Yes, I have the C677T mutation, but not the A1298C, so I need to take methylfolate. Still, I have a lot of neurological problems though, which would indicate issues with BH4, so I am not really sure what is going on.
I too get depressed if I lower methylfolate too much, but for me 400 mcg of FolaPro taken away from any vitamin C on an empty stomach seems to be about right. But I don't have your C667T mutation. I just have the A1298c in MTHFR. For me 500 mg TMG was too much, causes way more norepinephrine preferentially over dopamine which is not a good thing for an autoimmune disease since norepinephrine ramps the immune system in a vicious cycle. But then again I take supra-physiological levels of corticosteroids so I don't spend my time curled up in the fetal position with every muscle curling up on itself (not fun -- spent nearly two years that way).
I would also be careful not to increase the amount of R5p you ingest since that is the final rate limiting cofactor for 5MTHF production (P5p is for the intermediate step, but also shows up of course all over the place). I only mention this since the regular version of B-2 linearly saturates at 30 mg absorption per dose, above that you are not going to get much. But ... the sodium salted version of R5p has no such restriction to my knowledge. Still 50 mg is probably a fair target.
Ok let me see what I can suggest regarding NMDA receptors.These are not necessarily in order of priority. Just off the top of my head.
I am by no means an authority but since I have Stiff Person Syndrome regulating NMDA receptors activity is one of the most important things I have to do in my life every day. That is the curse of Stiff Person Syndrome.
1) Glorious magnesium glycinate (Albion chelated version); large dosages (i.e. 1000-1200 mg /day beyond diet or to bowel tolerance). Magnesium is an allosteric modulator of NMDA glutamate receptors. So is glycine. Ironically I used large dose glycine to knock me out at night along with some melatonin and 5HTP but that may just be me. But if you take 1000 mg of Mg-glycinate you will get lik3 2.5 (?) grams of glycine spread out through the day. Glycine is also an inhibitory neurotransmitter like GABA (though GABA is supposed to be the big boy on the block for inhibition).
2) Zinc ... it not only helps insulin and GABA production but also affects NMDA receptor activity not to mention a ton of other processes. But let's stay on topic. Molybdenum is a caretaker of the zinc-copper balance btw in favor of zinc. So if you are low copper then you need to be careful of course.
In my case though copper excretion over 24 hours is in normal bounds, when I take 2 mg of copper, I feel like garbage? Why? Copper inhibits the glutamic acid decarboxylase enzyme activity which I have been working so hard to allow to function with my corticosteroids. Meanwhile copper affect MAO-A and also is involved in converting dopamine to norepinephrine.
3) Taurine. Like GABA and glycine it too is an inhibitory neurotransmitter. But ... if you have CBS mutation this may cause redirection down the sulfite-sulfate path and burden the trans-sulfuration pathway. I use 2 grams per day as magnesium taurate. But results may differ. Take with food to avoid reflux.
4) Don't over-methylate! The more you methylate the more you stop histamine but the more you convert histidine into glutamate.Balance is key.
5) And these are generally obvious, no gluten, MSG, etc. They will all affect your glutamate / GABA balance and overload your body's machinery to process things into safe glutamine (which is BBBP) to glutamate which is not.
6) Try to make sure the Krebs cycle is not blocked. Mine was in lock down at the AKG stage with really high AKG intra-converting to glutamate and back. Meanwhile with insufficient ATP, I could not make glutathione. RIch Vank (bless his soul) identified that while I had one of the lowest glutathione levels he has ever seen, the methylation cycle was at best a minor player in that. He suggested working on the Krebs cycle and high dose vitamin C a la Dr Robert Cathcart and bam my glutathione tripled in six months.
As a side note: before talking to Rich, I had doctors who fruitlessly gave me glutathione IVs (hellaciously expensive but I didn't know any better since my body was in full revolt with SPS) that made my symptoms worse. Why? The darn glutathione breaks down into glutamate, cysteine and glycine anyways and if you can't make your own you get jacked with glutamate.
I agree with Freddd btw that people pushing glutathione injections or other forms as the end-all to everything should be carefully re-considered. The point is you are far better making your own end point chemical than supplementing directly imho. Then again I think the similar logic applies to SAMe but I know that will likely cause an argument with some people on the forum so I won't mention anything more about that one.
