S-Adenosyl Methionine as a food supplement:
Pros' and Cons'

Introduction

S-Adenosyl Methionine (SAM or SAM-e; pronounced "sammy") is an amino acid. SAM-e was discovered in 1952 in Italy, where it is manufactured. Until recently, it was exceedingly expensive to produce, and therefore unavailable to the public, although it is fairly well studied. It is manufactured in the brain from another amino acid, methionine. SAM-e is the most active methyl-donor in your body, meaning it donates methyl groups to other chemical compounds in your body including neurotransmitters, changing them into other compounds. SAM-e is then "recycled" through an ongoing re-methylation process.

By mechanisms that are still unclear, the natural methyl donor S-adenosylmethionine appears to promote production of cartilage proteoglycans, and is therapeutically beneficial in osteoarthritis in well-tolerated oral doses. These and other safe nutritional measures supporting proteoglycan synthesis, may offer a practical means of preventing or postponing the onset of osteoarthritis in older people or athletes.

It's one of the hottest supplements on the market. Not an herb, hormone, vitamin, or any kind of nutrient, SAM-e is a stabilized, synthetic form of S-adenosylmethionine (SAM), a chemical produced naturally in all animals. In the human body SAM is known to be essential to at least 35 biochemical processes, including maintaining the structure of cell membranes and manufacturing substances vital to transmitting nerve impulses and influencing emotions and moods. SAM-e was brought into the American marketplace with every form of hype, including enthusiastic articles in Newsweek, plenty of TV publicity, two promotional books, full-page ads in newspapers, and a plethora of websites. SAM-e is said to be an effective, indeed magical, treatment for depression, arthritis, and liver disease, among other things. Like other supplements, it is unregulated.

Regardless of the hype, there may actually be something to the claims-or maybe there will be some day. Unlike much of what's on the market, SAM-e has been the subject of some scientific research. First tested as a treatment for schizophrenia, it proved ineffective. But in the 1970s some clinical trials in Italy, Germany, and other European countries did suggest that SAM-e might be an effective treatment for depression, with fewer side effects than antidepressant drugs.

SAM-e might be an effective treatment for depression, with fewer side effects than antidepressant drugs. But the real benefits and risks of SAM-e are still unclear. In theory, it may increase the risk of heart disease. People with depression or joint pain should seek medical advice before trying SAM-e. If it works, it's a drug, and should be regulated and prescribed like one, as it is in Europe.

The brain of a healthy person manufactures all the S-Adenosyl Methionine it needs from methionine, but S-Adenosyl Methionine production is impaired in people who are depressed.¹ Supplementation with SAM-e increases levels of serotonin, dopamine and phosphatides, and improves serotonin and dopamine receptor site binding.² Interestingly, treatment with antidepressant drugs that results in improved mood (as determined by a 50% improvement in the Hamilton Depression Inventory) usually also results in increased levels of SAM-e, regardless of the drug used.³

SAMe appears to have central neuropharmacologic effects after systemic injection in high doses. Nevertheless, the functional consequences of these remain unclear and, indeed, the ability of exogenous SAMe to reach the brain, and especially neuronal cytoplasm, is limited. SAMe has small effects on monoamine metabolism and, after injection, appears to have effects on the microviscosity of cell membranes that may be related to stimulation of phospholipid synthesis.  With regard to osteoporosis, bone and cartilage formation there is only a paucity of study information obtained in the 1980's and early 1990's.

General Information

In 1990 Barcelo  induced degenerative arthropathy in the right knee of 24 rabbits. The animals were randomly divided in 3 groups of 8 rabbits each. S-Adenosyl-L-Methionine (SAMe) was administered intramuscularly to 2 groups. One group received 30 and 60 mg/kg/day i.m. The remaining group was a control and received only a diluent. After 12 weeks of therapy rabbits were sacrificed and tibial and femoral cartilage specimens of both knees were taken. The latter was stained with hematoxylin -eosine, Masson's trichromic and Safranine 0 stains and was microscopically studied. The thickness and cell density of the lesioned cartilages were significantly greater in both groups treated with SAMe than the group control (p less than 0.001). Statistical differences (p less than 0.05) were found within 60 and 30 mg/kg/day of SAMe. A greater concentration of proteoglycans in the cartilage matrix was found in animals treated were as, a severe reduction was found in controls. The severity of the lesions, based on the histologic-histochemical analysis, was significantly lower in rabbits receiving SAMe (p less than 0.0005).

Here is what is claimed to be known by some studies:

SAM-e plays an important role in cartilage formation and repair.

In in-vitro studies, SAM-e has been shown to increase the blood levels of proteoglycans - the starting point of cartilage formation.⁵

SAM-e has been shown in a number of studies to bring arthritis pain relief comparable to that of the oft-prescribed NSAID's, naproxin and piroxicam - without their side effects.^5,6

Marketers of SAM-e generally say a "dose" is 400 milligrams daily, but there's no way to find a standardized dose in the current market. In addition, raw SAM-e is said to degrade quickly unless stored at proper temperatures, and you have no guarantee that the pills you buy have been properly handled. One big conglomerate, the BASF company, is importing raw SAM-e from Europe, and it's being sold under various labels in General Nutrition Stores and elsewhere in the vast health-food marketplace. And SAM-e is very expensive. A daily dose can cost anywhere from $2.50 to $18. You have to take it over the long term to get any results, it's said. All this is wonderful for the seller, but may be less so for the user.

