for mood, liver, heart, joint, and brain protection
by James South MA
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 "lynch
pin" of three major biochemical pathways- transmethylation,
transsulfuration, and aminopropylation- which regulate or impact virtually every
biochemical reaction in humans and animals.
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 ones SAMe metabolism.
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)
SAMes 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
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
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.
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 SAMes
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!
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
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."
"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
These are just a few of
the many reports attesting to the efficacy and safety of SAMe.
SAMe- who might
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 possibly suffer from SAMe metabolism "bottlenecks." (10,11,12)
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).
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 SAMes 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).
suffering from chronic gastrointestinal lining irritation or ulceration, whether
from alcohol abuse chronic NSAID use, chemical irritation, or unknown cause (8).
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 HCy to the beneficial
detoxifiers cysteine, N-Acetylcysteine, glutathione and taurine (7,8).
wishing to protect their brains 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, SAMes
ability to enhance liver detoxification also protects the brain in our
over-chemicalized modern world.
SAMe- the dosages and
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
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.
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 times daily,
is probably the minimum "serious" dose. These five SAMe-metabolism
optimizing nutrients will also aid in reducing blood levels of the toxic SAMe
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)
(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.
(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),
(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 Alzheimers
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.