Role of S-adenosyl-L-methionine in the treatment of depression

A few years ago St. John’s wort shot to fame as the natural depression cure of choice—the preferred alternative to pre­scription antidepressants. Now comes a pill called SAM-e (“Sammy”) or S-adenosyl-methionine with rival powers. “It’s the best antidepressant I’ve ever prescribed,” says psy­chiatrist Richard Brown at Columbia University College of Physicians and Surgeons, and coauthor of a new book on SAM-e, Stop Depression Now.

Like St. John’s wort, SAM-e hails from Europe, where it has been used for two decades to relieve depression, as well as osteoarthritis. Extensive research (about forty stud­ies, most done in Europe) indicates that SAM-e combats depression as well as or sometimes better than state-of-the-art pharmaceuticals. Generally, controlled studies claim that SAM-e has a 70 percent success rate, about the same as conventional drug therapy. But SAM-e works faster and without troubling side effects, making it unique and prefer­able, say advocates.

Indeed, the first double-blind study of SAM-e by Italian researchers on severely depressed patients found that 100 percent of them improved on the supplement. A few almost completely recovered within four days. A major 1994 Ital­ian review of two decades of studies (a meta-analysis) involving more than 1000 patients showed that SAM-e always relieved depression better than a placebo and always at least matched the effectiveness of tricyclic anti‑depressants. In some cases, SAM-e surpassed prescription drugs.

Researchers at the University of California at Irvine, for example, pitted SAM-e against desipramine, a tricyclic anti­depressant, in a test of twenty-six depressed patients. Sixty-two percent of patients taking SAM-e improved compared with 50 percent taking desipramine.

SAM-e is something you make yourself. It is a natural constituent of cells, synthesized in the body from the essen­tial amino acid L-methionine and ATP, the cellular energy chemical. SAM-e is a star player in the cell’s energy pro­duction. Encouraged by folic acid and vitamin B12, SAM-e donates a bit of itself (methyl group) to nearby cells, which is “an important event at the molecular level,” as one sci­entist says. This crucial methyl transfer stimulates thirty-five vital chemical reactions in cells with widespread effects. Among other things, it promotes fluidity of cell membranes—a big thing in nerve cell functions—and pro­duction of good-mood neurotransmitters, mainly serotonin and dopamine. It’s thought that stimulating serotonin and dopamine is a prime way SAM-e fights depression. When depressed people take SAM-e, there’s evidence of increased serotonin and dopamine in their nervous systems.

SAM-e performs another miracle in your brain. Nerve cells must have SAM-e as raw material to synthesize glu­tathione, the main heavyweight antioxidant in neutralizing specific brain toxins and neuron-mutilating free radicals. Glutathione also has brain-protecting anti-inflammatory properties. Guaranteeing cells enough SAM-e to produce glutathione may be reason enough to take the supplement. Brain levels of both glutathione and SAM-e decline as we age. Oddly, taking glutathione supplements does not in­crease cellular or blood levels of the substance. But taking SAM-e does, making it one of the few reliable ways of boosting precious glutathione.

There’s also some evidence, says Teodoro Bottiglieri, Ph.D, director of neuropharmacology at Baylor University Medical Center in Dallas, that SAM-e may benefit people with dementia, including Alzheimer’s. Dr. Bottiglieri, who has studied SAM-e for nearly twenty years, found abnor­mally low levels of SAM-e in the cerebrospinal fluid of Alzheimer’s patients.

“The nicest thing about SAM-e is it works as well as standard prescription medications, but it has fewer side effects and it works faster, so people feel better sooner. “—Dr. Richard Brown, Columbia University


One of the great attractions of SAM-e is how rapidly it can bring relief. Conventional antidepressants usually take four to six weeks to elevate mood. Depression lifts in patients taking SAM-e sometimes within days. In a double-blind trial of depressed postmenopausal women, Italian re­searchers noted that SAM-e (in high daily doses of 1600 milligrams) relieved depression after ten days. Dr. Maur­izio Fava, director of the Depression Clinic and Research Program at Massachusetts General Hospital in Boston, found that injecting patients with 400 milligrams of SAM-e daily significantly reduced depressive symptoms in half of them within a week—and without any severe side effects.

Even though SAM-e works fast, if you are depressed, you must continue to take it, lest you suffer a relapse. Dr. Brown advises taking it for at least six to nine months.

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A huge drawback of prescription antidepressants is their miserable side effects, including sexual dysfunction, weight gain, dry mouth, blurred vision, constipation, bladder prob­lems, dizziness, headache, drowsiness, nausea, insomnia, and agitation. Obviously, this makes people not want to take them. In fact, 30 percent of people in clinical trials stop taking them, making the actual success rate of pre­scription antidepressants only 40 percent.

In contrast, SAM-e has none of these side effects, says Dr. Brown, and is nontoxic, even in high doses. Indeed, in studies SAM-e produced no more side effects than a placebo or sugar pill. Is there any downside to SAM-e? Yes, says Dr. Brown. SAM-e could exacerbate the manic phase of manic depression (bipolar disorder); thus, people with bipolar disorder should take SAM-e only under the close supervision of a psychiatrist, advises Dr. Brown. SAM-e has no known harmful interactions with other medications, including prescription antidepressants and St. John’s wort. However, don’t combine MAO inhibitor-type antidepres­sants and SAM-e, just in case, cautions Dr. Brown, and inform your doctor about what you are taking.


A typical effective dose for most people with mild to mod­erate depression is 400 milligrams a day, according to Drs. Brown and Bottiglieri. If you don’t see a 25 percent im­provement within two weeks, they suggest upping the dose of SAM-e to 800 milligrams a day. If you have a history of sensitivity to medications, start with 200 milligrams for the first week. They also suggest taking SAM-e on an empty stomach a half-hour before meals; if you experience heart­burn, take it with meals.

Where to get it? SAM-e is available in bottles or blister packs from health food stores, drugstores, and discount stores. Be sure to look for “enteric coated,” meaning it is best absorbed and most stable.

BOTTOM LINE: SAM-e appears to be a good alterna­tive to prescription drugs for treating mild depression. At about seventy-five dollars per month, it is less expen­sive than prescription drugs, but more expensive than St. John’s wort.

Caution: It can be dangerous to self-diagnose depres­sion and take supplements on your own without a doctor’s advice. Do not take such supplements along with antide­pressant drugs without consulting a physician. If you are more than mildly depressed (stressed out, down in the dumps, under the weather with fatigue, mild anxiety, lack of zest, less fun in life, less productive and creative than usual), see a health professional for an accurate diagnosis. More serious depression may be related to physical causes (brain tumor or malfunctioning thyroid) and may require additional medical treatment.

Jean-Paul Marat

Many tips are based on recent research, while others were known in ancient times. But they have all been proven to be effective. So keep this website close at hand and make the advice it offers a part of your daily life.

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