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SAMe and other methyl donors

SAMe – And other Methyl Donor Molecules

(Pronounced "Sammy" / S-adenosyl methionine)

SAMe – Precursor to 3 main pathways

SAMe provides an important precursor molecule to 3 main pathways of all cellular metabolism: methylation, transulfuration, and aminopropylation.

–    A sufficiency of SAMe sustains their normal function - an amount that depends on the daily availability of methionine synthesized by the body (involving folate (methyl-tretrahydrofolate) and vitamin B-12) and also methionine obtained mainly from breakdown of dietary proteins.

SAMe – In transmethylation

SAMe donates a methyl group (CH3) to another molecule to make it bio-active

Produced by all living cells, SAMe serves an important biological function as a universal methyl donor in a multitude of cellular methylation reactions – other methyl donors include: folate, B12, TMG (Betaine), DMGand DMAE. Also, some vegetables (E.g. onions, garlic, beets) contain methyl donors

A methyl group (CH3, a 4-atom appendage to the methione sulfur atom in SAMe) is donated to a neighbor molecule, to stimulate biochemical reactions that transform the recipient molecule into a bio-active substance -E.g. Methyl groups transferred from SAMe to certain phospholipids produce phosphatidylcholine. The presence or absence of this important lipid found in all cell membranes controls membrane accessibility to outside signals, and thus affects how cells react to outside stimuli.

SAMe functions as a donor of methyl groups in > 100 different reactions catalyzed by methlytransferase enzymes – Most cells contain numerous SAMe-dependent methyltransferases that can transfer the methyl group (CH3) to the oxygen, nitrogen, or sulfur atoms of both small and large molecules.

Cheng X, Blumenthal RM. S-Adenosylmethionine-dependent methyltransferases: structures and functions. World Scientific Publication Co, 1999.

Chiang PK, Gordon RK, Tal J, et al. S-Adenosylmethionine and methylation. FASEB J 1996;10:471–80.[Abstract]

Without methylation there is no life - occurring billions of times/second in the body:

–    Affects fetal development, brain function

Maloney C.A., Hay S.M., Reid M.D., Duncan G., Nicol F., Sinclair K.D., Rees W.D. (2012). A methyl-deficient diet fed to rats during the pre- and peri-conception periods of development modifies the hepatic proteome in the adult offspring. Genes Nutr., Aug 21.

Morse N.L. (2012). Benefits of docosahexaenoic acid, folic acid, vitamin D and iodine on foetal and infant brain development and function following maternal supplementation during pregnancy and lactation. Nutrients, 4(7):799- 840


–    Regulates gene expression

–    Preserves the fatty cell membranes - the greater the amount of SAMe-produced phosphatidylcholine (via phospholipid methylation), the more fluid or less viscous the cell membrane, which may facilitate the lateral movement of proteins, such as receptors, within the lipid bilayer.

Crews FT. Effects of membrane fluidity on secretion and receptor stimulation. Psychopharmacol Bull 1982;18:135–43.[Medline]

–   SAMe serves as the methylating agent (donates methyl groups) in the synthesis of:

✔ Various hormones and neurotransmitters - including SEROTONIN,  MELATONIN, NOREPINEPHRINE (adrenaline),  EPINEPHRINE. DOPAMINE, and HISTAMINE;  SAMe is also an important cofactor in the conversion of  NOREPINEPHRINE (adrenaline) ➔  EPINEPHRINE. (see Appendix, label 3). In doubleblind, randomized clinical studies, it has been shown to:

• Reduce low mood symptoms (Papakostas, 2010; Pancheri, 2002)

Papakostas, G.I., Mischoulon, D., Shyu, I., Alpert, J.E., Fava, M. (2010). S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry, 167(8), 942-8.

Pancheri, P., Scapicchio, P., Chiaie, R.D. (2002). A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate


• Support cognitive function

Levkovitz, Y., Alpert, J.E., Brintz, C.E., Mischoulon, D., Papakostas, G.I. (2011). Effects of S-adenosylmethionine augmentation of serotonin-reuptake inhibitor antidepressants on cognitive symptoms of major depressive disorder. Eur Psychiatry, 136(3), 1174-8.

