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April 2007

By Tiesha D. Johnson, BSN, RN

SAMe Protects Against Liver and Gall Bladder Disease

One of the hardest-working organs in the body, the liver detoxifies environmental contaminants and drugs, manufactures critical compounds needed for blood clotting, and manages cholesterol levels in the blood. Not surprisingly, these chemical reactions produce massive amounts of destructive reactive oxygen species in the liver, mainly in the cellular power plants known as mitochondria.

Mitochondria protect themselves from their own reactive oxygen species with glutathione they import from other parts of the cell. When glutathione levels drop, mitochondria become highly vulnerable to oxidative damage—a significant cause of cell death and aging.34 SAMe may help protect the liver by increasing glutathione content in its cells. When researchers added SAMe to cultured rat liver cells, for example, glutathione content nearly doubled, completely protecting cells from oxidative damage.35

SAMe thus offers promise for patients who suffer from various forms of liver and gall bladder disease. Elevated levels of the female hormone estrogen can increase the amount of cholesterol secreted into the gallbladder, putting women—especially those who have had multiple pregnancies and those who use estrogen-containing medications—at a higher risk of gallstones.36,37 Gallstones are hard formations that block the flow of fat-digesting bile and can trigger symptoms such as abdominal pain, fever, and difficulty digesting fatty foods. In a study of six healthy women taking oral estrogen contraceptives, daily treatment with 600 mg of SAMe reduced bile cholesterol by almost one third, suggesting that SAMe may prevent gallstones in women with increased estrogen levels.38

Patients with other bile-excretion problems can benefit from SAMe as well. One double-blind, placebo-controlled trial studied 220 patients with chronic liver disease and increased blood levels of bilirubin, the main pigment occurring in bile.7 Patients treated with 1600 mg per day of SAMe not only greatly reduced their blood levels of bilirubin and other evidence of liver damage, but also saw dramatic improvements in symptoms such as itching and fatigue. Patients tolerated SAMe as well as placebo.


SAMe is a naturally occurring biochemical that plays many essential roles in the body. It is manufactured from methionine and adenosine triphosphate (ATP) during a chemical cycle that recycles the sulfur-containing amino acid homocysteine.26 This cycle also relies on folate and B vitamins to work properly.27,28 SAMe acts as a precursor to glutathione, helping to maintain levels of this crucial antioxidant in the liver and brain. When glutathione stores drop, liver damage from oxidative stress begins within seconds of exposure to alcohol and many other toxins.29-31

SAMe contributes to many of the body’s essential physiological processes by acting as a methyl donor. By donating methyl groups (made of carbon and hydrogen), SAMe contributes to the production and recycling of chemical-signaling molecules such as hormones and neurotransmitters, including serotonin, dopamine, noradrenaline, and norepinephrine. Methylation (the process of adding methyl groups) also contributes to gene expression.2 Furthermore, SAMe modifies important molecules in cell membranes that control vital communication between and within cells.32 Since SAMe occurs in virtually all living cells, scientists believe that it has long assisted cells in coping with destructive influences.33

Cirrhosis, a serious, often-fatal liver condition resulting from inflammation, can be the end product of many different conditions, including alcoholic liver disease and hepatitis. Patients with cirrhosis were recently shown to have a blockage in the enzyme pathway that produces SAMe.39 Without this vital molecule, liver cells cannot carry out their normal detoxification reactions, resulting in further damage to liver tissue. Patients with cirrhosis may therefore require SAMe as an essential nutrient.32

Of course, preventing inflammation in the liver is a better strategy than treating it after it has already occurred. SAMe may work via several mechanisms to help guard against inflammation in the liver. Chemical messengers called cytokines, such as tumor necrosis factor-alpha (TNF-a) and interleukin-1 (IL-1), are intimately involved in the production of inflammation and its resulting tissue damage. In a deadly cycle, alcohol and other toxins reduce glutathione stores in liver cells, making them vulnerable to injury by cytokines, inflammation, and still more oxidative stress.29 In laboratory experiments, SAMe prevented the release of TNF-a by human white blood cells,40 as well as the release of both TNF-a and IL-1 in liver cells.35 In rats that were chronically administered alcohol, supplementation with SAMe restored glutathione levels to normal, thus protecting liver tissue against inflammation.34

Several well-conducted clinical trials have demonstrated SAMe’s benefits in protecting against the effects of alcohol consumption, which could have implications for alcoholic liver disease. As early as 1994, scientists demonstrated that SAMe increases glutathione levels in the red blood cells of chronic alcohol users.41 In a 1996 trial, 45 patients with alcoholic liver disease and reduced liver function were randomly assigned to receive either SAMe or placebo by intravenous (IV) injection.42 SAMe recipients greatly improved their blood measurements of cell membrane damage caused by oxidation reactions, thus demonstrating SAMe’s protective effect.

