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Advice Needed - Mitochondrial Dysfunction/Methylation Protocol/Worsening of Symptoms?

Hi All,

Apologies in advance for the lengthy post. I’m new to this forum and I’d love input on the following if you have the time.

I'm a 34-year-old female. I started a methylation protocol about 6-7 weeks ago, and as many of you have noted in your experience, my main symptom (intense leg muscle weakness) has worsened. I can’t tell if this is detox, or just an exacerbation of symptoms that has nothing to do with detox, or what.

For the past year and half, when my mitochondrial dysfunction/muscle weakness started, I’ve had difficulty walking up stairs, exerting myself, etc. I had and still have a profound muscle weakness in my legs, and an obvious lack of ATP. While sometimes I can become incredibly tired even after a lot of sleep, the muscle weakness is the one glaring symptom that prevents me from doing so many things.

Since starting the protocol several weeks ago, my symptoms have intensified and I’ve become considerably weaker. My muscles are tighter and insanely stiff. My legs feel even heavier than before. I added potassium into the mix about a month ago, and immediately took 1800mg a day (600mg each meal). That dosage really helped with the stiffness and I noticed a difference immediately, but now as a few more weeks have passed, the stiffness has returned (I’m still taking 1800mg potassium daily). Should I be taking more than that? I had my potassium checked during the midst of all of this (while taking that much) and my levels were 4.3, which is technically mid-range.

I’ve had my homocysteine and MMA tested, and both were within range. I had the Metametrix Organic Acids Urine test done a month or two ago, and learned that I had High B-Hydroxybutyrate, High Malate, High FIGLU, and High Homovanillate. Further to those tests, I had the Amino Acids panel from Vitamin Diagnostics Inc completed, and the following was found:

Glutathione oxidized - .52 (slightly high)
Glutathione Reduced – 3.2 (low)
SAM – 212 (low)
SAH – 49.8 (slightly high)
5-CH3-THF – 8.8
10-Formyl-THF – 3.3
5-Formyl-THF – 3.90
THF - .56 (low)
Folic Acid – 11.6
Folinic Acid – 9.3
Folic Acid, Active (RBC) – 356 (low)
Adenosine – 23.8 (high)

As part of my treatment protocol, I take the following daily per my clinician’s recommendations:

4 pumps of Methylmate B12 nasal spray (said to be absorbed better nasally)
2 capsules Thorne MethylGuard (contains B6, 5-MTFH. Methylcobalamin, and TMG)
200mg SAM-E
150mg CoQ10
100 mg Alpha-Lipoic Acid
400 mcg Chromium
200 mcg Vanadium
800mg magnesium citrate
4000iu vitamin d
10 mg NADH – heard this might help
PQQ – I just started this – heard it could help
D-Ribose – I tried this for two weeks but it didn’t really do anything so I have stopped it. Maybe I will try again
Vitamin C – I can’t take this any longer (even in small doses) because it ruins me digestively

My main question is this: How long does the said “exacerbation of symptoms” supposedly go on? I am trying my best to be optimistic about this, and I know this is going to be a long journey and it’s not a cure-all, but am feeling incredibly frustrated and saddened and I guess I just need some hope. My symptoms, while intense, are technically bearable (I CAN walk up stairs, it’s just really damn difficult and I have trouble breathing while doing so). I just want to make sure I’m not making things worse. Has anyone had similar experiences with this muscle weakness/mitochondrial dysfunction?

If anyone has any thoughts on the above, and feel like sharing, I’d love to hear your opinions.

Many thanks for your help, it means a lot.



Senior Member
I'm not sure how much of this will be of value to you, but for what it's worth here's my two cents.

I've definitely had that kind of muscle weakness. I imagine many of us have. But for me, the answer was to stop trying to go up stairs for a while. :) I had burned too far through my reserves, and needed time for my energy to replenish itself (which happens very slowly, and seems even slower the more of it I've used up). I still can't exert myself often, but if I space things out more, I don't often get to that totally out-of-energy place. In retrospect, I was worsening my condition severely by continuing to do things that left me feeling that way (which I say not at all in judgement, just because I myself really missed the boat on that one and wish I had realize how MUCH impact those little exertions could have in the state I was in).

