SAMe and other methyl donors
SAMe – And other Methyl Donor Molecules
(Pronounced "Sammy" / S-adenosyl
– Precursor to 3 main pathways
synthesis and metabolism
– Essential for various body functions
Supplementation – Study-supported
SAMe – Precursor to 3 main pathways
provides an important precursor molecule to 3 main pathways of all cellular
methylation, transulfuration, and aminopropylation.
A sufficiency of
normal function - an amount that depends
on the daily availability of methionine synthesized by the body (involving
folate (methyl-tretrahydrofolate) and vitamin B-12) and also methionine obtained
mainly from breakdown of dietary proteins.
SAMe – In transmethylation
donates a methyl group
another molecule to make it bio-active
Produced by all living cells,
important biological function as a universal methyl donor in a multitude of
cellular methylation reactions –
donors include: folate, B12, TMG (Betaine), DMG and DMAE. Also, some vegetables (E.g. onions, garlic, beets) contain
A methyl group (CH3, a
4-atom appendage to the methione sulfur atom in SAMe)
is donated to a neighbor molecule, to stimulate
biochemical reactions that transform the recipient molecule into a bio-active
E.g. Methyl groups transferred from SAMe
to certain phospholipids produce phosphatidylcholine. The presence or absence of
this important lipid found in all cell membranes controls membrane accessibility
to outside signals, and thus affects how cells react to outside stimuli.
a donor of methyl groups in > 100 different reactions catalyzed by
methlytransferase enzymes –
Most cells contain
numerous SAMe-dependent methyltransferases
that can transfer the methyl group (CH3) to the oxygen, nitrogen, or
sulfur atoms of both small and large molecules.
Cheng X, Blumenthal RM. S-Adenosylmethionine-dependent
methyltransferases: structures and functions. World Scientific Publication Co,
Chiang PK, Gordon RK, Tal J, et al. S-Adenosylmethionine
and methylation. FASEB J 1996;10:471–80.[Abstract]
Without methylation there is no life -
occurring billions of times/second in the body:
development, brain function
Preserves the fatty
cell membranes -
the greater the amount
of SAMe-produced phosphatidylcholine (via
phospholipid methylation), the more fluid or less viscous the cell membrane,
which may facilitate the lateral movement of proteins, such as receptors, within
the lipid bilayer.
Crews FT. Effects of membrane fluidity on secretion and receptor stimulation.
Psychopharmacol Bull 1982;18:135–43.[Medline]
serves as the
methylating agent in the synthesis of:
Various hormones and neurotransmitters -
NOREPINEPHRINE (adrenaline) -
Creatine (an important energy reservoir
in muscle tissue)
donors, such as SAMe enhance sleeping, mood,
energy, wellbeing, alertness, and concentration.
SAMe – In transulfuration
SAMe is the
precursor for synthesis of cysteine, glutathione and taurine - in the transulfuration pathway;
SAMe – In aminopropylation
and arginine serve as precursor molecules to the aminopropylation pathway -
which leads to
the synthesis of polyamines
spermine, spermidine and putrescine, which are involved in the control of cell
growth, gene expression, calcium homeostasis and neuron regeneration. They were
also shown to have analgesic and anti-inflammatory properties
Herby O. Role of polyamines in the control of cell proliferation and
differentiation. Differentiation 1981;19:1–20.[Medline]
Oyanagui Y. Anti-inflammatory effects of polyamines in serotonin and carrageenan
paw edemata—possible mechanism to increase vascular permeability inhibitory
protein level which is regulated by glucocorticoids and superoxide radical.
Agents Actions 1984;14:228–37.[Medline]
like transulfuration, also salvages and conserves methionine.
SAMe synthesis and
synthesized in the body
(mainly in the liver) - from methionine (an amino acid) catalyzed by the
MAT enzyme (methionine S-adenosyltransferase) using ATP molecule
(an amino acid in
protein-rich foods) – Body makes SAMe from
methionine and then recycles it. Once a SAMe
molecule loses its methyl group, it breaks down to form
homocysteine, which is potentially toxic if it builds up
Several B vitamins (B6, B12 and folate) are
(requires B6) - Convert Homocysteine -
► Glutathione (body’s
important ”in-house” antioxidant);
Remethylation (requires B12, folate)
- "Remethylate" homocysteine -
► (back into) Methionine.
Sitaram BR, Sitaram M, Traut M and CB Chapman. 1995. Neurochem 65: 1887-1894.
