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SNP in COMT enzyme, natural treatment

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mike1127

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Jul 26, 2013
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I have a question about the effect of SNPs (single nucleotide polymorphisms) in the COMT (catecholo-methyl-transferase) enzyme. COMT is involved in the breakdown of dopamine and I have a condition which probably involves too much dopamine activity. I have an SNP in COMT which makes it slower to act, causing a possible over-accumulation of dopamine.

I have bipolar disorder which manifests itself mostly as a mixed state--racing thoughts and irritability together with depressed, dark thoughts. I also have OCD. For the bipolar I take Lamictal, Risperdal, and Cymbalta. I also have fibromyalgia (widespread muscle tension and pain).

The Risperdal is critical. I can barely sleep without it. This has been true for many years, even before I started the Cymbalta. It calms my racing thoughts and manic irritability. At one point I took some Parkinson's drugs for restless legs syndrome, which I believe are intended to increase dopamine, and it messed me up pretty badly, like I didn't have the Risperdal in me.

The Cymbalta is great for my muscle pain and as an antidepressant, but as an SNRI it increases norepinephrine activity which seems to increase my racing thoughts. I needed more Risperdal when I started the Cymbalta.

I got genetic testing done through 23 And Me, and it shows I have the slow form of the COMT enzyme (specific SNPs are V158M +/+ and H62H +/+, where the +/+ means I have the homozygous form, same from both parents). This could partially explain why I have bipolar and irritability.

I have other problems for which it would be nice to supplement with certain substances that contain methyl groups, such as methylcobalomim and SAMe. The problem is that when I take any supplement with methyl groups I get irritability (extreme). This is a known phenomenon, related to having a slow COMT enzyme, within the community of doctors that are looking at supplementation to support the methylation cycle. The methyl groups speed up methylation which increases the production of dopamine. Without proper breakdown of dopamine a lot of it turns to norepinephrine causing irritability.

So my question is, is there some way to speed up the COMT enzyme or reduce the acitivity of dopamine and norepinephrine, possibly reducing my dependance on Risperdal and allowing me to supplement with methyl groups?
 
very interesting topic.

i don't know of any drug that increases comt levels or comt activity, but i've had another idea. what about trying a diet low in phenylalanine (PHE) and tyrosine (TYR). these are precursors to DA/NA, so that could help lower your levels of those neurotransmitters and therefore allow for a dose reduction of the risperidone. it's maybe worth a try. of course PHE is an essential amino acid, but avoiding it completely isn't really possible anyway. i wouldn't even go nearly as far as the people with phenylketonuria have to.

i'm no physician but rather work on the molecular side of it all, so don't take my word for it: but i wouldn't recomend taking anything that counteracts your risperidone given that you really seem to need it. so anti-parkinson drugs (of course depending in the exact drugs, some of them are even comt inhibitors) giving you a bad time comes as no surprise; it's like pushing the same thing from both sides expecting it to be in two places at once. so i would also abstain from supplements that are methyl-group donors for similar reasons, especially considering your COMT SNPs. are you sure that there aren't alternatives you could look into? i don't even think these are approved drugs in the EU (EMA at least doesn't have an entry for the two you listed). also one of the main contraindications of SAMe is bipolar disorder, so there's another reason for you to stay away.

i hope this post was of any use for you.
 
i've had another idea. what about trying a diet low in phenylalanine (PHE) and tyrosine (TYR). these are precursors to DA/NA, so that could help lower your levels of those neurotransmitters and therefore allow for a dose reduction of the risperidone. it's maybe worth a try.
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Given that phenylalanine is an essential amino acid and required for protein synthesis... I don't think restricting it is going to do anything good.

The problem is that when I take any supplement with methyl groups I get irritability (extreme). This is a known phenomenon, related to having a slow COMT enzyme, within the community of doctors that are looking at supplementation to support the methylation cycle. The methyl groups speed up methylation which increases the production of dopamine. Without proper breakdown of dopamine a lot of it turns to norepinephrine causing irritability.
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Reference for this? Methylation of what? Also: the amount of "methyl" in methylcobalamin is... trivial. it doesn't make sense that that would be the cause of its behavioural activity...

In any case, without very specific drugs designed to counteract the mutation and restore enzyme function (c.f. some cutting edge cystic fibrosis drugs and the like), it doesn't look like there's many known COMT inducers. So there's no much you can really do.
 
Thanks for the replies. "Methylation" refers to the cycle that converts homocysteine to methionine and back. My understanding is that this provides methyl groups to a lot of different processes... DNA replication, the immune system, and others. I'm working with a theory that methylation cycle dysfunction underlies many of my symptoms such as chronic fatigue. Here is a page with links to a set of papers.

http://phoenixrising.me/treating-cfs-chronic-fatigue-syndrome-me/treating-chronic-fatigue-syndrome-mecfs-glutathione-and-the-methylation-cycle

I know from experience that taking methylcobalamin causes extreme irritability (I'm talking doses of 1/2 to 1 mg, so these are high doses). But with hydroxycobalamin I'm fine. Perhaps my explanation, which I'm getting from the community of doctors who treat the methylation cycle dysfunctions resulting from genetic SNPs, is wrong.
 
