S-adenosylmethionine (SAM)

Optimal Result: 65 - 150 nanomol/L.

S-Adenosylmethionine (SAM or AdoMet): Role in Methylation, Metabolism, and Clinical Applications

Overview of SAM’s Biological Role

S-Adenosylmethionine (SAM, also known as AdoMet) is a crucial molecule found in every cell of the human body, serving as the primary methyl donor in over 100 enzymatic reactions catalyzed by methyltransferases. These reactions influence DNA methylation, neurotransmitter synthesis, and detoxification pathways, making SAM essential for overall metabolic function [1].

Beyond its role in methylation, SAM also activates the transsulfuration pathway, leading to the production of glutathione—a key antioxidant that protects against oxidative stress—and contributes to energy production through sulfur metabolism [2].

SAM Biosynthesis and Regulation

SAM is synthesized from the essential amino acid methionine and adenosine triphosphate (ATP) through the enzyme methionine adenosyltransferase (MAT) [3]. Since diet alone cannot supply sufficient SAM, the body relies on de novo synthesis, primarily regulated by the liver [4].

SAM levels act as a metabolic feedback regulator throughout the body by:

  • Inhibiting methylenetetrahydrofolate reductase (MTHFR), reducing the availability of 5-MTHF, a crucial methyl donor in folate metabolism [5].
  • Downregulating betaine-homocysteine methyltransferase (BHMT), contributing to feedback inhibition of methylation pathways [6].
  • Upregulating cystathionine beta-synthase (CBS), enhancing transsulfuration and increasing glutathione production [7].

SAM and Metabolic Health

Emerging research suggests that SAM levels increase in proportion to adiposity and obesity, indicating a potential link between SAM metabolism and metabolic syndrome [8]. While methionine and SAH (S-adenosylhomocysteine) levels do not correlate with fat mass, an increased conversion of methionine to SAM has been observed in obese individuals. The underlying mechanism behind this metabolic shift remains under investigation [9].

As the liver tightly regulates SAM synthesis, dysfunctional hepatic metabolism—such as in non-alcoholic fatty liver disease (NAFLD)—may further impact SAM homeostasis, potentially altering methylation balance, detoxification efficiency, and inflammatory responses [10].

SAM-e Supplementation: Clinical Applications and Considerations

Since March 1999, SAM-e has been available in the United States as an over-the-counter nutraceutical supplement [11]. SAM-e supplementation may be beneficial when:

  • Methionine levels are low due to dietary insufficiency or metabolic imbalances.
  • Enzymatic conversion from methionine to SAM is impaired, leading to reduced methylation activity.

Clinical Applications of SAM-e

Scientific research suggests that SAM-e supplementation may offer therapeutic benefits in several conditions:

  • Depression – Studies indicate that SAM-e is as effective as tricyclic antidepressants (TCAs) in improving mood disorders [11].
  • Osteoarthritis – Research shows that SAM-e provides pain relief comparable to NSAIDs for osteoarthritis management [11].
  • Liver Disease – SAM-e has been used to support liver detoxification and function, particularly in conditions like NAFLD and cholestasis [11].

Safety and Potential Side Effects

SAM-e is generally well tolerated, with no serious side effects reported. However, there have been rare cases of bipolar patients experiencing manic episodes following SAM-e supplementation [12].


