Sunday, November 24, 2013

New potential A-Ha: niacin, SAM-e, and methylation SNPs

I recently stumbled into a new bit of obscure biochemistry and have been hopeful about its potential implications ever since.  I don't know yet if the effects will be sustainable, but the initial results are promising.  There've still been some ups and downs, but the ratio of up seems considerably higher with the new strategy than it has been for a while.  That could be all due to placebo effect, but I hope it's more than that!

First, I need to make a confession.  For months I've been spending a great deal of time hiding and either reading escapist fiction or listening to podcasts rather than confronting and engaging with the challenges of life.  With the generous support of my husband, colleagues, and friends, I have managed to do enough (I hope) to keep disaster at bay and (I hope) not totally burn all my bridges, but I certainly haven't been proud of the way things have been going.

The dominant sensation in all this is a distressingly jittery, heart racy, fight-or-flighty feeling when considering confronting even very minor challenges.  This doesn't happen 100% of the time.  Some of the time, without any discernible change in circumstances, I can consider and execute on quite significant challenges without that distressing feeling being there.  Sometimes those gaps can last for months, sometimes just for hours.

The maddening thing is that I haven't been able to figure out how to predict or engineer those gaps.  It's like sunshine in Pittsburgh: sometimes the clouds part and the sun shines through, but I don't know when it's going to happen, it can go away suddenly, and I mostly can neither predict nor control it.  Unfortunately, the last several months have been mostly clouds with only rare patches of sun.

I know that the feelings I describe are typically labeled anxiety and that there are whole industries built around approaches to treating it.  However, I spent years pursuing many of those approaches and have mostly lost faith in them being the answer here.  Only one thing, beta blockers, ever made a significant difference and it wasn't sustainable.  

From that experience, I learned 1) that blocking reception of epinephrine (aka adrenaline) can make that distressing jittery feeling go away, and 2) that I'm a beta receptor mutant and, probably because of that, am hypersensitive to epinephrine (details at Beta blockers: good idea or trap?).

The new bits of obscure biochemistry that brought me hope were learning that 1) epinephrine is broken down by the COMT and MAO enzymes, 2) that I've got slowish versions of both of these (heterozygous for COMT V158M and COMT H62H, and homozygous TT for MAO A R297R), and 3) that niacin is a cofactor that can increase the activity of COMT.

The idea that epinephrine hangs around too long due to underperforming breakdown enzymes and conspires with the mutant beta receptors to cause the distressing jittery sensations seemed like a promising new lead.  So, could additional niacin dosing help improve the breakdown efficiency and lead to less of that sort of feeling?

I first encountered this possibility here while reading about methylation SNPs at  Dr. Lynch describes the use of ~50 mg of nicotinic acid (one of the two available supplement forms of niacin) to help a patient with anxiety caused by over-methylation.  He says: "Nicotinic acid is a cofactor for the COMT enzyme. This enzyme helps breakdown norepinephrine and epinephrine – and estrogen. These are all commonly elevated in those with anxiety. Since the COMT enzyme sped up, the breakdown of these occurred faster."

I went out and bought a bottle of nicotinic acid that same evening.  The closest I could find at the store was 500 mg, so I had to trim off 1/10 of a tablet to get the desired dosage.  Luckily my husband had bought a digital milligram scale for another project, so I could measure with enough precision to pull this off.

I took a dose that evening, and soon after felt noticeably more calm.  I fell right asleep, slept well, and woke with the jittery feeling still gone.  Twice during the next day I felt the jittery feeling starting, responded by taking another dose of the niacin, and felt the jittery feeling go away again.  I've taken it every day since then.  I usually take it once either in the morning when I get up or when I notice feeling jittery, and then at night before I go to bed.  It has consistently gotten rid of the jittery feeling pretty quickly.  The one night I forgot to take it before bed I woke up in the night with stress dreams, but have otherwise been sleeping quite well.