7) Take melatonin at night. Methylation is generally going to oppose the melatonin production spike at night. Melatonin will damp down NMDA receptor activity indirectly at night when you need to fall sleep. Then again maybe you make enough on your own. My melatonin 24 hour profile was essentially constant even before methylation support.I use melatonin and 5htp to fall asleep and glycine (high dose) at bed to throttle muscle pain in bed as best I can.
8) N-acetyl-cysteine. This one is tricky. NAC will drain glutamate in both brain and periphery (it is BBBP) by providing fuel to make glutathione. If you can make glutathione ok then so be it. But some people overdo it. Moreover the pharmacokinetics of typical NAC will mean you will have a transient spike in serum that will lead to transient dips in glutamate (assuming no GCL block) but that may not be what you want. If you hammer glutamate too much you will become tired and defocused with brain fog. So many people on these forums think the effect of high NAC is a detox reaction. Ummmm nope. It is what happens for most people when glutamate drops rapidly. Again balance.
Personally I have dabbled with NAC from time to time and it certainly forces a drain of glutamate, but even using a time release version (like from Jarrows) my reflux gets worse. My guess is the spike in glutathione production in the stomach kicks the parietal cells into HCL production. Not fun. And the last thing in the world I need is proton pump inhibitors - gah! I only mention NAC as an option but like I said personally I have some undesirable side effects that make me put it back in the cupboard (and no they are not detox events that get used to explain every negative effect sometimes).
9) CoQ10 regulates glutamate production. I forget the mechanism how. I used to take high dose at night to sleep and overcome glutamate excitotoxic effects (like a hypothalamus that is so amped it can hear a flea fart on the back of a dog three miles away when trying to sleep). Again though it creates reflux so I have to rely on small maintenance does during the day with food.
10) You can try to take supplements to augment GABA. Zinc and P5p are already in your mix I presume. Some people like theanine, that one is tricky since tolerance is often an inevitable result. Sadly I get a weird bounce back effect from theanine since it alters glutamate receptor transport at the synapses which would be great if my GAD enzyme containing glial cells were at full strength. But my immune system will never let that happen. There are other GABA promoters but for me I guess the situation is complicated so they don't seem to help that much over time.
Some people swear by pyncogenol and grapeseed extract. They never did anything for me. Valerian root caused me insomnia.
A cup of coffee is death to me since it releases massive amounts of glutamate into the extracellular space which is why people drink it to perk up. Kiss your neurology good by if your balance is off and you drink lots of caffeine.
Understand with SPS, I also take Baclofen 20-30 mg at bedtime (hate the neuro effects during the day) for GABA-B stimulation. Fortunately Baclofen is non-tolerant. I used to take 60 mg a day back before I found a real doctor to treat my SPS, get me off gluten and put me on HRT.
Moreover, I am still digging out of a long period of overmethylation that landed me on Klonopin which I have only recently been able to reduce by 50% by dialing back the methylation (histidine to glutamate). This is important to me since most SPS patients end up on massive doses of baclofen and benzos. So far I have beaten the odds. Knock on wood.
Summary:
I guess my main point would be that a lot of people on these forums focus on dopamine, serotonin, norepinephrine, etc. and rightly so.
But ... the big boy neurotransmitters for basic neurology (pain, sleep, relaxation, irritability, memory, etc.) are to my knowledge glutamate and GABA. If those are messed up, no amount of methylation support is going to fix that on its own. Their are other cycles that are of key importance (like the Krebs cycle) as well. And in fact over-methylation will distort the balance further in some cases.
Hope this helps give you some food for thought.
P.S. Memantine is the one drug way back before my diagnosis that abated my pain somewhat. But it gave me weird headaches and made me feel like I could not think at all. That was suppression of glutamate if one goes to far. But note suppression of glutamate is not entirely the same as increased GABA. The two have to be in balance with one another but also at a dynamic equilibrium with a large pool of brain glutamine. (note don't infer this means you should take glutamine supplements, some of the glutamine may convert to glutamate in the body, depends on the person).