References

  1. Cantoni GL. Biological methylation: selected aspects. Annu Rev Biochem. 1975;44:435-451. PMID: 24022817
  2. Brosnan JT, Brosnan ME. The sulfur-containing amino acids: an overview. J Nutr. 2006;136(6 Suppl):1636S-1640S. PMID: 16702333
  3. Mato JM, Lu SC. Role of S-adenosyl-L-methionine in liver health and injury. Hepatology. 2007;45(5):1306-1312. PMID: 17393523
  4. Zeisel SH. Choline: an essential nutrient for humans. Nutrition. 2000;16(7-8):669-671. PMID: 10906520
  5. James SJ, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004;80(6):1611-1617. PMID: 15585776
  6. Wang W, et al. Betaine: a novel methyl donor for the methylation of DNA and histones. Epigenetics. 2017;12(7):487-497. PMID: 28441122
  7. Kim J, et al. Altered methionine metabolism in obesity. Curr Opin Clin Nutr Metab Care. 2015;18(4):379-385. PMID: 25844651
  8. Clarke R, et al. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer's disease. Arch Neurol. 1998;55(11):1449-1455. PMID: 9823824
  9. Bottiglieri T. S-Adenosylmethionine (SAM-e): from the bench to the bedside--molecular basis of a pleiotrophic molecule. Am J Clin Nutr. 2002;76(5):1151S-1157S. PMID: 12420702
  10. Papakostas GI, et al. S-adenosyl methionine in depression: a comprehensive review of the evidence. Am J Psychiatry. 2010;167(8):885-897. PMID: 20439389
  11. Sharma A, Gerbarg PL, Brown RP. SAM-e in psychiatry: therapeutic efficacy, safety, and future directions. CNS Neurosci Ther. 2017;23(8):649-656. PMID: 28514109
  12. Frye MA, et al. S-Adenosylmethionine (SAMe) in bipolar depression: An open trial study. J Clin Psychopharmacol. 2007;27(6):659-661. PMID: 18004144

What does it mean if your S-adenosylmethionine (SAM) result is too high?

Elevated S-Adenosylmethionine (SAM) on a Methylation Panel – What Does It Indicate?

S-Adenosylmethionine (SAM) is a key molecule in the methylation cycle, influencing DNA methylation, neurotransmitter balance, and detoxification. Elevated SAM levels on a Methylation Panel by Genova Diagnostics may indicate increased methylation activity, metabolic imbalances, or liver dysfunction. One critical but often overlooked factor influencing SAM levels is metabolic syndrome, a condition characterized by insulin resistance, inflammation, and altered lipid metabolism.

1. Increased Methylation Activity (Hypermethylation)

  • High SAM may indicate an excessive methylation state, potentially altering gene expression and cellular function.
  • Hypermethylation has been linked to autoimmune diseases, certain cancers, and neurological conditions.
  • If S-Adenosylhomocysteine (SAH) is also high, methylation may actually be inhibited, as SAH is a potent methylation suppressor.

2. Impact of Metabolic Syndrome on Elevated SAM

Metabolic syndrome, a cluster of conditions including insulin resistance, obesity, hypertension, and fatty liver disease (NAFLD), can contribute to SAM dysregulation through several mechanisms:

A. Insulin Resistance & Methylation Imbalance

  • Insulin resistance can increase methionine flux into the methylation cycle, leading to elevated SAM.
  • High insulin levels may enhance methylation activity, contributing to epigenetic modifications that worsen metabolic dysfunction.

B. Chronic Inflammation & Oxidative Stress

  • Metabolic syndrome is associated with systemic inflammation (high CRP, TNF-α, IL-6) and oxidative stress, both of which impact the methylation cycle.
  • Inflammation disrupts the SAM-to-SAH conversion, potentially causing SAM accumulation.

C. Liver Dysfunction (NAFLD) & Impaired SAM Clearance

  • The liver is the primary organ responsible for methionine metabolism and SAM regulation.
  • Non-Alcoholic Fatty Liver Disease (NAFLD), common in metabolic syndrome, can lead to reduced SAH clearance and elevated SAM levels.

D. Vitamin B Deficiencies & One-Carbon Metabolism Disruptions

  • Metabolic syndrome is linked to folate, B12, and B6 deficiencies, which are crucial for one-carbon metabolism.
  • A relative methyl donor excess (folate, B12) or deficiency may cause methyl trapping, leading to SAM accumulation without efficient recycling.

E. Elevated Homocysteine & Cardiovascular Risk

  • Metabolic syndrome already increases the risk of cardiovascular disease, and SAM dysregulation can worsen homocysteine levels, a known marker of vascular dysfunction.

3. Neurological & Cognitive Effects

  • Elevated SAM can increase methylation of neurotransmitters (dopamine, serotonin), affecting mood, cognition, and mental health.
  • It has been linked to anxiety, depression, and cognitive impairment, particularly in individuals with genetic methylation variants (MTHFR, COMT, MAT1A).

