What is glutathione? What are glutathione supplements used for?

What is Glutathione?

Glutathione, often referred to as the “master antioxidant,” is a naturally occurring molecule found in the cells. Glutathione is a tripeptide, meaning it is made of three amino acids (cysteine, glutamine, and glycine). It is produced in the liver and plays a crucial role in maintaining overall health. Glutathione is involved in various biochemical processes that help protect and maintain the health of the body.

Functions of Glutathione in the Body:

Glutathione has several essential functions within the body. One of its primary roles is to act as a potent antioxidant. It neutralizes harmful free radicals and protects cells from oxidative stress, which can lead to various health issues, including chronic diseases.¹ Additionally, glutathione plays a vital role in the detoxification process, aiding in the removal of harmful substances and waste products from the body.

Neurological inflammation, a condition characterized by the brain’s immune response to various factors, has been implicated in a range of neurodevelopmental and psychiatric disorders, including depression, autism, and developmental delays.¹ This inflammatory process can lead to oxidative stress and damage brain cells, potentially contributing to the pathophysiology of these conditions.

One remarkable aspect of glutathione is its ability to be transported across the blood-brain barrier and enter the brain. By doing so, glutathione neutralizes harmful free radicals and reduces inflammation in the brain, protecting neurons and supporting overall neurological health. While further research is needed to fully understand these complex relationships, the link between neurological inflammation and conditions like depression, autism, and developmental delays is clear. Glutathione’s impactful role in maintaining a healthy brain could be a strategy for managing neurological inflammation and improving the quality of life in those with neurological conditions.

RDA (Recommended Dietary Allowance):

An RDA for glutathione has not been established because the body synthesizes it from dietary amino acids, primarily cysteine. Therefore, ensuring an adequate intake of cysteine and other amino acids through a balanced diet is crucial for supporting the body’s natural glutathione production.

Food Sources:

Diet can play a role in supporting glutathione levels, both by providing direct glutathione and the precursors it needs to be synthesized. Cruciferous vegetables like broccoli, cauliflower, cabbage and brussel sprouts, as well as garlic and onion are some of the richest sources of glutathione. Cysteine, an important glutathione precursor, can be found in chicken, turkey, pork, and dairy products. Other amino acids can be obtained through protein rich foods like meat, fish, eggs, dairy, legumes, nuts and seeds to support glutathione production.

Additionally, getting high quality sleep, eating a nourishing diet, and regularly exercising can reduce oxidative stress and thereby support healthy glutathione levels.

Supplementation: NAC vs. Liposomal Glutathione vs. Reduced Glutathione

The effectiveness of different forms of glutathione supplementation, including N-acetylcysteine (NAC), liposomal glutathione, and reduced glutathione, can vary based on their absorption, bioavailability, and ability to increase intracellular glutathione levels. Each form has its own set of advantages and potential limitations. Here’s a summary of the current understanding regarding these supplements:

N-Acetylcysteine (NAC):

NAC is a precursor to glutathione and has been shown to effectively increase intracellular glutathione levels. It is well-absorbed orally and can cross cell membranes to be converted into cysteine, a key amino acid for glutathione synthesis.

Liposomal Glutathione:

Liposomal glutathione is encapsulated in liposomes, making it more bioavailable than non-encapsulated forms of glutathione. The liposomal form can protect glutathione from being broken down in the digestive tract, allowing for better absorption. A study by Richie, et al., in “European Journal of Clinical Nutrition” (2015) showed that liposomal glutathione supplementation effectively increased body stores of glutathione, suggesting its potential efficacy.

Reduced Glutathione:

Reduced glutathione is the active form of glutathione, but when taken orally, it is not well absorbed due to the action of digestive enzymes. However, some studies suggest that when taken in high doses, it can still contribute to increased plasma glutathione levels.

Sublingual Glutathione

One study showed that sublingual gluathione (Sublinthion®) significantly improved glutathione levels in patients better than reduced glutathione and NAC. Liposomal glutathione was not compared to the proprietary formula.

Comparison and Recommendations:

Based on available research, liposomal glutathione and NAC are most recommended for their better absorption and effectiveness in increasing glutathione levels. Liposomal glutathione probably offers the may best bioavailability, while NAC, as a precursor, provides a more indirect but also effective approach to boost glutathione synthesis. Sublingual glutathione also shows promise.

Glutathione Deficiency:

Although there are no clear-cut symptoms of a glutathione deficiency, it’s important to recognize that inadequate levels of this essential molecule can result in greater susceptibility to oxidative stress and inflammation, which can contribute to various health issues. Low glutathione is a contributing factor in the development of chronic diseases associated with excess oxidative stress. Among these are metabolic syndrome, kidney disease, neurodegenerative diseases, liver disease, and cardiovascular diseases.¹ Decreased glutathione is common in alcoholics, smokers and people with chronic liver disease.

