English biochemist Frederick Gowland Hopkins, who renamed it "glutathione." However, Hopkins erroneously classified it as a dipeptide of glutamic acid and cysteine. Hunter and Eagles reported the error in 1927, stating that glutathione was a tripeptide; Hopkins accepted this designation in 1929.Bains 2015
Glutathione has been suggested to possess antimelanogenic properties; in the Philippines, glutathione is claimed to produce "magical skin whitening."Sonthalia 2018
Chemistry
Glutathione is a low-molecular-weight tripeptide formed by the sequential, catalyzed addition of cysteine to glutamate, followed by the addition of glycine. Importantly, glutathione is a thiol, bearing the characteristic sulfhydryl group (glutathione disulfide is its oxidized form) and serving to maintain the redox status of the cell and protect against endogenous and exogenous toxins. In healthy cells, the ratio of reduced to oxidized glutathione is greater than 1:100, whereas in cells under oxidative stress, this ratio decreases to 1:10. Glutathione is produced in the cytosol and is actively pumped into the cellular mitochondria where glutathione appears to regulate apoptosis, while in the nucleus it plays a role in regulating cell division.Bains 2015, Ballatori 2009, Forman 2009, Martin 2009, Peter 2015, Pizzorno 2014, Wu 2004 Glutathione has a molecular mass of 307.3232 g/mol, a melting point of 195°C (383°F), and is water soluble.Bains 2015
Uses and Pharmacology
Glutathione is a tripeptide that can be synthesized in all cells of the body. Glutathione is involved in many biological processes such as free radical neutralization, detoxification, transport and storage of cysteine, maintenance of cellular redox, ascorbic acid and vitamin E regeneration, transport of mercury out of cells and brain, and serving as a coenzyme.Peter 2015, Pizzorno 2014, Smeyne 2013 Glutathione is also involved in iron metabolism, including sensing and regulation of iron levels, iron trafficking, and synthesis of iron cofactors.Berndt 2017 It is believed to help maintain the integrity of the blood-brain barrier.Rae 2017 Glutathione is important for supporting functions of both the innate and adaptive immune systems, including T-lymphocyte proliferation, phagocytic activity of polymorphonuclear neutrophils, dendritic cell function, and antigen presentation by antigen-presenting cells.Ghezzi 2011 Additionally, some bacteria synthesize glutathione in response to oxidative stress.Morris 2014
Diseases associated with inborn errors in glutathione metabolism are rare but provide insight into the role of glutathione in the body. A study of community-based elderly patients found that increased glutathione levels were associated with higher levels of self-rated health, fewer illnesses, and reduced cholesterol, body mass index, and blood pressure.Julius 1994 Depletion of glutathione has been linked to neuroinflammation; neurodegeneration; infection; cancer; and diseases such as Alzheimer disease, Parkinson disease, HIV, cystic fibrosis, periodontitis, diabetes, schizophrenia, and bipolar disorder, among others. However, while levels of glutathione are often reported to be low in neurodegenerative diseases, causality has not been directly attributed to glutathione. Depletion of glutathione is also a part of the aging process.Bains 2015, Berndt 2017, Morris 2013, Pizzorno 2014, Pouvreau 2018
Cancer
An early marker of apoptosis progression is the depletion of intracellular glutathione.Kizhakkayil 2012
Animal and in vitro data
In vitro studies and animal experiments have shown that glutathione protects against DNA damage and demonstrates a protective role against carcinogens through inactivation. However, some cancers are associated with a higher expression of glutathione S-transferase activity and a higher glutathione level, making the cancer cells more chemoresistant.Ballatori 2009, Miko Enomoto 2005, Traverso 2013 In an in vitro study, supplementation of glutathione to human leukemic cells led to resistance against doxorubicin treatment.Thayyullathil 2011
Clinical data
Based on animal and in vitro data, use of supplemental glutathione may be contraindicated in cancer. Strategies to deplete glutathione levels during chemotherapy have been suggested, but potentially major disadvantages to this approach exist due to effects of low glutathione levels on noncancerous tissues.Balendiran 2004, Ballatori 2009 A glutathione analog prodrug, ezatiostat hydrochloride, has been studied in patients with myelodysplastic syndrome.Miko Enomoto 2005, Raza 2009 In one study, reduced glutathione, in combination with anthocyanins, was superior to placebo and standard skin care as a protective agent against skin irradiation injury in patients undergoing whole breast external-beam irradiation.Miko Enomoto 2005
Cardiovascular effects
Impaired oxidative status is associated with certain aspects of cardiovascular disease, particularly atherosclerosis, and a role for glutathione in cardiovascular disease has been described.Ballatori 2009
Animal and in vitro data