A powerful clinical trial in 1999 demonstrated benefits even more impressive. Researchers studied 123 patients with alcoholic liver cirrhosis43 who took 1200 mg per day of SAMe or placebo for two years. Among patients with mild or moderate cirrhosis, rates of death or liver transplant in SAMe patients were less than half those of placebo recipients. Even in patients with severe disease, survival time was greater in the SAMe group. The study authors concluded that SAMe supplementation can improve survival and delay the need for liver transplantation in patients with alcoholic liver cirrhosis.

This powerful evidence of SAMe’s efficacy in treating alcoholic liver disease prompted the National Institutes of Health to hold a symposium on the subject in 2001. According to the published report of the proceedings,44 SAMe treats alcoholic liver disease by at least four mechanisms: increasing glutathione levels, repairing the transport of glutathione into the mitochondria, reducing the toxicity of inflammatory cytokines, and protecting DNA from oxidative damage.

SAMe has also shown value in treating patients with non-alcoholic chronic liver disease. Russian researchers administered 800 mg per day of SAMe intravenously to 32 such patients for 16 days, then followed with oral administration of 1600 mg per day of SAMe. Most of the study subjects improved their symptoms of itching, jaundice, and weight loss, and those who had hepatitis or cirrhosis exhibited significantly less evidence of liver damage on blood tests.45

SAMe Relieves Osteoarthritis Pain

As early as 1975, published scientific studies indicated that SAMe may reduce inflammation and relieve the pain of osteoarthritis. This debilitating condition involves the slow accumulation of microscopic damage to the tissues that line joints, triggering the release of inflammatory cytokines and a destructive cycle of oxidative damage, tissue injury, and further cytokine release. Scientists believe that SAMe’s dramatic success in treating osteoarthritis (also called degenerative arthritis) stems from its ability to reduce inflammatory cytokine activity.46,47

By the late 1980s, numerous laboratory studies had shown that SAMe protects against experimental arthritis in animals by increasing the number and depth of joint-cushioning cartilage cells.48 Researchers found that, compared with cartilage of a placebo group, the cartilage of SAMe-treated animals had greater concentrations of vital joint-cushioning proteins called proteoglycans.49 In a study of joint-lining cells in rabbits,50 SAMe protected against progressive arthritis by restoring joint tissue to its normal state following cell damage by TNF-a.

For more than 20 years, human clinical trials have demonstrated SAMe’s effectiveness in managing arthritis. In 1985, scientists conducted a double-blind, controlled trial comparing SAMe (1200 mg/day) to ibuprofen (Advil® or Motrin®, 1200 mg/day) among 150 patients with osteoarthritis of the hip and/or knee.51 The study results indicated that SAMe was slightly better than ibuprofen in treating painful manifestations of the disease. Side effects were three times more common in those taking ibuprofen than in those given SAMe.

A wave of studies published in 1987 showed that SAMe was just as effective as various NSAIDs in treating arthritis, with far fewer side effects. For example, in a randomized, controlled Italian study comparing SAMe (1200 mg/day) with naproxen (Naprosyn®, 750 mg/day) in 734 subjects, SAMe exhibited the same pain-relieving activity as naproxen, with far better tolerability as assessed by both physicians and patients.52

Subsequent human studies have demonstrated that SAMe is equal in almost all measures to other anti-inflammatory drugs—including piroxicam (Feldene®),53 indomethacin (Indocin®),54 and celecoxib (Celebrex®)55—in relieving pain and improving function in subjects with osteoarthritis of the knee.

To verify the effects of a specific course of treatment, scientists often conduct a “meta-analysis” of multiple small trials. A 2002 meta-analysis led scientists to conclude that SAMe appears to be as effective as NSAIDs in reducing pain and improving functional limitation in patients with osteoarthritis, without the adverse effects often associated with NSAIDs.5 This impressive conclusion should convince even the most skeptical critics of SAMe’s potent effects in relieving arthritis pain and inflammation.