Methylation is a crucial epigenetic process in the body that affects how various genes are expressed, contributing to chronic disease prevention, hormone and neurotransmitter regulation, and DNA repair. The ability to optimize methylation has been linked to mental health, with hypo- or hypermethylation increasing an individualβs risk for various mental health conditions, including anxiety, depression, bipolar disorder, and schizophrenia.
Considering methylationβs role in mental health disorders may be an essential component of a personalized health strategy to support mental well-being. Factors such as genetics, lifestyle, and even diet can impact methylation, and may also be used by practitioners to help support optimal methylation in those struggling with mental health.Β
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Basics of Methylation
Methylation refers to the process by which a methyl group is added to DNA, RNA, or histone proteins to modify gene expression, without impacting the actual DNA sequence itself. It is a reversible modification and plays a crucial role in gene silencing, or inactivation of a gene. Both excessive and reduced methylation can lead to various changes in physiological processes in the human body that can affect mood, hormone metabolism, DNA repair, and even inflammation. Methylation is crucial for normal growth and development, with enzymes known as DNA methyltransferases playing key roles in the process.Β Β
Methylation plays an important regulatory role in DNA transcription, replication, and repair, serving as a regulator of gene expression and gene integrity. For example, DNA damage such as a break in a strand can lead to an increase in methylation, which decreases gene expression while the gene is repaired. Once the damaged sections are removed and new strands are produced to replace them, methylation decreases and genes are expressed again, producing various proteins needed for metabolism.Β Β
When it comes to hormone regulation, methylation plays a key role in inactivation and detoxification of hormones, particularly catechol estrogens.Β Methylation essentially neutralizes harmful 4-OH estrogen metabolites via the catechol-O-methyltransferase (COMT) enzyme, allowing the body to clear out and eliminate estrogen metabolites without unwanted inflammation and DNA damage.Β
Methylation also impacts the neurotransmitter production of both glutamate and GABA, while also playing a role in the regulation of dopamine and serotonin. Irregular methylation can therefore impact levels of neurotransmitters, which may present as different mental health symptoms including anxiety, depression, and others.Β Β
Various factors can influence the rate of methylation, including genetics, diet, and lifestyle. Genetic variants such as variants of the MTHFR genes directly impact the rate of methylation, as they encode an enzyme that methylates folate and begins the process of methylation. Because many micronutrients are essential to the methylation process, including folate and other B vitamins, an individualβs diet may also positively or negatively impact methylation efficiency.Β Lifestyle also plays a role, with exercise, smoking, and alcohol use all linked to changes in methylation.
Methylation and Mental Health Disorders
Methylation abnormalities appear to be connected to various mental health disorders, including depression, anxiety, bipolar disorder, and schizophrenia. Higher or lower-than-average methylation activity has been identified in various studies of individuals with bipolar disorder and schizophrenia and has been linked to the etiology of other neuropsychiatric disorders including depression and anxiety. Additionally, DNA methylation has been associated with brain volume, structure, or function, with abnormal methylation potentially impacting how well the brain can perform and regulate various aspects of cognitive function and mood.
Methylation of various genes has been linked to anxiety, with early life stressors or ongoing chronic stress playing a role in the mechanism of how methylation is altered. Additionally, endocrine disruptors and medication use may also alter methylation and put individuals at risk of mental health symptoms like anxiety.Β Higher levels of methylation in particular have been linked to anxiety, with genes such as DNA methyltransferase (DNMT) genes, BDNF, and GAD-related genes all affected. BDNF and GAD genes impact cognitive function, GABA production, and regulation of other neurotransmitters, explaining the link between methylation of these genes and symptoms of anxiety. Methylation of genes including COMT, GAD65, and BDNF are also risk factors for the development of schizophrenia due to their impact on neurotransmitter behavior.
Variants in the MTHFR gene have also been studied for their potential impact on mental health. The MTHFR C677T polymorphism has been significantly related to the development of depression and bipolar disorder. These genes encode for DNA methyltransferases, enzymes that metabolize folate to its active form. The other main variant, the MTHFR A1298C, has been marginally linked to depression.Β Β
Additionally, life events (such as childhood maltreatment, trauma, and ongoing stress) as well as daily lifestyle choices (including diet, tobacco smoking, and alcohol use) modify DNA methylation levels and are also strongly associated with the risk of neuropsychiatric disorders, creating the potential for methylation modifications to contribute to the underlying etiology of mental health symptoms.
