SAM-E is the abbreviation for a naturally occurring compound called S-adenosyl-L-methionine. This compound is synthesized from an amino acid, methionine, and adenosine triphosphate (ATP). SAM-E is important for enzymatic transmethylation. SAM-E also contributes to the synthesis, activation, and metabolism of such compounds as; hormones, neurotransmitters, nucleic acids, proteins, phospholipids, and certain drugs.
SAM-E provides a methyl group for conjugation of toxins which occurs in the liver. It also plays a critical role in the synthesis of polyamines and provides cysteine for the production of glutathione (GSH), the major endogenous hepatoprotective agent. SAM-E is able to inactivate estrogens, making it a useful adjunct treatment to problems associated with estrogen excess, like premenstrual syndrome. 
In a study of depressed men, treatment with S-adenosyl-L-methionine resulted in a significant reduction in prolactin and TSH in response to TRH stimulation; this outcome suggests that SAM-E may increase dopaminergic tone. 
Additionally, the recent Hoorn study showed that high levels of SAM-E have a significant positive effect on endothelium-dependent, flow-mediated vasodilation (FMD), and endothelium-independent, nitroglycerin-mediated dilation (NMD). Both are considered important factors in the formation of cardiovascular disease.  However, the mechanism by which SAM-E affects endothelial and smooth muscle cell function needs further clarification.
SAM-E formation requires methionine, choline, vitamin B12, and folic acid. Therefore, an adequate supply of these nutrients is necessary. Good sources of these nutrients include: folic acid (green leafy vegetables, fortified cereals); vitamin B12 (animal products and brewer’s yeast); choline (egg yolks, legumes, meat, especially liver, milk, soybeans and whole grains). Methionine is widespread in the human diet and can be found in beans, eggs, fish, garlic, lentils, meat, onions, soybeans, seeds, and yogurt. 
The main therapeutic application for SAM-E exists within the treatment of depression. Numerous controlled clinical trials have been conducted over the years demonstrating SAM-E‘s effectiveness as an antidepressant, as well as its comparative effect to standard antidepressant therapies. [5-8] In addition, SAM-E treatment usually provides improved tolerability due to its lower incidence of, and less severe, side effects. A review published in 2003 stated that SAM-E has an extensive history of investigation for more than three decades, demonstrating its effectiveness as an antidepressant.  It has also shown efficacy in treating HIV positive patients with depression. 
SAM-E demonstrated acute effectiveness, acting within one week, and continued a progressive effect throughout the eight week treatment period as measured by the Hamilton Rating Scale for Depression (HAM-D) and the Beck Depression Inventory (BDI). SAM-E may also augment SSRIs, although a placebo-controlled trial is necessary.  SAM-e has also shown the ability to speed the onset of action of the antidepressant imipramine. 
A published review of SAM-E summarized its effectiveness in restoring normal hepatic function in the presence of various chronic liver diseases (including alcoholic and non-alcoholic cirrhosis, oestrogen-induced and other forms of cholestasis), and its ability to prevent or reverse hepatotoxicity due to several drugs and chemicals such as alcohol, paracetamol (acetaminophen), steroids, and lead. 
Patients with liver disease have depleted levels of a compound called glutathione, which is vital to normal liver function. A controlled study in patients with alcoholic and non-alcoholic liver disease was conducted using an oral dose of 1.2 grams per day of SAM-E for six months.  This treatment demonstrated a significant increase of hepatic glutathione levels both in patients with alcoholic and non-alcoholic liver diseases as compared with placebo-treated patients.
Another study of subjects with Gilbert’s syndrome (an inherited disorder which affects the processing of specific pigments by the liver) showed that 800 milligrams (mg) of SAM-E administered intravenously for 10 days significantly reduced unconjugated bilirubin level, bilirubin time curve concentration, and plasma nicotinic acid level in comparison to placebo. 
Another related application is in treating pruritis (itching) from gestational cholestasis. A randomized controlled trial of women at <36 weeks of gestation with severe gestational cholestasis was carried out from June 1996 to December 2001.  Five hundred milligrams of SAM-E, administered twice daily, was compared to ursodeoxycholic acid at a dose of 200mg twice per day. Results showed that ursodeoxycholic acid was more effective than SAM-E at improving the concentration of serum bile acids and other tests of liver function; however, both therapies were equally effective at improving pruritus.
SAM-E has shown efficacy in treating patients with osteoarthritis as well. A multi-center open clinical trial of 108 patients with osteoarthritis of the knee, hip, and spine took place over a two year period.  Patients were given three tablets of 200mg SAM-E (600mg) each day for the first two weeks and 400mg daily until the end of the 24th month of treatment. Clinical symptoms were assessed by a scale at the end of each of the first two weeks of treatment, then monthly.
The results showed that clinical improvement was evident during the first two weeks and continued for the remaining two years of study. Depressive mood was also improved in this group of patients. Furthermore, side effects were mild with most resolving during the study period and none being recorded in the last six months. Pathologic changes were not observed as evidenced by laboratory tests. An extensive review also had similar findings.
A total of 22,000 patients over 5 years of clinical studies observed clinical efficacy and optimal tolerability of SAM-E for the treatment of osteoarthritis.  The review also concluded that the intensity of therapeutic activity of SAM-E in treating osteoarthritis is similar to non-steroidal anti-inflammatory drugs (NSAIDs), but with improved tolerability. A recent double-blind cross-over trial comparing 1200mg of SAM-E to 200mg of celecoxib (Celebrex), concluded that SAM-E has a slower onset of action but is as effective as celecoxib in the management of symptoms of knee osteoarthritis.  In light of recent recalls and risks of certain prescription NSAIDs, SAM-E offers a safe and effective treatment option to patients suffering form painful and debilitating osteoarthritis.
SAM-e may also be beneficial for other disorders, including; migraine, hepatotoxicity from acetaminophen and from chemotherapy, fibromyalgia, alcoholic liver cirrhosis, and premenstrual syndrome. [21-24]
Most studies use an oral dose in the range of 400 - 1600mg daily, taken in divided doses. Some trials have administered intravenous doses of SAM-E. Clinical improvements with depression and osteoarthritis are often seen within 1 week and effects seem to continue, as treatment progresses.
In order to synthesize SAM-E, adequate levels of methionine, choline, vitamin B12, and folic acid are needed. Methionine is widespread in the diet, however, the other nutrients may be lacking based on dietary habits. Low levels of SAM-E may contribute to problems with detoxification pathways in the liver, depression, and osteoarthritis.
SAM-E is generally considered a safe therapeutic substance when taken in recommended doses. The majority of studies reveal few adverse effects in patients taking SAM-E, which usually resolve with time and do not require discontinuation of the supplement. Adverse effects include gastrointestinal discomfort, nausea, vomiting, and headaches.
SAM-E should not be given to patients with bipolar disorder as it may result in mania or hypomania. 
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