SAMe (S-adenosyl-L-methionine) is a substance naturally found in many of the body’s tissues. It is made up of the amino acid methionine (a sulfur-containing amino acid) combined with adenosine, SAMe is used in several of the body’s processes that require sulfur, especially methylation reactions. Many favorable clinical studies on SAMe indicate it has potential as a therapy for osteoarlhrilis, depression, and liver disease. SAMe’s general mechanism of action as a supplement is as a methyl donor for rnethylation reactions in our body’s natural processes. A deficiency of SAMe could be caused by a deficiency in the cofactors of its production, such as melhionine, choline, and B vitamins. A defect in methylalion may also cause a deficiency in SAMe. Overall, SAMe has been found to have anti-inflammatory, analgesic, and antidepressive effects.

One theory on depression and other netiropsychiatric disorders is lhat they are caused by a defect in biochemical methylation reactions. Low levels of folate (used in rnethylation reactions) and serotonin have been linked to lower levels of SAMe in depressed patients; in clinical studies, SAMe supplementation has been shown to have an a tili depress ant effect that may increase serotonin levels (Bressa, 1 994; Fetrow and Avila, 2001).

The National Institute on Alcohol Abuse and Alcoholism and the Office of Dietary Supplements sponsored a conference examining the possible role of SAMe in treating alcoholic liver disease. Because oxidant stress is known to play a major role in the development of liver disease, and SAMe is involved in the manufacture of important liver antioxidant compounds (glulathione), SAMe is being studied for its role in the treatment of alcoholic liver disease. SAMe’s potential for osteoarthritis is based on its ability to support a higher production of proteoglycans, a substance that makes up cartilage.

SAMe seems to be a relatively safe and effective way of correcting our biochemical methylalion reactions, which may lead to causes of depression, osteoarthrilis, liver disease, and other conditions. More clinical studies are needed to understand the kinds of depression for which SAMe works best, its specific risks and therapeutic side effects, and its potential for other disease processes before it can be accepted as a treatment method for these and other conditions.

Depression

A review of the published literature (from 1966 to 2001) on SAMc found that most of the clinical evidence for its use has been conducted on various depressive disorders, osteoarthritis, and fibramyalgia and sample sizes and the doses used varied widely (Fetrow and Avila, 2001). Several reviews and meta-analyses have been published, all concluding that SAMe was better than placebo in treating depression and equally as effective as the standard tricyclic antidepressants. The authors pointed out, however, that even though SAMe seems well tolerated, with most side effects being presented as gastrointestinal complaints, it may have the potential risk of psychiatric and cardiovascular adverse side effects. They con eluded that until the side effects are more thoroughly researched, people should not be consuming it in an unmonitored fashion, and health care providers should be aware of the need for more research into the potential for adverse events (Bressa, 1994; Fetrow and Avila, 2001).

SAMe was tested in depressive patients and compared with unipramine in two mullicenter studies. In one study (involving 143 patients over 6 weeks), 1,600 mg/day of SAMe was given orally, and in the second study (involving 138 patients over 4 weeks), 400 mg/day of SAMe was given intramuscularly. In both studies, the SAMe treatment was compared (in 138 patients over 6 weeks) to the effects oi 150 mg of imipramine given orally each day in a double-blind manner. The assessment measures were the Hamilton Depression Rating Scale (HAM-D) and the Clinical Clobal Impression Scale at the endpoint. The authors staled that SAMe is the most important methyl donor in the central nervous system, and they concluded that both treatments of SAMe were as effective as 150 mg/day of imipramine orally and were associated with significantly fewer adverse events (Delle Chiaie et al., 2002).

In one pilot study involving 13 depressed patients with Parkinson disease, for which no other previously tried antidepressant agents were effective (and were with intolerable side effects), SAMe was administered in doses of 800 to 3,600 mg/day for 10 weeks. Ten of the 11 patients that completed the study showed at least a 50% improvement in the HAM-D score. One patient did not improve, and two dropped out because of increased anxiety. The only side effects noted in the others were mild nausea (in one patient) and mild and transient diarrhea (in two others). The authors concluded lhat this preliminary trial showed that SAMe is well tolerated and may be a safe alternative to current antidepressant agents used in Parkinson patients (Di Rocco etal., 2000).