– Essential for various body functions
is the daytime equivalent of
hormone) - and like MELATONIN, it is produced
under control of the master biological clock;
Natural synthesis of
SEROTONIN) depends on adequate
synthesis during the day -
SAMe donates a methyl group molecule to the
that converts the acetylated form of SEROTONIN
/ SAMe ↓↓↓
and in the day
SAMe ↑↑↑ /
SEROTONIN is also produced at night.
Maintains effective mitochondrial function
Prevents and curtails DNA mutations during cell
Restores cellular membrane fluidity / cellular communication
phosphatidylcholine in cell membranes to make them pliant -
in contrast to cholesterol, which makes them
stiff. Stiff membranes do not transmit signals as well as pliant membranes.
With age, the ratio of
phosphatidylcholine- to-cholesterol decreases causing the membrane to “harden” -
Increased methylation provided by SAMe
enhances cell membrane function and integrity.
improves cellular communication between nerve cells -
SAMe helps neurotransmitters deliver their messages to
the receptor sites by methylating phospholipids, from which nerve cell membranes
Supplementation – Study-supported
for Depression – 40 clinical supporting studies involving
~1400 patients. In 1994 Dr. Giorgio Bressa, a psychiatrist at the University
Cattolica Sacro Cuore in Rome, pooled results from a dozen controlled trials and
found that "the efficacy of SAMe
in treating depressive syndromes... is superior [to] that of placebo and
comparable to that of standard... antidepressants."
Janicak PG, Lipinski JD, Comaty JE, et al. S-Adenosylmethionine: a literature
review and preliminary report. Ala J Med Sci 1988;25:306–13.[Medline]
Friedel HA, Goa KL,
Benfield P. S-Adenosyl-L-methionine: a review of its therapeutic
potential in liver dysfunction and affective disorders in relation to its
physiological role in cell metabolism. Drugs 1989;38:389–416.[Medline]
Bressa GM. S-Adenosyl-L-methionine
as antidepressant: meta-analysis of clinical studies. Acta Neurol Scand
Link to several supporting studies for
In a dozen clinical trials
involving more than 22,000 patients, researchers have found
SAMe as effective
as pharmaceutical treatments for pain and inflammation - but unlike the NSAIDs, SAMe shows no
sign of damaging the digestive tract. The Arthitis Foundation medical experts
Joint-protective - after
SAMe loses a methyl group to become
homocysteine, it can be broken down to form glutathione, which reaction also
yields sulfate groups, which help generate joint-protective proteoglycans.
SAMe accumulates in the synovial fluid that
lubricates joints. Certain chemicals resulting from
SAMe breakdown can relieve pain and inflammation
SAMe for liver diseases - "The
administration of a stable salt of SAMe, either orally or parenterally, has been
shown to restore normal hepatic function in the presence of various chronic
liver diseases (including alcoholic and non-alcoholic cirrhosis,
estrogen-induced and other forms of cholestasis (bile impairment or blockage),
to prevent or reverse hepatotoxicity due to several drugs and chemicals such as
alcohol, paracetamol (acetaminophen), steroids and lead, and to have
Friedel HA, Goa KL, Benfield P
"S-adenosyl-L-methionine. A review of its pharmacological properties and
therapeutic potential in liver dysfunction and affective disorders in relation
to its physiological role in cell metabolism." Drugs 1989 Sep;38(3):389-416.
(ADIS Drug Information Services, Auckland, New Zealand).
has been found to prevent or reverse liver
damage caused by certain drugs, alcohol, and cytokines -
It protects against liver damage caused by MAO inhibitors and anti-convulsants.
Rat study showed the
beneficial effects of
on liver disease - Fetal rat liver cells were exposed to ethanol, causing a 40% reduction in
DNA synthesis, a doubling of free radicals, a 30% decrease in cellular ATP,
altered mitochondrial function, and cell damage. Pretreatment with
SAMe maintained cell replication, decreased
free radicals and prevented ATP and glutathione depletion.
study in Hepatology
Lieber CS. Role of
S-adenosyl-L-methionine in the treatment of liver diseases. J Hepatol
Williams R, Lieber CS. The role of
SAMe in the treatment of liver disease. Drugs 1990;40(suppl):1–2.
