Quite a few PWMEs who have tried the methylation protocol have reported that they have experienced an increase in symptoms associated with excitotoxicity when they began (anxiety, insomnia, nervousness). In the past, I have suggested trying acetyl glutathione or liposomal glutathione to counter this. One or two people reported that they thought this helped them.
Now I would like to suggest something else that I think would help with this, which is less expensive: L-cystine. Note here that I do mean L-cystine, not L-cysteine. (Cystine is the oxidized form of cysteine, consisting of two cysteine molecules bound together by a disulfide bond.) Douglas Laboratories is one producer of L-cystine, and there are at least a couple of suppliers of it
on the internet advertising 60 capsules, 500 mg each, for $16.50. I would suggest starting with a dosage of 500 mg and increasing to as much as 1,500 mg, depending on the response. L-cystine should not be taken by people who have a tendency to develop cystine kidney stones, or people who suspect that they have a high body burden of mercury, because L-cystine may move mercury around. And as always, I recommend working with a physician while on this protocol.
Here is the rationale:
I believe that the increase in excitotoxicity results from a further drop in the glutathione levels in the astrocytes (helper cells) in the brain, when the protocol is begun. (We know
from the recent MRS measurements of Shungu et al. that glutathione is already somewhat depleted in the brain in ME/CFS.) The further drop in glutathione lowers the production of ATP by the mitochondria of these cells, and they then have less energy for pumping glutamate out of the synapses and recycling it. When glutamate builds up, it overexcites the NMDA receptors, and that produces excitotoxicity.
If this is true, then it would seem that we may be able to lower the excitotoxicity if we can support the glutathione levels in the astrocytes as this protocol is begun.
According to the Dringen model, the astrocytes make their glutathione using cystine as their source of cysteine. Cystine is obtained from the blood, and is able to pass through the blood-brain barrier.
How does cystine normally get into the blood? The liver produces glutathione from the constituent amino acids that it receives from the diet via the intestine and the portal vein blood flow. The liver exports some of its glutathione to the circulating blood, and enzymes break down the glutathione into its constituent amino acids. The cysteine is mostly oxidized to cystine, and some of this is taken up from the blood by the brain.
When the methylation protocol is begun, the activity of the methionine synthase enzyme in the liver is increased by supplementing B12 and folate forms. This causes more of the homocysteine to be converted to methionine, so less is available to support synthesis of glutathione. One result of this is that the cystine level in the blood goes down, so that less of it is available to the brain.
It would therefore seem that if L-cystine were supplemented, it would augment the cystine in the blood and increase the supply available to the brain, and hence to the astrocytes. Hopefully, this would raise the glutathione levels in these cells, and increase their ability to remove glutamate from the synapses, lowering the excitotoxicity. Ingested cystine is not metabolized significantly by the liver, because it does not import cystine readily.
If anybody decides to try this, I would be interested to hear the results, whatever they turn out to be. Thanks.
Best regards,
Rich
