Why MTHFR genetic test and therapy with methylated folates is not advisable for treating undermethylated persons with depression or other mood disorders.
MTHFR genetic test is a predictor of one element of methylation biochemistry. But persons who are undermethylated also have low serotonin. And folic acid lowers serotonin in the brain by increasing teh expression of SERT, serotonin reuptake transporter proteins.
There is a great deal of confusion on the internet and in clinical practices among those who advocate methylated folate treatments for low serotonin depression. In many cases, patients have been tested for genetic mutations and found to have the MTHFR or COMT genetic SNP.
The argument has been that by increasing methylation, based solely on genetics, with methylated folates, that methylation will improve. Biochemically this is correct, supplementing with folic acid will increase methylation if someone is deficient. And if there is in fact low methylation, improving folic acid can in some cases be of benefit. But there are over 70 genes involved in various aspects of methylation. Just because we are familiar with these particular genes does not give enough of a picture to make a strong case for treating with methylated folates. Biochemically we can improve methylation, but the problem is that methylation affects many systems and so does folic acid. For instance, persons with mood disorders such as depression, autism, ADHD, OCD and schizophrenia often do have undermethylation. The consequence is that they have reduced activity of serotonin and dopamine. But folic acid has a greater effect in lowering dopamine by a mechanism related to a enzymes in the brain called serotonin and dopamine reuptake transporters.
Pharmacological Research History: Since biochemistry revolution in psychiatry began in the mid 1960’s, it was learned that many persons with depression and mood disorders had low serotonin. Treatment regimens focused on medicines that increase serotonin at the nerve synapse, where the impulse from one nerve is carried to the next by the presence of serotonin once released at the junction. Drugs like MAO inhibitors increased serotonin at the synapse. Cofactors such as 5HTP and tryptophan were given to increase the production of serotonin. To some degree this was effective. However, in the mid 1980’s it was learned that a greater influence on serotonin neurotransmission is the rate of serotonin reuptake from the synapse after neuron firing. Psychiatry once again changed and treatment focused on serotonin reuptake by medicines classified as SSRI’s, such as Prozac, Lexapro, Celexa, Paxil Zoloft and Viibryd. These “selective serotonin reuptake inhibitors” increase the time that the neurotransmitter activates the receptors at the synapse, once released into the synaptic space.
Conventional Nutrient Therapy: Since the advent of epigenetic research and the influence on DNA expression by methylation, it has been learned that a far more powerful impact can be had with nutrients that alter the gene expression of serotonin reuptake transporter proteins, “SERT proteins. SERT proteins can be regulated by nutrients that have an epigenetic influence on the DNA that releases these reuptake proteins. Methylators, such as SAMe and methionine inhibit the genetic expression of the transport proteins and thereby cause serotonin to remain present at the synapse longer. In other words, they behave similarly to how we believe SSRI drugs work, only they do so naturally. Methionine and SAMe are products of a biochemical process that takes place in all cells of the body, called the One Carbon Cycle.
Methylation is important in the product of serotonin and we now understand that it is even more important in the function of the DNA among brain cells that produce SERT proteins.
By increasing methylation, serotonin increases through production, and it also increases by the action of inhibiting the SERT reuptake transporter proteins.
Where the problem arises is that while many seem to understand that increasing methylation improves serotonin production, most do not recognize that folates, do more than improve methylation production within the one-carbon cycle. They also accelerate the expression of SERT transport proteins. By doing so, they reduce serotonin presence at the synapse and so lower the activity of serotonin. In other words, they increase production of serotonin, but lower the activity of it at the synapse.
Treating depression with folates, methylated or otherwise, is not advisable unless it is clear whether or not the depressed patient is experiencing overmethylated depression or undermethylated depression. Undermethylated depressives have an excess of serotonin reuptake and so low serotonin activity. Overmethylated depressives have low serotonin reuptake and a high level of serotonin activity.
It is extremely important that folates are not given without clarification of one’s methylation status. Nutritional therapy for undermethylated persons involves supplements that support the One-Carbon Cycle throughout the cycle.
While we understand that genetic mapping helps us predict the likelihood methylated folates will be important to improve methylation, it does not accurately reflect the actual methylation status. There are more that 70 genes involved in the influence of methylation.
A more useful test is whole blood histamine and homocysteine, plus a detailed history of symptoms and medications use. Low whole blood histamine is typically associated with high levels of serotonin and may be treated with supplements that increase SERT protein activity. High whole blood histamine correlates with low serotonin. For these we treat with methylation therapy and restriction of folates, acetylators and other nutrients. This must be done carefully since lowering serotonin of someone who is depressed with low serotonin will likely worsen their condition. As will increasing serotonin in a depressed person with elevated depression.
- Methylation increases serotonin production
- Methylation reduces SERT transporter protein action
- One Carbon Cycle is a biochemical pathway that produces methylators SAMe and methionine
- Folates are involved in the methylation cycle, thereby increasing methionine and SAMe
- Folates, methylated or not, have a more pronounced influence on increasing the activity of SERT transporters and thereby lower serotonin activity. Without a proper test, treating depression with folic acid is not advisable.
- It is important to utilize a test such as whole blood histamine and homocysteine along with a good history taking prior to attempting to treat a patient with methylation therapy.
(Video of William Walsh PhD from the Walsh Research Institute elaborating on depression and methylation)
A good history can help determine one’s methylation status
In addition to the complexities of interpreting a methylation lab test, there are a good number of similar symptoms shared by overmethylators and undermethylators and for that reason alone it is important to get a qualified physicians impressions.
While it is not advisable to treat with medications or even nutritional supplements, some symptoms can be predictive of methylation status.
Common Signs and Symptoms among Undermethylators
- Chronic depression
- Oppositional Defiance
- Obsessive Compulsive Disorders
- Psychosis prior to the onset of depression or other conditions.
- Strong willed
- Seasonal allergies
- Elevated libido
- Competitive in sports
- Overachiever prior to the onset
- Protein deficiency and vegetarian diets
- Tends to do better on SSRI medications
- Tends to do well with antihistamines
Common Signs and Symptoms among Overmethylators
- Acute depression
- Panic disorders
- High anxiety
- Schizophrenia with auditory hallucinations
- Dry eyes
- Highly artistic, sociable and empathetic
- Poor response to SSRI medications
- Poor response to antihistamines
- Food and chemical sensitivities
- Not typically competitive