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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

I’m at the ASAM State of the Art Conference in Washington and just heard 2 really good talks on Addiction where food is the drug or overeating is the process. Of course, the presenters didn’t put it quite that way. The first talk was by Gene-Jack Wang who has done a lot of the neuroimaging in Addiction and found a lot of evidence that Addiction is a single disease. Unfortunately, he interprets his findings differently and so titled his talk, “Overlapping Neural Circuits in Addiction and Obesity.” You can see from the title of the talk the focus on obesity still doesn’t look at the disease but the result; we might as well try to study diabetes by focusing on people who lost their feet. The other place I differ with Dr Wang’s conclusions is that he interprets his findings to mean that it’s the increased dopamine reward response that makes us eat more. I don’t think that’s true for most of the addicts I treat, and they are the target of his work.

The second talk was by Eric Stice called “Reward Circuitry Responsivity Predicts Weight Gain.” While Dr Wang’s talk was quite good, it’s Dr Stice’s talk that really gives us some information we didn’t have. He presented a number of studies that built a picture of determines who gains weight over the next year and who doesn’t.  Right there, you can see this is new because he’s not talking about rats and he’s not looking at people after the fact. He’s looking at the biology that determines their eating, not the biology caused by their eating. Rather than going into all the studies he presented, I want to just give you the pricture he presented as I see it.

He showed that one would normally expect a dopamine response in the brain from food and even from thinking about food. He’s the first scientist I’ve heard who has said what addicts have long known, that the problem is low dopamine in the brain, not the dopamine from the drug.

In the studies they looked at people who had two different forms of the dopamine receptor. One form has a lower response to seeing the brain’s dopamine and the other was normal. So those with the first form will presumably have a lower dopamine tone and need more of something to feel the dopamine release caused by it. The second form will feel normal dopamine release with a normal reward. Let’s call these two forms of the dopamine receptor A1 and A2.

For the A1 people the less their brain lit up when presented with food, the more likely they were to gain weight over the next year. That makes sense because they will need more food to feel the dopamine. For the A2 people it was just the opposite. For them, the more their brain responded to food the more likely they were to gain weight. Both groups can become obese.

The A2 people seem to act like Dr Wang expects; they far outnumber A1 people at about 75% to 25%, so he would mostly see the A2 people. The A1 people are the people I’m used to seeing that come for treatment for addiction regardless of what food or behavior they use.

For A2 people the more rewarding foods are the more they’ll gain weight – just like Dr Wang suggests. However for the A1 people it’s the less reward they feel from food, the more they’ll eat to feel normal and the more they’ll gain weight. So not every obese person has Addiction, it depends on why they’re obese. Just as I’ve suggested with alcohol.

Again we come to the importance of knowing our genetic makeup. It’s really important for us to know what risks there are in genes so we can know how to modify our lives. Also, it’s important for treatment Dr Stice’s A1 people need augmentation of their dopamine tone so that they can eat less food and the A2 people perhaps need attenuation of their dopamine tone so they can eat less and lose weight. I recommend to all my patients that they go to 23andme.com to get their genetic testing done.

Growing up, I was taught that Jewish people couldn’t be alcoholics. That was a bit of wishful thinking. The people who taught me this rationalized it by saying that the Sabbath Kiddush socialized us in such a way as alcohol became something used only in a religious way. This never made sense to me as several Christian religions have sacramental use of wine and they didn’t report lower frequencies of alcoholism. So I just passed the whole thing off as a cultural myth and went about my business.

It turns out that Jews do have a lower frequency of alcoholism, but it has nothing to do with the religion or the culture. It’s in the genes.

As alcohol is processed in the body it is first turned from ethanol to ethylaldehyde on it’s way to becoming acetic acid. Ethylaldehyde, like formaldehyde, is not something the body likes, but it isn’t there long or in great quantities when the average person takes a drink. However a point mutation in the enzyme that turns ethanol into ethylaldehyde makes the enzyme run very fast and makes more ethylaldehyde than the body can process. It also gets rid of the ethanol more quickly. So someone with that mutation gets less enjoyment from alcohol and more of the aldehyde with its negative effects, it would sort of be like taking antabuse.

This point mutation is very rare in Europeans, occuring in less than 5%. In east Asians it is very common with more than 90% of Japanese and Chinese having at least one copy of the mutated gene. In Jews the prevalence is greater than 20% or more than 4 times higher than a European population. In fact more and more genetic studies are coming out showing Jews of European ancestry to be genetically more like a Middle Eastern population than a European one. (A professor from Jerusalem is hoping to ignite a grassroots peace process by showing that the Palestinian population are actually the Jews left by the Romans to man the farms in the area. It’s a fascinating topic with a lot of evidence but too much to get into here.)

