Everything You Need to Know About Using SAMe for Depression

If you tried SAMe in recent years and didn’t get results, you might want to try again with a higher-quality, properly-packaged brand.
Alita Ong / Stocksy

Several years ago, when Sandy Cooper felt her major depression return, she was dreading going back on Lexapro. She had stopped taking the antidepressant more than a year before, after it led her to gain more than 20 pounds in a few months. Still, Cooper, of Louisville, Kentucky, knew she needed to do something to counter the weepiness, irritability, fatigue, and feelings of hopelessness that had begun to overtake her.


She felt encouraged when an online search led to her discovery of SAMe, a natural supplement. And she was even more excited when, after buying a box over the counter at Target, she started feeling better in a couple of weeks.

“The feeling that I couldn’t see my life clearly because everything was very dark went away, as if someone opened a window shade and let the light in,” Cooper recalls, noting that this happened within a few weeks—faster than an antidepressant typically works. She stayed on the supplement for months, until she felt well enough to work on staying healthy via lifestyle changes, something she was familiar with as a blogger helping women maintain balance in their lives.

What is SAMe?

SAMe (pronounced sam-E) stands for S-adenosyl-L-methionine. It’s a chemical found naturally in the body, which is thought to play a role in many metabolic pathways. Its effectiveness for depression stems from its key part in the physiological process known as methylation, which turns our biological switches on and off. According to a 2017 review of the research on SAMe published in the Journal of Clinical Psychiatry, methylation has been documented to be a factor in depression.

Still, researchers are in the early stages of fully understanding exactly how SAMe and other methyl-group chemicals work. What they do know is that preliminary studies of SAMe for depression have been encouraging. (SAMe is also being studied for osteoarthritis, liver disease, Alzheimer’s and other conditions.) The experts we spoke to for this story are especially high on this remedy now that a high-quality version has returned to the US market after a long lull.


Would my psychiatrist actually recommend a natural supplement for depression?

As with the better-known herb St. John’s wort, at least some mainstream psychiatrists are open-minded about SAMe’s possible value. “The nice thing about SAMe is that there is some evidence of efficacy, unlike a lot of other supplements that you can get, which either have not been tested or the evidence does not support their benefit,” says Cynthia M. Stonnington, psychiatrist and chair of the department of psychiatry and psychology at the Mayo Clinic College of Medicine and Science. Stonnington has recommended SAMe to some of her patients with depression who, like Cooper, couldn’t handle the side effects of prescription drugs, although in her experience it works best in patients with a milder disease.

Patricia Gerbarg, psychiatrist and assistant clinical professor in psychiatry at New York Medical College, has been recommending SAMe for 20 years. A coauthor of a seminal 2017 Journal of Clinical Psychiatry review, she says that “SAMe works faster and doesn’t cause many of the side effects that occur with prescription antidepressants, like weight gain or sexual dysfunction.”

Does research back up SAMe’s effectiveness?

Gerbarg’s review found that more than 50 clinical trials have been done on SAMe. Nineteen studies compared the chemical to a placebo, while 21 tested it against prescription antidepressants. (The others tested it alone.) As with most of the research on supplements, whose manufacturers don’t have the deep pockets of a drug company, all of these studies are small. The placebo-controlled trials together total fewer than 900 people.

Nonetheless, the results are relatively promising. After reviewing the research, the coauthors wrote that there is “encouraging evidence for the safety and efficacy” of SAMe for people with depression. One of the studies described in the review, for example, published in 2002 in the American Journal of Clinical Nutrition, found that patients with major depression recovered as well on SAMe as on the tricyclic antidepressant Tofranil. And those taking SAMe had many fewer side effects.


Other research supports the benefit of adding SAMe to an antidepressant regimen. In one study cited in the 2017 review and published in Cell Biology Reviews in 1987, depressed people who took both pills together improved in just ten days—practically unheard of for an antidepressant alone.

And in a study in the ScientificWorldJournal in 2013, “treatment resistant” patients who hadn’t responded to an antidepressant who had SAMe added on improved within two months; some 60 percent reported improvement, and more than a third went into remission from their depression.

Does the brand of SAMe make a difference in how effective it is?

You can buy SAMe in most drugstores and health food stores. But before grabbing the first packet off the shelf, you should know that experts say not all SAMe is the same. “The quality of SAMe products is critical. Low-quality products can lack 50 percent or more in potency, while the poor quality production of tablets, which allow exposure to air or to stomach acids, degrade it badly,” Gerbarg says.

The best tablets are not only carefully manufactured, she says, they are “enteric-coated” (made with a substance around the outside that keeps it from being damaged by stomach acids) and protected in individual blister packs. These packs should not be refrigerated in the store or at home, because condensation can develop inside the package and degrade the pills.

There are several brands on the market that fit this criteria, but Gerbarg especially recommends Azendus, a high quality, potent brand that only recently came on the market in the US. Gerbarg, who is unaffiliated with the brand, adds that products similar to this one used to be more readily available here, but were swapped for those with cheaper ingredients. So if you tried SAMe in recent years and didn’t get results, you might want to try again with a higher-quality, properly-packaged brand.


What type of dose would I start with?

The usual starting dose for an otherwise healthy adult is 400 mg of oral SAMe daily. After a few days, if you tolerate it well, you can increase to an optimal dose of 800 mg to 1600 mg, Gerbarg says. You’ll want to take SAMe on an empty stomach (unless this causes nausea) about 30 to 40 minutes before breakfast or lunch. Avoid taking it after 3 pm, as then it’s more likely to disturb your sleep. While many people have no untoward reactions, some people do experience diarrhea, abdominal discomfort, nausea, or vomiting.

Are there any risks and should I keep my doctor in the loop?

Even though SAMe is sold without a prescription, you should consult with your doctor about your depression rather than simply try to treat yourself. “If someone has depression, they really need to seek evaluation by a mental health professional to be adequately diagnosed and monitored. So even if you get this over the counter, it is important to seek professional evaluation and treatment,” Stonnington says.

Occasionally, SAMe can increase agitation or anxiety, which is why the National Institutes of Health says that SAMe may not be safe for people with bipolar disorder.

The Mayo Clinic also warns against taking SAMe if you have a compromised immune system, since it’s possible that SAMe can boost the growth of a particular microorganism that can cause problems in people with weak immune systems. Mayo also cautions against taking SAMe if you’re on cough suppressants, narcotics, amphetamines or St. John’s wort because of the possibility that these combinations will lead to imbalances in the neurochemical serotonin .

Is SAMe covered by my insurance?

Like most supplements, SAMe is not covered by most insurance. SAMe supplements are generally sold in pill or tablet form. And the pills aren’t cheap: Azendus costs $35 for 60 400 mg pills , which would last for between 15 and 30 days, depending on whether you're taking two or four per day. But for a supplement that might “open the window shade and let the light in,” as Cooper experienced, curbing depression faster and with fewer, more benign side-effects than prescription drugs, it could be worth a try.

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