Some research has shown that SAM-e provides relief from arthritis pain, without the stomach irritation caused by aspirin and similar drugs. And there are other possibilities, too. For instance, SAM-e may aid in joint repair. The possibilities are encouraging. Most studies so far have been small and brief (and some have used large intravenous doses), but since SAM is so important to life, SAM-e might have uses as a drug.

But the problem is threefold: first of all, the possible benefits and risks of SAM-e remain unclear. In Europe it is sold as a prescription drug for arthritis, depression, and liver disease. At least that means a doctor is overseeing the treatment. Here, where SAM-e can be bought as easily as a multivitamin, people can simply dose themselves-which may be unwise when so much remains to be discovered.

Secondly, its promoters, particularly Richard Brown, the author of Stop Depression Now, say SAM-e has no side effects, but anything that works like a drug has side effects of some kind, and may interact with medications or foods.

But the most important potential problem: SAM is converted into homocysteine in the body. High levels of homocysteine may raise the risk of heart disease. SAM-e is likely to promote higher levels, though no one knows how high.

Interestingly, SAM-e breaks down into the potentially harmful homocysteine, which has recently made press as a substance strongly correlated with heart disease if it is left to build up within your cells. The good news is that SAM-e, which is so good for you does NOT have to turn into a toxic build-up of homocysteine. With the proper complement of B-complex vitamins (especially B-6, B-12 and folic acid, which are all methyl-donors), homocysteine is re-methylated into good old methionine (used to produce S-Adenosyl Methionine) or convert to the antioxidant glutathione.
 
People taking SAM e should be well advised to supplement with B vitamins. This will ensure adverse reactions and prevent homocysteine build-up.  Thus one health problem is combated only to introduce a different problem?

Pointers for people wishing to take SAM-e

. For healthy people SAM-e has no value. Don't take it as a tonic or mood booster. It does not prevent any known disorder.

. Contrary to rumor, SAM-e will not repair the liver damage caused by heavy drinking.

. Side effects have been reported, including stomach upset and other gastrointestinal problems.

. If you are suffering from depression, seek medical advice before trying this supplement. Depression is a treatable illness, requiring professional care. Don't try it on your own or combine it with antidepressant drugs. For those with bipolar disorder (manic depression), SAM-e may have unpredictable adverse effects.

. If you have joint pain, talk to your doctor before taking SAM-e. Make sure it's actually arthritis that's causing the pain. Don't give up conventional treatments in favor of SAM-e with-out at least telling your doctor of your decision.

. If you do decide to try it, make certain your diet is rich in fruits and vegetables, and take a multivitamin. A high intake of three B vitamins (folic acid, B-6, and B-12) can lower homocysteine levels, in case SAM-e raises them.

CONCLUSION

SAM-e appears to be selectively beneficial in depressive disorders, but other medicinal effects require more defined studies to prove its efficacy.  This report is a review of existing published clinical evidence surrounding the dietary supplement SAMe (S-adenosyl-L-methionine) MEDLINE search (1966-February 2001). Information was obtained through secondary and tertiary sources. Most articles identified from data sources were evaluated and all relevant information included. The majority of clinical trial evidence surrounds the application of SAMe for various depressive disorders, osteoarthritis, and fibromyalgia. Sample sizes of these trials and the dose employed have varied considerably. Several reviews and at least two meta-analyses have examined the available evidence surrounding SAMe in the therapy of depression for trials completed prior to 1994 and concluded that SAMe was superior to placebo in treating depressive disorders and approximately as effective as standard tricyclic antidepressants. Much of this information exists in the form of isolated case reports or solitary clinical trials. SAMe appears to be well tolerated, with the majority of adverse effects presenting as mild to moderate gastrointestinal complaints. However, it is apparent that this agent is not without risk of more significant psychiatric and cardiovascular adverse events. Information documenting drug or food interactions with SAMe is very limited.

Consumers should be instructed to avoid unmonitored consumption of this dietary supplement until sufficient discussion has taken place with their primary healthcare provider. Although there exists significant potential for therapeutic application of SAMe, its uncertain risk profile precludes definitive recommendation at this time. Healthcare providers and consumers should likely temper their enthusiasm for this dietary supplement until sufficient information becomes available.

Selected references

1   Murray, MT, Natural Alternatives to Prozac. Quill. New York. p174-5,1996.

2   Baldessarini, RJ, Neuropharmacology of S-Adenosyl Methionine. Am J Med. 83:95-103, 1983.

3   Bell, KM, et al, S-Adenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand. 154:15-18, 1994.

4   Stramentinoli G. Pharmacologic aspects of S-adenosylmethionine. Pharmacokinetics and pharmacodynamics. Am J Med. 1987; 83(5A):35-42.

5   Harmand MF, et al. Effects of S-adenosylmethionine on human articular chondrocyte differentiation. An in vitro study. Am J Med. 1987; 83(5A):48-54.

6   di Padova C. S-adenosylmethionine in the treatment of osteoarthritis. Review of the clinical studies. Am J Med. 1987; 83(5A):60-65.

7   Weatherby, Craig and Gordin, Leonid, MD, The Arthritis Bible. Rochester. Healing Arts Press, 1999.

8  Barcelo HA, Wiemeyer JC, Sagasta CL, Macias M, Barreira JC. [Experimental osteoarthritis and its course when treated with S-adenosyl-L-methionine].[Article in Spanish] RevClin Esp 1990 Jun;187(2):74-8.