All this could certainly be placebo effect.  However, even if it is placebo it's the first ray of hope I've seen in a long time for being able to engineer gaps in the clouds and function well.  If it is a real effect, I am hopeful that this could lead to a more sustainable solution than the beta blockers.  I expect that achieving this goal will take continued effort.

The best sources I've found in trying to understand all this are an amazing 90 minute extravaganza on MTHFR and Methylation by Dr. Benjamin Lynch, ND of, and the results from feeding the raw data from 23andme into an analyzer at  The heavy biochemistry diagrams begin at 33:08.  They show many of the interconnections where various genetic polymorphisms and variations on intake/supplementation can cause issues.

One of the big concerns is that niacin sponges up SAM-e, which is important for supporting methylation, producing melatonin, etc.  I know that methylation is an issue for me since I've also got an underperforming MTHFR version (heterozygous for C677T).  Knowing that and reading an article by Chris Kresser last year had led me to read up on the topic of methylation and add a methylated folate supplement back in early 2012, which had led to a significant and noticeable uptick in energy and oomph (the last a-ha before this one).  I definitely don't want to screw up methylation, glutathione production, etc.

The most obvious thing to try to keep things happy is to also supplement with SAM-e.  In the comments of the page where Dr. Lynch talks about niacin, he says:
One may look at dealing with MTHFR and COMT mutations together as ‘driving with one foot on the gas and one on the brake.’ 
It is common for those with COMT mutations to suffer anxiety, irritability while on methylfolate and/or methylcobalamin. These signs of irritability can be reduced by taking niacin, using less methylfolate and using less methylcobalamin – while at the same time supporting your liver via nutrients, diet and lifestyle changes.
I tried to buy some SAM-e the same night I got the niacin, but that store was sold out.  The second store I tried was also sold out, so I guess I'm not alone in suddenly being interested in SAM-e.  My husband eventually found some in stock at a local Walgreens.  I've been taking it each day since, usually one first thing in the morning.  I don't notice any dramatic reaction to the SAM-e, but I've been doing generally better on steadiness of energy and oomph since then.

I hadn't tried SAM-e before.  Many years ago in Seattle my husband did try SAM-e, but stopped after a few days because it made him agitated.  I noticed in Dr. Lynch's presentation that SAM-e is a co-factor in the conversion of norepinephrine to epinephrine.  My husband also turns out to have the lame versions of COMT and MAO, so I imagine SAM-e supplementation potentially contributing to increased epinephrine production could be consistent with his earlier experience, and potentially a concern for both of us.

It's clear from the diagrams that SAM-e and niacin work against each other in some ways: niacin sponges up SAM-e methylation capability, and SAM-e acts as a co-factor to encourage norepinephrine to epinephrine conversion while niacin counteracts that effect and acts to encourage epinephrine breakdown.   If I understand right, the trick is to use enough niacin to keep epinephrine down to where I don't feel jittery and enough SAM-e to keep methylation, melatonin, etc. happy.

There's no way other than experimentation to tell whether that potential happy zone exists and is practically attainable for someone with their particular mix of circumstances and mutations.  I think my current strategy is working for me, but it's too early to tell if it'll lead to a stable result or cause other problems.  Please wish us luck!


  1. How did you do with this strategy?

  2. Hi Sue,

    I'm still doing it, and I still feel like it's helping. I've kept the SAM-e the same (one 200 mg tablet each morning), but have increased the dosage on the Niacin a couple times.

    I started with ~50 mg of the extended release niacin (~1/10 of a 500 mg tablet, roughly crushed, weighed, and put in capsules) twice a day -- morning and before bed -- plus sometimes another as needed when feeling particularly jittery. Now I'm putting about double that amount in each capsule, and keeping the timing the same.