Diagnosing Methylation Imbalances
A root cause medicine approach to mental health includes analysis of methylation to help create a personalized treatment plan. Looking at various genetic variants and the status of micronutrients important to methylation can help practitioners ensure a patient has a comprehensive plan in place to support methylation based on their unique methylation profile.Β
The Methylation Panel by Genova Diagnostics looks at various genetic SNPs and methylation metabolites to gain a comprehensive understanding of an individualβs methylation ability. It reveals a patientβs nutritional support needs relative to the ability to properly methylate, and can be useful for understanding a wide array of symptoms, from mood disorders like anxiety or depression to chronic fatigue.Β Β
The DNA Methylation Pathway Profile by Doctorβs Data screens for different genetic variants that can impact the function of metabolic processes like detoxification, hormone balance, methionine metabolism, and vitamin D function. This test can be helpful for those individuals dealing with symptoms from systems related to the aforementioned metabolic pathways and provides a detailed analysis of how efficient oneβs methylation pathway is functioning. This can help support optimal mental health as the methylation pathway is vital for neurotransmitter production, hormone regulation, and DNA repair.
Elevated levels of the amino acid homocysteine can indicate methylation issues and are linked to a higher risk of cardiovascular diseases. The Homocysteine test from Access Medical Labs is particularly beneficial for individuals at risk for heart disease, or who have a family history of cardiovascular issues. By looking for elevated homocysteine levels, healthcare providers can recommend specific dietary interventions if need be to help reduce said levels, such as increased intake of methyl-nutrients like folate and other B vitamins.
Last, the Micronutrient Test by SpectraCell Laboratories can help identify any deficiencies in methyl-nutrients like folate, vitamin B6, and vitamin B12, all important cofactors in methylation that must be present in adequate levels for methylation to occur.Β
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Nutritional Interventions to Support Methylation
The link between nutrition and methylation status is an important connection to understand to support methylation and create an effective, personalized plan to support mental health and overall well-being. Micronutrients including folate, vitamin B6, vitamin B12, betaine, and choline are all important cofactors needed for methylation to occur properly. These methyl-nutrients can impact the function of DNA methyltransferases and limit the availability of methyl group donors needed for methylation to occur.
DNA, RNA, and histone methylation are all dependent on folate as a source of carbon donation needed for methylation to occur. Under normal conditions in the body, folate from the diet is metabolized to 5-methyltetrahydrofolate (5-MTHF) with the enzyme MTHFR. 5-MTHF goes on to methylate the amino acid homocysteine to methionine, with methionine being the precursor to SAM, the primary methyl group donor in methylation. So, both folate and the amino acid methionine are important for SAM production and the process of methylation itself.
Other B vitamins, including B6 and B12, also work in conjunction with folate for that initial 1-carbon donation and also help to manage homocysteine levels and keep cardiovascular risk at bay. Betaine and choline are also important for methyl group donations important to methylation and can aid in regulating levels of SAM and homocysteine.Β
To support methylation, incorporating a wide range of nutrient-dense foods into the diet is key for patients looking to support mental health. Foods rich in the methyl nutrients described above promote overall well-being by supporting efficient methylation and reducing the risk of experiencing mental health symptoms.Β
Folate is found in leafy greens like spinach, kale, and Brussels sprouts, and also in legumes such as lentils and chickpeas. Those with MTHFR mutations may need a higher intake of methyl folate through supplementation because the gene impacts how effectively the body can metabolize folate to its active form.
Choline is mostly found in egg yolks and chicken liver (or other organ meats), and to a lesser extent in broccoli, soybeans, and brussel sprouts. Supplementation may be important for those following a plant-based diet to ensure adequate intake and can be guided by functional medicine lab testing.Β
βCholine has neuroprotective effects and plays a role in the production of the neurotransmitter acetylcholine, further contributing to mental health and neuroprotective effects beyond methylation as well. Betaine can be consumed through wheat germ, spinach, beets, and shellfish.
Vitamin B6 is found in foods like poultry, fish, potatoes, and non-citrus fruits, while vitamin B12 is typically obtained from meat, fish, or dairy products.
