SAM-e (S-adenosylmethionine) is a molecule your body makes naturally from the amino acid methionine and ATP (adenosine triphosphate). It’s involved in a process called methylation, which affects everything from DNA regulation to neurotransmitter production. Your liver, brain, and muscles all use it.

The supplement version has been available in Europe since the 1970s for depression, and was introduced to the US market in 1999. It’s sold over-the-counter as a dietary supplement, though in some European countries it’s available only by prescription.

Here’s the thing about SAM-e: it’s actually been studied quite a bit, which is unusual for a supplement. Most of what you’ll find on supplement shelves has minimal research behind it. SAM-e has dozens of clinical trials. The question isn’t whether it’s been studied, but whether those studies are good enough to draw firm conclusions.

What does SAM-e actually do in the body?

SAM-e participates in what biochemists call the “methyl cycle.” It donates a methyl group (a carbon atom with three hydrogen atoms) to other molecules. This might sound abstract, but methylation affects:

Neurotransmitter synthesis (dopamine, serotonin, norepinephrine)
DNA and RNA regulation
Phospholipid production for cell membranes
Glutathione production (an antioxidant)
Cartilage maintenance

When SAM-e donates its methyl group, it becomes SAH (S-adenosylhomocysteine), then homocysteine, which can be recycled back to methionine with the help of vitamin B12 and folate. This is why B-vitamin deficiency can affect SAM-e levels.

1. SAM-e for depression

This is where most of the interest lies, and where the most research has been done.

Major depression affects around 17% of people at some point in their lives. Current antidepressants take weeks to start working, don’t work for everyone, and come with side effects that make many people stop taking them. There’s genuine need for alternatives.

A 2020 systematic review looked at 8 randomised controlled trials involving 1,011 participants [1]. The studies tested SAM-e either as a standalone treatment or combined with standard antidepressants. The results were described as “encouraging and generally positive.”

But here’s my honest assessment: most individual studies had small sample sizes. A 40-person study might show statistically significant improvement, but that’s not the same as knowing the effect is reliable across different populations.

The proposed mechanism involves SAM-e’s role in making neurotransmitters. By providing more methyl groups, the theory goes, you get more efficient production of serotonin, dopamine, and norepinephrine. SAM-e may also increase phosphatidylcholine in cell membranes, which could affect receptor function.

One potentially useful finding: SAM-e may work faster than conventional antidepressants. Some studies reported improvements within a week or two, compared to the typical 4-6 weeks for SSRIs. If this holds up in larger trials, it could be genuinely useful for the early treatment period when people are most vulnerable.

The NHS notes that while some people try SAM-e for depression, it should not replace conventional treatment, and anyone with depression should speak to their GP [2].

What the evidence supports: SAM-e shows promise for depression, particularly as an add-on to existing antidepressants. The research is limited by small sample sizes and short study durations. It’s not a replacement for conventional treatment.

2. SAM-e for osteoarthritis

Osteoarthritis affects about 45% of people over their lifetime, with obesity being a major risk factor. It involves cartilage breakdown, bone changes, and inflammation in joints.

The theory behind SAM-e for osteoarthritis is that it might help maintain cartilage by supporting proteoglycan synthesis. Proteoglycans are molecules that help cartilage retain water and stay resilient.

A Cochrane review examined 4 randomised controlled trials involving 656 participants [3]. The conclusion was underwhelming: while there might be some clinically relevant benefit, the improvements in pain and function were small. The reviewers noted problems with study quality and recommended against using SAM-e for routine osteoarthritis care.

Some individual studies compared SAM-e to NSAIDs like ibuprofen or celecoxib. The results suggested similar pain relief, but SAM-e took longer to work (about 4 weeks vs. 1 week for NSAIDs). The potential advantage would be fewer gastrointestinal side effects than long-term NSAID use.

If you’re interested in joint health supplements, you might also look at glucosamine and chondroitin, which have been more extensively studied for osteoarthritis.

What the evidence supports: SAM-e might offer modest benefits for osteoarthritis pain, but the evidence is weak. It’s not recommended for routine use by major review bodies.

3. SAM-e for liver disease (cirrhosis)

This one caught my attention because the single large trial that exists showed genuinely interesting results.

Cirrhosis is the end stage of chronic liver disease, where normal liver tissue gets replaced by scar tissue. The most common causes are alcohol abuse, hepatitis B and C, and non-alcoholic fatty liver disease.

A 2-year randomised, double-blind trial followed 123 patients with alcoholic cirrhosis [4]. Those who took SAM-e had better overall survival and needed fewer liver transplants, particularly among patients whose disease hadn’t yet progressed to the most severe stage.

The mechanism here involves glutathione. The liver uses SAM-e to make glutathione, which protects liver cells from oxidative damage. In alcoholic liver disease, glutathione levels are typically depleted.

There’s a catch: this is essentially one good study. It was well-designed and the results were statistically significant, but medicine generally requires replication before accepting a treatment as effective. I haven’t found follow-up trials of similar quality.

For those interested in liver health, we’ve covered foods and supplements for fatty liver in a separate article.

What the evidence supports: One well-designed trial showed survival benefits in alcoholic cirrhosis. This is promising but requires confirmation from additional studies.

