S-Adenosylmethionine, more popularly known as "SAMe", is hardly a household word, even among life-extension and anti-aging medicine enthusiasts, yet its pivotal importance in human health and biochemistry is hard to over-estimate. As SAMe research pioneer G. Stramentinol notes; "[SAMe] is an important physiologic compound that occurs in every living cell... SAMe is probably second only to ATP in the variety of reactions in which it serves as a cofactor." (1)

SAMe is the "linch pin" of three major biochemical pathways- transmethylation, transsulfuration, and aminopropylation- which regulate or impact virtually every biochemical reaction in humans and animals.

Neurochemistry, liver biology, heart and artery function, cartilage, bone and joint health, stomach/ intestinal lining resistance to ulceration, immune health, cell membrane integrity and pain and inflammation, are just some of the realms HEAVILY influenced by the efficiency (or inefficiency) of one’s SAMe metabolism.

Transmethylation is essential to many biochemical processes "...methyltransferase reactions.. shift the ‘active’ methyl group of SAMe to a wide variety of methyl ‘acceptor’ molecules, including... biogenic amines [noradrenaline, serotonin], fatty acids and phospholipids, proteins, nucleic acids, polysaccharides and porphyrins, in this role SAMe is the most important methyl group donor in mammalian tissue." (2)

SAMe’s methyl groups make possible the production of the "fat burner," carnitine; the neuronutrient, acetyl-L-carnitine; the primary ATP energy reservoir, creatine phosphate; the stress hormone and neurotransmitter, adrenaline; the neuronutrient and chief membrane phospholipid, phosphatidyl choline; and the DNA bases methyladenine and methylcytosine, among many other critical methyl biochemicals (3).

The transsulfuration pathway starts with the "leftovers" from transmethylation- S-Adenosylhomocysteine (SAH). SAH yields homocysteine, which will (hopefully) be converted to cysteine and then to a family of key sulphur biochemicals- glutathione (GSH), GSH peroxidase, GSH-S-transferase, and taurine. SAMe also provides the sulphur for the important cartilage building blocks, glucosamine sulphate and chondroitin sulphate. GSH, GSH compounds and taurine play critical life-preserving roles in liver detoxification- both of foreign toxins and those produced by our normal metabolism.

Because dietary cysteine is low in many (especially vegetarian) foods, and because as much as 80% of dietary cysteine may lose its bioactive sulfhydryl groups passing through the stomach, SAMe provides the main source of cysteine for life-essential GSH production (3,4).

Aminopropylation reactions utilizing SAMe convert putrescine to spermidine and sepermine, two polyamines which play key roles in cell growth and differentiation and the stabilizing of DNA and RNA.

Methylthioadenosine (MTA) is a major beneficial by-product of polyamine production. MTA possesses powerful analgesic and anti-inflammatory properties, and is at least partly responsible for the superb clinical results achieved in treating osteoarthritis, rheumatoid arthritis and fibromyalgia with SAMe (1,5,6).

Yet in spite of SAMe’s critical importance to optimal human health, SAMe metabolism can be "derailed" in many ways. Deficiencies of any of the active coenzyme forms of vitamins B2, B6, B12 and folic acid will disrupt SAMe production, and conversely diminished SAMe production will impair conversion of folic acid and B12 to their coenzyme forms!

Furthermore impaired B6-B12-folate-SAMe metabolism will lead to the blood/ cellular accumulation of the heart/ artery toxic metabolite homocysteine (HCy).

HCy is now commonly accepted by the medical community as one of the most important risk factors for heart and artery disease- far more important than the more frequently touted cholesterol- heart disease risk (7). The two enzymes necessary to convert HCy to cysteine and ultimately to the detoxicant glutathione (GSH), are two that commonly suffer slight genetic abnormalities that may impair normal cysteine/ GSH production, especially when dietary B6 is low (7).

SAMe- the findings and studies

Naturally occurring tissue levels of SAMe show a marked decrease in older rats compared with younger animals.

Similar findings with humans’ show decreased blood SAMe levels with aging, dementia, liver disease, alcoholism and depression (2).

Fortunately, in 1974 a stabilized form of SAMe- SAMe sulphate-paratouluene sulphonate- was introduced into clinical use in Europe.

