Chemistry and Forms

Sulfuradenosylmethionine, S-adenosyl-L-methionine; S-adenosylmethionine butanedisulfonate, S-adenosylmethionine tosylate.

Physiology and Function

S-Adenosylmethionine (SAMe) is a naturally occurring compound functioning in a multitude of biochemical reactions and biosynthetic processes throughout the central nervous system (CNS), liver, connective tissue, and detoxification systems and within cellular metabolic activities. Dietary methionine is primarily metabolized in the liver, where it is combined with adenosine triphosphate (ATP) to form SAMe in a reaction catalyzed by methionine adenosyltransferase I/III (MAT I/III), the product of the MAT1A gene, which is exclusively expressed in the liver. SAMe serves as a precursor molecule to three main metabolic pathways within all cells: methylation, transulfuration, and aminopropylation.

S-Adenosylmethionine is the body's main biological methyl donor. After donating a methyl group in the synthesis of nucleic acids (DNA and RNA), choline, creatine, carnitine, proteins, phospholipids, catecholamines, epinephrine, and various neurotransmitters, SAMe is converted to S-adenosylhomocysteine (SAH). Subsequent trans-sulfuration reactions enable and regulate formation of sulfur-containing amino acids such as cysteine, glutathione, and taurine. After donating sulfur in this way, SAH gives up adenosine and is rapidly metabolized to homocysteine. Through the pathway known as aminopropylation, SAMe is metabolized to decarboxylated SAMe and functions as a cofactor in the synthesis of polyamines, including spermidine, puescine, and spermine, which are essential for cellular growth and differentiation, gene expression, DNA repair, protein phosphorylation, and neuron myelination and regeneration. As a key facilitator of phosphatidylcholine synthesis, SAMe plays a role in promoting flexible and responsive cellular membranes and supports healthy bile production and flow. SAMe influences levels of 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite, and homovanillic acid, a dopamine metabolite, in the cerebrospinal fluid (CSF) and appears to cross the blood-brain barrier via carrier-mediated transport.

Known or Potential Therapeutic Uses

Human clinical trials investigating SAMe have reported positive outcomes in the treatment of a range of conditions, reflecting the broad and diverse functions of this substance in human physiology. In particular, researchers have focused on depression, osteoarthritis, and liver disorders. Although a number of studies have shown clinical benefit, most have been limited by small numbers, brief duration, and preliminary or flawed design. Further, the research findings from human trials cannot be extrapolated readily to self-prescribed use or typical clinical practice, since oral dosages in European clinical trials have usually been significantly higher than those typically used by many individuals, and many studies have used intravenous (IV) or intramuscular (IM) modes of administration.

Historical/Ethnomedicine Precedent

S-Adenosylmethionine has not been used historically as an isolated nutrient.

Possible Uses

Alzheimer's disease, attention deficit–hyperactivity disorder (ADHD), cardiovascular disease, cirrhosis, dementia, depression, fibromyalgia, Gilbert's syndrome, infertility (male), insomnia, intrahepatic cholestasis of pregnancy, migraine, osteoarthritis, rheumatoid arthritis, Sjögren's syndrome, vacuolar myelopathy.

Dietary Sources

Methionine, from which SAMe is formed, can be obtained from a variety of dietary sources, but SAMe itself is not available through foods in any significant amounts. Dietary deficiencies in methionine, folate, or vitamin B12can reduce SAMe levels.

Nutrient Preparations Available

S-Adenosylmethionine butanedisulfonate, S-adenosylmethionine tosylate.

In Europe, pharmaceutical preparations of SAMe are available mainly as IV, IM, and oral forms. In the United States, SAMe is primarily available in an over-the-counter (OTC) nutraceutical oral form as a capsule or tablet. SAMe is extremely hygroscopic and highly unstable; enteric-coated tablets packaged in foil or foil blister packs are considered the most stable form to avoid degradation.

Dosage Forms Available

Enteric-coated tablets. Parenteral preparations are available in Europe.

Source Materials for Nutrient Preparations

Biofermentation or synthesis from adenosine and methionine, generally complexed with a stabilizing salt, such as tosylate, disulfate tosylate, disulfate ditosylate, or 1,4-butanedisulfonate.

