Exploring the Use of Advanced Testing for Methylation Pathway Imbalances in Undermethylated Individuals: An Evaluation of SAH, SAM, Methionine, and Homocysteine Levels and Nutritional Treatment Strategies
Determining Methylation Status in Undermethylators and Overmethylators: The Role of Whole Blood Histamine
Dr Walsh trained physicians utilize two tests for measuring methylation status. The easiest and most accurate general assessment of both undermethylation and overmethylation is whole blood histamine. This test is used as an indirect measure of methylation as research suggests that methylation plays a role in regulating histamine metabolism and breakdown, particularly in the central nervous system and other tissues outside the gut. This is in contrast to DAO, which is primarily responsible for breaking down histamine in the gut. Dr. William Walsh has found an inverse correlation between methylation status and whole blood histamine levels in patients who exhibit symptoms of undermethylation. Whole blood histamine is primarily metabolized through two pathways, with methylation by histamine-N-methyltransferase (HNMT) being a key step in histamine metabolism and responsible for the breakdown of a significant portion of histamine in the body. Research suggests that methylation status may influence the activity of HNMT and, therefore, impact the regulation of histamine levels in the body. For example, low methylation status has been associated with decreased HNMT activity and increased histamine levels in some studies, indicating that methylation may play an important role in regulating histamine metabolism and preventing histamine accumulation in the body.
The Methylation Pathway and Its Impact on DNA Function; The Plasma Methylation Pathway Panel
Natural methylation processes in the body can enhance brain DNA cellular activity and decrease the output of reuptake promoters, providing a non-pharmaceutical alternative to conventional antidepressant therapy. Methylation is a chemical process that involves the transfer of a methyl group (-CH3) to a molecule, and it plays a crucial role in gene expression and regulation. Methylation can affect neurotransmitter production and function by influencing the expression of genes involved in neurotransmitter synthesis and breakdown.
By identifying genetic variations in the methylation pathway and providing targeted nutritional support, it is possible to optimize methylation processes and neurotransmitter function. This can potentially improve mood and reduce symptoms of depression by enhancing the brain's ability to regulate mood-related neurotransmitters such as serotonin, dopamine, and norepinephrine. This approach can be particularly beneficial for individuals who do not respond well to conventional antidepressant therapy or who experience significant side effects from antidepressant medications.
In contrast to selective reuptake inhibitors (SSRIs), which specifically target the reuptake of serotonin, natural methylation processes can influence neurotransmitter production and function more broadly, potentially providing a more holistic approach to mood regulation. While more research is needed to fully understand the efficacy of this approach, it offers a promising non-pharmaceutical alternative to conventional antidepressant therapy.
The Significance of the Methylation Pathway in Cellular Function and Health: Implications for Disease and Potential Therapies
The methylation pathway is a biochemical process that is essential for the proper function of cells in the body. It involves the transfer of a methyl group (a carbon atom with three hydrogen atoms attached) from a molecule called S-adenosylmethionine (SAM) to other molecules, including DNA, proteins, and neurotransmitters. Methylation of DNA can impact gene expression, which can affect cellular function and health. Specifically, methylation can turn genes on or off, and alterations in the pattern of DNA methylation can lead to changes in gene expression, which may contribute to the development of various diseases, including cancer, autoimmune disorders, and neurological conditions. Therefore, understanding the methylation pathway and its effects on DNA function is crucial for understanding and potentially treating various health conditions.
Natural Methylation Processes as a Non-Pharmaceutical Alternative to Conventional Antidepressant Therapy
Natural methylation processes in the body can enhance brain DNA cellular activity and decrease the output of reuptake promoters, providing a non-pharmaceutical alternative to conventional antidepressant therapy. Methylation is a chemical process that involves the transfer of a methyl group (-CH3) to a molecule, and it plays a crucial role in gene expression and regulation. Methylation can affect neurotransmitter production and function by influencing the expression of genes involved in neurotransmitter synthesis and breakdown.
By identifying genetic variations in the methylation pathway and providing targeted nutritional support, it is possible to optimize methylation processes and neurotransmitter function. This can potentially improve mood and reduce symptoms of depression by enhancing the brain's ability to regulate mood-related neurotransmitters such as serotonin, dopamine, and norepinephrine. This approach can be particularly beneficial for individuals who do not respond well to conventional antidepressant therapy or who experience significant side effects from antidepressant medications.