In the intervening years SAMe has been given, both orally and intravenously, to tens of thousands of patients, with great clinical success and extremely minimal side effects. A 1987 review of studies on SAMe treatment in osteoarthritis found 22,000 patients enrolled in clinical trials just in the previous 5 years! (5)

SAMe is one of the most well studied and well proven life-enhancement "drugs" (actually a key cellular nutrient) available. "SAMe can be considered a safe drug; no toxicity was ever evidenced even at much higher doses than the therapeutic ones, and signs of damage to the gastrointestinal [lining] were not observed." (1)

"SAMe was very well tolerated so that it was possible to administer the compound for long periods (up to 24 months without side effects). The majority of patients... in this long term trial experienced improvement [of their osteoarthritis], and none had to stop the treatment for the appearance of side effects." (5)

"The current study demonstrates that the [intestinal lining] tolerates SAMe as well as it does distilled water... Previous human and animal studies showed that SAMe may exert a cytoprotective effect on the [stomach lining] against aspirin- and ethanol-induced injury." (8)

"In conclusion, SAMe, because of its analgesic properties and lack of major side effects, deserves to be ranked among the most adequate drugs for the ... management of osteoarthritis." (9)

These are just a few of the many reports attesting to the efficacy and safety of SAMe.

SAMe- who might benefit?

1. People suffering from cirrhosis, chronic liver disease, alcoholic liver damage, toxic chemical exposure, NSAID-liver damage, estrogen induced liver problems, bile disorders, and environmental chemical hypersensitivity may all benefit from SAMe, as well as people who possibly suffer from SAMe metabolism "bottlenecks." (10,11,12)

2. People who suffer from osteoarthritis, rheumatoid arthritis, fibromyalgia, joint injuries and osteoporosis may all benefit from SAMe. SAMe stimulates chondrocytes to increase production of new cartilage, UNLIKE NSAIDS (aspirin, ibuprofen, etc.) chronically consumed by many joint inflammation/ degeneration sufferers, which actually INHIBIT proteoglycan synthesis needed to renew cartilage and synovial fluid (5). Furthermore SAMe is actually protective of the stomach lining, while NSAIDs tend to damage and irritate the gut lining with chronic use (8).

3. People suffering from depression, especially people who cannot tolerate standard antidepressant drugs (e.g. tricyclics, SSRIs, etc.), or who have minimal or no response to them (2,13,14).

SAMe has been shown to significantly increase cerebrospinal fluid levels of HVA and 5HIAA, the chief metabolites of dopamine and serotonin, two key biogenic amine antidepressant neurotransmitters. This is evidence of SAMe’s enhancing brain biogenic amine metabolism and activity (2).

SAMe has also shown considerable efficacy in treating depression secondary to chronic diseases such as arthritis, fibromyalgia, liver disease and alcoholism (5,6).

4. People suffering from chronic gastrointestinal lining irritation or ulceration, whether from alcohol abuse chronic NSAID use, chemical irritation, or unknown cause (8).

5. People who are concerned with their heart/ artery disease risk due to elevated blood levels of homocysteine. SAMe activates the key B6-dependant enzyme, cystathionine synthase, which helps convert toxic homocysteine to the beneficial detoxifiers cysteine, N-Acetylcysteine, glutathione and taurine (7,8). 

6. People wishing to protect their brain’s from the entrophy of aging, or who are in early stages of dementia (15). SAMe helps maintain youthful neuronal membrane ratios of phosphatidyl choline; cholesterol. This promotes more optimally fluid membranes, which in turn promotes optimal hormonal, neurotransmitter and electrical neuron signal reception and processing (2).

SAMe also possesses mood-elevating and behaviorally arousing effects, due to SAMe increased dopamine/ serotonin activity and to a selective excitatory action on cortical neurons in the brain (2). Also because neurons are so toxin sensitive, SAMe’s ability to enhance liver detoxification also protects the brain in our over-chemicalized modern world.

SAMe- the dosages and uses

SAMe has been given orally in doses ranging from 400mg/ day (16) to 1600mg/ day (13). SAMe is usually given in two or three doses daily, with 10AM and 3PM being a common time for twice-daily administration (13).

Starting with low dose (200-300mg) twice daily and slowly working up to higher doses if needed is the best strategy. Because SAMe tablets are enterically coated, they should NOT be cut in half to achieve a lower dose- the SAMe may then break down before absorption.

SAMe- the side effects

In general, side effects in SAMe studies are few and mild. In some studies, SAMe induced fewer or less serious side effects than placebo! For example, in a double-blind study with 734 people comparing SAMe with the NSAID Naproxen and placebo, 10 people withdrew from the study due to side effects from SAMe, compared to 13 from placebo and 17 from Naproxen side effects (9).

In a double blind study using SAMe to treat depression, there were five reported side effects from SAMe (three in one patient) versus six reported due to placebo (13). The most commonly reported side effects are gastrointestinal- primarily heartburn, nausea and stomachache (16). However, the GI effects seem to be mediated through the brain- they are NOT the result of direct GI tract irritation. Indeed, SAMe actually inhibits and protects against GI lining damage and irritation apparently through formation of non-protein sulphur compounds (e.g. glutathione) in the GI lining.

