Courtney Snyder, MD
Before I delve at length into the amazing process of methylation and its impact on personality and mental health, I'll lay some groundwork. For those who don't need or want such background, I've tried to make it easy for you to hit the highlights or jump ahead to your own starting point.
Genetics is basically the study of how parents pass some of their characteristics to their children. Genes are the units by which this occurs. The job of a gene is to make a specific protein. We have two of each gene - one from our mother and one from our father. Every cell in the body has the same genes, but only some of those are used/expressed in each cell. This selective expression is what allows our brain to be a brain and our liver to be a liver and not the other way around.
Despite our incredible diversity, we all generally have the same genes as others of our same sex. We are only about 0.1% different from one another. SNPs or Single Nucleotide Polymorphisms are genetic mutations that developed over thousands of years. Of more than 10 million SNPs identified in the human genome, most of us have more than (but closer) to one thousand. Those that are expressed explain some of our differences including our unique vulnerabilities to certain health conditions. If you’ve ever looked at your SNPs, this can be a bit frightening. For many, doing so can cause more harm than good. Most of these mutations or SNPs are never expressed and have no significant effect. Walking around thinking you are destined for a serious or fatal health condition when you're not, can be a problem.
Until recently we believed our genes and mutations were written in stone. We now know that during pregnancy, chemical bookmarks (methyl groups) can attach to DNA to enhance or inhibit gene expression in each tissue. Environmental insults in utero can produce deviant bookmarks resulting in more serious conditions or birth defects. Throughout our lives, a severe environmental insults can alter these bookmarks and produce an epigenetic disorder. Such insults can be psychological/emotional (inadequate or disrupted attachment, trauma, severe stress) or physical (exposures to toxic metals, radiation, chemicals). This field of research is called "Epigenetics" and it is revolutionizing our understanding of cancer, heart disease, developmental disorders such as autism and psychiatric disorders all which seem to be epigenetic in nature.
With this comes good news - we have a degree of control over the expression or the turning on or off of our SNPs. Many disorders previously thought of as genetic and untreatable, are actually epigenetic and treatable using certain nutrients and/or lifestyle changes that powerfully affect gene expression.
The most dominant factor in epigenetics is methylation. This is a biochemical process, which occurs a billion times every second, and involves the addition of a methyl group to an atom or a molecule. Meet methyl with it's carbon and three hydrogen atoms:
I'm including a "simplified" diagram below, only to make two points about the process of methylation:
#1 - Its complicated
#2 - There are a number of genes (in colored boxes) which collectively determine how much methyl someone has. Certain genes, including the infamous MTHFR, if expressed can result in undermethylation (not enough methyl), while others, such as CBS, if expressed can result in overmethylation (too much methyl).
The most important methylation gene is MTHFR. While having a mutation at the C677T location can result in someone having undermethylation, this isn't always the case. It is possible (though less likely) to be homozygous (have both genetic mutations) for MTHFR C677T, and have normal methylation or even be overmethylated. The presence of the genes matter less than whether or not they are expressed. What matters most is the net sum of all of the expressed methylation genes.
Accurate diagnosis of someone’s methylation status is essential for treatment. A convenient and simple marker for methylation status is the whole blood histamine test. This is because methyl is the primary mechanism for breaking down histamine. If you have a low histamine level, your methyl is too high. If your histamine is high, your methyl is low.
Aside from playing a role in whether or not our genetic mutations are expressed, methylation is essential for almost every system in our body, including:
A database of 30,000 people by Dr. William Walsh, PhD (referred to by some as the father of methylation) found that 60-70% of people have normal methylation, 22% undermethylation (too little methyl) and 8% overmethylation (too much methyl). Abnormal methylation doesn’t translate to mental illness. Many highly successful CEO’s and athletes are undermethylated and many talented artists, writers and musicians are overmethylated. Of individuals with behavioral or mental disorders, however, 70% have a serious methylation imbalance. This is due to the impact of methylation on both genetic expression and on neurotransmitter activity.