In contrast to selective reuptake inhibitors (SSRIs), which specifically target the reuptake of serotonin, natural methylation processes can influence neurotransmitter production and function more broadly, potentially providing a more holistic approach to mood regulation. While more research is needed to fully understand the efficacy of this approach, it offers a promising non-pharmaceutical alternative to conventional antidepressant therapy.
Why Selective Reuptake Inhibitors (SSRIs) Are More Commonly Used than Earlier Generation Antidepressants and the Promise of Non-Pharmaceutical Alternatives for Treating Depression
Selective reuptake inhibitors (SSRIs) are used more commonly than earlier generation drugs such as MAO inhibitors because they specifically target the reuptake of serotonin, which is found to be a more important mechanism in neurotransmission than the increase of serotonin and dopamine levels achieved by MAO inhibitors. SSRIs are thought to have fewer side effects than earlier generation drugs, such as MAO inhibitors, and have a wider therapeutic window, allowing for safer dosing. However, while SSRIs can be effective for some patients, they are not effective for everyone and may have significant side effects, such as sexual dysfunction, weight gain, and insomnia. Given the limitations of conventional antidepressant therapy, the use of non-pharmaceutical approaches, such as methylation pathway identification and nutrient support or inhibition, offers an alternative approach to treating depression. By identifying genetic variations and providing targeted nutritional support, it is possible to optimize neurotransmitter production and function, potentially improving mood and reducing symptoms of depression. While more research is needed to fully understand the efficacy of this approach, it has the potential to offer a safe and effective alternative to conventional antidepressant therapy.
Why the DDI Methylation Panel is a More Comprehensive Assessment of Methylation Status Than Genetic Testing
The DDI methylation panel provides a more comprehensive view of an individual's methylation status than an MTHFR genetic test. While the MTHFR gene is involved in the methylation cycle, it is just one of many genes and enzymes involved in the complex process. Additionally, genetic testing only provides information on potential mutations or variations in the MTHFR gene, but does not necessarily reflect the actual activity or expression of the gene. On the other hand, the DDI methylation panel measures actual levels of SAMe, SAH, and other key metabolites involved in the methylation cycle, providing a more accurate assessment of an individual's methylation status. Furthermore, the DDI methylation panel can help identify underlying nutrient deficiencies or imbalances that may be contributing to methylation issues, which cannot be detected through genetic testing alone. Overall, while genetic testing can provide useful information, the DDI methylation panel offers a more comprehensive and personalized assessment of an individual's methylation status.
The Role of Methylation in Neurotransmitter Production and Mental Health: The Walsh Approach to Personalized Treatment
Methylation is a process that involves the transfer of a methyl group (-CH3) to a molecule, which can affect its function. Methylation plays a significant role in the production of neurotransmitters such as serotonin and dopamine. Increased methylation can lead to increased production of these neurotransmitters.
However, as taught by Dr William Walsh PhD, the activity of neurotransmitters like serotonin and dopamine is more important than their production. This is why newer antidepressant medications selectively inhibit reuptake to allow for more precise modulation of neurotransmitter activity. For example, selective serotonin reuptake inhibitors (SSRIs) work by binding to the serotonin transporter (SERT) and reducing the reuptake of serotonin.
Undermethylation, which is characterized by low levels of SAMe and or methionine and high levels of S-adenosyl homocysteine (SAH), can impact the activity of the SLC6A4 gene that encodes for SERT, leading to an increased production of both SERT and DERT. This can result in a lower presence of the neurotransmitters serotonin and dopamine, which can contribute to depression, autism, and other mood disorders. Some B-Vitamins can actually accelerate this reuptake process. Targeted nutrient therapy protocols developed by Walsh, recognize the importance of testing all patients methylation status with either a whole blood histamine test or plasma methylation panel. Because undermethylators and overmethylators have different degree of activity of the SERT and DERT transport proteins, their therapy protocols must is entirely different. It is important to note that prior to taking medicines or supplements that affect reuptake, some persons with depression are overmethyated and some are undermethylated. This is one major reason persons may perform terribly to SSRI medications and certain B-vitamins, while others do very well.
At Second Opinion Physician, our telemedicine practitioner is a Walsh-trained physician who specializes in treating mood disorders using the Walsh Approach. Dr. William J. Walsh is a prominent researcher and educator in the field of methylation study and trains physicians worldwide in this approach. By using a comprehensive methylation panel, our practitioner can provide a personalized treatment plan for individuals with mood disorders based on their unique methylation status. This can lead to improved outcomes and quality of life. It's important to understand the complex interplay between genes, neurotransmitters, and mental health to inform more targeted and effective treatment approaches.
