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Scientific Name(s): ADE-SD4, Ademetionine, S-adenosyl-L-methionine, S-adenosylmethionine
Common Name(s): SAM, SAMe

Clinical Overview


SAMe has been studied for the treatment of depressive disorders. It has been shown to be equivalent to tricyclics, and there is a paucity of comparative data versus newer agents. Information regarding its use in osteoarthritis is conflicting and information regarding its use in liver disorders and cholestasis is limited.


Depression: 200 to 1,600 mg/day. Liver disease: 800 to 1,000 mg/day. Osteoarthritis: 1,200 mg/day initially; then maintenance 400 mg/day in some studies.


SAMe should not be used in patients with bipolar depression because of reports of increased anxiety and mania.


Trials conducted in pregnant women documented no harmful effects.


None well documented.

Adverse Reactions

Available data indicate nausea, diarrhea, constipation, mild insomnia, dizziness, irritability, anxiety, and sweating are the most commonly reported adverse reactions associated with SAMe use. Data from long-term use are lacking.


Toxicological studies concluded that SAMe is safe at high doses.


SAMe is a naturally occurring molecule produced endogenously by a reaction of the amino acid methionine with adenosine triphosphate. Although SAMe is found in all living cells, the liver is where approximately 85% of transmethylation chemical reactions and 50% of methionine metabolism occur.1 SAMe acts as a substrate in many biological reactions and is the precursor of certain essential amino acids.2, 3 A supplement or biochemical commercially produced in yeast cell cultures, one SAMe manufacturing process utilizes fermentation of the yeast Saccharomyces cerevisiae enriched in the presence of methionine.2


Since SAMe's discovery in Italy in 1952, numerous clinical studies have been performed to determine its efficacy. SAMe has been used in Europe, where it has been available by prescription since the 1970s, to treat arthritis and depression. It has been available in the United States as a supplement under the Dietary Supplement and Health Education Act since 1999.3


SAMe is produced from L-methionine and is the principle contributor of methyl groups in a number of biochemical reactions involving enzymatic transmethylation.4 It is a precursor of the amino acids cysteine, taurine, and glutathione. SAMe initiates 3 metabolic pathways in the human body: transmethylation, transsulfuration, and polyamine synthesis.1

Transmethylation is the methyl-group transfer to other molecules, enabling them to proceed to certain anabolic or catabolic reactions. Transsulfuration is the exchange resulting in sulfates and reduced glutathione, an important antioxidant, which provides sulfhydryl groups to bind to and detoxify certain compounds. After donating the methyl group, SAMe is converted to cysteine, which is important for synthesis of glutathione and other sulfur-containing compounds.2, 3, 5

Determination of SAMe using high performance liquid chromatography has been reported.6 The native form of SAMe is labile and rapidly degrades. Stable toluenedisulfonate and 1,4-butanedisulfonate salts have been developed, and stable enteric-coated forms are now used in clinical studies.3, 7

Uses and Pharmacology

Experiments found that orally administered SAMe crosses the intestinal wall, leading to increased plasma concentrations. Oral and parenteral SAMe have been demonstrated to cross the blood-brain barrier and increase concentrations in cerebrospinal fluid.3


Because SAMe is a methyl donor in over 100 methyltransferase reactions, it is postulated that supplementation with SAMe may be effective in patients with atypical methylation processes that occur in CNS disorders such as depression.8 The exact mechanism of action is unclear, but preclinical studies demonstrated that SAMe treatment affected monoamine metabolism, as well as increased norepinephrine, dopamine, and serotonin levels. Vitamin B12 or folate deficiency are also known to decrease SAMe levels, with an associated link to depression.3, 8, 9, 10, 11, 12, 13

Animal data

The relevance of animal data for the treatment of depression with SAMe is limited by the availability of clinical trial data.

