ARI Publication 40 – 2013 Version

Therapies for
Methylation/GIutathione/Oxidative Stress

Rationale: Many children with autism have impairments in methylation, glutathione, and oxidative
stress, which are all closely connected metabolically (see figures 1 and 2).

Methylation is the process of donating a methyl group (CH3, or a carbon atom with three hydrogens
attached) to another molecule, like DNA, RNA, proteins, phospholipids, and neurotransmitters,
which basically can turn them on or off. The primary methyl donor in the body is SAM (Sadenosylmethionine), and several studies have shown it to be low in autism.

Glutathione is the primary antioxidant in the body, and it is also an important defense against toxic
metals (it binds to them and is excreted with them in the bile and urine). It also indirectly supports
many metabolic reactions, including DNA synthesis/ repair and protein synthesis. Every cell in the
body and every system in the body is affected by glutathione, especially the immune system,
nervous system, gastrointestinal tract, and lungs. Glutathione is a tri-peptide made from three
amino acids – cysteine, glycine, and glutamate, and is the major antioxidant and detoxification
system in cells. The amount of cysteine precursor is usually the limiting factor in how much
glutathione is made by the body. Some cysteine is made from SAM, so low levels of SAM can result
in low levels of cysteine. Several studies have found that children with autism have low cysteine
and low glutathione, probably due in part to low SAM.

Oxidative stress occurs when too many free radicals are produced and glutathione antioxidant
capacity is insufficient. Free radicals are highly-reactive molecules that can attack any cell in the
body, interfering with their function and causing damage. One common cause is when
mitochondria (energy-producing organelles in every cell of the body) are functioning incorrectly
when they “burn” oxygen when it reacts with “fuel” (sugars, fats, etc) to make energy. Glutathione
and other anti-oxidants can reduce oxidative stress by quenching free radicals, but they need to be
recycled after each time they act. Several studies have demonstrated that children with autism
often have impaired mitochondrial function, impaired glutathione recycling, and increased oxidative
stress.

Treatment:
There are many ways to improve SAM, glutathione, and oxidative stress, but some are more
effective than others. They include:

Less-effective methods:
1) Oral glutathione: Only about 10% of oral glutathione is absorbed, so this method is not very
effective at raising body levels. One small study of children with autism found that oral doses of
15 mg/kg bodyweight led to a 19% increase in reduced (active) glutathione in plasma, and
increased the total level of glutathione in whole blood by 12%. However, it did not improve the
level of oxidized glutathione in plasma, so oxidative stress was still high.

Kern JKet al, A clinical trial ofglutathione supplementation in autism spectrum disorders. Med Sci
Monit 2011 Dec 1;17(12):CR677-682

2) Transdermal glutathione: Glutathione is a relatively large molecule, and is not easily absorbed
through the skin. One small study of 13 children found that a transdermal dose of 350-500 mg

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