Signs of deficiency may not be apparent, but maintaining a balanced lifestyle and diet that supports glutathione production is essential.

Glutathione Excess:

Excessive glutathione levels are less common and can potentially lead to digestive discomfort or skin rashes. No side effects have been reported with dietary glutathione, but it’s important not to over-supplement. As always, consult with your medical provider before starting a new supplement.

Glutathione and Neurological Inflammation:

Neurological inflammation can contribute to various conditions, including depression, autism, and developmental delays. Glutathione, with its powerful antioxidant properties, is believed to play a role in reducing inflammation in the brain and central nervous system. It can cross the blood-brain barrier, making it particularly supportive for protecting brain cells from oxidative stress and inflammation.

While research is ongoing, there’s evidence to suggest that maintaining optimal glutathione levels may have a protective effect on neurological health. Reducing oxidative stress and inflammation through lifestyle changes, such as a balanced diet and stress management, may help spare glutathione and support overall brain health.

Research and the use of glutathione in naturopathic medicine

Glutathione, as a master antioxidant and essential component of cellular defense mechanisms, has garnered considerable attention in the context of various health conditions. While the direct application of glutathione as a treatment remains an evolving area of research, its potential implications in conditions like diabetes, autism, and ADHD are subjects of growing interest.

Glutathione and Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition, and oxidative stress has been proposed as one of the contributing factors. Notably, glutathione is the brain’s primary antioxidant and glutathione is fundamental in maintaining oxidative balance, protecting neural cells from damage caused by reactive oxygen species (ROS) and other free radicals. The brain is particularly susceptible to oxidative stress due to its high oxygen consumption, abundant lipid content susceptible to peroxidation, and relatively lower antioxidant defenses compared to other tissues. Glutathione directly neutralizes free radicals and reactive oxygen species, thereby protecting cells from oxidative damage.

Furthermore, glutathione is notable for its ability to provide detoxification support. Glutathione conjugates with various toxins and xenobiotics, facilitating their removal from the brain tissue. This process is mediated by the enzyme glutathione S-transferase, which attaches glutathione to toxic substances, making them more water-soluble and thus easier to excrete. Glutathione is involved in the regulation of cellular proliferation, apoptosis (programmed cell death), and signal transduction pathways within the brain. Its levels can influence various cellular functions and the expression of genes related to stress response and cell survival.

Interestingly, glutathione may have a role in modulating neurotransmitter activity. For instance, it can influence the release and reuptake of glutamate, the most abundant excitatory neurotransmitter in the brain, by modulating the activity of glutamate-cysteine ligase and other enzymes involved in glutathione metabolism.⁵

Research linking low glutathione levels or problems with glutathione metabolism to autism in children has been explored through various studies, highlighting the potential connection between oxidative stress, detoxification processes, and the development of autism spectrum disorders (ASD). Here are some key studies and their findings:

1. James SJ, Cutler P, Melnyk S, et al. – “Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism.” In this study, published in the American Journal of Clinical Nutrition (2004), researchers found that children with autism had significantly lower levels of total glutathione and higher levels of oxidative stress compared to control subjects. The study showed that children with autism had lower levels of methionine, SAM and homocysteine in addition, suggesting that children with autism had impaired methylation. Their conclusions: “An increased vulnerability to oxidative stress and a decreased capacity for methylation may contribute to the development and clinical manifestation of autism.”⁶
2. Rose S, Melnyk S, Pavliv O, et al. – “Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain.” This study reported on the brain tissue of individuals with autism, finding evidence of oxidative stress and inflammation associated with a low glutathione redox status. This research points to the critical role of glutathione in maintaining oxidative balance and suggests its involvement in the neuropathology of autism​​.⁷
3. Geier DA, Kern JK, Garver CR, et al. – “Biomarkers of environmental toxicity and susceptibility in autism.” This study discusses how environmental toxins may exacerbate the symptoms of autism in genetically susceptible individuals. It also noted that patients with severe ASD had significantly lower plasma levels of reduced glutathione, cysteine and sulfate compared to control participants. Authors also discuss that transsulfuration abnormalities were noted among the study patients with autism. This study highlights the role of glutathione in detoxifying these environmental insults and suggests that impaired glutathione metabolism could increase vulnerability to autism​​.⁸
4. Ghanizadeh A, Akhondzadeh S, Hormozi M, et al. – “Glutathione-related factors and oxidative stress in autism, a review.” Published in Current Medicinal Chemistry (2012), this review synthesizes findings from various studies on oxidative stress and glutathione levels in individuals with autism. It concludes that there is a consistent pattern of increased oxidative stress and altered glutathione metabolism in autism, advocating for further research into therapeutic interventions targeting these pathways​​.
5. Adams JB, Audhya T, McDonough-Means S, et al. – “Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity.” This study, found in the journal Nutrition & Metabolism (2011), evaluates the nutritional and metabolic status of children with autism compared to neurotypical controls. It found that children with autism had significantly different levels of certain metabolites, including those related to glutathione metabolism, suggesting that metabolic abnormalities may be associated with the severity of autism