Clinical data

Despite showing a positive effect, many of the earlier trials conducted in depression had methodological limitations.14 However, several meta-analyses of quality trials and newer multicenter trials3, 9, 10, 15, 16 have confirmed SAMe's efficacy in depression to be equivalent to that of tricyclic antidepressants and greater than placebo.3, 9, 10 It has been suggested that SAMe has a more rapid onset of action compared with conventional antidepressants, the effect generally seen within a few days to 2 weeks.13 Doses of 200 to 3,200 mg/day have been used in some trials, whereas others have suggested efficacy with doses of up to 3,000 mg/day.9, 81

A randomized, double-blind, placebo-controlled 12-week study (N = 189) compared SAMe 1,600 to 3,200 mg/day to escitalopram 10 to 20 mg/day and placebo in adults with major depressive disorder (MDD). No significant differences between groups were seen, with all 3 treatments yielding a 5 to 6 point improvement in 17-item Hamilton Depression scores (HAMD-17). Response rates were 36%, 34%, and 30% for SAMe, escitalopram, and placebo, respectively. Remission rates were 28% for both SAMe, and escitalopram, and 17% for placebo.81 A subsample from this study was assessed for antidepressant efficacy of SAMe as well as contribution of histamine or carnitine to any antidepressant effects. After 12 weeks of SAMe (1,600 mg/day), data from 102 participants supported a significant group x time difference for SAMe versus placebo at every time point from week 1 to 12. Additionally, significant differences were seen in remission rates between placebo and SAMe (P = 0.003) as well as escitalopram 10 mg/day (P = 0.023). No correlation in response and either histamine or carnitine were found.87 SAMe augmentation was found to be beneficial in SSRI nonresponders. Specifically, 73 patients with MDD received SAMe 800 mg twice daily or placebo for 6 weeks, and responses and remission rates on the Hamilton rating scale for depression scores were higher for those receiving SAMe compared with placebo (36.1% vs 17.6% and 25.8% vs 11.7%, respectively).17 Seconday analysis of that study’s data showed that those receiving SAMe augmentation had significantly improved self-rated information recall, and nonsignificantly improved word finding ability.82, 83 Another study in 30 postpartum women found that SAMe 1,600 mg/day improved symptoms of depression.18, 19 Whereas a small (n = 17) double-blind trial found no statistically or clinically significant differences between SAMe or placebo add-on therapy in Hamilton Depression Scale or Montgomery-Asberg Depression Rating Scale scores among adults with refractory bipolar disorder experiencing a depressive episode of at least moderate severity.88

SAMe does not appear to be associated with an increased risk of suicide.19

Trials reported few adverse reactions with SAMe except increased anxiety and mania in patients with bipolar disorder. Methionine has increased symptoms of schizophrenia when administered in large doses.9

Other uses of SAMe may include the treatment of depression in opioid detoxification, Parkinson disease, and alcoholism.9, 20

Guidelines have been published concerning SAMe and major depressive disorder. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Major Depressive Disorder (MDD) recognizes that evidence for SAMe is modest at best either as monotherapy or augmentation therapy; data are insufficient to make a recommendation for its use in the treatment of major depressive disorder. The guidelines also state that in patients who prefer complementary and alternative therapies, SAMe may be considered.78 The Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of MDD in adults (2016) recommends SAMe as second line monotherapy in mild to moderate MDD (Level 1) and moderate to severe MDD (Level 2).79


The liver is the main organ involved in the conversion of methionine to SAMe. Oral and parenteral SAMe increase hepatic glutathione, the primary antioxidant involved in hepatic detoxification.3, 21 Studies suggest a link between abnormal SAMe synthesis and chronic liver disorders. SAMe may act through multiple mechanisms, including inhibition of normal hepatocytes apoptosis.22

Animal data

In a study of mice, SAMe was found to attenuate liver damage caused by acetaminophen when given both before and after acetaminophen administration. Specifically, SAMe was found to reduce ALT elevations and lipid peroxidation caused by acetaminophen.23

