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SAMe (S-adenosylmethionine)

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

Depression
Liver diseases
Osteoarthritis and other pain-related conditions

Formulations

Formulation	Characteristics
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

Chronic liver disease
General outcomes from A-level evidence	Improved fatigue, (53) pruritus, & liver function via reductions in total bilirubin & AST but not ALT (27)
Dosing & administration	400 mg (SAMe p-toluene-sulfonate) three times per day for 6-24 months to Px with alcoholic liver disease or non-alcoholic liver disease
Outcomes	↓ rate of mortality/liver transplantation from 29% to 12%, improving survival/delaying need for liver transplant in Px with less severe disease (40) ↑ total hepatic glutathione by 71% and reduced glutathione by 69% in Px with alcoholic liver disease & by 79% and 76%, respectively, in Px with non-alcoholic liver disease (67)
Class of evidence	B
Dosing & administration	800 mg (as SAMe p-toluene-sulfonate) twice per day for two weeks to Px with chronic liver diseases (chronic active hepatitis, cirrhosis, & primary biliary cirrhosis)
Outcomes	↑ likelihood of therapeutic response (18%) to achieve >50% reduction in total bilirubin beginning within one week & likelihood of >50% reduction in pruritus score (44%) and fatigue (45%) after two weeks compared to placebo ↓ alkaline phosphatase (27%) & alanine aminotransferase (33%) after two weeks compared to placebo Note: effects reversed within 30 days of discontinuation (22)
Class of evidence	B
Dosing & administration	800 mg (intravenously) per day for two weeks, followed by 800 mg (oral) twice per day for eight weeks to Px with intrahepatic cholestasis secondary to hepatitis or chronic liver disease
Outcomes	Improves pruritus, serum total and conjugated bilirubin, aminotransferases, γ-glutamyl transferase & alkaline phosphatase levels (39)
Class of evidence	B
Dosing & administration	1000 mg (intravenous) per day for four weeks to pregnant women with chronic hepatitis B
Outcomes	↓ ALT (88%) and AST (84%) compared to baseline Normalized ALT levels in 21% of patients (but not as effectively as stronger neo-minophagen C) (65)
Class of evidence	C
Dosing & administration	250-1000 mg (intravenously) per day for four weeks to children with drug-induced liver disease
Outcomes	↑ relief from severe pruritus compared with control (82% vs. 19%) & remission/recovery from jaundice within two weeks ↓ total bilirubin, AST, & GGT within two to four weeks (75)
Class of evidence	C