• Studies also suggest that patients who do not adequately respond to attempts to modulate serotonin function may benefit greatly from methylation support by supplementing with SAMe (Papakostas, 2010; Levkovitz, 2011 above).


✔ Protein

✔ Creatine (an important energy reservoir in muscle tissue)

✔ Phospholipids

Thus, methyl donors, such as SAMe enhance sleeping, mood, energy, wellbeing, alertness, and concentration.

SAMe – In transulfuration

SAMe is the precursor for synthesis of cysteine, glutathione and taurine - in the transulfuration pathway;

SAMe – In aminopropylation

SAMe and arginine serve as precursor molecules to the aminopropylation pathway - which leads to the synthesis of polyaminesspermine, spermidine and putrescine, which are involved in the control of cell growth, gene expression, calcium homeostasis and neuron regeneration. They were also shown to have analgesic and anti-inflammatory properties

Herby O. Role of polyamines in the control of cell proliferation and differentiation. Differentiation 1981;19:1–20.[Medline]

Oyanagui Y. Anti-inflammatory effects of polyamines in serotonin and carrageenan paw edemata—possible mechanism to increase vascular permeability inhibitory protein level which is regulated by glucocorticoids and superoxide radical. Agents Actions 1984;14:228–37.[Medline]

This pathway, like transulfuration, also salvages and conserves methionine.

SAMe synthesis and metabolism

SAMe is synthesized in the body (mainly in the liver) - from methionine (an amino acid) catalyzed by the MAT enzyme (methionine S-adenosyltransferase) using ATP molecule

SAMe ⇔ methionine (an amino acid in protein-rich foods) – Body makes SAMe from methionine and then recycles it. Once a SAMe molecule loses its methyl group, it breaks down to form homocysteine, which is potentially toxic if it builds up within cells.

Several B vitamins (B6, B12 and folate) are required for:

(1) Transulfuration (requires B6) - Convert Homocysteine ➔  Glutathione (body's important ”in-house”antioxidant);


or (2) Remethylation (requires B12, folate) - "Remethylate" homocysteine ➔  (back into) Methionine.

Sitaram BR, Sitaram M, Traut M and CB Chapman. 1995. Neurochem 65: 1887-1894.

SAMe – Essential for various body functions

SAMe is essential for MELATONIN and SEROTONIN production

–   SAMe is the daytime equivalent of MELATONIN (the darkness hormone) - and like MELATONIN, it is produced under control of the master biological clock;

–   Natural synthesis of MELATONIN (and SEROTONIN) depends on adequate SAMe synthesis during the day - SAMe donates a methyl group molecule to the enzyme (hydroxyindole-O methyltransferase) that converts the acetylated form of SEROTONIN to MELATONIN;

–   At night MELATONIN ▲  ▲  ▲  / SAMe ▼  ▼  ▼  and in the day SAMe ▲  ▲  ▲  / MELATONIN▼  ▼  ▼  -SEROTONIN is also produced at night.


Maintains effective mitochondrial function

Prevents and curtails DNA mutations during cell replication

Restores cellular membrane fluidity / cellular communication

–   Methylation puts phosphatidylcholine in cell membranes to make them pliant - in contrast to cholesterol, which makes them stiff. Stiff membranes do not transmit signals as well as pliant membranes.

–   With age, the ratio of phosphatidylcholine- to-cholesterol decreases causing the membrane to “harden”-Increased methylation provided by SAMe enhances cell membrane function and integrity.

–   SAMe improves cellular communication between nerve cells -SAMe helps neurotransmitters deliver their messages to the receptor sites by methylating phospholipids, from which nerve cell membranes are made.

SAMe Supplementation –Study-supported Health benefits

Reference: http://www.ajcn.org/content/76/5/1151S.long#R4

SAMe for Depression – 40 clinical supporting studies involving ~1400 patients. In 1994 Dr. Giorgio Bressa, a psychiatrist at the University Cattolica Sacro Cuore in Rome, pooled results from a dozen controlled trials and found that "the efficacy of SAMe in treating depressive syndromes... is superior [to] that of placebo and comparable to that of standard... antidepressants."

