S-adenosylmethionine (SAMe) is an important methyl donor that is involved in more than 50 methylation reactions in the body. Methylation reactions are crucial to many biochemical processes, such as the expression of genes, suppression of viruses, synthesis and signaling of cytokines, synthesis of phospholipids that maintain membrane fluidity, and regulation of various hormones and neurotransmitters including serotonin, melatonin, and dopamine. SAMe is synthesized in the body from methionine, an essential amino acid. Adenosine triphosphate (ATP) and methionine adenosyl transferase are required for its formation. Methionine is only able to donate its methyl group to other compounds while in its active, SAMe, form.

Once SAMe donates its methyl group to choline, creatine, carnitine, DNA, tRNA, epinephrine, and other compounds, it is transformed into S-adenosyl-homocysteine, or SAH. A transsulfuration reaction occurs when SAH donates its sulfur molecule to sulfur-containing amino acids such as cysteine, from which glutathione is formed. SAH then gives up its adenosine molecule to yield homocysteine. Homocysteine is a potentially toxic amino acid and an independent risk factor for coronary disease. Folic acid, choline, or betaine can re-methylate homocysteine back to methionine in the presence of vitamin B₁₂, or convert homocysteine into cysteine and glutathione in the presence of vitamin B₆. SAMe also is involved in the production of polyamines. These substances regulate gene expression and are involved in the binding and repair of DNA.

A significant amount of research supports the use of SAMe for treating depression, osteoarthritis, fibromyalgia, and liver disorders. Furthermore, because SAMe participates in so many different methylation processes throughout the body, it may prove useful for other conditions. Preliminary research has been conducted with SAMe in the areas of Parkinson's disease, cardiovascular disease, migraine, attention-deficit/hyperactivity disorder, rare infantile skin disorders, gastrointestinal protection (from NSAIDs), and cellular aging.

SAMe was first introduced into the U.S. dietary supplement market in 1999. It has been available in Europe since 1975. SAMe is an approved treatment for arthritis in Germany and a popular antidepressant drug in Italy.

A small amount of SAMe is found in food, but it is highly unstable and an unreliable means of increasing blood levels.

S-adenosyl-L-methionine

• S-adenosylmethionine butanedisulfonate 
• S-adenosylmethionine tosylate

SAMe is extremely hygroscopic and highly unstable. It is important to purchase enteric-coated tablets packaged in foil or foil blister packs to ensure a stable product. SAMe should be stored in a cool, dry place, but not refrigerated. Tablets should not be removed from the blister pack until they are to be taken.

Depression: SAMe has been shown to be as effective as, if not more effective than, conventional antidepressants at treating symptoms of depression.

Osteoarthritis: A significant amount of research supports the use of SAMe in treating osteoarthritis. SAMe has been shown to be at least as effective as NSAIDs, if not more so, without causing the gastrointestinal side effects associated with NSAID use.

Fibromyalgia: SAMe has been shown to improve symptoms of pain, fatigue, morning stiffness, and mood in patients with fibromyalgia.

Liver disease: SAMe is highly concentrated in liver tissue. Clinical studies indicate that SAMe treatment can reverse hepatic glutathione depletion in patients with liver disease; improve survival or delay liver transplantation in patients with alcoholic liver cirrhosis; and reduce biochemical parameters of intrahepatic cholestasis, such as bilirubin and bile salts, and subjective symptoms, such as pruritis, fatigue, and general discomfort.

Depression: The majority of studies have used between 800 and 1,600 mg SAMe per day for treating depression. The daily dosage is typically split between morning and afternoon.

Osteoarthritis: A dosage of 600 mg (200 mg tid) for the first two weeks and thereafter 400 mg (200 mg bid) for another 22 weeks has been shown to improve clinical symptoms of osteoarthritis. Another study demonstrated clinical improvement using 1,200 mg (400 mg tid) for 30 days.

Fibromyalgia: A dosage of 800 mg per day for six weeks was shown to improve clinical symptoms in patients.

Alcoholic liver disease: 1,200 mg/day orally for six months enhanced glutathione levels.

Intrahepatic cholestasis: 800 mg/day IV or 1,600 mg/day orally improved symptoms.

SAMe should not be taken at night because it may cause restlessness. Dosage and timing may vary according to individual body physiology and the condition being treated.

High doses of SAMe are nonmutagenic in vitro and in vivo. Side effects associated with SAMe include dry mouth, elation, nausea, and restlessness. No toxic effects have been reported in humans.

• SAMe is contraindicated in bipolar disorder. It may exacerbate manic episodes. 
• The safety of SAMe has not been assessed in children or pregnant or nursing women. 

Intraperitoneal administration of SAM-e (2.5 mmol/kg) within 1 to 5 hours of reduced the lethality of toxic doses of acetaminophen (APAP) (2 to 3 mmol/kg) in mice; lower doses of SAM-e (0.5 mmol/kg) did not reduce mouse mortality (Bray et al. 1992). SAM-e reduced the hepatotoxic effects of APAP by metabolizing the active moiety to glutathione. SAM-e may be a useful antidote, along with N-acetylcysteine, for the treatment of APAP poisoning.

In a double-blind, placebo-controlled trial, 40 patients with moderate to severe depression received imipramine (titrated from 50 mg/day to 150 mg/day) with either SAM-e (200 mg/day IM) or placebo; improvements on the Hamilton Rating Score for Depression (HRSD) occurred as early as day 4 for patients treated with both SAM-e and imipramine (Berlanga et al. 1992). However, there is a case report of serotonin syndrome associated with the combination of tricyclic antidepressants and SAM-e (Iruela et al. 1993). Specifically, a 71-year-old female became increasingly anxious, agitated, and confused within 48 to 72 hours after ingesting a higher dose of clomipramine (75 mg/day) while she was taking SAM-e (100 mg/day IM). Patients should be cautioned about this possible interaction.

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