Dosage Range

Adult

Dietary: Not applicable.

• Estimated safe and adequate daily dietary intake: Not applicable.
• Average U.S. daily intake: Not applicable.
• Recommended dietary allowance (RDA): None established.

Supplemental/Maintenance: Not applicable.

Pharmacological/Therapeutic: 400 mg three or four times daily, based on clinical trials.

Oral: 200 to 1600 mg daily.

Adequate dose-escalation studies using the oral formulation of SAMe have yet to be performed to demonstrate the most effective oral dose of SAMe.

The most common dosage is 400 mg daily, even though this level is significantly below the efficacy threshold indicated by research and clinical experience. Its relatively high cost has often been considered a limiting factor in the effective use of SAMe as a nutraceutical, especially when self-prescribed.

Toxic: No dietary reference intake (DRI) has been set for S-adenosylmethionine.

Pediatric (<18 Years)

No guidelines have been established for therapeutic or toxic dosage levels of SAMe for infants or children. Use within such populations is not usually recommended as appropriate.

Laboratory Values

Plasma levels of SAMe. Levels ofL-methionine S-adenosyltransferase activity in erythrocytes, SAMe concentrations in CSF, and concentrations of SAMe and S-adenosylhomocysteine (SAH) in whole blood have also been used in clinical trials.

Overview

In clinical trials and reported clinical use, SAMe has generally been well tolerated and considered safe.

Nutrient Adverse Effects

No toxic effects have been reported in research or clinical experience involving SAMe. Dry mouth, nausea, restlessness, and skin rashes are among the several minor adverse effects occasionally associated with SAMe intake and generally reported at higher doses. One case report of “serotonin syndrome” involving concomitant use of IM SAMe (100 mg/day) and clomipramine (75 mg/day) represents the most severe adverse event known. ^1-4

Adults

Mutagenicity: Research thus far indicates that SAMe is nonmutagenic in vitro and in vivo, even using high doses.

Adverse Effects Among Specific Populations

S-Adenosylmethionine use may trigger a manic episode in individuals with bipolar disorder. ^5-7

Pregnancy and Nursing

The safety of SAMe use in pregnant or breast-feeding women has not been established. However, several studies investigating SAMe in the treatment of intrahepatic cholestasis of pregnancy (ICP) have reported the agent as apparently safe during pregnancy.

Infants and Children

The safety of SAMe administration in infants and children has not been established.

Contraindications

Bipolar disorder, migraines, Parkinson's disease; individuals with active bleeding.

Precautions and Warnings

Given that SAMe is a precursor to homocysteine and that methionine may elevate homocysteine, it would be prudent to assess homocysteine levels before treating with SAMe in individuals with a significant family history of coronary heart disease.

Strategic Considerations

S-Adenosylmethionine's central role in several critical metabolic pathways indicates that both excessive intake and drug-induced depletion are likely to produce significant consequences. Well-designed studies will be required to clarify and articulate the particulars of these patterns in a systematic manner. Likewise, further research is needed to determine therapeutic approaches to synergistic use of SAMe as part of integrative therapeutics employing the nutraceutical in conjunction with various conventional therapies for treatment of the conditions for which SAMe shows promise.

The issue of SAMe use by individuals diagnosed with bipolar disorder continues to be controversial; well-designed research is needed to assess its efficacy as a therapeutic agent, alone or in conjunction with conventional pharmacological treatments.

The scientific understanding of the physiology and pharmacology of SAMe is generally in a preliminary state, particularly with regard to genetic variability and its pharmacogenomic implications. In particular, the critical roles of SAMe in the areas of DNA methylation, neurotransmitter self-regulatory processes, and hepatic conjugation of pharmaceutical agents all deserve continued research and will undoubtedly reveal significant implications for SAMe's therapeutic application and interactions with other medications. Recent clinical trial data suggest that SAMe appears to augment the antidepressant effect of SSRI and SSRI/SNRI agents. Large, randomized, placebo-controlled trials addressing the difficult clinical problem of antidepressant-refractory depression are warranted.

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