I think you're reading too far into this SNP.. it's a single change in the amino acid sequence of just a single enzyme. Yes, this SNP does have some apparent correlations with mental disorders, but even that evidence is mixed at best. Your issues are much more complex than a single SNP, and trying to pharmacologically change the expression of an enzyme based on this evidence alone is silly at best.
 
I'm looking at around 20 SNPs and what one doctor (Dr. Amy Yasko) refers to as "nutritional bypass"--adjusting your diet and supplements to accommodate the SNP. My goal is not to get off medication or treat all my issues, but to further recover. Evidence-based medicine has only gotten me halfway there, so it's time to look at alternative medicine, and I'm focusing on ideas demonstrated by the biochemistry. And demonstrated in rats and mice. It's the best I can do.
 
It's funny you post this because I was just about to post the same thing in this forum. I have multiple COMT gene mutations that cause slow functioning of the enzyme. I also have a MAO mutation which increases the neurotransmitter levels even more. Basically I live in my head due to these gene mutations. That is the best way I can describe it. I am also prone to dopamine excess fatigue. If you have any information on treating this please PM me. I know it is the cOMT enzyme because I tried a prescription COMT inhibitor and it amplified all of my negative symptoms tremendously. Also I have the same reaction to taking methyl donors as you do. We are essentially "overmethylaters".
 
I've got the same. Double homozygous COMT mutations and as well a MAO homozygous, and a few others. I totally get the "living in my head" feeling, though I'm not sure it is just this. I haven't been diagnosed with bipolar or anything, but have had odd behaviors. Schizotypal, obsessive, compulsive. But I tend to be able to function normally for a lot of part. But, I don't have any relationships outside of work, people I see at the grocery, and touching base with childhood friends, and family. Not to blame these mutations, but I imagine they didn't help in ways.

As well although not a mutation I don't think, I don't know- I have an allele type on an SNP dealing with the oxytocin receptor that is associated with less empathy, and more of a reaction to stress. But I've considered this as part of the reason I've felt 'not with' others, often. In myself. But it could be these other mutations too.

I don't have any advice. I take no meds. But I have noticed certain supplements make me irritable. And psychedelics seem to last longer for me. Not overt effects but afterglow. Not sure on that one, but not being able to break things down as fast seems to tie in.
 
I agree with moredopamine very much on this.
You guys are placing way to much value on genetics alone for your psychological states.
The nature vs. nurture debate comes to mind here, never forget that your brain is not a complete slave to your genetics.
 
If both COMT and MAO are working less effective than normal, maybe a low dose of reserpine could help to stabilize catecholamine levels?
 
That is horrible advice. Reserpine is not specific for dopamine and also depletes serotonin. There are very good reasons why reserpine is not used to treat mental illness.
 
It was not stated which MAO (a or b) was deficient, so it could very well be that a, which metabolizes serotonin, was affected. Reserpine should theoretically be effective.
 
immad said:
It was not stated which MAO (a or b) was deficient, so it could very well be that a, which metabolizes serotonin, was affected. Reserpine should theoretically be effective.
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Reserpine can cause crippling depression and its use has resulted in suicide. And even worse, its effects are persistent, so it's not like everything would return to normal once it washes out. Something like alpha-methyl-p-tyrosine, which selectively depletes catecholamines, would theoretically be more appropriate. But it is horrible advice to recommend that someone with a mood disorder should try reserpine.
 
The effects are long lasting, sure, but they will go away.

Because of the nasty mood effects of a higher dose, I suggested a low dose.
 
immad said:
The effects are long lasting, sure, but they will go away.

Because of the nasty mood effects of a higher dose, I suggested a low dose.
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The side effects to reserpine do not show an obvious dose-dependence. Some people who became depressed were taking low doses (<0.5 mg/day), and others were taking high doses (4 mg/day).
 
immad said:
Well, titration is the key then.
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It can take months for the depression to develop, so I'm not sure how you would go about titrating the dose to avoid depression. The effect of reserpine is cumulative, and the amount of vesicular monoamine depletion gradually increases over time. You could be taking the lowest effective dose, and be fine for months, but then develop crippling psychotic depression. The problem with reserpine is that any dose that is effective at depleting monoamines will also potentially cause depression. There may be some patients (severe hypertension, which can be fatal) where a risk-benefit analysis favors use of reserpine, but this is not such a case, especially since it would not be used under medical supervision. Have you actually read any of the literature about reserpine and depression?
 
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Does this 23andme place send you a bunch of stuff about what it finds out about your DNA? I'm somewhat curious to do it myself and see what shows up. I'm curious about a few things but I wouldn't know what most of it meant.
 
^23andme used to give you health reports but the FDA stepped in and put a halt on it, for the time being. They do however give you access to your raw genetic data, which you can download and input into other sites/programs, like

http://www.promethease.com
(Uses http://www.snpedia.com as a reference and shows you health related and other information about your DNA. Costs $5.)

http://www.geneticgenie.org
(Identifies key mutations such as those mentioned in this thread. Free.)

There are also some other places that you can use your data with, such as http://www.gedmatch.com (Various ancestry tools and some other tools).

As some have inferred here, genes don't fully determine things... But, I believe that some neglect that they do play a role, and for me personally, I'm glad I got tested, and looked into this stuff. It's been insightful.
 
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