S-adenosylmethionine (SAM)

check icon 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.

All Your Lab Results.
One Simple Dashboard.

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)

Laboratories

Bring All Your Lab Results Together — In One Place

We accept reports from any lab, so you can easily collect and organize all your health information in one secure spot.

lab corp logo
genova diagnostics logo
quest diagnostics logo
dutch test logo
doctors data logo
vibrant america logo
diagnostic solutions logo
zrt laboratory logo
the great plains laboratory logo
cyrex laboratories logo
spectracell logo

Pricing Table

decoration

Personal plans

$15/ month

Complete Plan

Access your lab reports, explanations, and tracking tools.

  • Import lab results from any provider
  • Track all results with visual tools
  • Customize your reference ranges
  • Export your full lab history anytime
  • Share results securely with anyone
  • Begin with first report entered
  • Cancel or upgrade anytime

$250/ once

Unlimited Account

Pay once, access everything—no monthly fees, no limits.

  • Import lab results from any provider
  • Track all results with visual tools
  • Customize your reference ranges
  • Export your full lab history anytime
  • Share results securely with anyone
  • Receive 10 reports entered for you
  • Skip the $15/month subscription — no recurring payments ever

$45/ month

Pro Monthly

Designed for professionals managing their clients' lab reports

  • Import lab results from any provider
  • Track lab results for multiple clients
  • Customize reference ranges per client
  • Export lab histories and reports
  • Begin with first report entered by us
  • Cancel or upgrade anytime

About membership

What's included in a Healthmatters membership

microscope icon Import Lab Results from Any Source

person icon See Your Health Timeline

book icon Understand What Your Results Mean

textbook icon

textbook icon Visualize Your Results

folder icon

folder icon

card icon Securely Share With Anyone You Trust

Let Your Lab Results Tell the Full Story

What Healthmatters Members Are Saying

5 stars rating

I have been using Healthmatters.io since 2021. I travel all over the world and use different doctors and health facilities. This site has allowed me to consolidate all my various test results over 14 years in one place. And every doctor that I show this to has been impressed. Because with  any health professional I talk to, I can pull up historical results in seconds. It is invaluable. Even going back to the same doctor, they usually do not have the historical results from their facility in a graph format. That has been very helpful.

Anthony

Unlimited Plan Member since 2021

5 stars rating

What fantastic service and great, easy-to-follow layouts! I love your website; it makes it so helpful to see patterns in my health data. It's truly a pleasure to use. I only wish the NHS was as organized and quick as Healthmatters.io. You've set a new standard for health tracking!

Karin

Advanced Plan Member since 2020

5 stars rating

As a PRO member and medical practitioner, Healthmatters.io has been an invaluable tool for tracking my clients' data. The layout is intuitive, making it easy to monitor trends and spot patterns over time. The ability to customize reports and charts helps me present information clearly to my clients, improving communication and outcomes. It's streamlined my workflow, saving me time and providing insights at a glance. Highly recommended for any practitioner looking for a comprehensive and user-friendly solution to track patient labs!

Paul

Healthmatters Pro Member since 2024

Use promo code to save 10% off any plan.

Frequently asked questions

Healthmatters is a personal health dashboard that helps you organize and understand your lab results. It collects and displays your medical test data from any lab in one secure, easy-to-use platform.

  • Individuals who want to track and understand their health over time.
  • Health professionals, such as doctors, nutritionists, and wellness coaches, need to manage and interpret lab data for their clients.

With a Healthmatters account, you can:

  • Upload lab reports from any lab
  • View your data in interactive graphs, tables, and timelines
  • Track trends and monitor changes over time
  • Customize your reference ranges
  • Export and share your full lab history
  • Access your results anytime, from any device

Professionals can also analyze client data more efficiently and save time managing lab reports.

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.

shield icon

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.

gdpr compliance image hipaa compliance image