Janicak PG, Lipinski JD, Comaty JE, et al. S-Adenosylmethionine: a literature review and preliminary report. Ala J Med Sci 1988;25:306–13.[Medline]

Friedel HA, Goa KL, Benfield P. S-Adenosyl-L-methionine: a review of its therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism. Drugs 1989;38:389–416.[Medline]

Bressa GM. S-Adenosyl-L-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurol Scand 1994;154:7–14.

Link to several supporting studies for SAMe with depression

SAMe for pain/inflammation/arthitis

–   In a dozen clinical trials involving more than 22,000 patients, researchers have found SAMe as effective as pharmaceutical treatments for pain and inflammation - but unlike the NSAIDs, SAMe shows no sign of damaging the digestive tract. The Arthitis Foundation medical experts concur.

–   Joint-protective - after SAMe loses a methyl group to become homocysteine, it can be broken down to form glutathione, which reaction also yields sulfate groups, which help generate joint-protective proteoglycans. SAMe accumulates in the synovial fluid that lubricates joints. Certain chemicals resulting from SAMe breakdown can relieve pain and inflammation

SAMe for liver diseases - "The administration of a stable salt of SAMe, either orally or parenterally, has been shown to restore normal hepatic function in the presence of various chronic liver diseases (including alcoholic and non-alcoholic cirrhosis, estrogen-induced and other forms of cholestasis (bile impairment or blockage), to prevent or reverse hepatotoxicity due to several drugs and chemicals such as alcohol, paracetamol (acetaminophen), steroids and lead, and to have antidepressant properties."

Friedel HA, Goa KL, Benfield P"S-adenosyl-L-methionine. A review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism." Drugs 1989 Sep;38(3):389-416. (ADIS Drug Information Services, Auckland, New Zealand).

–    SAMe has been found to prevent or reverse liver damage caused by certain drugs, alcohol, and cytokines - It protects against liver damage caused by MAO inhibitors and anti-convulsants.

–   It reverses hyperbilirubinaemia


–   Rat study showed the beneficial effects of SAMe on liver disease - Fetal rat liver cells were exposed to ethanol, causing a 40% reduction in DNA synthesis, a doubling of free radicals, a 30% decrease in cellular ATP, altered mitochondrial function, and cell damage. Pretreatment with SAMe maintained cell replication, decreased free radicals and prevented ATP and glutathione depletion. A study in Hepatology

Lieber CS. Role of S-adenosyl-L-methionine in the treatment of liver diseases. J Hepatol 1999;30:1155–9. Medline

Williams R, Lieber CS. The role of SAMe in the treatment of liver disease. Drugs 1990;40(suppl):1–2. Medline

Mato JM, Camara J, Fernandez de Paz J, et al. S-Adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. J Hepatol 1999;30:1081–9. Medline

SAMe for INSULIN resistance

–   SAMe “improved whole body INSULIN sensitivity, and prevented body weight gain”- in animal model of type 2 diabetes mellitus and INSULIN resistance.

"S-Adenosyl-L-Methionine Increases Skeletal Muscle Mitochondrial DNA Density and Whole Body Insulin Sensitivity in OLETF Rats1".

SAMe for osteoarthritis

Bradley JD, Flusser D, Katz BP, et al. A randomized, double blind, placebo controlled trial of intravenous loading with S-adenosylmethionine (SAM) followed by oral SAM therapy in patients with knee osteoarthritis. J Rheumatol 1994;21:905–11.[Medline]

Padova C. S-Adenosylmethionine in the treatment of osteoarthritis: review of the clinical studies. Am J Med 1987;83:60–5.[Medline]

SAMe for schizophrenia

SAMe for demyelination diseases - has a variety of pharmacological effects in the CNS, especially on monoamine neurotransmitter metabolism and receptor systems

–    Protects against neuronal death caused by lack of oxygen(anoxia).

–    Regenerates nerves and provokes remyelination of nerve fibers

–   SAMe Treatment with methyl donors (betaine, methionine and SAMe) is associated with remyelination in patients with inborn errors of folate and C-1 (one-carbon) metabolism


SAMe for Dementia, Alzheimers

–    Alzheimer's patients have severely decreased levels of SAMe in their brains –a turnaround from an idea that the brain had too much SAMe!