The other occasionally reported side effect of SAMe is mania or hypomania- (excessive mood elevation and over-stimulation). This side effect is reported far more rarely than the GI side effects. SAMe-induced mania may on rare occasions be serious enough to warrant lithium treatment to end the mania.

SAMe- synergists

In order to maximize the effectiveness of the interlocking SAMe pathways, folic acid (0.4mg to 1mg per day), vitamin B12 (0.1mg to 1mg per day), vitamin B6 (10mg to 100mg per day), and vitamin B2 (5mg to 50mg per day) may be useful, and indeed supplementing at least the lower levels of the vitamins just mentioned is probably wise for safe and effective long-term SAMe use.

The methyl donor, trimethyglycine (TMG), also called "glycine betaine," can help to convert dietary and cellular methionine into SAMe, possibly reducing the dose of oral SAMe needed to achieve results. 1-2 grams TMG, two or three time’s daily, is probably the minimum "serious" dose. These five SAMe-metabolism optimizing nutrients will also aid in reducing blood levels of the toxic SAMe metabolite homocysteine.

People taking SAMe as part of a long-term brain protection program may also wish to add the following to their SAMe program:
phosphatidyl-choline (1-10 grams daily)
vitamin E (400 IU to 800 IU daily)
and deprenyl (1 to 5mg daily).

Those taking SAMe for depression might benefit by adding the following to their SAMe program:
tryptophan (500mg to 1500mg daily at bedtime)
5-hydroxy-tryptophan [5-HTP] at 50mg to 200mg daily at bedtime, or
deprenyl (1-5mg daily).

For those taking SAMe for joint degeneration/ cartilage problems:
glucosamine sulphate (500mg to 2000mg daily)
chondroitin sulphate (500mg to 2000mg daily)
vitamin C (1 to 3 grams daily)
lysine (1 to 3 grams daily)
manganese (5 to 20mg daily)
may prove useful SAMe synergists.

Those taking SAMe for liver problems or to aid liver detoxification might benefit by adding the following to their SAMe program:
lipoic acid (100mg to 500mg daily)
silymarin (400mg to 1000mg daily)
vitamin C (1 to 3 grams daily)
selenium (50mcg to 200mcg daily)
vitamin E (100iu to 400iu daily)
N-Acetylcysteine (NAC- 400mg to 1200mg daily)

References

(1). G. Stramentinoli (1987) "Pharmacologic aspects of [SAMe]" Am J Med 83 (suppl 5A), 35-42.

(2). R. Baldessarini (1987) "Neuropharmacology of [SAMe]" Am J Med 83 (suppl 5A), 95-103.

(3). C. Mathews & K. van Holde, Biochemistry, pp. 708-715, Redwood City, CA: Benjamin/ Cummings Pub. Co. (1990).

(4). L. Bonanomi & A. Gazzaniga (1980) "Toxicological, Pharmacokinetic and Metabolic Studies on Acetylcysteine" Eur J Repir Dis 61, 45-51.

(5). C. di Padova (1987) "[SAMe] in the treatment of osteoarthritis" Am J Med 83 (suppl 5A), 60-65.

(6). A. Tavoni et al, (1987), "Evaluation of [SAMe] in Primary Fibromyalgia" Am J Med *3 (sippl 5A), 107-110.

(7). K. McCully, The Homocysteine Revolution, New Canaan CT; Keats (1997).

(8). O. Laudonno (1987) "Cytoprotective effect of [SAMe] compared with... Misoprostol against... gastric damage" Am J Med 83 (suppl 5A), 43-47.

(9). I. Caruso & V. Pietrogrande (1987) "... Comparing [SAMe], Naproxen and placebo in the treatment of degenerative joint disease" Am J Med 83 (suppl 5A), 66-71.

(10). M. Frezza et al, (1988) "Prevention by [SAMe] of estrogen induced hepatobiliary toxicity in... women" Am J Gastroent 83, 1098-1102.

(11). G. Vendemiale et al, (1989) "Effects of oral [SAMe] on hepatic glutathione.. liver disease" Scand J Gastroent 24, 407-14.

(12). F. Corrales et al, (1991) "Inhibition of glutathione synthesis in the liver leads to [SAMe] synthetase reduction" Hepatol 14, 528-33.

(13). B. Kagan et al, (1990) "Oral [SAMe] in depression: a... double-blind, placebo controlled trial" Am J Psychiat 147, 591-95.

(14). E. Reynolds et al, (1984) "Methylation and mood" Lancet II, 196-98.

(15). L. Morrison et al, (1996) "Brain [SAMe] levels are severely decreased in Alzheimer’s disease" J Neurochem 67, 1328-31.

(16). B Konig (1987) "A long term (2 years) clinical trail with [SAMe] for the treatment of osteoarthritis" Am J Med 83, (suppl 5A), 89-94.

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