The amino acid methionine is found in animal products like meat or fish, or nuts and seeds, particularly Brazil nuts.Β
Lifestyle Modifications to Enhance Methylation
Lifestyle modifications play an important role in methylation and may positively or negatively influence the efficiency of the methylation pathway. Considering sleep quality, stress management, exercise, and minimizing toxin exposure are all practical ways that patients can help support healthy methylation and mental well-being.
Sleep quality has been linked to changes in methylation, with poor sleep decreasing the rate at which methylation occurs or a loss in methylation altogether. Sleep deficiency has been linked to an array of mental health symptoms, including mood swings, depression, anxiety, anger, and low motivation. Prioritizing sleep hygiene and taking steps to get more restorative sleep can help optimize methylation and support mental health.Β Β
Stress management is also key for supporting methylation and mental well-being, with stress having links to altered methylation even from a young age in life. Stress-related disorders including post-traumatic stress disorder and major depressive disorder have been found to have changes in methylation efficiency, and methylation ability may serve as a biomarker of risk for stress-related neuropsychiatric disorders. Stress management techniques including mind-body therapies, restorative movement, or therapy can help support the reduction of stress levels and help to restore efficient methylation while also supporting mental health and wellbeing.Β Β Β
Exercise can also modulate DNA methylation throughout the body and as a result can help reduce the risk of chronic disease and mental health symptoms. Physical exercise supports mental clarity, reduces the risk of neurodegeneration, and contributes to a sense of overall well-being.Β
Last, being mindful of exposure to environmental toxins and supporting detoxification pathways can be a key action step in supporting healthy methylation. Methylation plays a key role in detoxification, with impaired methylation affecting our ability to detoxify efficiently. Various environmental pollutants have been linked to a higher risk of psychological distress and cognitive decline, underlining the importance of limiting toxin exposure for good mental health.Β
These exposures have also been linked to changes in DNA methylation, underlining the intimate connection between methylation, detoxification, and mental health. A root cause medicine approach to supporting detoxification can be helpful for those looking to reduce their toxin exposure and support their overall health and well-being.Β Β
A Root Cause Medicine Approach
A root cause medicine approach to supporting optimal methylation can complement conventional psychiatric treatments for various mental health disorders. Conventional approaches are often aimed at reducing symptoms and trying to affect brain neurochemistry through medication use and psychotherapy.
While these approaches may be important to help with a patientβs quality of life, they often overlook the root cause etiology of mental health symptoms, which may include abnormal methylation or other changes in biological processes. Supporting methylation and identifying any individual genetic variants that may impede efficient methylation can help personalize a plan to support optimal health and set up an individual for long-term success by empowering them to support their unique physiology.Β Β
Integrative approaches to mental health conditions are becoming more mainstream, with studies linking various therapies to improvement in symptomatology. For example, SAM supplementation is a second-line treatment for depression due to its beneficial impacts on methylation efficiency, while the combination of SAM, folate, and B12 is being studied for its effect on mood disorders in general. Supporting methylation can be a great complement to conventional therapies to truly support those with mental health disorders in a highly personalized way.Β
Challenges and Future Directions
While supporting methylation as a means of addressing mental health disorders is a promising intervention, there is a wide variability of individual responses to methylation support strategies and a need for further research to explore supplement dosages and dietary interventions to reduce symptoms effectively. Methylation is a highly variable process, and too little or too much methylation activity can lead to unwanted consequences for gene expression.
Additionally, the etiology of mental health conditions is complex and methylation is just one variable that affects the development and severity of symptoms and must be evaluated in relationship to each personβs unique presentation. Each individual may have different genetic variants, lifestyle factors, and stress levels that affect how well they respond to treatment plans that support methylation, and the research into genes related to methylation is still relatively new.Β Β
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Key Takeaways
Methylation plays a critical role in mental health disorders, with methylation abnormalities linked to a higher risk of anxiety, depression, bipolar disorder, and schizophrenia.
Evaluating and supporting methylation can help with a more personalized approach to the treatment of mental health symptoms, one that considers each personβs biochemical ability to function optimally and how that may contribute to the development of symptoms.
Methylation-focused strategies in mental health care can provide another layer of personalized care to enhance patient outcomes and can help support processes including detoxification, hormone balance, and DNA repair that may contribute to mental health symptoms but arenβt being addressed in a conventional care model.Β Β
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