4. SAM-e for fibromyalgia

Fibromyalgia involves widespread pain, fatigue, sleep problems, and often depression. The cause remains unclear, though it seems to involve how the nervous system processes pain signals.

A 6-week double-blind study tested SAM-e (800 mg daily) in 44 people with fibromyalgia [5]. Compared to placebo, SAM-e improved pain, morning stiffness, and mood assessments.

Forty-four people over six weeks. That’s the main evidence. I’m not saying it doesn’t work, but the sample size is tiny and the study duration is short. Fibromyalgia is a chronic condition; we’d want to know whether benefits persist over months or years.

The connection to depression treatment might be relevant here, since fibromyalgia and depression commonly occur together. If SAM-e helps mood, that could indirectly help fibromyalgia symptoms.

What the evidence supports: Very limited. One small study showed benefit, but this isn’t enough to recommend SAM-e for fibromyalgia.

5. SAM-e for menopausal hot flushes

I’m including this because it gets searched for, but the news isn’t good.

Hot flushes affect about 75% of women during menopause, and also occur in breast cancer patients taking anti-oestrogen drugs like tamoxifen (60-70% of these patients experience them).

A phase II trial tested SAM-e (400 mg twice daily) in 43 women with hot flushes over 7 weeks [6]. The result: no clinically significant improvement compared to baseline. No benefit for quality of life either.

What the evidence supports: SAM-e does not appear to help hot flushes.

Side effects of SAM-e

In studies, SAM-e has generally been well tolerated at doses up to 1,600 mg per day. Reported side effects include:

Nausea and vomiting
Diarrhoea or constipation
Dry mouth
Headache
Dizziness
Insomnia (especially if taken late in the day)
Anxiety or restlessness
Increased sweating

Higher doses tend to cause more gastrointestinal symptoms. Taking SAM-e with food may help reduce nausea.

Safety precautions and drug interactions

This section is genuinely important. SAM-e has several significant interactions and contraindications.

Who should avoid SAM-e:

Pregnant or breastfeeding women (insufficient safety data)
Children (not studied)
People with bipolar disorder (may trigger manic episodes)
People with Parkinson’s disease (may interfere with levodopa)
People with Lesch-Nyhan syndrome
People with compromised immune function

Drug interactions:

The most serious concern is serotonin syndrome when SAM-e is combined with other drugs that affect serotonin. This can cause rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, and hyperthermia. It can be life-threatening.

Avoid combining SAM-e with:

SSRI antidepressants (fluoxetine, paroxetine, sertraline)
Tricyclic antidepressants (amitriptyline, imipramine)
MAO inhibitors (phenelzine, tranylcypromine)
St. John’s Wort (another supplement that affects serotonin)
Dextromethorphan (found in many cough medicines)
Tramadol and other opioids
L-tryptophan supplements

SAM-e may also lower blood sugar, so people taking diabetes medications should monitor their glucose carefully.

If you’re scheduled for surgery, stop taking SAM-e at least 2 weeks beforehand because of its effects on the central nervous system.

Dosage

Typical study doses have ranged from 400 mg to 1,600 mg daily, usually divided into two doses. For depression, most studies used 800-1,600 mg. For osteoarthritis, 600-1,200 mg was common.

SAM-e supplements come in enteric-coated tablets to protect them from stomach acid degradation. They should be stored in cool, dry conditions as the molecule is relatively unstable.

My honest take

SAM-e is unusual among supplements because it has actual mechanism-based reasoning for its effects and a reasonable body of clinical research. It’s not snake oil. But “not snake oil” isn’t the same as “proven effective.”

For depression, the evidence is promising but not conclusive. If someone has tried conventional antidepressants without success, discussing SAM-e with their doctor as an add-on treatment seems reasonable. I wouldn’t recommend it as a first-line treatment.

For osteoarthritis and fibromyalgia, the evidence is weak. There are better-studied options.

For liver disease, there’s one genuinely interesting study, but it needs replication.

The interaction profile is concerning enough that anyone considering SAM-e should discuss it with a healthcare provider, particularly if they take any other medications affecting the brain.

St. John’s Wort: benefits and side effects - another natural supplement studied for depression
Vitamin B12: what the research shows - involved in SAM-e metabolism
Supplements for osteoarthritis

References

Sharma A, Gerbarg P, Bottiglieri T, et al. S-Adenosylmethionine (SAMe) for Neuropsychiatric Disorders: A Clinician-Oriented Review of Research. J Clin Psychiatry. 2017;78(6):e656-e667. PMID: 28682528
NHS. Vitamins, supplements and nutrition in pregnancy. https://www.nhs.uk/conditions/vitamins-and-minerals/
Rutjes AW, Nüesch E, Reichenbach S, Jüni P. S-Adenosylmethionine for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2009;(4):CD007321. PMID: 19821403
Mato JM, Cámara J, Fernández de Paz J, et al. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. J Hepatol. 1999;30(6):1081-9. PMID: 10406187
Jacobsen S, Danneskiold-Samsøe B, Andersen RB. Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. Scand J Rheumatol. 1991;20(4):294-302. PMID: 1925418
Thompson MA, Peck JR, Kumar A, et al. A Phase II trial of oral SAMe for hot flashes. Support Care Cancer. 2016;24(6):2729-2735. PMID: 26838116