Mato JM, Camara J, Fernandez de Paz J, et al. S-Adenosylmethionine
in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind,
multicenter clinical trial. J Hepatol 1999;30:1081–9.
prevented body weight gain” -in animal model
of type 2 diabetes mellitus and
Skeletal Muscle Mitochondrial DNA Density and Whole Body Insulin Sensitivity in
Bradley JD, Flusser D, Katz BP, et
al. A randomized, double blind, placebo controlled trial of intravenous loading
with S-adenosylmethionine (SAM) followed by oral SAM therapy in patients
with knee osteoarthritis. J Rheumatol 1994;21:905–11.[Medline]
Padova C. S-Adenosylmethionine
in the treatment of osteoarthritis: review of the clinical studies. Am J Med
demyelination diseases -
has a variety of pharmacological
effects in the CNS, especially on monoamine neurotransmitter metabolism and
neuronal death caused by lack of oxygen
and provokes remyelination of nerve fibers
methyl donors (betaine, methionine
and SAMe) is associated with remyelination in
patients with inborn errors of folate and C-1 (one-carbon)
for Dementia, Alzheimers
patients have severely decreased levels of
in their brains –
a turnaround from an idea that the
brain had too much
Morrison LD, Smith DD
and SJ Kish. 1996.
J Neurochem 67: 1328-1331.
showed that high homocysteine levels that precede heart disease
Stampfer MJ, Malinow MR, Willett WC, et al. 1992. A prospective study of plasma
homocysteine and risk of myocardial infarction in US physicians. JAMA 268:
correlate with a deficiency of an enzyme that converts
folate to its active form - SAMe plays a crucial role preventing
the breakdown of this enzyme.
Loehrer MTF, Angst CP, Haefeli WE, Jordan PP, Ritz
R and B Fowler. 1996. Low whole-blood S-adenosylmethionine and correlation
between 5- methyltetrahydrofolate and homocysteine in coronary artery disease.
Arth Throm Vasc Biol 16: 727-733.
also remethylates homocysteine back into methionine
Scientists suspect that
adequate methylation of DNA can prevent the expression of harmful genes
comes in two
forms - tosylate and a newer, more stable form
called butanedisulfonate. Only Nature Made and GNC sell the new
butanedisulfonate version, but several U.S. retailers import reliable tosylate
is absorbed mainly through the intestine, it's
best taken in "enteric coated" tablets -
to pass through the
- a 400-mg dose ranges from $2.50 (Nature
Made) up to $18.56 for an uncoated Natrol product called SAM sulfate.
Experts advise taking it twice a day on an empty
Different people may require different amounts - studies suggest 400 mg a day is an effective dose for arthritis, but the
daily doses used in depression trials have ranged as high as 1,600 mg.
(Generally with mood problems start at 400 and increase as necessary).
may alter one's mood in an unexpected fashion -
should begin a SAMe regimen with the lowest
dosage available and maybe even take SAMe
every other day for the first month.
ALWAYS supplement with vitamins B6, B12 and
folate when taking
- to ensure that homocysteine created is converted to methionine, glutathione or
other beneficial molecules.
Alternatives to SAMe Supplementation
For most people, the real
problem is undermethylation of homocysteine -
simply upping your intake of B vitamins could deter such as low moods, bad
joints, dysfunctional liver, weak hearts . . .
SAMe donates its methyl group, it is
transformed into homocysteine. When
present, SAMe's main cofactors:
Vitamins B6, B12 and folate, normally help body produce
SAMe and convert homocysteine back to
methionine, SAMe or cysteine,
glutathione, and other useful substances.
However, if adequate
amounts of the vitamins B6, B12, and folate are not present -
SAMe may not break down properly, such that its full benefits will not be
obtained, and homocysteine may increase
to unsafe levels., which can cause inflammatory damage. This shortage of
B vitamins is going to lead to problems associated with homocysteine buildup –
including: CVD (atherosclerosis,
heart attack/stroke), liver damage, risk of spina bifida and other birth defects
Deficiencies of folate have been
found to reduce SAMe concentrations in the
CNS and may be involved in neurological and psychiatric problems, including
depression, dementia, myelopathy and peripheral neuropathy.
Many nutrients work similarly to SAMe,
particularly other methyl donors:
TMG - dose of
250 mg a day.
chemically similar to choline, used for years to enhance focus and clarity of
thought. Studies do NOT support its use with Alzheimer’s or memory recall, but
it seems to help mood/motivation in elderly dementia patients
The following combination of 4 supplements actively combat high levels of
homocysteine and enable one's body to produce
(without the expense of supplementing
Vitamin B6, Folic Acid (B9), Vitamin B12 –
convert toxic homocysteine into beneficial
amino acids, whilst simultaneously producing SAMe.
converted into dimethylglycine (DMG),
a popular, but expensive supplement to enhance energy/vitality.