Research into the use of N-acetylcysteine (NAC), a precursor to glutathione, in ASD treatment has shown promising results. In one clinical trial, children with ASD saw improvements in social engagement and repetitive behaviors following NAC supplementation.⁷ While the mechanisms of action are not yet fully understood, these studies suggest that supporting glutathione levels through NAC supplementation may support individuals with ASD.

Glutathione and ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition characterized by persistent patterns of inattention, hyperactivity, and impulsivity. While the exact causes of ADHD are multifactorial, oxidative stress and inflammation have been suggested as potential contributors, much like in ASD.

Research examining the connection between glutathione and ADHD is ongoing. Some studies have reported lower glutathione levels in individuals with ADHD, while others have highlighted the potential therapeutic benefits of antioxidants in managing the symptoms of ADHD.⁶

The role of N-acetylcysteine (NAC) as a glutathione precursor has also been explored in relation to ADHD. Several clinical trials have examined the effects of NAC supplementation in individuals with ADHD. One study reported improvements in ADHD symptoms, including reduced irritability and hyperactivity, following NAC treatment.⁸ These findings suggest that glutathione support through NAC may offer a complementary approach to managing ADHD symptoms, though more extensive research is needed to gain deeper understanding and establish specific protocols.

Glutathione and Diabetes

The relationship between glutathione and diabetes centers on oxidative stress, its impact on insulin resistance, and glucose metabolism. Several studies have explored the role of glutathione in diabetes, particularly in type 2 diabetes. Research shows that individuals with diabetes often have lower glutathione levels, potentially contributing to increased oxidative stress. Elevated oxidative stress can impair insulin sensitivity and promote inflammation, exacerbating diabetes.

Recent investigations have focused on the potential benefits of glutathione supplementation in diabetes management. A study published in the American Journal of Medicine highlighted the potential role of glutathione in improving insulin sensitivity and reducing inflammation, offering promising prospects for those with diabetes.⁴

Furthermore, research into N-acetylcysteine (NAC), a precursor of glutathione, has demonstrated potential benefits in reducing oxidative stress and improving glycemic control in diabetic patients.⁵ While more research is needed to establish precise dosages and protocols, these findings suggest that optimizing glutathione levels may contribute to better management of diabetes.

Other conditions:

A lot of the information we have regarding glutathione supplementation and specific disease states, especially in children, is theoretical. However, we know that inflammation and immune system dysfunction are two major drivers of disease. Glutathione (or NAC) supplementation can be effective tools for reducing inflammation and oxidative stress and at the very least, spare the body from using its stores. In theory, glutathione or NAC supplementation would be beneficial in conditions driven by oxidative stress (i.e., most of them!).

Summary and my clinical experience with glutathione

While the clinical applications of glutathione in conditions like diabetes, autism, and ADHD are still evolving areas of research, the evidence suggests that optimizing glutathione levels may hold promise for improving health and managing the symptoms associated with these conditions. Supporting natural glutathione production through a balanced diet, including cysteine-rich foods, and lifestyle choices can contribute to improved health and protection against conditions linked to oxidative stress and inflammation. Supplementing glutathione and glutathione precursors is supported by research, but further studies and clinical trials are necessary to establish precise dosages in these neurodevelopmental and metabolic disorders.

In practice I do see clinical improvement in many children with ASD-like symptoms, and some children with ADHD-like symptoms (e.g., neuroinflammatory ADHD). In my practice I typically use liposomal glutathione in liquid form, or NAC in capsule form for children that can swallow capsules. Do note that glutathione is a sulfur-containing compound and it does have an odor that many children find unpleasant. Liposomal glutathione is also relatively expensive, especially compared to NAC. NAC, however, has a very unpleasant taste, and is typically only tolerated in capsule form. Quercetin/Ascorbate mixed in applesauce or pear sauce covers the unpleasant taste of NAC, but only in relatively low doses.

