Ingredient review

SAMe (S-adenosylmethionine)


What is it?

S-adenosylmethionine (SAMe) is an endogenous metabolite involved in several metabolic pathways that utilize methyltransferases to donate methyl groups to enzymes, receptors, DNA, cellular membranes, and neurotransmitters. Methylation reactions can alter enzymatic activity, regulate cell membrane structure, regulate membrane receptor activity, and activate or deactivate DNA. SAMe can also methylate other metabolites such as free amino acids or neurotransmitters, and it is a precursor to the antioxidative metabolite glutathione. Dysregulation of balanced methylation reactions may lead to a number of conditions related to liver, musculoskeletal, or neurocognitive dysfunction. (6)(33)(35)(36)(60) In the United States, SAMe has been available as a dietary supplement since 1999, while in Europe, various pharmaceutical formulations have been available for decades. (6) As a complementary and alternative medicine, SAMe may not be widely covered by health insurance; however, it may be a viable substitution for expensive prescriptions, including those used to treat depression. (60)

Main uses

Liver diseases
Osteoarthritis and other pain-related conditions


In its natural form, the SAMe ion is relatively unstable and subject to rapid degradation in the stomach or with air exposure. As a result, many trials have used parenteral administration methods (i.e., intramuscular or intravenous injections) to circumvent issues of stability. However, orally administered products are available as enteric-coated tablets formulated with stabilizing salt compounds to improve bioavailability and may come in blister packs to reduce air exposure and degradation. (49)(60) Oral SAMe possesses low bioavailability (0.5-1.0%), (42) though enteric-coated formulations may elevate bioavailability to 2-3%, (72) possibly raising plasma SAMe levels six-fold. (43) Unfortunately, there is limited research directly comparing various oral formulations.

SAMe (ion)
Unstable, with low oral bioavailability
As SAMe’s molecular weight is roughly equivalent to the salts used to stabilize it (listed below), SAMe’s elemental amount is ~half of what is shown on a product label (15) (49)
Look for the “true” amount of SAMe or use cues such as “200 mg from SAMe sulfate-p-toluenesulfonate” to know how much SAMe is provided per tablet/capsule.
SAMe tosylate (also known as sulfate-p- toluenesulfonate)
Bioavailability is ~1% (63)
May be labeled to indicate content of its active (SS) or inactive (RS) isomer; for example, standardized to contain a 65:35 mixture of SS to RS isomers (62) or standardized to 74% of SS isomer in other products (26)
SAMe disulfate tosylate (also known as disulfate-p- toluenesulfonate)
Enteric-coated bioavailability was 2-3% (71)
SAMe 1,4 -butanedisulfonate
Bioavailability is ~5% (63)

Dosing & administration

Adverse effects

SAMe is considered safe with a mild and non-clinically relevant side effect profile. Some common adverse effects may include anxiety, dizziness, gastrointestinal symptoms, insomnia or restlessness, sweating, tachycardia, and vertigo. (12)(60) However, compared to a placebo, SAMe does not increase the prevalence of adverse effects in conditions it is commonly used to treat, including chronic liver diseases (27), osteoarthritis, (55) or major depression (23). Additionally, there was no difference in the number of dropouts compared with various antidepressant medications including tricyclic antidepressants or when used as an adjunct to SSRIs (e.g., escitalopram) compared with a placebo. (23) In patients with depression, SAMe has been linked to an increased risk of switching between hypomanic or manic states, but this is mainly observed in bipolar disorder (10)(60) or when using intravenous or intramuscular administration rather than oral formulations. (47)(57

While there may be speculative concerns that SAMe administration may lead to increased homocysteine, and thus higher cardiac risk, there was no significant elevation in total homocysteine when SAMe was provided to patients with depression (800-1,600 mg) over six weeks (43) or to healthy subjects using 800 mg per day for four weeks. (66)



  • SAMe possesses low bioavailability (0.5-1.0%); (42) however, enteric-coated SAMe formulations may have 2-3% bioavailability in humans. (72)
  • Peak concentrations typically occur within 2-5 hours in humans. (34)(72)


  • SAMe can be incorporated into cellular membranes throughout the body with a single oral dose being retained for more than five days. (6)
  • SAMe can be found in cerebrospinal fluid and may cross the blood-brain barrier in humans. (6)(7)
  • SAMe may be uptaken by hepatocytes. (6)


SAMe’s metabolism involves the donation of its methyl group via three potential pathways (below): 

  • Methylation: SAMe donates its methyl group to DNA, proteins, phospholipids, neurotransmitters, etc., producing S-adenosylhomocysteine and, subsequently, homocysteine. Homocysteine may be metabolized to methionine (using vitamin B12) or undergo transsulfuration.
  • Transsulfuration: Homocysteine can be metabolized to cystathionine (using vitamin B6), eventually leading to the production of the antioxidative nutrient glutathione.
  • Aminopropylation: Leads to the production of polyamines that regulate cell growth and may provide analgesic or anti-inflammatory effects. SAMe is decarboxylated, a process during which its aminopropyl group is utilized to also eventually produce methionine.
  • Note that SAMe can be resynthesized from methionine. (6)(13)(41)


  • SAMe may be excreted in urine or feces. (6)(24)
  • SAMe’s half-life was approximately 2-6 hours in humans. (34)(72)