Investigating SAM-e
by Leslie Knowlton and GT Staff
| Geriatric Times |
 |
September/October 2001 |
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Vol. II |
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Issue 5 |
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 (SAM-e) to treat
an estimated 400 patients suffering from depression, many of whom were
previously treatment-resistant.
Brown also has co-authored the book Stop Depression Now: SAM-e, 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 SAM-e for 15 years.
In an interview with Geriatric Times, Brown reviewed research on, and
his clinical experience with, SAM-e. Although SAM-e 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 SAM-e 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 SAM-e from the
Internet.
According to Brown, SAM-e was discovered in Italy about four decades ago
(Cantoni, 1952). Since then, SAM-e "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).
Biochemistry
Brown explained that SAM-e is produced in the body from methionine, a
sulfur-containing amino acid, and the energy-producing compound adenosine
triphosphate. SAM-e 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, SAM-e 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, 1989).
Brown said that donation of carbon groups by SAM-e protects catecholamine
neurons and that SAM-e 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.
"SAM-e 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 SAM-e either for
wellness or treatment of illness. Moreover, the form of SAM-e found in food is
not stable. It oxidizes too rapidly to absorb well. Our bodies can only
generate a small amount of SAM-e...Therefore, SAM-e levels are most easily
increased through dietary supplementation."
Reviewing the Literature
According to Brown, lower than normal levels of SAM-e 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 SAM-e (Crellin et al., 1993) and reported that SAM-e 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 SAM-e were more
effective than placebo and comparable to imipramine [Tofranil], amitriptyline
[Elavil, Endep] and clomipramine [Anafranil] for treatment of major
depression," Brown said.
In 1988, American psychopharmacologists Bell and colleagues conducted a
double-blind, randomized, two-week trial comparing intravenous SAM-e to oral
imipramine. By the end of week 2, 66% of the patients treated with SAM-e "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 SAM-e
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
reported.
"Rapid response to SAM-e was shown in a double-blind trial of 30 depressed
inpatients who received either 1600 mg/day of oral SAM-e or imipramine
(averaging 140 mg/day) for six weeks," Brown added. "The SAM-e 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 SAM-e (1600 mg/day) versus 250 mg/day of desipramine
(Norpramin), improvement in depression in those who responded to either SAM-e
or desipramine correlated with their SAM-e blood levels (Bell et al.,
1994).
"These findings highlight the need for larger and longer-term studies to
elucidate the role of SAM-e in recovery from depression and the use of SAM-e in
combination with prescription antidepressants," he said. He added that the
longest controlled-trial studies of SAM-e 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 SAM-e 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.
Practical Considerations
Brown noted that American companies only sell SAM-e 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.
SAM-e, 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, SAM-e has not been systematically studied in well-defined
samples of psychotic depressed patients-Ed.)
Brown noted that SAM-e 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 SAM-e, the physician must be sure that the patient is using
a potent brand.
"Only about 3% to 5% of patients discontinue SAM-e 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 effect
rate."
The biggest study of SAM-e, Brown said, was a two-year postmarketing study
of 20,641 patients conducted in Germany after SAM-e 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 SAM-e. 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 SAM-e effects on cytochrome P450 metabolism or
on the binding of prescription drugs to serum proteins (Brown et al.,
2000).
Treatment Resistance
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 SAM-e even
after failing on prescription antidepressants.
Brown said he has treated more than 30 patients with treatment-resistant
depression who responded well to SAM-e augmentation of all categories of
antidepressants without adverse reactions, and noted a review of four studies
suggesting that SAM-e 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 SAM-e to augment imipramine.
Brown said accumulated evidence indicates that SAM-e in higher doses is
perhaps as effective for major depression as TCAs.
"SAM-e starts to work in approximately half the time needed for tricyclics.
Studies show very few side effects, and SAM-e does not cause the sexual
dysfunction or weight gain associated with other medications," he said.
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 SAM-e'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
antidepressants.
Further Research Needed
"Further research is needed to clarify SAM-e's role as a possible first-line
treatment for affective disorders," Brown said.
There have been about eight controlled studies comparing SAM-e 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.,
2000).
"What everybody wants right now is a study comparing SAM-e to an SSRI," he
said. "There are five studies showing that SAM-e 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 SAM-e 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 SAM-e
and an SSRI to an SSRI alone, but it has not yet been funded.
"In the future, perhaps SAM-e 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 SAM-e in order to advise
patients on its appropriate use as a complementary treatment or as an
alternative to traditional pharmacotherapy."
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