The Crucial Role of SAM/SAH Ratio in Evaluating Methylation Status and Managing Elevated SAH Levels
Importance of SAM/SAH ratio in evaluating methylation status
Dr. William Walsh considers the SAM/SAH ratio to be a crucial factor in determining a patient's methylation status. This ratio is calculated by dividing the level of S-adenosylmethionine (SAM), the primary methyl donor in the body, by the level of S-adenosylhomocysteine (SAH), a byproduct of methylation that inhibits the methylation process. A ratio of 3.5 or less indicates undermethylation, which means that the patient's methylation process is not working optimally. This can have far-reaching consequences for their health, including potential psychiatric and neurological symptoms.
Elevated SAH levels and their significance
When a patient has significantly elevated SAH levels (well above 50th percentile), it indicates a block in the conversion of SAH to homocysteine and adenosine. This block can be caused by several factors, such as a genetic variation in the SAHH enzyme or impaired metabolism or removal of homocysteine or adenosine.
Dr. Walsh has some objections to the levels defined as normal by the lab that prepares the DDI methylation panel. Specifically, he emphasizes the importance of the SAM/SAH ratio as the best index of methyl status, especially in cases involving patients with high SAH levels. However, the DDI report does not seem to provide a clear interpretation of this ratio or its significance in relation to methylation status.
Moreover, Dr. Walsh also points out that the DDI reference range for undermethylation is too narrow, and that the SAM/SAH range of 0 to 4 only picks up fewer than 2.5% of the population, whereas more than 20% of the population exhibits some degree of undermethylation. This suggests that the DDI report may not be providing a complete picture of the patient's methylation status, and may be underestimating the prevalence of undermethylation.
Reduction of SAH levels as primary therapy
Dr. Walsh explains that in a patient with below-normal levels of methionine, below levels of SAMe, and very high levels of SAH, it makes little sense to provide additional SAMe or methionine as an early therapy, even if the patient is clearly undermethylated. Instead, the focus should be on reducing SAH levels. Impaired adenosine metabolism and zinc depletion as contributing factors
Dr. Walsh suggests that in such cases, the inability to metabolize adenosine may be the cause of the elevated SAH levels. He also notes that the enzyme responsible for removing adenosine from the scene is zinc-dependent. Thus, if the patient exhibits zinc depletion or pyrrole elevation, SAH levels may be nicely lowered by bringing plasma zinc to the ideal level of about 100-130 mcg/dL, along with strong antioxidant support. In addition, a gluten-free, casein-free diet may help normalize adenosine.
Role of the kidney in sulfur amino acid metabolism
Of relevance to the subject of SAH management in some patients, a well-cited article "The kidney is the major site of S-Adenosylhomocysteine "The kidney is the major site of S-Adenosylhomocysteine disposal in humans," finds that the kidney plays a pivotal role in sulfur amino acid metabolism which directly impacts levels of SAH. To Walsh's point regarding the importance of recognizing the SAM:SAH ratios, it also states SAH is the by-product of methionine transmethylation and the metabolic precursor of homocysteine in all tissues. As SAH is a potent feedback inhibitor of most methyltransferases, including the methionine remethylation pathway, this compound plays an essential role in the control of the overall transmethylation rates. Thus, the efficiency of methyltransferase reactions is dependent on the efficient tissue removal of SAH.
Dr. Walsh's Responses to Physician Inquiries Regarding Patient Lab Results from Doctor's Data Methylation Profile
Dr. Walsh recently responded to inquiries from physicians seeking assistance in evaluating patient lab results from Doctor's Data Methylation Profile. In his replies, he provided insights on how to interpret the results of patients with varying levels of SAM, SAH, and methionine, who are experiencing symptoms of undermethylation with mental health conditions and biochemical imbalances. The examples included in his responses provided a overview of how the plasma methylation panel test results can guide the treatment of patients.
Example 1: Elevated SAH with pyroluria and or low zinc could also play a role:
The report above is from Doctors Data Plasma Methylation Panel. The blood sample was drawn on a patient who presented to Second Opinion Physician recently. The patient is a 63 year old man, chronic smoker, who had liver transplant six years ago. Previously an alcoholic with severe pyroluria he has benefitted greatly by taking zinc supplements over the years. However, he also has kidney disease, which is not uncommon in post transplant individuals. IN addition to zinc and antioxidant therapy, per the kidney article referenced above, it would be important to give attention to improving kidney function utilizing various diet and therapeutic modalities, to control sugar levels, reduce protein and improve kidney perfusion.