Atherosclerotic mice given liposomal glutathione achieved improved oxidative status and decreased macrophage cholesterol mass.Ballatori 2009 Another study in mice found that oral reduced glutathione 5 g/kg combined with training enhanced resistance to ischemia-reperfusion–induced damage and increased myocardial glutathione levels and antioxidant defense capacity.Ramires 2001
Clinical data
In a small study evaluating the effects of glutathione infusion in patients with peripheral obstructive arterial disease, improvements in pain-free walking distance measurement were observed, but there was no significant benefit for other hemodynamic measures.Arosio 2002 In a small (N=21) clinical trial of patients with coronary artery disease (CAD), IV glutathione protected against contrast medium–induced oxidative stress to a greater extent than oral N-acetylcysteine.Saitoh 2011
In another study of patients with CAD, glutathione levels were inversely related to glucose levels.Karolczak 2017
CNS effects
CNS dysfunction is apparent in all cases of inborn errors of glutathione metabolism. In patients with neurodegenerative diseases, levels of glutathione are often reported to be low; however, causality has not been directly attributed to glutathione.Ballatori 2009, Martin 2009, Peter 2015, Pocernich 2012
Animal and in vitro data
Animal studies in mice, rats, gerbils, and guinea pigs and in vitro studies using postmortem brain tissue form the basis for most of the available data on glutathione in CNS disorders. Evidence exists regarding a potential neuromodulator or neurotransmitter role for glutathione.Ballatori 2009, Hauser 2009, Martin 2009
Clinical data
Alzheimer disease
In general, antioxidants are considered to be important in the prevention of Alzheimer disease based on evidence suggesting an association between increasing signs of oxidative stress and progression of the disease. The main endogenous antioxidant glutathione has been shown to decline in Alzheimer disease. However, there is debate regarding an association between cognitive status and declining glutathione levels.Ballatori 2009, Martin 2009, Peter 2015, Pocernich 2012 Clinical trials with glutathione supplementation are lacking, primarily because of the poor uptake of supplemental glutathione via the blood-brain barrier.Peter 2015 Limited studies focusing on N-acetylcysteine as a precursor to glutathione reported improvement in cognition; further study is needed to evaluate effects on disease progression.Pocernich 2012
Autism
A role for glutathione in autism has been suggested,Ghanizadeh 2012 with the potential for glutathione to serve as a biomarker for diagnostic evaluation.Khemakhem 2017 A case report describes an 8-year-old boy with autism who experienced improvements in social impairment and aggressive behaviors after receiving N-acetylcysteine 800 mg/day, divided 3 times daily, for at least 30 days.Ghanizadeh 2012 In an 8-week, open-label trial, plasma sulfate, cysteine, and taurine levels improved in patients with autism spectrum disorder receiving either oral or transdermal glutathione. However, reduced glutathione plasma levels improved in the oral group only.Kern 2011
Chemotherapy-induced peripheral neuropathy
The American Society of Clinical Oncology (ASCO) guideline update for prevention and management of chemotherapy-induced peripheral neuropathy (2020) recommends that clinicians not offer glutathione for the prevention of chemotherapy-induced peripheral neuropathy in adults with cancer undergoing treatment with neurotoxic agents (Intermediate; Moderate).Loprinzi 2020
Parkinson disease
Decreased levels of glutathione in the substantia nigra of patients with Parkinson disease have been described, and some researchers consider glutathione depletion to be a precursor to and potential marker of the disease.Ballatori 2009, Martin 2009, Smeyne 2013 A case report describes improvements in mental function and speech quality in a patient receiving supplemental IV glutathione 1,400 mg 2 to 3 times weekly in addition to a standard treatment regimen for Parkinson disease. Symptom improvement was not noted until after 3 weeks of treatment. The patient described these improvements as being maintained for 24 hours, with a decline to baseline function within 36 hours of receiving the injections.Otto 2017 In another small study of patients with Parkinson disease (N=21) randomized to receive IV glutathione 1,400 mg or placebo administered 3 times weekly for 4 weeks, the possibility of a mild symptomatic effect was suggested based on improvement in Unified Parkinson Disease Rating Scale (UPDRS) scores with glutathione.Hauser 2009 In a phase 2b study, intranasal glutathione improved UPDRS scores; however, an improvement was also seen with placebo, and it was determined intranasal glutathione was not superior to placebo.Mischley 2017
Schizophrenia
