Trendy pill should be taken with a grain of salt

She’s a young woman from the South Shore, finally able both to work and to study for an advanced degree.

But for years, she’s been plagued by severe depression that stems, she says, from physical abuse she suffered as a child, and from sexual abuse when she was 17.

She tried Prozac and, by her count, 30 other antidepressant drugs. Nothing worked. Psychotherapy helped some, and still does, but not enough.

She’s been suicidal. She still has nightmares and flashbacks. Until a few months ago, the woman, who did not want her age, occupation or town published, felt she had no options left.

Then she tried SAM-e, the European prescription antidepressant that in recent months has been growing here in popularity, despite its $10-a-day price tag. The preparation is now available as an over-the-counter remedy in US health food stores.

“I haven’t felt as depressed,” says the woman, who has been taking 800 milligrams a day of SAM-e for several months. “It sounds corny, but I just have experienced more joy lately.”

Neither an herb nor a vitamin, SAM-e (pronounced “Sammy”) is a synthetic form of a chemical made in the body from methionine, an amino acid, and an energy molecule called ATP. It helps with dozens of metabolic functions from preservation of cell membranes to DNA replication.

In fact, it’s been studied and used for years in Italy as an antidepressant. In the US, the potential market for it is huge – 18 million Americans suffer from depression.

Because it is sold as a dietary supplement, SAM-e did not have to pass safety or efficacy review by the US Food and Drug Administration. But because it contains a “new ingredient” (S-adenosylmethionine), manufacturers must inform the FDA of their intent to sell it. By law, if the FDA does not object within a defined time period – and it has not with SAM-e – the new ingredient may be sold.

It’s not at all clear how SAM-e might combat depression. It does not work as Prozac-type drugs do, by blocking re-uptake of a brain chemical called serotonin. It may act by improving the elasticity of cell membranes or by stabilizing receptors on cell membranes, but this is unproved.

Still, there’s evidence that some depressed people may be low in SAM-e, and that taking SAM-e supplements may help. In a 1990 study of 30 depressed people, one third had low levels of SAM-e in the cerebrospinal fluid, says Teodoro Bottiglieri, the leader of that research and director of the neuropharmacology lab at Baylor Institute of Metabolic Disease in Dallas.

Several animal studies and one placebo-controlled human study suggest that SAM-e can boost serotonin levels. Other evidence suggests SAM-e may also raise levels of dopamine and norepinephrine, two other brain chemicals often involved in depression.

But the best – albeit flawed – evidence for SAM-e comes from a 1994 Italian analysis of pooled data from 13 clinical trials. Taken together, six studies showed SAM-e was better than a placebo at reducing depression. The other studies suggested SAM-e was equal in efficacy to older, tricyclic antidepressants, which have been shown to be about as effective as newer antidpressants such as Prozac.

Yet even psychiatrists who recommend SAM-e are cautious.

“It is not a good first-line drug. It’s something to consider as a possible alternative when other things have failed,” says Dr. Maurizio Fava, a psychiatrist at Massachusetts General Hospital. So far, he says, most studies are too small to carry much statistical weight and use poorly defined groups of depressed patients.

Dr. Scott Ewing, director of the depression and anxiety disorders clinic at McLean Hospital in Belmont, agrees.

“Every year or so, there’s a new antidepressant du jour. Right now SAM-e is it. A couple of years ago, it was St. John’s wort,” he says. But SAM-e research “is not of the highest quality.”

The studies have typically followed patients for four weeks or less. Since many depressed patients feel better in a few weeks even taking a placebo, these results may be meaningless. A study that followed people for 8 to 12 weeks would be more convincing, say psychiatrists, because the placebo effect often wears off by this point.

Still, Ewing supports the use of SAM-e in his patients who can’t tolerate side-effects of other antidepressants, partly because it appears to have few side effects and to be safe.

It may also take effect sooner than standard antidepressants and may, if taken with them, boost their effectiveness, he says. But this is unproven, warns Ewing, and there are other ways to boost the potency of antidepressants for which there is good evidence.

Dr. Jerry Rosenbaum, associate chief of psychiatry for clinical research at MGH, keeps SAM-e for “situations where I’m striking out with the patient on side effects.” But even when it helps, he says, the benefits don’t always last.

On the other hand, Dr. Richard Brown, associate professor of clinical psychiatry at Columbia University in New York, is an unabashed SAM-e proponent. In his book [see sidebar], Brown calls SAM-e a “breakthrough supplement” and claims that it “begins to relieve depression in seven days.” In a telephone interview, he adds that he’s now treated hundreds of people with SAM-e.

In order for the body to make SAM-e, a person must have adequate levels of folate (which in turn is made from folic acid, a vitamin) and vitamin B-12. (In fact, adding folate to standard antidepressants may increase their benefit.)

Once it’s made, enzymes interact with SAM-e, causing it to give up a part of its chemical structure called a methyl group. In particular, SAM-e donates methyl groups to cell membranes, to big proteins inside cells and to small ones outside cells like the neurotransmitters serotonin, norepinephrine, and dopamine.

For instance, when lipids in cell membranes are well supplied with methyl groups, the membranes remain elastic, says Bottiglieri. This allows receptors in the membrane, including those for some neurotransmitters involved in depression, to move around as they need to, carrying chemical signals.

Still, nobody really understands how SAM-e might work in depression, so if you try it, do so under a doctor’s supervision, assuming you can find a doctor open-minded enough to read what research is available.

Because SAM-e is poorly understood, don’t try it if you have manic-depression, because some antidepressants may make mania worse. It’s also important to take tablets that are enterically coated so they dissolve in the intestines, not the stomach, where they can be absorbed, and that are foil-wrapped so they do not absorb moisture.

Also make sure that your SAM-e product contains 1,4-butanedislfonate, a stabilizer. If not stabilized, SAM-e products can degrade and become useless. In fact, that’s what happened a decade ago when MGH researchers Fava and Rosenbaum did a SAM-e study with 40 patients.

The study was “a bust,” they say, because the tablets they had ordered from Italy sat unrefrigerated over a hot weekend at Logan airport. The pills became discolored, suggesting oxidation, and perhaps because of this, patients who took them did no better than those on a placebo.

There’s also a theoretical possibility that SAM-e might raise levels of homocysteine, an amino acid that can raise the risk of heart disease.

And there’s one final caveat. Several US researchers now at the forefront of SAM-e research have in the past or are now planning to do research supported by Nature Made, which sells a SAM-e product.

This does not necessarily mean the researchers are unethical or their findings won’t be credible. But it’s something to chew on.