Supplementation
Raising GSH levels through direct supplementation of glutathione is difficult. Research suggests that glutathione taken orally is not well absorbed across the gastrointestinal tract. In a study of acute oral administration of a very large dose (3 grams) of oral glutathione, Witschi and coworkers found "it is not possible to increase circulating glutathione to a clinically beneficial extent by the oral administration of a single dose of 3 g of glutathione." However, it is possible to increase and maintain appropriate glutathione levels by increasing the daily consumption of cysteine-rich foods and/or supplements.
Calcitriol, the active metabolite of vitamin D synthesized in the kidney, increases glutathione levels in the brain and appears to be a catalyst for glutathione production.
In addition, plasma and liver GSH concentrations can be raised by administration of certain supplements that serve as GSH precursors. N-acetylcysteine, commonly referred to as NAC, is the most bioavailable precursor of glutathione. Other supplements, including S-adenosylmethionine (SAMe) and whey protein have also been shown to increase glutathione content within the cell.
NAC is available both as a drug and as a generic supplement. Alpha lipoic acid has also been shown to restore intracellular glutathione. Melatonin has been shown to stimulate a related enzyme, glutathione peroxidase, and silymarin, an extract of the seeds of the milk thistle plant (Silybum marianum), has also demonstrated an ability to replenish glutathione levels in lab rats.
Glutathione is a tightly regulated intracellular constituent, and is limited in its production by negative feedback inhibition of its own synthesis through the enzyme gamma-glutamylcysteine synthetase, thus greatly minimizing any possibility of overdosage. Glutathione augmentation using precursors of glutathione synthesis or intravenous glutathione is a strategy developed to address states of glutathione deficiency, high oxidative stress, immune deficiency, and xenobiotic overload in which glutathione plays a part in the detoxification of the xenobiotic in question (especially through the hepatic route). Glutathione deficiency states include, but are not limited to, HIV/AIDS, chemical and infectious hepatitis, myalgic encephalomyelitis chronic fatigue syndrome ME / CFS, prostate and other cancers, cataracts, Alzheimer's disease, Parkinson's disease, chronic obstructive pulmonary disease, asthma, radiation poisoning, malnutritive states, arduous physical stress, and aging, and has been associated with suboptimal immune response. Many clinical pathologies are associated with oxidative stress and are elaborated upon in numerous medical references.
Low glutathione is also strongly implicated in wasting and negative nitrogen balance, as seen in cancer, AIDS, sepsis, trauma, burns and even athletic overtraining. Glutathione supplementation can oppose this process, and in AIDS, for example, result in improved survival rates. However, studies in many of these conditions have not been able to differentiate between low glutathione as a result of acutely (as in septic patients) or chronically (as in HIV) increased oxidative stress, and increased pathology as a result of preexisting deficiencies.
Schizophrenia and bipolar disorder are associated with lowered glutathione. Accruing data suggest that oxidative stress may be a factor underlying the pathophysiology of bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). Glutathione (GSH) is the major free radical scavenger in the brain. Diminished GSH levels elevate cellular vulnerability towards oxidative stress; characterized by accumulating reactive oxygen species. Replenishment of glutathione using N-acetyl cysteine has been shown to reduce symptoms of both disorders.
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