Dysregulation of glutathione and decreased oxidative status have been associated with schizophrenia, as well as with bipolar and major depressive disorders. Additionally, reductions in plasma glutathione levels have been noted in patients with schizophrenia and bipolar disorder.Nucifora 2017 However, clinical studies have focused on the role of supplemental N-acetylcysteine and reported increased levels of glutathione in the blood. Although improved outcomes have been reported, at this stage studies are too limited in scope and size to recommend a place in therapy.Berk 2008, Lavoie 2008
Cystic fibrosis
A decrease in blood glutathione has been observed in cystic fibrosis. Extracellular fluid in normal lungs usually contains a substantial amount of glutathione covering the air spaces where gaseous exchange occurs; in cystic fibrosis, it is depleted. Additionally, the airways in patients with cystic fibrosis have increased activity of gamma-glutamyltransferase (GGT), an enzyme that degrades glutathione, rendering exogenously administered glutathione inactive.Corti 2017 Glutathione may play a role in regulating the viscosity of mucus, inflammation, and immune response.Ballatori 2009, Forman 2009, Laube 2015
Animal and in vitro data
Studies have been conducted in mice; however, the role of glutathione in cystic fibrosis is complex, and animal studies are limited.Ballatori 2009
Clinical data
Data are conflicting regarding the usefulness of glutathione supplementation in patients with cystic fibrosis.Ciofu 2014
Given the complex medical histories and drug regimens that cystic fibrosis patients receive, it is difficult to discern the full impact of glutathione in patients with chronic infection without assessment of a very large population sample and long-term study period.Ciofu 2014
Clinical data suggest that GGT activity correlates with neutrophilic inflammation in the setting of cystic fibrosis, and differentiation in the level of activity in patients may be important for determining if glutathione should be administered. Patients with decreased GGT activity and reduced inflammation may benefit from inhaled glutathione therapy, whereas those with increased GGT activity and active inflammation may experience worsening of the disease with glutathione therapy.Corti 2017 A study found that urinary glutathione sulfonamide levels were elevated in children with cystic fibrosis who had pulmonary infections with Pseudomonas aeruginosa compared to those without infections. Urinary glutathione sulfonamide was also associated with markers of neutrophilic inflammation, suggesting urinary glutathione sulfonamide measurements could possibly serve as a noninvasive biomarker in patients with cystic fibrosis.Dickerhof 2017
Inhaled
A few studies have examined the use of inhaled buffered glutathione in cystic fibrosis,Laube 2015 with positive findings. However, a randomized, double-blind, placebo-controlled trial found that 6 months of therapy with inhaled glutathione twice daily did not improve lung function in patients with cystic fibrosis.Griese 2013 In another study, inhaled glutathione given for 12 months did not improve forced expiratory volume in the first second of expiration (FEV1) in adult or pediatric patients. However, in patients with moderate lung disease, improvements in FEV1 were noted after 3, 6, and 9 months of therapy.Calabrese 2015
Oral
In a study of children with cystic fibrosis receiving 6 months of oral reduced glutathione 65 mg/kg/day, glutathione administration was associated with improvements in measures of growth status (ie, height and weight) and gut inflammation (ie, fecal calprotectin).Visca 2015 Oral N-acetylcysteine is used as a mucolytic agent in cystic fibrosis and appears to increase systemic glutathione levels, whereas inhaled N-acetylcysteine does not.Ballatori 2009, Tirouvanziam 2006
Dermatological effects
Glutathione has been suggested to possess antimelanogenic properties, which may be attributable to inhibition of tyrosinase, impacting melanogenesis and free radical scavenging.Sonthalia 2018
Clinical data
A review article discusses 4 studies evaluating oral (2 studies), topical (1 study),Watanabe 2014 and IV (1 study) formulations of glutathione for skin-whitening or skin improvement effects. Both topical and oral formulations produced positive results for skin lightening in patients with hyperpigmentation, as measured by the melanin index, and the formulations were considered to be well tolerated. The study evaluating the IV formulation found improvements in skin lightening; however, all glutathione-treated patients experienced adverse effects, including liver dysfunction in 32% of patients and 1 case of anaphylactic shock.Sonthalia 2018
HIV
Low glutathione levels are associated with HIV, and reduced glutathione levels decrease natural killer cell cytotoxicity.Allen 2015, Morris 2013 Reduced levels of enzymes involved in glutathione synthesis have been observed in the red blood cells of patients with HIV.Morris 2014 Limited studies have evaluated N-acetylcysteine and glycine as precursors to glutathione.Ballatori 2009, Sekhar 2015
Clinical data