    I experimented a bit with instant release niacin since Carlson's makes that in 50 mg doses, which sounded more convenient. However, I found that that much much more frequently caused a flush (the extended release doses only very rarely do for me), and it seemed to wear off too quickly. I toy with it occasionally for the sporadic jittery during the day usage, but mostly stick with smushing the extended release tablets into capsules.

    I notice that the times I forget it I often realize and regret it. Sometimes I wake up from disturbing dreams and/or wake sweating in the night and realize I forgot the before bed niacin. Sometimes I feel strangely jittery during the day and realize I forgot the morning niacin. I've taken to putting one in a little box in my pocket for such times.

    I'm also doing much much better in terms of energy, waking early, and wanting to be productive lately (started during trip to Amsterdam in early May for QSEU14 conference). I don't know to what extent the niacin/SAM-e strategy has contributed to that shift vs other factors (spring time, fresh salads from the garden, etc.), but I'm inclined to keep with what's currently working.

  3. Exactly the same situation with my husband. Had depression and anxiety all of his life and since he started Niacin two weeks ago, it is almost gone. It seems to depend on his stress level how much Niacin he needs. 2x50mg seems to be good at normal days, more at stressful days. Maybe he needs to increase dosage over time, I wonder. I also wonder about his overall methylation status. He tried Methylfolate and MethylB12 once with horrible results. He was so jittery that he even started physically shaking.I read the book from Dr. Walsh and we are considering SAMe. Will also try to measure homocystein to get an idea about his methylation status.
    I haven't red that much about this approach in Methylation because usually people try to get their methylation up and only using Niacin for slowing down side effects. But with COMT++ the strategy might be a bit different.
    I am curious: how are you doing now?
    Best, Violet

  4. Hi Anne, Thank you so much for sharing your experience. You story resonates with me. Everyday I am challenged by ongoing bouts of confusion, anxiety and jitters that come on with no rhyme or reason. In my job, I've noticed a signficant variation with executive functioning - which is non-existent under stress and deadlines. I too have had a similar experience with beta blockers. Three years ago I was diagnosed a condition called POTs which I thought that was at the root of my low energy and brain fog, started taking Inderal which helped immensely but for some reason I am not tolerating it as well now. For the past 3mos, I've been learning about methylation. I suspect that some of the reason I dont feel well is due to an imbalance of neurotransmitters. Like you I have significantly reduced COMT function (ValMet ++ and HC2H ++). I am also homozygous for MTHFR 677TT MAOATT and MTRR snyps. I have started supplementing with folate and B12 to get my methylation going. Now I am going to focus on supporting the COMT issues with small doses of SAM E and Niacin. Keep us updated on how you're doing and any articles you come across. Wishing you all the best on this journey. Here's to a healthy 2017!

    1. Its not mentioned in above posts but Dr Ben Lynch recommends SAMe to be taken at night. . . if taken at bedtime you should fall asleep within 30 minutes and it will help clear your dopamine and epinephrine during the night. Niacin is an energy so should be taken in the daytime (morning) unless using to bring down excess methyls. Niacin depletes SAMe so I wouldn't take them at the same time.

    2. I meant to add that you need to try the SAMe at night on a night and next day that doesn't matter as if your methylation isn't working correctly it could keep you awake all night!

  5. I tend to get all jittery when I take a supplement like folate or B12 on its own. They say they can work through the same pathways as cafeine, therefore stimulating adrenalin production. Makes sense. Strange thing is, doesn't happen when I take a B-complex. Vitamins seem to depend upon each other to balance things. Basically you can't take uppers without taking downers. I've suffered some pretty severe anxiety, hoping niacin can do something for me. I have several food sensitivities, so I'm hoping and praying it will. Good to hear that it worked for you.

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  7. You have the same SNPs for COMT and MAO A as my son. But I really though that homozygous TT for MAO A R297R is making the MAO enzyme faster not slower. I read on other blogs other ppl are suplemeting 5-HTP to increase their serotonin with a MAO-A TT mutation, yet you do the opposite. i am very confused on what action is should take for my son.