Almost everyone has heard of the B vitamin, folate or the form you can commonly buy in a drug store, Folic Acid. Folate is used by many biological processes to donate methyl groups to other compounds. Its active form is L-methylfolate which is produced through a reaction catalyzed by Methylenetetrahydrofolate Reductase (MTHFR). So if there’s a problem with MTHFR, then folate isn’t activated into L-methylfolate and there aren’t the methyl groups needed for all the biological reactions they’re used for. Mutations in this enzyme have been linked to everything from heart disease to cancer, but not, until recently, addiction. It turns out that L-methylfolate is needed to donate a methyl group during the production of all three monoamine neurotransmitters, serotonin, dopamine, and norepinephrine. That means that a reduction in the function of MTHFR can lead to a reduction in the production of all three.
I’ve been on the hunt for any mutations that can lead to functional changes that affect addiction in any way, especially those that are measured by 23andme ( 23andme.com ), a service I recommend to all my patients. I recently ran across a paper in the 2008 Proceedings of the National Academy of Sciences that gave a great list of MTHFR SNPs in humans, which ones changed function and which ones were remediated by adding more folate. (Marini, et al . The prevalence of folate-remedial MTHFR enzyme variants in humans. PNAS 105, no 23: pp 8055-8060.) The study was focused on function of the enzyme and they noted that the only mutations that effected function were in the catalytic region as opposed to the regulatory region. Of course someone with a problem in the regulatory region may not make enough enzyme so even with good function may have a problem. This study did not address such people.
Of the polymorphisms in the catalytic region, five only effected 0.1% of the alleles tested and one effected 29% of alleles tested. That more prevalent one is the A222V mutation, rs1801133. It is tested for by 23andme, it does impair the function of the enzyme and it is remediable by folate. Those who are heterozygous for the SNP have 65% of enzyme activity and homozygotes only have 33%. Of the other rare polymorphisms in this region, only one, rs45550133, was not folate remediable. It is not tested for by 23andme.
There were seven SNPs found in the regulatory region, all of which effected less than 1% of alleles except two. Those two are both tested for by 23andme, rs1801131 (23.6%) and rs2274976 (4.4%). Neither had functional effects. There are a number of studies that show a difference between those with rs1801131 and those without but it is not clear from what I’ve read whether that difference represents over or underexpression of the gene. While underexpression is most likely, I would not want to hazard a guess at the moment. There’s not much on rs2274976 that I can find. Hypothetically if someone had a mutation that caused a decrease in function but another that caused them to make extra copies of the enzyme, it could balance out so it’s important to know about the regulatory SNPs.
But, putting the regulatory SNPs aside right now and focusing on rs1801133, the question is should someone with the mutation take extra folate. Most of what I can find says yes. There are some writers who suggest that since the enzyme doesn’t work well, adding folate won’t help but will just back up the system, but the Marini study suggests that function is returned to normal with adding folate. The other option is to take L-methylfolate directly. It isn’t clear what one should do from the literature. It’s also not clear that there should only be one intervention for the problem. You might need one treatment to lower risk of gastric cancer and a different one to boost dopamine production. On top of that, there are many other enzymes involved in single methyl group metabolism and there’s probably a great deal of interaction so that someone with a MTHFR mutation and no other mutation needs a different intervention than someone who has the same MTHFR mutation and a mutation in another related enzyme as well.
However, having made all those disclaimers, taking extra folic acid or even L-methylfolate, both of which are over the counter, seems a pretty benign thing to do if you’re in treatment for addiction and things aren’t going well. Getting your genetic testing via 23andme or some other such company seems like a no brainer, as long as you don’t mind finding something your doctor doesn’t exactly know what to do with yet.
© Howard C Wetsman MD FASAM