References:

1. Lu, S. C. (2013). Glutathione synthesis. Biochimica et Biophysica Acta (BBA) – General Subjects, 1830(5), 3143–3153.
2. Kerksick C, Willoughby D. The antioxidant role of glutathione and N-acetyl-cysteine supplements and exercise-induced oxidative stress. J Int Soc Sports Nutr. 2005;2(2):38-44. 2005. doi:10.1186/1550-2783-2-2-38
3. Witschi, A., Reddy, S., Stofer, B., Lauterburg, B. H. The systemic availability of oral glutathione. European Journal of Clinical Pharmacology. 1992. 43(6), 667–669
4. Schmitt B, Vicenzi M, Garrel C, Denis FM. Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: A comparative crossover study. Redox Biol. 2015 Dec;6:198-205. doi: 10.1016/j.redox.2015.07.012. Epub 2015 Jul 29. PMID: 26262996; PMCID: PMC4536296.
5. Ballatori, Nazzareno, Krance, Suzanne M., Notenboom, Sylvia, Shi, Shujie, Tieu, Kim and Hammond, Christine L.. “Glutathione dysregulation and the etiology and progression of human diseases” Biological Chemistry, vol. 390, no. 3, 2009, pp. 191-214. https://doi.org/10.1515/BC.2009.033
6. Janáky R, Ogita K, Pasqualotto BA, Bains JS, Oja SS, Yoneda Y, Shaw CA. Glutathione and signal transduction in the mammalian CNS. J Neurochem. 1999 Sep;73(3):889-902. doi: 10.1046/j.1471-4159.1999.0730889.x. PMID: 10461878.
7. James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, Neubrander JA. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004 Dec;80(6):1611-7. doi: 10.1093/ajcn/80.6.1611. PMID: 15585776.
8. Rose S, Melnyk S, Pavliv O, Bai S, Nick TG, Frye RE, James SJ. Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Transl Psychiatry. 2012 Jul 10;2(7):e134. doi: 10.1038/tp.2012.61. PMID: 22781167; PMCID: PMC3410618.
9. Geier DA, Kern JK, Garver CR, Adams JB, Audhya T, Nataf R, Geier MR. Biomarkers of environmental toxicity and susceptibility in autism. J Neurol Sci. 2009 May 15;280(1-2):101-8. doi: 10.1016/j.jns.2008.08.021. Epub 2008 Sep 25. PMID: 18817931.
10. Schafer FQ, Buettner GR. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med. 2001 Jun 1;30(11):1191-212. doi: 10.1016/s0891-5849(01)00480-4. PMID: 11368918.
11. Diaz-Villanueva, J. F., Diaz-Molina, R., & Garcia-Gonzalez, V. Role of Nrf2 and GPx4 in N-acetylcysteine protection against oxidative stress induced by tertiary butyl hydroperoxide in rat hepatocytes. The American Journal of the Medical Sciences, 2020. 360(1):49–57.
12. Pizzino, G., Irrera, N., Cucinotta, M., Pallio, G., Mannino, F., Arcoraci, V., & Squadrito, F. Oxidative stress: Harms and benefits for human health. Oxidative Medicine and Cellular Longevity. 2017. 8416763. 6. Ghanizadeh, A. Increased glutamate and homocysteine and decreased glutamine levels in autism: A review and strategies for future studies of amino acids in autism. Disease Markers. 2013. 570634.
13. Hardan, A. Y., Fung, L. K., Libove, R. A., Obukhanych, T. V., Nair, S., Herzenberg, L. A., & Frazier, T. W.. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Translational Psychiatry. 2012. 2(5): e91.
14. Dean, O. M., Gray, K. M., Villagonzalo, K. A., Dodd, S., Mohebbi, M., Vick, T., … Berk, M. A randomized, double blind, placebo-controlled trial of a fixed dose of N-acetylcysteine in children with autistic disorder. Journal of the American Academy of Child & Adolescent Psychiatry. 2017. 55(10); 864–874.
15. Hristov BD. The Role of Glutathione Metabolism in Chronic Illness Development and Its Potential Use as a Novel Therapeutic Target. Cureus. 2022;14(9):e29696. 2022. doi:10.7759/cureus.29696
16. Wróblewska J, Wróblewski M, Hołyńska-Iwan I, Modrzejewska M, Nuszkiewicz J, Wróblewska W, Woźniak A. The Role of Glutathione in Selected Viral Diseases. Antioxidants (Basel). 2023 Jun 22;12(7):1325. doi: 10.3390/antiox12071325. PMID: 37507865; PMCID: PMC10376684.