Supplementation of HIV-infected patients with liposomal glutathione for 13 weeks improved Tн1 cytokine, interleukin 1beta (IL-1beta), IL-12, interferon-gamma, and tumor necrosis factor alpha levels. Additionally, it was noted that low glutathione levels increased susceptibility to Mycobacterium tuberculosis.Ly 2015 Specifically, glutathione has been shown to be useful in controlling M. tuberculosis infections by exerting direct antimycobacterial effects, enhancing the functions of natural killer cells and T-lymphocyte cells, exerting antioxidant effects, serving as a carrier molecule for nitric oxide, and reducing levels of proinflammatory mediators.Morris 2013 Additionally, supplementing older HIV-infected individuals with glycine and cysteine for 14 days was associated with improved glutathione synthesis, fasted and fed mitochondrial fuel oxidation, insulin sensitivity, body composition, anthropometry, forearm muscle strength, and lipid profiles.Nguyen 2014
Male infertility
Clinical data
The effects of glutathione on male infertility have been evaluated, and positive effects have generally been observed. An intramuscular formulation of glutathione 600 mg given every other day for 2 months improved sperm motility and morphology in men with varicocele or male germ-free genital tract inflammation.Lenzi 1993, Majzoub 2017
Nonalcoholic fatty liver disease
Clinical data
An open-label pilot study (N=34) evaluated effects of oral glutathione 300 mg/day for 4 months in patients with nonalcoholic fatty liver disease.Honda 2017 Serum ALT levels were significantly decreased from baseline, as were levels of triglycerides and ferritin. Researchers also noted that diabetic status and age were correlated with ALT response.
Ophthalmic effects
Because glutathione levels are usually high in the lens, cornea, aqueous humor, and retina, declining levels are associated with age-related cataracts, glaucoma, and macular degeneration. As a patient ages, glutathione levels decline in the lens nucleus, rendering the lens prone to damage from oxidative stress. As a result, proteins aggregate, and the development of cataracts can ensue.Nye-Wood 2017 In rat glaucoma models, decreased glutathione levels are apparent. One study found that patients with either primary-open angle or normal tension glaucoma had lower reduced glutathione levels compared with age-matched controls.Gherghel 2013
Supplementation
Clinical data
In one study evaluating the long-term effectiveness of glutathione supplementation with 250 mg or 1,000 mg orally daily for 6 months, both dosages were associated with an increase in glutathione levels in erythrocytes, plasma, lymphocytes, and buccal cells. The levels returned to baseline following a 1-month washout period.Richie 2015
Dosing
Glutathione has been evaluated in clinical trials in various formulations, including oral, IV, topical, intranasal, and nebulized. The oral formulation has shown mixed results, with some data suggesting it does not increase RBC glutathione and other data showing efficacy.Allen 2011, Pizzorno 2014 Liposomal formulations of glutathione may confer better effects, but further research is needed. N-acetylcysteine, as the precursor to glutathione, has demonstrated efficacy in raising glutathione levels and is frequently chosen for this purpose.Pizzorno 2014
Cystic fibrosis
In a clinical trial of children with cystic fibrosis, oral reduced glutathione 65 mg/kg/day (divided into 3 doses per day at mealtimes) was administered for 6 months.Visca 2015
Parkinson disease
A small clinical study used IV glutathione at a dosage of 1,400 mg 3 times per week for 4 weeks.Hauser 2009
Supplementation
In one study evaluating the long-term effectiveness of glutathione supplementation, 250 mg or 1,000 mg of glutathione was administered orally daily for 6 months.Richie 2015
Pregnancy / Lactation
Information regarding safety and efficacy in pregnancy and lactation is lacking.
Interactions
Information regarding drug interactions is lacking; however, glutathione is likely to interact with chemotherapeutic agents, and concomitant use is theoretically contraindicated.Balendiran 2004, Ballatori 2009 Acetaminophen in high doses is known to deplete glutathione, especially in the liver.Perricone 2009
Adverse Reactions
No serious adverse events were noted in a clinical study of healthy volunteers using oral glutathione 500 mg twice a day for 4 weeks. Increased flatulence and loose stools, flushing, and weight gain were reported.Allen 2011
IV glutathione 1,400 mg given 3 times per week for 4 weeks was well tolerated in a small (N=21) clinical studyHauser 2009; however, a case report shows reversible, severe hepatic injury related to IV glutathione 1,200 mg given daily, for a cumulative dose of 36,000 mg in 1 month.Naito 2010
Nebulized glutathione caused bronchial hyperreactivity, cough, and breathlessness in patients with mild asthma, possibly due to sulfite formationReynaert 2011 or lack of buffering.Ballatori 2009
Toxicology
Risks of supplemental antioxidant use have been described.Bast 2002 Glutathione has received GRAS status from the FDA for use in food products.FDA 2018
References
Disclaimer
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