Nutrient therapies for methylation imbalances aim to normalize methylation, which normalizes neurotransmitter activity, which can alleviate symptoms. For example, methionine and SAMe are serotonin "reuptake inhibitors" and thus increase serotonin activity at the receptor site. Folate reduces synaptic activity of serotonin, dopamine and norepinephrine at the receptor site. For me, as a psychiatrist, this is incredible. For many struggling with brain related disorders, addressing methylation can mean never needing to start on medication. For others, treatment of a methylation imbalance can mean coming off or being on less or fewer medications. In some cases, such as when there is toxicity, such as mold toxicity, methylation treatment may not be tolerated until this is addressed first.
What has been both fascinating and satisfying for those of us who have trained with Dr. Walsh, is being able to often predict someone’s methylation status even before seeing lab results.
UNDERMETHYLATION: [Think low methyl, high folate , high histamine and low neurotransmitters (serotonin and dopamine) activity.]
Symptoms & Traits:
The Incidence of Undermethylation:
Nutrient therapies, which include methionine and/or SAMe, aim to increase methionine and increase serotonin activity. Because folate reduces neurotransmitter activity and these individuals are already low in neurotransmitter activity, folate should be avoided. In fact for better brain health, these individuals do better on a high protein diet (and thus high in methionine). They should avoid supplements that contain folic acid.
******Because multivitamins usually contain folic acid, they're problematic for many individuals with mental health symptoms. They contain copper and copper overload too, is very common in brain related disorders.
OVERMETHYLATION: [Think high methyl, low folate and high neurotransmitter (serotonin, dopamine and norepinephrine) activity.]
Symptoms and Traits:
The Incidence of Overmethylation:
Nutrient therapies aim to increase folate and thus lower what is high neurotransmitter activity. Most important is folic acid, which reduces neurotransmitter activity. Niacin/niacin-amide also lowers dopamine activity. These individuals will do better with a high folate diet (veggies and fruit) as opposed to a high protein diet.
THE FUTURE OF PSYCHIATRY
Knowing that someone is depressed or psychotic or manic doesn’t tell you if they are undermethylated or overmethylated. It also doesn't tell you if they have copper overload, metal toxicity or pyrrole disorder - the other common biochemical imbalances. If everyone with depression took an antidepressant that raises serotonin activity, those with undermethylation would likely have significant benefit, however, those with overmethylated would likely get worse. Tragically for some, this can mean suicide or even homicide. Currently in conventional psychiatry, there's no specific way to know who those people are. Dr. Walsh's biochemical approach removes that guess work. His database and research informs physicians on how to evaluate and treat methylation disorders (and other nutrient imbalances) using targeted nutrient therapies.
The fact that many conventionally trained psychiatrists are testing for MTHFR C677T and using the highly promoted methylfolate (Deplin) show that the psychiatric field is starting to grapple with these important concepts. However, adding Deplin to an antidepressant is missing the mark. Some may benefit; many will not and some will get worse. Again a mutation at the MTHFR gene doesn't tell you someone's methylation status. Also, if someone is undermethylated and depressed and likely low in serotonin, they can become more depressed if given more folate. To quote Dr. Walsh (from an interview on the ACN website)
"... blindly using methylfolate (Deplin) for patients with C677T MTHFR or other weakened enzymes can produce negative results in patients afflicted by low serotonin activity. Folate supplements including Deplin tend to drive serotonin activity even lower.... The bottom line is that methylfolate and other folate supplements are very effective in enhancing methylation for autism and other conditions that are not dominated by low serotonin activity." (apathetic depression and anxiety typically involve low serotonin activity)
Thank you for sticking with this lengthy post. My hope with some of these early articles (ie. on the microbiome, nutrient therapies and copper overload) is to provide resources and background for those wanting to better understand these complicated issues. Having done this, I look forward to more specific and shorter posts.
If you'd like to go deeper into these topics, I recommend the following book and youtube videos:
Nutrient Power: Heal Your Biochemistry and Heal Your Brian - book by William Walsh, PhD
The Role of Methylation and Epigenetics in Brain Disorders - video presentation by William Walsh, PhD
"MTHFR and Mental Health: Understanding the Overall Effect of Individual Genetic Mutations SNPs" - video presentation by Dr. Albert Mensah
If you're looking for a physician trained in this area or are a physician interested in training, visit the Walsh Research Institute.
I'm a conventionally trained child, adolescent and adult psychiatrist. My current approach to health is both holistic (pertaining to the whole person) and functional (addressing the root causes of illness). I write this blog to share what I've learned.