S-Adenosyl methionine

Overview
S-adenosyl methionine (SAM) is a coenzyme involved in methyl group transfers. SAM was first discovered 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, and lipids.

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 EC 2.1.1.13 or 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-adenosyl-5'-3-methylpropylamine. 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 of SAM
In the United States, SAM is sold as a nutritional supplement under the marketing name SAM-e (also spelled SAME or SAMe; pronounced "sam ee"). SAM is also known as Gumbaral, Samyr, Adomet, and Admethionine. Some research has shown that taking SAM on a regular basis can help fight depression,  liver disease, and the pain of osteoarthritis.

Therapeutic use of SAM has increased 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 dietary supplement, and therefore allowed it to bypass the regulatory requirements for drugs of the Food and Drug Administration (FDA).

An emerging line of evidence suggests that 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. 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. In that study (available online), Tchantchou et al also explain the biomechanics that in addition to the above findings make low SAM a likely causal component of AD pathology.

Oral forms
Oral SAMe achieves peak plasma concentrations 3 to 5 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. Because of structural instability, stable salt forms of SAM are required for its use as an oral drug. Although more-stable salt forms have been developed, SAM is still liable to degradation, leading to distributors that may advertise a dose higher than what is actually being ingested. In 1999, two forms of SAM-e were available: sulfate-p-toluenesulfonate (also called tosylate) and butanedisulfonate. The butanedisulfonate form appears more stable. According to one study, the oral bioavailability of the tosylate salt is 1%, and the oral bioavailability of the butanedisulfonate salt is 5%. One study used the disulfate monotosylate salt. At least five salts are currently available, including SAM tosylate, SAM butanedisulfonate, SAM disulfate tosylate (Swanson) (Nature Made), SAM disulfate ditosylate (Natrol), and SAM disulfate monotosylate (GNC). One study using SAM disulfate monotosylate (GNC) suggests a loss of potency to 49% at day 595 while kept under refrigeration. The comparative stability and bioavailabilty of these various salt forms is unknown at this time, although one review is available.

Usage
As noted above, if improperly handled, the raw material used to make SAMe can deteriorate rapidly, making these costly supplements weak or even inactive. A small amount of data appears to be available on various manufacturers. Further, the original manufacturing date is not usually marked on packages, so the age of the off-the-shelf product cannot be determined. The butanedisulfonate or newer salts may be preferred to the tosylate salt in that they may be more stable and more bioavailable. SAMe is best absorbed on an empty stomach. Enteric-coated tablets packaged in foil or foil blister packs may increase stability and improve absorption, although scientific data on this importance appears lacking. SAMe should be stored in a cool, dry place to prevent deterioration.

Possible side effects
SAM-e & Homocysteine: Once SAM-e donates its methyl group to choline, 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, B12, and folic acid (SAM-e's main co-factors), will eventually be converted back into methionine, SAM-e, or cysteine, glutathione, and other useful substances. However, if adequate amounts of these vitamins are not present, SAM-e will not break down properly. As a consequence, the full benefits of SAM-e will not be obtained, and homocysteine may increase to unsafe levels. 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-e. These vitamins help metabolize the homocysteine into other useful compounds. 

Another reported side effect of SAMe is insomnia, therefore the supplement is often taken in the morning.

Therapeutic doses range from 800 mg/day to 1600 mg/day, although lower and higher doses are used. Consult with your physician before and during use.

Adverse effects
Gastrointestinal disorder, diarrhea, dyspepsia, anxiety, headache, psychiatric, insomnia, allergy, and rashes. Long-term effects are unknown.

Serotonin syndrome
There is concern and one report of the potentially fatal serotonin syndrome in association of SAMe with other medications.

Induction of mania
In an extensive MEDLINE search on SAMe, Kagan found induction of mania in one patient out of fifteen treated with parenteral SAMe. 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 hypomania and/or mania.