The SAM-e Story

Thoroughly natural SAM-eis no mundane molecule.

By Hara Estroff Marano, published on March 1, 2002 - last reviewed on June 9, 2016

It's available in the U.S. as a dietary supplement, but that is
merely a technicality, its pharmacologic green card. SAM-e is a bona-fide
prescription drug in Europe, where it has been shown effective against
depression, osteoarthritis, and liver disease.

Such a list of disorders might suggest the kind of elixir, popular
on late-night TV, guaranteed to make discerning eyeballs roll, and
indeed, lavish claims heralded the 1999 arrival of SAM-e in America. But
S-Adenyl-Methionine is no mundane molecule.

A thoroughly natural substance, SAM-e is present in every cell of
body and brain. It plays a pivotal role in cellular metabolism, fueling
more than 100 different reactions. It activates such big-time
biochemicals as the neurotransmitters serotonin and dopamine and
increases the fluidity of nerve cell membranes to make neurons more

First developed as an antidepressant in the early 1970s, it has
been studied in over 40 clinical trials involving 23,000 adults,
primarily in England and Europe.

It's now getting a smattering of serious attention by
neuroscientists in the U. S., but it's not on any fast track to
prescription fortune. With patent time on SAM-e running out, there's
little incentive for drug-makers to finance clinical trials.

Nevertheless, says Jonathan Alpert, M.D., associate professor of
psychiatry at Harvard, "it is likely to have some enduring place in the
range of treatments we have for depression." He finds it especially
useful as an adjunct to standard antidepressants in people who fail to
respond fully to an SSRI.

It slices from weeks to days the time it takes other
antidepressants to work, and cuts the dose needed, thereby minimizing
side effects. A formal study of SAM-e with SSRIs is just getting

"We don't know a lot about combining dietary supplements with
prescription antidepressants," says Dr. Alpert. "Both have central
nervous system effects." He is exploring whether for some people they
have significant side effects.

"We're always looking for better treatments for major depression,"
he notes, "because about 50% of people don't respond to a given
antidepressant and 10-15% don't respond to multiple courses of them. We
in psychiatry spend most of our time with people with treatment-resistant

What makes SAM-e of special interest is that its mechanism of
action is novel, says Baylor University neuropharmacologist Teodoro
Bottiglieri, Ph.D. And if there's one thing researchers now know it's
that there are many pathways into depression -- and it's necessary to
develop many out of it.

Animal studies show that SAM-e increases levels of serotonin, but
not the same way as SSRI or tricyclics work. They prolong the effect of a
neurotransmitter by blocking its reuptake after it ferries a signal
across the gap from one nerve cell to the next.

SAM-e, by contrast, appears to actually build neurotransmitters by
donating part of its own chemical makeup, a methyl group. A common
currency in metabolic processes, methylation also feeds the fats that
stabilize nerve cell membranes and the receptors on them, making brain
cells more responsive to a broad array of operations.

SAM-e is also effective as an antidepressant in its own right.
Studies Dr. Bottiglieri and others have conducted show it is better than
placebo and equal to tricyclics.

Those are "fairly compelling reasons" for studying SAM-e further,
even though it was long ignored in the U.S. "We are now in a period of
reassessing its strengths and limitations for major depression," says Dr.

He also expects to test SAM-e as a solo treatment for minor
depression (the same symptoms, just fewer of them). "These people have
some impairment in function but not enough to feel like taking
medications," he observes. "Often people are more willing to take dietary
supplements. It's a reasonable stepping stone, if we have the right
information on safety and efficacy."

The doses of SAM-e used in clinical studies, 800 to 1600
milligrams, tend to be higher than over-the-counter preparations furnish.
Still, SAM-e has been shown to have side effects equivalent to

There remains one big caveat. As with any antidepressant, there is
always the risk of mania in someone who has not been formally evaluated
for depression or who is experiencing a first episode of it. That's why
it's best to be closely monitored when taking any active agent.