4. Discussion
ASD and gastrointestinal abnormalities, mitochondrial dysfunction, irritability, psychiatric
SIDE EFFECT, STOMACH, CYSTIC FIBROSIS, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS
Our pilot investigation examined the utility and tolerability of oral supplementation with glutathione as a treatment for patients with ASD. A similar study by Kern et al. looked at glutathione supplementation for the treatment of ASD. Kern et al. demonstrated the safety profile of oral glutathione supplementation and significant increases in plasma reduced glutathione using glutathione dosages significantly lower (ranging from 50–200 mg/30 lbs or 3.67–14.7 mg/kg) than those used in this pilot study; however, they did not demonstrate a statistically significant difference in the increased whole blood glutathione. As previously mentioned in the study design, patients with cystic fibrosis require ~65 mg/kg of glutathione for adequate absorption. Our study utilizes a more conservative approach of ~32.5 mg/kg of glutathione, which is still well above the range used by Kern et al. Even at higher glutathione doses, our study once again demonstrates a good safety profile for glutathione use.The study by Kern et al. also showed statistically significant increases in plasma transsulfuration metabolites including sulfate, cysteine, and taurine following glutathione supplementation, but they were unable to delineate whether the increased metabolites were truly due to glutathione’s effect on the transsulfuration pathway or whether the increases in transsfulfuration metabolites were due to the increased breakdown of glutathione [Glutathione was generally well-tolerated except in the case of one subject, who experienced a significant increase in irritability and ultimately discontinued their participation in the study. Stomach upset was reported in four of the six subjects in the study as a side effect with oral glutathione treatment. Stomach upset and GI side effects may not necessarily be attributed to oral glutathione alone. With the exception of irritability, all other reported side effects with oral glutathione (The baseline oxidative stress analysis was crucial in understanding the redox imbalance in the patients with ASD. In the case of the subject that dropped out of the study, the pre-treatment laboratory work shows a baseline depletion of the glutathione reserve, high levels of superoxide dismutase despite normal glutathione peroxidase, and elevated lipid peroxides. Another subject shows baseline low levels of antioxidant capacity, significantly elevated glutathione peroxidase, and significantly elevated superoxide dismutase. Both subjects had high oxidative burdens prior to treatment and did not seem to experience any clinical or redox benefit with oral glutathione supplementation. A possible explanation for this phenomenon is that these subjects are at maximum physiologic compensation with a high baseline oxidative burden. The further addition of glutathione is unable to surpass the physiologic cap on the redox balance. The results may indicate that subjects with high baseline oxidative burden may be poor responders to oral glutathione supplementation. All other subjects showed improved total antioxidant capacity, increased sulfate levels, and significant increases in glutathione peroxidase and superoxide dismutase. Another observation is that oxidative burden does not necessarily translate to clinical severity, as indicated via the CGI scores.The clinical progress in this study was monitored via ABC. There were decreases in the post-treatment mean scores across all ABC domains as compared to the pre-treatment scores, but the mean differences were not statistically significant. However, it is important to note that despite the lack of statistical significance, there was a mild improvement in the severity of ASD symptoms in 66.7% of the patients, according to the CGI-I. This translates to an observable clinical significance and improvement in the quality of life of some patients with ASD.As referenced, an imbalance in redox reactions is only one of the many factors that contribute to ASD. Impaired neurotransmission, immune dysregulation in the brain, mitochondrial dysfunction, and a mix of environmental factors may also contribute to treatment response. A recent study by Huang et al. demonstrates the critical role of glutathione in astrocytes to help maintain blood–brain barrier stability by suppressing endothelial cell tight junction phosphorylation and delocalization [Given the association between ASD and gastrointestinal abnormalities, food picking, and food aversion, many individuals with ASD have concurrent deficiencies in macro and micronutrients. The most well-studied agents are vitamin A, vitamin BAnother key component in the baseline redox balance involves genetics. Glutathione S-transferases (GST) are a family of enzymes that aid in the conjugation of reduced GSH to xenobiotics for detoxification and also helps reduce endogenous oxidative species. All four major classes of GST have been shown to exhibit genetic polymorphisms reducing their antioxidative ability and are associated with psychiatric pathologies such as ASD [The method of delivery is an important consideration in this study. Opitac