Research Grade SAMe 400
SAMe was shown to mitigate
depressive symptoms in as little as 7 days
For more than eight years, Richard P. Brown, M.D., associate professor of
clinical psychiatry at Columbia University College of Physicians and Surgeons,
has used the natural dietary supplement S-adenosylmethionine (SAMe) to treat an
estimated 400 patients suffering from depression, many of whom were previously
Brown also has co-authored the book Stop Depression Now: SAMe, the
Breakthrough Supplement that Works as Well as Prescription Drugs in Half the
Time... With No Side Effects. His primary collaborator was Teodoro
Bottiglieri, Ph.D., director of neuropharmacology and senior research scientist
at Baylor University's Institute for Metabolic Disease. Bottiglieri, also
associate professor of biomedical studies at Baylor, has been conducting
research on SAMe for 15 years.
In an interview with Geriatric Times, Brown reviewed research on, and
his clinical experience with, SAMe. Although SAMe has only been on the U.S.
market since 1999, it has been studied for decades internationally and is
approved as a prescription drug in Spain, Italy, Russia and Germany. More than 1
million Europeans have used it, primarily for depression and arthritis.
"I first heard about SAMe 20 years ago when I was doing my residency in
psychiatry at New York Hospital, Cornell Medical Center," Brown recalled.
"At a meeting of the American College of Neuropsychopharmacology, a
colleague had learned about an exciting new antidepressant being studied in
Europe that was nontoxic, without side effects, and worked better and faster
than traditional medications."
Fifteen years later, after Brown had developed a subspecialty practice
treating patients resistant to conventional drug therapy by integrating
alternative approaches such as nutrients and herbs with prescription
medications, a patient brought him information about SAMe from the Internet.
According to Brown, SAMe was discovered in Italy about four decades ago (Cantoni,
1952). Since then, SAMe "has been evaluated for various disorders in more
than 75 clinical trials involving over 23,000 people," Brown added.
However, the first clinical study of its use for depression was not completed
until the 1970s (Agnoli et al., 1976).
Brown explained that SAMe is produced in the body from methionine, a
sulfur-containing amino acid, and the energy-producing compound adenosine
triphosphate. SAMe is a physiologically essential compound, he said, adding that
some chemists believe it ranks with adenosine triphosphase (ATP) as a pivotal
molecule in living cells. Distributed throughout the body, SAMe is most
concentrated in the brain and liver and is crucial to three central pathways of
metabolism that stimulate more than 35 different reactions.
"The three major pathways are transmethylation, transulfuration and
transaminopropylation," he said. "Animal studies show that the
transmethylation pathway boosts levels of the neurotransmitters serotonin,
dopamine and norepinephrine. This process probably contributes to the
antidepressant action" (Andreoli et al., 1978; Curcio et al., 1978; Czyrak
et al., 1992; Fava et al., 1990; Losada and Rubio, 1989; Otero-Losada and Rubio,
Brown said that donation of carbon groups by SAMe protects catecholamine
neurons and that SAMe improves nerve cell membrane uptake of phospholipids,
enabling the coupling of protein receptors to second messengers within a more
fluid lipid bi-layer and enhancing transmission of impulses by neurons.
"SAMe is vital to the production of our most important antioxidant
glutathione, as well as the secondary antioxidants cysteine and taurine,"
he noted. "The American diet yields insufficient quantities of SAMe either
for wellness or treatment of illness. Moreover, the form of SAMe found in food
is not stable. It oxidizes too rapidly to absorb well. Our bodies can only
generate a small amount of SAMe...Therefore, SAMe levels are most easily
increased through dietary supplementation."
Reviewing the Literature
According to Brown, lower than normal levels of SAMe are found in
cerebrospinal fluid in some patients with depression, Alzheimer's disease,
dementia, Parkinson's disease treated with levodopa (Atamet, Sinemet), disorders
of folate metabolism and other illnesses (Bottiglieri et al., 1994, 1990).
He cited a study indicating that folate, B12 and B6 are necessary for
efficient use of SAMe (Crellin et al., 1993) and reported that SAMe has been
effective for treating major depressive disorder in 13 trials comparing it to
placebo and 19 trials comparing it to tricyclic antidepressants (TCAs), with
more than 1,400 patients studied.
