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!