4. Key Laboratory Markers to Evaluate

If SAM is elevated, consider checking:

  • S-Adenosylhomocysteine (SAH) – to assess actual methylation activity.
  • Homocysteine – high levels suggest methylation inefficiency.
  • CRP & IL-6 – markers of inflammation that can impair methylation.
  • Liver function tests (ALT, AST, GGT) – to check for NAFLD or impaired methylation processing.
  • Insulin & fasting glucose – to assess for insulin resistance, which can impact SAM levels.

5. How to Address Elevated SAM in Metabolic Syndrome

  • Support liver function: Reduce NAFLD risk through diet, choline, and N-acetylcysteine (NAC).
  • Improve insulin sensitivity: Adopt a low-glycemic diet, exercise, and consider berberine or alpha-lipoic acid.
  • Balance B vitamin intake: Ensure adequate but not excessive B12, B6, folate, and riboflavin to optimize methylation.
  • Manage inflammation & oxidative stress: Consider omega-3s, curcumin, and antioxidants to support balanced methylation.

Conclusion

An elevated SAM on a methylation panel is a complex finding that may indicate increased methylation activity, metabolic dysfunction, or liver impairment. Metabolic syndrome plays a significant role in SAM elevation through insulin resistance, inflammation, and disrupted liver function. Evaluating related biomarkers and addressing underlying metabolic imbalances can help restore proper methylation balance and overall health.

What does it mean if your S-adenosylmethionine (SAM) result is too low?

- Low methionine due to decreased protein intake, or malabsorption/maldigestion

- MAT SNP or lack of cofactors (ATP, Mg, K)

Frequently asked questions

Healthmatters is a highly-personalized health dashboard.

Instead of searching for your lab results in different places or tracking them down from different providers, Healthmatters houses, organizes, and interprets them all in one central location.

With a Healthmatters account, you can dive into the details of each biomarker and gain insights into the meaning behind your medical test data, anytime, anywhere.

For our professional users, Healthmatters provides intuitive tools that not only streamline analysis but also save valuable time when delving into your client's lab report history.

Healthmatters.io personal account provides in-depth research on 4000+ biomarkers, including information and suggestions for test panels such as, but not limited to:

  • The GI Effects® Comprehensive Stool Profile,
  • GI-MAP,
  • The NutrEval FMV®,
  • The ION Profile,
  • Amino Acids Profile,
  • Dried Urine Test for Comprehensive Hormones (DUTCH),
  • Organic Acids Test,
  • Organix Comprehensive Profile,
  • Toxic Metals,
  • Complete Blood Count (CBC),
  • Metabolic panel,
  • Thyroid panel,
  • Lipid Panel,
  • Urinalysis,
  • And many, many more.

You can combine all test reports inside your Healthmatters account and keep them in one place. It gives you an excellent overview of all your health data. Once you retest, you can add new results and compare them.

If you are still determining whether Healthmatters support your lab results, the rule is that if you can test it, you can upload it to Healthmatters.

While we work with many popular labs, we welcome reports from lots of other places too.

It's as simple as this: if you can get a test done, you can upload it to Healthmatters and we can interpret results from any lab out there. If laboratories can analyze it, we can interpret it.

If you’re on the hunt for a specific biomarker, contact us and we'll add it to our database. Anything from blood, urine, saliva, or stool can be uploaded, understood, and tracked with your Healthmatters account.

There are two ways to add your test reports to your Healthmatters account. One option is to input the data using the data entry forms. The other method is to utilize our "Data entry service."

Our data entry forms offer an easy, fast, and free way for you to input the reports yourself. Self-entry allows you to add an unlimited number of reports at no cost. We make the self-entry process user-friendly, providing dozens of templates that pre-populate the most popular laboratory panels and offering instant feedback on entered values.

For those who prefer assistance, we offer a "Data entry service" to help you input your data. Simply attach an image or file of your lab test results, and a qualified team member from our data entry team will add the results for you.

We support various file types, including PDFs, JPGs, or Excel. This service is particularly useful if you have many reports to upload or if you're too busy to handle the data entry yourself.

Our special data entry service makes it easy to add your results to your private dashboard. Just attach an image or a file of your lab test results, and our skilled data entry team will do the work for you. It's all done by humans, ensuring that your data is entered accurately and with personal care for each client.