"From 1973 to 1988, 14 double-blind, European studies [Janicak et al.,
1988] showed that intravenous and intramuscular preparations of SAMe were more
effective than placebo and comparable to imipramine [Tofranil], amitriptyline [Elavil,
Endep] and clomipramine [Anafranil] for treatment of major depression,"
In 1988, American psychopharmacologists Bell and colleagues conducted a
double-blind, randomized, two-week trial comparing intravenous SAMe to oral
imipramine. By the end of week 2, 66% of the patients treated with SAMe
"had a clinically significant improvement in depressive symptoms, compared
to 22% of the imipramine patients," the study authors reported.
Since 1988, double- and single-blind studies using higher doses of SAMe have
shown it to be effective in treating major depression (Bressa, 1994; Delle
Chiaie and Boissard, 1997; Delle Chiaie et al., 2000), depression secondary to
medical illness (Criconia et al., 1994), postmenopausal depression (Salmaggi et
al., 1993) and treatment-resistant depression (Rosenbaum et al., 1990), Brown
"Rapid response to SAMe was shown in a double-blind trial of 30
depressed inpatients who received either 1600 mg/day of oral SAMe or imipramine
(averaging 140 mg/day) for six weeks," Brown added. "The SAMe group
was significantly better by day 10. Both groups were comparably improved by week
6" (De Vanna and Rigamonti, 1992).
Furthermore, Brown reported that in a small, double-blind, four-week
inpatient study of oral SAMe (1600 mg/day) versus 250 mg/day of desipramine (Norpramin),
improvement in depression in those who responded to either SAMe or desipramine
correlated with their SAMe blood levels (Bell et al., 1994).
"These findings highlight the need for larger and longer-term studies to
elucidate the role of SAMe in recovery from depression and the use of SAMe in
combination with prescription antidepressants," he said. He added that the
longest controlled-trial studies of SAMe efficacy for depression were 42 days (Delle
Chiaie et al., 2000; De Vanna and Rigamonti, 1992; Fava et al., 1992).
Brown said he has also found SAMe effective for fibromyalgia (Jacobsen et
al., 1991; Tavoni et al, 1998, 1987, as cited in Brown et al., 2000), depression
in Parkinson's disease, the aging brain, liver diseases (Friedel et al., 1989)
and arthritis (Bradley et al., 1994, as cited in Brown et al., 2000; Konig,
1987). It also seems to reverse some effects of alcoholic hepatitis and
cirrhosis (Mato et al., 1999) and is used to dissolve gallstones.
Brown noted that American companies only sell SAMe in 50 mg, 100 mg and 200
mg tablets. He recommended a daily dose of 400 mg for mild depression.
"Keep in mind that absorption is better on an empty stomach," he
said. "Starting patients with 200 mg 30 minutes before breakfast and 30
minutes before lunch minimizes the overstimulation and insomnia which some
patients report in the first few weeks [Berger and Nowak, 1987]. This can be
switched to 400 mg before breakfast after a few weeks." Patients typically
notice improvement in energy within two weeks.
Brown continued, "As with most medications, clinical sense indicates
starting with lower doses in geriatric, medically ill and anxious patients. SAMe,
like all antidepressants, should be used with some caution in patients with a
history of cardiac arrhythmia."
Treatment for severe depression, Brown said, generally requires higher doses.
"Some studies have started unipolar patients on 800 mg or 1600 mg per
day," he said. Side effects occurring at the higher doses include mild
jitteriness, loose bowels and headaches.
(To date, SAMe has not been systematically studied in well-defined samples
of psychotic depressed patients-Ed.)
Brown noted that SAMe is generally available in two forms: a
butanedisulfonate form and a tosylate form.
"In my practice, the butanedisulfonate seems superior, particularly the
enteric-coated form," he said, adding that good brands currently available
in this country include Nature Made and GNC. "If a patient hasn't responded
to an appropriate dose of SAMe, the physician must be sure that the patient is
using a potent brand.
"Only about 3% to 5% of patients discontinue SAMe because of side
effects, primarily gastrointestinal," Brown said. "That is a
relatively low rate compared to placebo discontinuation rates. In study after
study, the investigators said there was no difference from placebo in the side
The biggest study of SAMe, Brown said, was a two-year postmarketing study of
20,641 patients conducted in Germany after SAMe was approved for treatment of
osteoarthritis (Berger and Nowak, 1987).
"The investigators found that 80% of patients said they basically felt
great on it and had no side effects, [while the other] 20% complained of mild
side effects in the first month on high doses like 1200 mg/day to 1600
mg/day," Brown said.
At starting doses of 400 mg/day to 600 mg/day for mild depression, Brown
said, there are no significant side effects. At higher doses, there are some
"mild, temporary side effects."
