S-Adenosyl methionine

S-Adenosyl methionine (SAM, SAMe, SAM-e) is a common cosubstrate involved in methyl group transfers. SAM was first discovered in Italy by G. L. Cantoni in 1952. It is made from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase (EC 2.5.1.6). Transmethylation, transsulfuration, and aminopropylation are the metabolic pathways that use SAM. Although these anabolic reactions occur throughout the body, most SAM is produced and consumed in the liver.

The methyl group (CH3) attached to the methionine sulfur atom in SAM is chemically reactive. This allows donation of this group to an acceptor substrate in transmethylation reactions. More than 40 metabolic reactions involve the transfer of a methyl group from SAM to various substrates, such as nucleic acids, proteins, lipids and secondary metabolites.

In bacteria, SAM is bound by the SAM riboswitch, which regulates genes involved in methionine or cysteine biosynthesis.

SAM cycle
The reactions that produce, consume, and regenerate SAM are called the SAM cycle. In the first step of this cycle, the SAM-dependent methylases (EC 2.1.1) that use SAM as a substrate produce S-adenosyl homocysteine as a product. This is hydrolysed to homocysteine and adenosine by S-adenosylhomocysteine hydrolase EC 3.3.1.1 and the homocysteine recycled back to methionine through transfer of a methyl group from 5-methyltetrahydrofolate, by one of the two classes of methionine synthases (i.e. cobalamin-dependent (EC 2.1.1.13) or cobalamin-independent (EC 2.1.1.14)). This methionine can then be converted back to SAM, completing the cycle.

Polyamine biosynthesis
Another major role of SAM is in polyamine biosynthesis. Here, SAM is decarboxylated by adenosylmethionine decarboxylase (EC 4.1.1.50) to form S-adenosylmethioninamine. This compound then donates its n-propylamine group in the biosynthesis of polyamines such as spermidine and spermine from putrescine.

SAM is required for cellular growth and repair. It is also involved in the biosynthesis of several hormones and neurotransmitters that affect mood, such as dopamine and serotonin. Methyltransferases are also responsible for the addition of methyl groups to the 2' hydroxyls of the first and second nucleotides next to the 5' cap in messenger RNA.

Therapeutic uses
In the United States and Canada, SAM is sold as a nutritional supplement under the marketing name SAM-e (also spelled SAME or SAMe; pronounced "sam ee" or "Sammy"). SAM is also marketed under the Gumbaral, Samyr, Adomet, Heptral and Admethionine brand names as a prescription drug approved in Russia, Italy, and Germany. Some research, including multiple clinical trials, has indicated taking SAM on a regular basis may help fight depression,  liver disease, and the pain of osteoarthritis. All other indications are not yet proven.

Therapeutic use of SAM has increased in the US, as dietary supplements have gained in popularity, especially after the Dietary Supplement Health and Education Act was passed in 1994. This law allowed the distribution of SAM as a dietary supplement, and therefore allowed it to bypass the regulatory requirements for drugs of the Food and Drug Administration (FDA).

At first, a line of evidence suggested abnormally low levels of endogenous SAM may play an important role in the development of Alzheimer's disease (AD), and that SAM may therefore have therapeutic potential in the treatment of AD. However, further research has indicated this effect is likely due to vitamin B12 deficiencies, which result in neurologic defects due to the inability to conduct one carbon transfers (with folate) in the absence of B12. Severely low levels of SAM have been found in the cerebrospinal fluid and in all brain regions of AD patients examined. Preliminary research suggests SAM may have therapeutic potential in treating AD patients and a recent study using a mouse model of AD found that supplementary SAM prevented oxidative damage and cognitive impairment.

Oral forms
Oral SAM achieves peak plasma concentrations three to five hours after ingestion of an enteric-coated tablet (400–1000 mg). The half-life is about 100 minutes. It may require up to one month for it to reach full effectiveness in treating osteoarthritis. Because of structural instability, stable salt forms of SAM are required for its use as an oral drug. The University of Maryland lists the commonly used salts: tosylate, butanedisulfonate, disulfate tosylate, disulfate ditosylate, and disulfate monotosylate.

With the advent of FDA-mandated good manufacturing practices (GMPs) in 2008, manufacturers are required to confirm their products contain what is listed on the label through the end of shelf life. Whether they achieve this goal or not has been questioned. This testing has shown that properly produced and packaged SAM has a shelf life in excess of three years; however, most manufacturers label for a two-year shelf life.

Claims that the SAM butanedisulfonate salt is more stable or better absorbed are not supported by the references usually cited as evidence. Different salts have successfully been used in clinical trials, but there is no published head-to-head comparison.

Usage
SAM is best absorbed on an empty stomach. Enteric-coated tablets packaged in foil or foil blister packs increase stability and improve absorption. SAM should be stored in a cool, dry place to prevent deterioration.

Adverse effects
Gastrointestinal disorder, diarrhea, dyspepsia, anxiety, headache, insomnia, allergy, and rashes can occur with SAM consumption. Long-term effects are unknown. SAM is a weak DNA-alkylating agent, and may thus act as a weak carcinogen.

Possible side effects
Once SAM donates its methyl group to choline, in the formation of creatine, carnitine, DNA, tRNA, norepinephrine, and other compounds, it is transformed into S-adenosyl-homocysteine, (SAH). Under normal circumstances, homocysteine, in the presence of vitamin B6, vitamin B12, and folic acid (SAM's main cofactors), will eventually be converted back into methionine, SAM, or cysteine, glutathione, and other useful substances. However, if adequate amounts of these vitamins are not present, SAM may not break down properly. As a consequence, its full benefits will not be obtained, and homocysteine may increase to unsafe levels. Small studies have not shown a consistent effect of SAM on homocysteine levels, but more research is needed. High levels of homocysteine have been associated with atherosclerosis (hardening and narrowing of the arteries), as well as an increased risk of heart attacks, strokes, liver damage, and possibly Alzheimer's disease. Therefore, vitamin B supplements are often taken along with SAM. These vitamins help metabolize the homocysteine into other useful compounds.

Another reported side effect of SAM is insomnia; therefore, the supplement is often taken in the morning. Other reports of mild side effects include lack of appetite, constipation, nausea, dry mouth, sweating, and anxiety/nervousness, but in placebo-controlled studies, these side effects occur at about the same incidence in the placebo groups. Some users report increased anxiety with as little as 50 mg/day.

Therapeutic doses range from 400 mg/day to 1600 mg/day, although higher doses are used in some cases. Some physicians recommend even lower doses, ranging from 50 to 200 mg/day, to treat mild depression without triggering negative side effects.

Induction of mania
In an extensive MEDLINE search on SAM, Kagan found induction of mania in one patient out of 15 treated with parenteral SAM. In the same review, Lipinski found the apparent induction of mania in two patients with bipolar disorder (total of nine depressed patients studied). Both depression and mania can be life-threatening conditions that may cause cognitive dysfunction even after remission. There is concern that antidepressants in general can induce mania or hypomania in bipolar persons.

Interactions and contraindications

 * SAM reduces insulin resistance.  This may lead to hypoglycemia when used with antidiabetic drugs.