Depression
General outcomes from A-level evidence	↓ depressive symptoms (9)(12)(70) with reductions in HDRS scores by clinically relevant six points, (28) particularly as adjunct therapy (23)(57) or when Px are unresponsive to SSRIs and SNRIs (13) May also improve depressive symptoms in co-morbid conditions such as fibromyalgia, HIV, liver diseases, Parkinson’s disease, neurocognitive and psychotic disorders, or sexual dysfunction (60) Note: Changes in depressive symptoms may be similar to those observed with tricyclic antidepressants (e.g., imipramine) or SSRIs (e.g., escitalopram) (9)(12)(23)(28)
Dosing & administration	1000-1600 mg (orally), 200-800 mg (intravenously), or 45-200 mg (intramuscularly) as monotherapy, or 800-1600 mg (orally) or 100-200 mg (intramuscularly) as adjunct therapy to antidepressants per day to patients with major depression
Outcomes	↓ depressive symptoms in major depression & treatment-resistant depression (13)
Class of evidence	A
Dosing & administration	800 mg (as SAMe tosylate disulfate) twice per day for six weeks and up to 1600 mg twice per day to non-responders for an additional six weeks to adults with major depression
Outcomes	↑ likelihood of response to therapy (SAMe was 45%, escitalopram was 31%, and placebo was 26%) & remission rates (SAMe was 34%, escitalopram was 23%, and placebo was 6%) in post-hoc analyses (58) ↑ HAM-D score by 48% in males compared with placebo in post-hoc analyses (59) Note: SAMe provided similar effects to escitalopram from weeks 8-12 but was superior during the first six weeks; (58) however, original trial showed no improvement compared with placebo or escitalopram when analysis pooled males and females (44)
Class of evidence	B
Dosing & administration	800 mg twice per day (as oral SAMe 1,4-butanedisulfonate containing 400 mg of elemental SAMe per dose) or 400 mg (as injection) per day for six weeks to Px with major depression
Outcomes	↓ HAM-D & MADRS scores by ~50% compared to baseline with either formulation Note: effects on depression scores & rate of moderate or better improvements (measured by CGI) were similar to 150 mg of imipramine per day but with fewer adverse events (9.5% vs. 33%) (15)(51)
Class of evidence	B
Dosing & administration	800 mg twice per day for six weeks to serotonin reuptake inhibitor (SRI)-non-responsive adults with major depression as adjunct therapy
Outcomes	↑ HAM-D response (18.5%) and remission rates (14.1%) compared with placebo (52) Improved ability to recall information compared with placebo (32)
Class of evidence	B
Dosing & administration	Dosing & administration 1,600 mg per day for one month in postmenopausal women with depressive symptoms
Outcomes	↓ HAM-D and RDI at day 10 by 21% and 13% and at day 30 by 32% and 22%, respectively, compared with placebo ↓ somatic (gastrointestinal, cardiovascular, respiratory, and genital) symptoms compared to placebo (56)
Class of evidence	B
Dosing & administration	Up to 800 mg twice per day for three to four weeks to Px with depression
Outcomes	↓ HAM-D (36%) and Caroll depression self-rating scale (26%) compared to placebo after three weeks, with difference starting within one week (30) ↑ likelihood of treatment response by 12% compared with up to 250 mg of desipramine (2)
Class of evidence	C
Dosing & administration	Up to 400 mg (intravenous) per day for two weeks to Px with major depression
Outcomes	↓ HAM-D scores (53%) & Beck inventory scores (45% vs. 32%) compared to imipramine after two weeks ↑ likelihood of treatment response compared to imipramine (66% vs. 22%) (1)
Class of evidence	C
Dosing & administration	75-200 mg (intramuscular) per day for two to three weeks to Px with major depression either alone or as an adjunct to imipramine
Outcomes	↓ depressive symptoms with greater therapeutic speed than imipramine alone & Hamilton rating scores to a similar extent as 75 mg of imipramine (3)(38)
Class of evidence	C

Fibromyalgia
General outcomes from A-level evidence	No data currently available.
Dosing & administration	800 mg (as SAMe disulfate-p-toluenesulfonate containing 400 mg elemental SAMe) twice per day for six weeks to Px with fibromyalgia
Outcomes	↑ rate of feeling “much better” or “better” compared to placebo (23.5% vs. 4.8-9.5%, respectively) ↓ pain, fatigue, morning stiffness, & poor mood (29)
Class of evidence	B
Dosing & administration	200 mg (intramuscularly), followed by 200 mg (oral) twice per day for six weeks to Px with fibromyalgia
Outcomes	↓ number of tender points and score (~45%) & scores for pain and fatigue compared to transcutaneous electrical nerve stimulation (TENS) therapy after six weeks Improved Hamilton Depression and Anxiety Rating scales after six weeks compared to TENS, with effects improving from baseline by two weeks (16)
Class of evidence	C