As for the protocol and the worsening of symptoms, it's frustratingly hard to tell. You definitely have my sympathy, and I know that many of us can relate to the mystery worsenings. :rolleyes: I got sicker because of starting a couple of things in my regime, but it passed within a weak or two of starting each one. Would it be possible to try a couple weeks at least of more active rest for a while, and see how you feel after? Sometimes I think my body just needs time to focus on healing and getting rid of the backlog of nastiness when I start something new.

Alternately, it seems like methylfolate tends to be one of the worst offenders in terms of triggering symptoms, but also a critical piece (and one that you seem to need more of). You could do a trial period without it and see what happened, then restart it in tiny doses if needed until you can tolerate it better. Did you start all the supplements around the same time? If the methylfolate doesn't seem to be the culprit, you might want to try stopping them all and adding them back in one or two every week so that you can identify what's causing the reaction. It's frustrating to take SO long to get anywhere, but I've found it tends to save me time in the long run. From the list you gave, I would say the most likely sources of temporary issues would be methylfolate, B12, SAMe, or possibly the alpha lipoic acid, but that's just based on what I've experienced and heard from others. Might give you a starting point, though.

It seems like much of the time, the "start-up" reaction means that it's working and doing something for you, but that doesn't necessarily mean that it's best to just wait it out. It also seems to mean that something might be off at the moment. You may get as good, or better, results by easing up for a bit and going more slowly (as hard as I know that is).

But don't lose hope! A few weeks in is a very short time in the long run. And I do know that lots of people have started out with poor reactions to the protocol but have later been really helped by it. I know that I'm doing much better now than I was a year ago. Not anywhere near where I want to be at all yet, but VASTLY better than where I was when I started.

As a side note, if you wanted to take the vitamin C, you could try changing from Magnesium Citrate to a glycinate or something else. Means you'll get some extra glycine, but your digestive tract might be able to handle the extra strain of the C better.

Good luck!! It's a tough road.


Senior Member
I second the advice to discontinue, then restart one thing at a time, so you know what's doing what. In addition, I keep a symptom journal to note doses and reactions.

I like BioEnergyC - vitamin C + ribose. You can take large amounts, and no stomach problems. The ribose even helps my energy a bit.



Have you had your ferritin levels checked? I had terrible trouble climbing stairs and feeling out of breath years ago due to low iron stores. Also low magnesium levels can give us leg weakness and make us feel out of breath easily. Just a thought, sometimes we overlook the obvious.
Thanks for the advice, everyone. I really appreciate it. I added the SAM-e into the mix a few weeks ago, and the Alpha-lipoic acid I'm taking (100mg) doesn't seem like enough (dosage-wise) to be the culprit. And then the methylmate before that. And before that the methylguard. I keep a journal every day of everything I eat and the medicine/dosage I take, but it's tough to tell what causes what and how long the reactions take to get started. I try to minimize taking stairs when I can, but I live in New York City, and have to take the subway to work, and have a flight or two of stairs in my apt building which are unavoidable twice a day:). So I can't really avoid the bare minimum exertion. I've had my ferritin checked a few times and it was normal. I have a Hashimoto's and SIBO (Small Intestinal Bacterial Overgrowth), so certain things really mess up my digestion, one of them being Vitamin C, even in the smallest doses. It's very frustrating because I know how important Vit C is as an anti-oxidant, etc.

Anyway, i appreciate the input across the board!
Caitlin R,
100 mg Alpha-Lipoic Acid
Have you taken it as an antioxydent? ALA is also a chelator. It can transfers kinds of heavy metals, at least mercury, but there are protocols for taking this. The recommended dosages are different and much more smaller, at least in the begining. Protocols that are consider as safe, as Cutler protocol, talking about periods of taking it, 3-4 days and then days off, which can last longer. ppl with problems with the methylation cycle are probably basically/also chemically sensitive and it can be hard on the liver and other organs. I try products and nutrition in separate to check their influence.