Reports of drug interactions have been nearly nonexistent, according to
Brown. He mentioned a case report of an elderly woman who was given clomipramine
together with SAMe. The patient exhibited symptoms of what the clinicians
diagnosed as serotonin syndrome (Iruela et al., 1993). The investigators
attributed the side effects to a "toxic interaction produced by S-adenosylmethionine
and clomipramine association."
Brown had some misgivings about the case report, however, explaining,
"If you look at the world's literature of serotonin syndrome, the
preponderance of cases are from clomipramine."
There have been no reports of SAMe effects on cytochrome P450 metabolism or
on the binding of prescription drugs to serum proteins (Brown et al., 2000).
Research studies (Bell et al., 1994; Criconia et al., 1994; De Vanna and
Rigamonti, 1992; Kagan et al., 1990) and his own clinical experience, Brown
said, demonstrate that some patients have a dramatic response to SAMe even after
failing on prescription antidepressants.
Brown said he has treated more than 30 patients with treatment-resistant
depression who responded well to SAMe augmentation of all categories of
antidepressants without adverse reactions, and noted a review of four studies
suggesting that SAMe boosted and hastened response to TCAs, mianserin and
fenoterol, a ß-agonist (Friedel et al., 1989). He also cited a randomized,
double-blind study (Berlanga et al., 1992) of 40 outpatients with moderate to
severe major depression that confirmed his own clinical experience of using SAMe
to augment imipramine.
Brown said accumulated evidence indicates that SAMe in higher doses is
perhaps as effective for major depression as TCAs.
"SAMe starts to work in approximately half the time needed for
tricyclics. Studies show very few side effects, and SAMe does not cause the
sexual dysfunction or weight gain associated with other medications," he
Brown expressed concern about the need for most depressed patients to take
antidepressants for long periods of time.
"Conventional medicine hasn't yet tackled the issue of long-term effects
of prescription drugs," he said. "We hope they are insignificant, but
there are no studies to assure us that these drugs are safe in the long-term.
Part of our confidence derives from the clinical experience of prescribing
tricyclics for over 35 years. Our experience with fluoxetine [Prozac] is only 12
years and with other SSRIs is even less."
Brown said that considering SAMe's efficacy in treating depression, its mild
side-effect profile, and its ability to boost antioxidants and protect DNA
through methylation, this nutrient has advantages over prescription
Further Research Needed
"Further research is needed to clarify SAMe's role as a possible
first-line treatment for affective disorders," Brown said.
There have been about eight controlled studies comparing SAMe in the oral
version in decent doses from 1989 through 1997, Brown said, adding that a
published review article describes the details of those studies (Brown et al.,
"What everybody wants right now is a study comparing SAMe to an SSRI,"
he said. "There are five studies showing that SAMe boosts regular
antidepressants [e.g., TCAs] in both their efficacy and speed of onset of
therapeutic efficacy (Berlanga et al., 1992; Friedel et al., 1989; Torta et al.,
1988). And we need more controlled studies showing that SAMe can be a booster
for other antidepressants…Those studies will probably get going in the United
States within the next year or two."
He added that there is a planned study comparing the combination of SAMe and
an SSRI to an SSRI alone, but it has not yet been funded.
"In the future, perhaps SAMe will become
available...as a prescription drug approved by the [U.S. Food and Drug
Administration]," Brown said. "In the meantime, physicians should be
knowledgeable about SAMe in order to advise patients on its appropriate use as a
complementary treatment or as an alternative to traditional pharmacotherapy."
Additional Information on the use of SAMe use these links below to visit our
SAMe was shown to be an effective antidepressant without the side effect profile often associated with several prescription treatments such as weight gain, dry mouth, loss of libido, insomnia. . .
How Does SAMe Work?
Click here to read the full US Government report on the efficacy of taking SAMe for depression, liver infirmity, and
What's new on the SAMe front--does SAMe boost other antidepressants?
SAMe is involved in over 40 biochemical reactions
1. SAMe was shown to mitigate depressive symptoms in as little as 7 days.
2. SAMe is non-toxic and relatively free of side effects.
3. SAMe was shown to be effective in mitigating signs and symptoms of postpartum psychological distress.
4. SAMe was shown to be effective in treating depressed postmenopausal women.
5. SAMe was shown to be effective in reducing prolactin levels in depressed patients-high prolactin levels are associated with decreased libido.
6. SAMe was shown to be effective in treating depression in patients with fibromyalgia and Parkinson's disease.
7. SAMe was shown to be effective in treating depression in patients with HIV.