Regarding the of zinc, Walsh explains that elevated SAH, would to some degree is a consequence of low zinc due to the patients condition of pyroluria. This is because the primary route for metabolizing adenosine requires a Zn-dependent enzyme, and oxidative overload can impair adenosine metabolism. Therefore, in cases where SAH is seriously elevated, Dr. Walsh would prioritize reducing the patient's SAH levels by addressing the inability to metabolize adenosine, bringing his plasma zinc to the ideal level of about 100-130 mcg/dL and providing strong antioxidant support. He also suggests that a gluten-free, casein-free diet may help normalize adenosine. Additionally, Dr. Walsh cautions against providing methionine or SAMe until SAH levels are reduced. It's possible that addressing these imbalances along with addressing the kidney function, could help normalize the patient's methylation status.
Example 2: SAH elevated Homocysteine Normal
In this example, Walsh points out that SAH levels are elevated, but homocysteine levels are normal. This can suggest that the high SAH is due to adenosine build-up, rather than a problem with the methylation cycle. This is important to note because it suggests a different approach to treatment than if the problem was with the methylation cycle itself.
Example 3: Prediction SAH levels with undermethylation with low or normal homocysteine:
In this example, Walsh is discussing a case where a patient has undermethylation and low-normal homocysteine levels. This suggests a block in either SAMe synthesis or severe SAH elevation, which is more likely. It's important to identify the cause of the high SAH levels in order to determine the appropriate treatment approach.
In this example, Walsh is discussing a case where a patient has undermethylation and low-normal homocysteine levels. This suggests a block in either SAMe synthesis or severe SAH elevation, which is more likely. It's important to identify the cause of the high SAH levels in order to determine the appropriate treatment approach.
Example 4: Elevated SAH with Normal or low serum copper and undermethylation:
In this example, Walsh is discussing how low-normal serum copper is typical of undermethylated patients, and normalizing the methylation cycle will likely require approaches to promote conversion to adenosine and homocysteine, possibly augmented by nicotinamide riboside to improve the function of the SAHH enzyme. However, providing methionine or SAMe is not recommended until SAH levels are reduced.
Example 5: Elevated SAH with undermethylation is often associated with increased NMDA activity:
In this example, Walsh is discussing how treatment for undermethylated patients should focus on adjusting the misbehaving neurotransmitter systems rather than adjusting the one-carbon (methylation) cycle. It's important to note that undermethylated DNA is associated with low serotonin activity and excessive activity at NMDA receptors. Increasing serotonin activity would require successful nutrient therapy to lower SAH followed by SAMe or resorting to an SSRI. However, in cases where the primary issue may be excessive glutamate activity at NMDR, high-dose NAC therapy plus robust antioxidants are recommended.
Example 6: Elevated SAH, SAMe and methionine with undermethylation symptoms:
In this example, Walsh is discussing how even in cases where SAMe and methionine levels are elevated, the patient may still be undermethylated based on the DDI methylation profile. This highlights the importance of using diagnostic testing to accurately identify methylation status and guide treatment approaches.
Example 7: Undermethylation, pyroluria and Multiple Sclerosis (MS)
There is evidence that Vitamin D deficiency is associated with MS risk and that Vitamin D supplements have helped many MS patients. Mainstream medicine recommends normalization of Vitamin D levels for these persons. However, I'm not aware of any solid evidence that abnormally-high D3 levels are beneficial for MS, and excess Vitamin D can cause calcium imbalance and increased liver stress. I believe MS patients should have D3 levels that are normal or high-normal, but not the extreme levels found in this patient. We've known for 40 years that more than 50% of MS patients exhibit elevated pyrroles. Robust supplementation of B-6 and antioxidants is recommended. Note that a SAM/SAH ratio of 4.8 is equivalent to a whole-blood histamine level exceeding 100 ng/ml.
In this example, Walsh discusses the association between undermethylation, pyroluria, and Multiple Sclerosis (MS). He mentions that Vitamin D deficiency is linked to MS risk and that Vitamin D supplements have helped many MS patients. However, he also cautions against having abnormally high levels of Vitamin D, as excess Vitamin D can cause calcium imbalance and increased liver stress. He recommends that MS patients should have D3 levels that are normal or high-normal, but not the extreme levels found in some patients.
Walsh then highlights that more than 50% of MS patients exhibit elevated pyrroles, which is a condition where certain byproducts from the breakdown of hemoglobin are excreted excessively in the urine. He recommends robust supplementation of B-6 and antioxidants in these cases. Lastly, Walsh notes that a SAM/SAH ratio of 4.8 is equivalent to a whole-blood histamine level exceeding 100 ng/ml.