In an open, multicenter study involving 195 patients, 400 mg of SAMe was given pa re literally for 15 days. Depressive symptoms were found to decrease after clays 7 and 5 of treatment, with no serious adverse events responded. The authors concluded that further double-blind studies are needed to confirm the findings thai SAMe not only is a safe and effective antidepressant but also is fast-acting and may be a method for reducing the delay in antidepressant response (Fava et al., 1995).

The antidepressive effect of SAMe was compared with desipramine in a double-blind randomized clinical study involving 26 patients. In the SAMe group, 62% showed significant improvement compared with 50% in the desipramine group. Regardless of the treatment group, the plasma SAMe concentration was shown lo have been significantly improved in all patients that showed a 50% decrease in their HAM-D assessment. The authors concluded that this latter finding showed that SAMe played a major role in regulating mood (Bell et al., 1994).

Another study examined the effect of SAMe in depressed post-menopausal women in a 30-day double-blind, placebo-controlled, randomized design. Highly women who were diagnosed with DHM-ltl-R major depressive disorder or dysthymia 6-36 months subsequent to menopause (either natural or through hysterectomy) were given 1,600 mg/day of SAMe or a placebo. A significant improvement was found in depressive symptoms compared with placebo starting on day 10 of the study, and side effects were mild and transient (Salmaggi el al., 1993).

In an effort to study the effect of speeding up the onsel of action of the antidepressant imipramine, SAMe was given lo 40 patients in a double-blind manner alongside imipramine at 150 mg/day. SAMe was administered at 200 mg/day intramuscularly and was found to effectively increase the onsel of the antidepressive action of imipramine (lierlanga et al., 1992).
In an earlier study, SAMe was administered both orally and intravenously, and levels of SAMe were found lo significantly rise in the cerebro-spinal fluid, indicating that it crossed the blood-brain barrier. The authors also poinled oui that SAMe levels were low in a group of Alzheimer patients and thai this suggested a problem in melhylation lhat the use of SAMe might treal (Bottiglieri et al., 1990).

Osteoarthritis

A meta-analysis of randomized, controlled, clinical irials was conducted on the use of SAMe compared with nonsteroidal anti-inflammatory drugs (NSAlDs) for osteoarlhritis. SAMe was found to be as effective as NSAIDs in reducing pain and the functional limitations of Osteoarthritis but without the side effects associated with NSAIDs (Soeken et al., 2002).

In another meta-analysis of the use of SAMe in osleoarthritis, all randomized clinical trials on SAMe and oxaceprol were reviewed for their efficacy in osteoarthritis. Assessments of clinical trials were based mostly on pain scores and pain and function scores. Because there were only a few trials that had a mixture of results, the authors cautioned that the results of the me la-ana lysis had to be interpreted very carefully. The authors concluded lhat overall, the evidence was insufficient to recommend using SAMe and oxaceprol for the treatment of osteoarthritis, but that the effect of the substances was comparable to that of NSAIDs (Witte et al., 2002).

SAMe was tested in a bicentric, randomized, double-blind, placebo-controlled study on its effectiveness for treatment on 81 patients with osteoarthritis. After a 7-day washout period, patients were administered either 400-mg boluses of SAMe intravenously for 5 days followed by 200 mg 3 times daily for 23 days or a matching placebo regimen. The major outcome measures were the Stanford Health Assessment Questionnaire disability and pain scales and supplemental visual analog scales for rest and walking pain. In one center, where the patients tended to have a milder baseline of osteoarthritis, the SAMe showed a significantly greater effect in reducing overall pain and resting pain than the placebo. In the other center, the baseline osteoarthriiis was much more severe, and no difference was seen between treatment groups in outcome measures. The authors concluded lhat SAMe is beneficial to the treatment of osteoarthritis in some patients and that intravenous loading of SAMe may be a more effective strategy than beginning oral treatment (Bradley et al., 1994).

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