Gestational intrahepatic cholestasis
General outcomes from A-level evidence	↓ odds of requiring C-section (45%), preterm birth (36%), and fetal asphyxia (27%) when used in combination with ursodeoxycholic acid (UDCA) vs. UDCA alone, & odds of requiring C-section (39%) of fetal asphyxia (23%), and amniotic fluid pollution (45%) compared with SAMe alone (74) May reduce liver biomarkers within 2-8 weeks, including ALT, AST, ALP or GGT, as well as some symptoms of cholestasis including fatigue, depression, or pruritis (19)(28)(50) Note: other evidence indicates that there is insufficient for the use of SAMe to treat cholestasis in pregnancy, (69) but monotherapy may be as equally effective as UDCA (74)
Dosing & administration	500 mg twice per day (intravenous) for 12 days followed by 500 mg twice per day orally to pregnant women (<36 weeks gestation) with cholestasis
Outcomes	↓ pruritis to a similar extent as 750 mg of UDCA but not as effective to improve bile acids, ALT, or AST (4)(5)
Class of evidence	C
Dosing & administration	800-1000 mg per day (SAMe disulfate-p-toluenesulfonate intravenously) for 2-3 weeks to pregnant women (between 28-35 weeks gestation) with cholestasis
Outcomes	↓ pruritus intensity score (41-64%), total bile acids (30%), ALT (41%), AST (38%), & total bilirubin (22%) compared to baseline Note: similar efficacy to improve pruritus was noted with 1,000 mg UDCA and the combination of the two therapies (20)(21)(73)
Class of evidence	C
Dosing & administration	500 mg twice per day until delivery to pregnant women (<36 weeks gestation) with cholestasis
Outcomes	↑ pruritis to a similar extent as 300 mg of UDCA, but not as effective to improve serum bile acids, ASA, ALA, or bilirubin (54)
Class of evidence	C

Osteoarthritis
General outcomes from A-level evidence	↓ dysfunction (61) and pain (14) Note: Effects on osteoarthritis are inconclusive, but there may be some evidence of similar efficacy to NSAIDs with reduced reports of side effects (55)(61)(71)
Dosing & administration	400 mg three times per day for 3-12 weeks to Px with knee or hip osteoarthritis
Outcomes	↓ pain, functional activity difficulty, morning stiffness, & joint immobility (45) Improves pain score by 7% after four weeks and 15% after eight weeks, & patient’s global assessment of disease status score (15%), physician’s global assessment of response to therapy score (22%), and total WOMAC (for pain, stiffness and function) score (13%) after eight weeks Note: provides similar efficacy, therapeutic speed, and tolerability as 1,000 mg of nabumetone, (31) similar therapeutic speed as 20 mg of piroxicam but can maintain benefits for longer upon discontinuation, (37) & similar efficacy to 750-800 mg naproxen but with better tolerability (11)(17)
Class of evidence	B
Dosing & administration	600 mg (as SAMe disulfate monotosylate salt standardized to 45% SS and 55% RS isomer) twice per day for eight weeks to Px with knee osteoarthritis
Outcomes	↓ VAS pain score by 25% after four weeks & by 48% after eight weeks while various subscores on functional health measures (COOP, SF-36, Biodex, & WOMAC) also improved Note: SAMe had slower onset of action compared with 200 mg of celecoxib, but equivalent efficacy after eight weeks (48)
Class of evidence	B
Dosing & administration	Up to 400 mg (intravenous) per day for five days, followed by 200 mg (oral) three times per day for remainder of one month to Px with symptomatic knee osteoarthritis
Outcomes	↓ overall pain and resting pain in milder osteoarthritis within two weeks (8)
Class of evidence	B
Dosing & administration	400 mg three times per day for four weeks to Px with knee, hip, or spinal osteoarthritis
Outcomes	↓ total osteoarthritis scores (55%) with similar efficacy to 1,200 mg of ibuprofen per day but with fewer side effects (5 vs. 16), or 150 mg of indomethacin but with fewer reported adverse events than indomethacin (11% vs. 29%) (25)(46)(68)
Class of evidence	C

Sexual function (male)
General outcomes from A-level evidence	No data currently available.
Dosing & administration	Up to 800 mg (as SAMe tosylate) twice per day for six weeks to Px with treatment-resistant (SSRI/SNRI) depression as adjunct to antidepressants
Outcomes	↓ arousal dysfunction & erectile dysfunction (18)
Class of evidence	B

Schizophrenia
General outcomes from A-level evidence	No data currently available.
Dosing & administration	400 mg twice per day for eight weeks to Px with schizophrenia and low catechol-O-methyltransferase enzyme activity
Outcomes	↓ Over Aggression Scale score (76%), Clinical Global Impression (CGI) Scale-Severity (26%), & Calgary Depression scale score in females compared to baseline (no change in placebo) ↑ Quality of Life Scale score (62%) compared to baseline (no change in placebo) (64)
Class of evidence	C

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)

Pharmacokinetics

Absorption

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)

Distribution

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)

Metabolism

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)

Excretion

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