So as Europeans go, a greater percentage of Ashkenazi Jews than normal “get no kick from Champagne.” This really would lower the prevelence of alcoholism in the Jewish population. However it doesn’t say much about Addiction in general.

If you look at Addiction as the addictions, depending on what drug the person uses, all you need to do is avoid the drug and you can’t get the addiction. But what if Addiction is one disease with multiple drugs? What if compulsive overeating and heroin addiction have the same common cause in the brain? That would mean that being protected from over drinking doesn’t protect someone from the illness called Addiction. This has become an important idea because recent findings at the National Institute of Drug Abuse show the same PET scan results in obese compulsive overeaters, alcoholics, cocaine addicts and heroin addicts.

There is no evidence that the disease of Addiction, taken together in all it forms, varies from population to population. The drug used does and some of that is genetic, but the genetic causes of Addiction seem to be old enough and strong enough to span across all human populations equally.

© Howard C Wetsman MD FASAM

Just swing a cat these days and you’ll hit a new paper on genetics in Addiction. This is how they usually go: “We got together a big group of people with addiction to a chemical and another group that doesn’t have addiction to that chemical. We measured single nucleotide polymorphisms (SNPs) of genes that we think may have to do with addiction to the drug and this is what we found.” The results are either positive or negative for a correlation between the group with addiction and a particular SNP. These studies are very interesting and usually end up in a lot of press response that “the gene for (fill in the blank) addiction has been found.” The problem is that there are a lot of problems with this common methodology and the studies don’t mean what everyone thinks they mean.

The first problem is selection of the subjects. Currently DSM IV divides Addiction (which it calls Substance Dependence) into different diagnoses based on the drug used. So when scientists go to select subjects they select for those with a particular DSM diagnosis. The problem is that a lot of things other than the illness go into what drug the person comes to treatment with. Culture, availability and family upbringing all have to do with what drug is used and confound the genetic biology of the illness. For instance, a good percentage of people that come to treatment for “opioid dependence” have a strong history of cocaine use. Many of these will say that they didn’t like cocaine much and didn’t use it much, but other’s will say that cocaine worked well to relieve the symptoms of Addiction, in fact it worked better than opioids, however the cocaine crash was horrible and opioids last longer. So biologically what’s the difference between someone who is using opioids because that’s the best drug and someone who is using opioids because it’s their second best drug and they don’t like the first because of a pharmacokinetic rather than reward phenomenon? We’ll never know if they both get stuck in the same group of opioid addicts for a study.

Another problem is the reporting of the SNPs that are associated with the addicted group without any knowledge of what the SNP does to the active protein. That, in itself, isn’t bad but most of these studies never hold out the possibility of the effect going both ways. It’s pretty easy to assume that if a receptor is mutated it doesn’t work as well as the normal, but that’s not a good assumption. There are many examples of polymorphisms where the mutation causes over activity rather than underactivity of the protein. For instance there is a commonly studied mutation of the COMT enzyme that breaks down dopamine. The people who did the original work didn’t say this but many people assumed that this meant that the mutation kept COMT from working and therefore there was too much dopamine causing enhanced reward and leading to drug use and abuse. However, it turned out that the COMT enzyme actually works better with this polymorphism and so one would suppose a lower dopamine level leading to underactivation and craving. The difference here may seem small but it leads to two entirely different world views of addiction: that drugs cause reward via dopamine and we should block the effect to stop drug use or that people who are addicted have a generally lower dopamine tone and need dopamine increasing treatments to stop using.

The third problem is that of using a SNP by itself. Increasingly, and I’m glad, studies are dropping associations with single SNPs for associations with haplotypes. A haplotype is a grouping of SNPs. For instance lets say that Gene A has 4 SNPs (1,2,3, and 4) each can be either A or G. The haplotypes would be groups of these combinations such as AAGA or AGGA. This is important because one SNP may change the way the protein works and another change it back or cause some other effect. So if we only look at the first one we’ll see an association that may not be there or fail to see one that is.

So, simply, these three problems stand in our way. Of course, there are more problems, but I’m keeping this simple. We don’t know the function of the SNPs we’re measuring and without that we don’t know what to do with the information. We don’t have biological divisions that make sense when testing subjects so we aren’t going to find out the biologically important information. And lastly we should focus on the thing that actually works, the whole protein, not a single amino acid in the protein and therefore we should study hapoltypes more so than single SNPs.

When these three problems get more attention it will become much more common that genetic studies inform treatment for illnesses, including Addiction. People like me who spend all day treating addicts will be much happier when this day comes. So all you genetic researchers out there, get too it. I need a whole lot more informing.

© Howard C Wetsman MD FASAM