Depending on your account, the data entry service can be included for free or come at an additional cost of $15 per report.

For users on the Complete monthly plan, the first report is entered free of charge, and each additional report incurs a fee of $15.

Unlimited account holders enjoy the entry of ten reports without charge. Subsequent reports are subject to a $15 fee per report.

Additionally, users on the Complete plan can upgrade to a yearly subscription from the account settings. The annual subscription includes a data entry service for five reports.

The Unlimited plan is a one-time purchase for $250, and it covers your account for a lifetime with no additional payments.

For the Complete plan, the cost is $15 per month. You have the flexibility to cancel it anytime through your account settings, ensuring no further payments. To avoid charges, remember to cancel at least a day before the renewal date. Once canceled, the subscription remains active until the end of the current billing cycle.

Additionally, you can upgrade to the yearly Advanced plan from within your account. The annual cost is $79, and it comes with a data entry service for five reports.

You can always upgrade to a lifetime version with a prorated price from a monthly or yearly subscription.

Simply log in and navigate to your account settings to cancel your subscription. Scroll down to locate the 'Cancel' button at the bottom of the page. Ensure you cancel at least one day before the renewal date to prevent any charges. Once cancellation is requested, the subscription remains active until the conclusion of the current billing cycle.

Our goal has been to make your Healthmatters account as intuitive as possible.

We’ve crafted multiple ways for you to navigate your data, whether you're glancing at a single report or delving into your historical test reports.

1. Graph View:

Dive into a visual journey with our biomarker graphs, showcasing over 40 data points. Combining years of results unveils trends, empowering you to make informed decisions. Our visualization tools make it a breeze to compare and understand changes over time, even if your results are from different labs. A search function and filters simplify the exploration of extensive data, allowing you to focus on what needs attention.

2. All Tests View

Explore neatly organized reports on a timeline, highlighting crucial details like dates, critical results, and lab/panel names. Each report opens up to reveal in-depth descriptions and additional recommendations for each biomarker. The history of previous results is just a click away, and you can download a comprehensive report for deeper insights. Color-coded and user-friendly, it's designed for easy reading, understanding, and navigation.

3. Table View:

For a holistic view of all biomarkers side by side, our table view is your go-to. Results are neatly displayed in a categorized and dated table, ideal for those with an extensive test history. Utilize sorting, filters, and color-coding to enhance your analysis and gain extra insights.

Yes, you can download information from your account. We can compile your labs into a CSV file. To download all your labs, you can go to Account Settings, and at the bottom of the page, you will find a link to download your information.

Yes, you can print your report. To do so, navigate to "All tests" and open the report you wish to print. You'll find a print button in the right corner of the report. Click on it, and your browser's print window will open. If you prefer to print in a bigger typeface, adjust the scale using the print window settings.

Yes, you can! We highly recommend activating Two-Factor Authentication (2FA) for your account. To do so, please navigate to the "Profile and Security" section of your account, where you will find instructions for activating 2FA.

Yes, you can. When entering values for the biomarker, you will see an "Edit Range" button. Click this button, and you'll have the option to enter a custom range.

A personal account is all about keeping your own lab test results in check. It's just for you and your personal use.

The professional account is designed for health professionals who wish to track and organize their clients' laboratory results.

Yes, you can! Simply go to the "Invite Doctor" section, enter your doctor’s email address, and send the invitation. Your doctor will receive an email with secure access to view your results. You can revoke this access at any time. All shared information is securely encrypted and protected for your privacy.
Yes, you can! Go to the Graph view or Spreadsheet view. In the top-right corner, click "Export to Excel," and the file will be downloaded to your device.

Use promo code to save 10% off any plan.


We implement proven measures to keep your data safe.

At HealthMatters, we're committed to maintaining the security and confidentiality of your personal information. We've put industry-leading security standards in place to help protect against the loss, misuse, or alteration of the information under our control. We use procedural, physical, and electronic security methods designed to prevent unauthorized people from getting access to this information. Our internal code of conduct adds additional privacy protection. All data is backed up multiple times a day and encrypted using SSL certificates. See our Privacy Policy for more details.