Morrison LD, Smith DD and SJ Kish. 1996. J Neurochem 67: 1328-1331.

SAMe for CVD

–    Swiss researchers showed that high homocysteine levels that precede heart disease

Stampfer MJ, Malinow MR, Willett WC, et al. 1992. A prospective study of plasma homocysteine and risk of myocardial infarction in US physicians. JAMA 268: 877-81

–    Low blood SAMe levels are correlated with the development of CAD - SAMe deficiency has a deterimental effect on homocysteine metabolism. SAMe plays a crucial role preventing the breakdown of MTHFR -The enzyme methylenetetrahydrofolate reductase (MTHFR) needed to convert folate to its active form, 5-methyltetrahydrofolate (5-MTHF). This folate form is directly involved in homocysteine metabolism. 

Loehrer MTF, Angst CP, Haefeli WE, Jordan PP, Ritz R and B Fowler. 1996. Low whole-blood S-adenosylmethionine and correlation between 5- methyltetrahydrofolate and homocysteine in coronary artery disease. Arth Throm Vasc Biol 16: 727-733.

–   SAMe also remethylates homocysteine back into methionine


SAMe for Cancer

–   Scientists suspect that adequate methylation of DNA can prevent the expression of harmful genes

SAMe Supplementation

Pharmaceutical-grade SAMe comes in two forms - tosylate and a newer, more stable form called butanedisulfonate. Only Nature Made and GNC sell the new butanedisulfonate version, but several U.S. retailers import reliable tosylate products.

Since SAMe is absorbed mainly through the intestine, it's best taken in "enteric coated" tablets - to pass through the stomach intact.

SAME is expensive - a 400-mg dose ranges from $2.50 (Nature Made) up to $18.56 for an uncoated Natrol product called SAM sulfate.

Experts advise taking it twice a day on an empty stomach

Different people may require different amounts - studies suggest 400 mg a day is an effective dose for arthritis, but the daily doses used in depression trials have ranged as high as 1,600 mg. (Generally with mood problems start at 400 and increase as necessary).

SAMe may alter one's mood in an unexpected fashion - one should begin a SAMe regimen with the lowest dosage available and maybe even take SAMe every other day for the first month.

ALWAYS supplement with vitamins B6, B12 and folate when taking SAMe - to ensure that homocysteine created is converted to methionine, glutathione or other beneficial molecules.

Alternatives to SAMe Supplementation

For most people, the real problem is undermethylation of homocysteine - simply upping your intake of B vitamins could deter such as low moods, bad joints, dysfunctional liver, weak hearts . . .

Once SAMe donates its methyl group, it is transformed into homocysteine. When present, SAMe's main cofactors: Vitamins B6, B12 and folate, normally help body produce SAMe and convert homocysteine back to methionine, SAMe or cysteine, glutathione, and other useful substances.

However, if adequate amounts of the vitamins B6, B12, and folate are not present - SAMe may not break down properly, such that its full benefits will not be obtained, and homocysteine may increase to unsafe levels., which can cause inflammatory damage. This shortage of B vitamins is going to lead to problems associated with homocysteine buildup –including: CVD (atherosclerosis,heart attack/stroke), liver damage, risk of spina bifida and other birth defects in pregnancy.

Deficiencies of folate have been found to reduce SAMe concentrations in the CNS and may be involved in neurological and psychiatric problems, including depression, dementia, myelopathy and peripheral neuropathy.

Many nutrients work similarly to SAMe, particularly other methyl donors:

✔ TMG - dose of 250 mg a day.


✔ DMAE – chemically similar to choline, used for years to enhance focus and clarity of thought. Studies do NOT support its use with Alzheimer's or memory recall, but it seems to help mood/motivation in elderly dementia patients

The following combination of 4 supplements actively combat high levels of homocysteine and enable one's body to produce SAMe naturally (without the expense of supplementing SAMe).

–    Vitamin B6, Folic Acid (B9), Vitamin B12 - convert toxic homocysteine into beneficial amino acids, whilst simultaneously producing SAMe.

–    Trimethylglycine (TMG) - is converted into dimethylglycine (DMG), a popular, but expensive supplement to enhance energy/vitality.


On SAMe methylation