Example 8. Early intervention with Schizophrenia in a teen with severe overmethylation
In this example, Walsh emphasizes the importance of early intervention in schizophrenia, particularly within the first 3-5 years after onset. He notes that he has worked with more than 3,000 patients diagnosed with schizophrenia and has seen many cases of striking improvement in those who receive early intervention, including three medical students who were incapacitated by severe psychosis but resumed medical school and are now doctors.
Walsh recommends immediately ordering a methylation panel (SAM/SAH ratio, etc.) to determine the patient's methylation status, as he believes this test can help identify the misbehaving neurotransmitters. He notes that severe overmethylation is associated with excessive dopamine and norepinephrine activities, as well as depressed activity at NMDA receptors. In contrast, undermethylation suggests low serotonin activity and excessive glutamate activity at NMDA receptors.
By identifying the patient's methylation status, appropriate treatment can be provided. In the case of severe overmethylation, Walsh suggests that the patient may benefit from interventions that decrease dopamine and norepinephrine activity while increasing NMDA receptor activity. He recommends nutrient therapy, such as zinc and magnesium, to promote NMDA receptor activity and decrease dopamine and norepinephrine activity. In contrast, undermethylated patients may benefit from interventions that increase serotonin activity and decrease glutamate activity, such as nutrient therapy with 5-HTP or tryptophan.
Overall, Walsh emphasizes the importance of early intervention in schizophrenia and the need for personalized treatment based on an individual's methylation status. By identifying and addressing imbalances in neurotransmitter activity, patients with schizophrenia may experience significant improvement in symptoms.
Methylation Pathway Biochemical Steps
METHYLATION PATHWAY:
Step 1: Formylation of tetrahydrofolate
The one-carbon cycle begins with the formylation of tetrahydrofolate (THF) by the enzyme serine hydroxymethyltransferase (SHMT). This reaction transfers a formyl group from serine to THF, producing 5,10-methylene-THF. This reaction requires vitamin B6 as a cofactor.
Step 2: Conversion of 5,10-methylene-THF to 5-methyl-THF
The next step in the cycle is the conversion of 5,10-methylene-THF to 5-methyl-THF. This reaction is catalyzed by the enzyme methylenetetrahydrofolate reductase (MTHFR) and requires vitamin B2 as a cofactor. The reaction involves the transfer of a methyl group from 5,10-methylene-THF to homocysteine, producing methionine.
Step 3: Conversion of methionine to S-adenosylmethionine
Methionine is converted to S-adenosylmethionine (SAM) by the enzyme methionine adenosyltransferase. This reaction requires ATP and is the major methyl donor in the cell.
Step 4: Transmethylation reactions SAM is used as a methyl donor in a number of transmethylation reactions, where it transfers a methyl group to another molecule.
For example, SAM can methylate DNA, RNA, proteins, and other small molecules. The reaction is catalyzed by a variety of enzymes, including DNA methyltransferases and histone methyltransferases.
Step 5: Formation of S-adenosylhomocysteine (SAH)
After donating its methyl group, SAM is converted to S-adenosylhomocysteine (SAH), which is a competitive inhibitor of many SAM-dependent methyltransferases. This reaction is catalyzed by the enzyme SAH hydrolase.
Step 6: Regeneration of methionine Homocysteine can be converted back to methionine by either of two pathways:
the remethylation pathway or the transsulfuration pathway. In the remethylation pathway, homocysteine is methylated by 5-methyl-THF, which is generated from 5,10-methylene-THF in the first step of the one-carbon cycle. This reaction is catalyzed by methionine synthase and requires vitamin B12 as a cofactor. In the transsulfuration pathway, homocysteine is converted to cystathionine by the enzymes cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CGL). Cystathionine can then be converted to cysteine, which is a precursor for the synthesis of glutathione.
Step 7: Fate of SAH and adenosine SAH is hydrolyzed to adenosine and homocysteine by SAH hydrolase.
Adenosine can be further degraded to inosine and hypoxanthine, which are then metabolized to uric acid. Homocysteine can either be remethylated back to methionine as described in Step 6, or it can enter the transsulfuration pathway as described above.
Understanding and Treating Methylation Imbalance
Testing for Undermethylation and Overmethylation
All Walsh Biotype Tests
Walsh Biotype Panels
Methylation Test Panel – Whole Blood Histamine & Homocysteine
All Walsh Biotype Tests
Other Single Item Tests