Clinical data

The majority of SAMe trials in hepatic disease and cholestasis resulted in improved biochemical markers (eg, serum bilirubin, alkaline phosphatase) and subjective clinical symptoms (pruritus, fatigue).20, 22, 24 Improvements in mortality and time to liver transplant have not been clearly demonstrated,7, 20, 22 although a subgroup analysis of patients with mild and moderate alcohol liver cirrhosis (Child-Pugh class A and B) found a trend toward improvement.20, 24

The few trials evaluating the efficacy of SAMe versus placebo in gestational cholestasis show improvement in laboratory indices and measures of pruritus, but it appears to be less effective than ursodeoxycholic acid. Synergism between these 2 agents has been suggested.25, 26 Trial methodology has been too variable to allow for meta-analysis.25A 2013 Cochrane review involving 4 clinical trials reported SAMe as effective in reducing pruritus associated with cholestasis in pregnancy.47 In a small study of 78 women less than 36 weeks pregnant with moderate to severe intrahepatic cholestasis, the combination of SAMe and ursodeoxycholic acid improved the serum concentration of bile acids and transaminases.48

Thirty-six pregnant women with chronic hepatitis B were randomized to receive SAMe 1,000 mg intravenously (IV) once daily or stronger neo-minophagen C (containing glycyrrhizin 160 mg, glycine 1,600 mg, and L-cysteine 80 mg) IV once daily for 4 weeks. Both treatments were found to be effective therapies in normalizing ALT levels (ie, 21.4% vs 64.3%, respectively; odds ratio 6.60; 95% confidence interval, 1.2 to 35.44; P = 0.054) as well as in reducing ALT and AST levels compared with baseline, with stronger neo-minophagen. All infants were found to be healthy up to 1 year postpartum.27

A study was conducted using SAMe in patients with hepatitis C genotype-1 who did not respond to combination treatment with interferon or peginterferon and ribavirin. Specifically, patients received peginterferon and weight-based ribavirin for 2 weeks, which were then discontinued for a 1-month washout period. Patients were then given SAMe 800 mg twice daily for 2 weeks followed by peginterferon and ribavirin with SAMe for 48 weeks. SAMe was found to improve viral decline and greater induction of interferon-stimulated gene expression also occurred with the addition of SAMe. Four patients developed mild GI symptoms with SAMe, which were believed to be due to lactose in the formulation. The inclusion of lactase supplementation resulted in improvement of symptoms in 3 of these patients. It was concluded that SAMe, when added to standard therapy for hepatitis C in nonresponders, improves early viral kinetics, most likely through its effects on interferon signaling.28

A small, open-label, dose-escalation pilot study (N = 6) evaluated the effect of SAM-e among children (mean age, 14 years) with functional abdominal pain. SAM-e doses were initiated at 200 mg/day and increased 200 mg/week to a maximum of 1,400 mg; a daily multivitamin was recommended to maintain folate and vitamin B12 levels. Self-reported pain scores improved significantly over the 2-month study.80


SAMe's efficacy in osteoarthritis was noted in earlier depression trials.3 SAMe appears to enhance native proteoglycan synthesis and secretion in human chondrocyte cultures in the cartilage of patients with osteoarthritis.29 Other postulated mechanisms for its efficacy in osteoarthritis include reducing mediators of inflammation; reversing depletion of glutathione to increase levels of the antioxidant enzyme, glutathione peroxidase; inhibiting enzymes that break down cartilage; and signaling of cartilage synthesis and maintaining DNA methylation.30, 31, 85 It also restored basal conditions after cytokine-induced cell damage in in vitro experiments, but no clinical studies have validated this observation.3, 32 The antidepressant activity of SAMe is a possible mechanism of action for the effects seen in osteoarthritis.33

Animal data

In a 6-week study of dogs with osteoarthritis, clinical signs of the disease as measured by the peak vertical force, the vertical impulse, goniometry, the Canine Brief Pain Inventory score, and the examination score, did not improve with SAMe treatment compared with placebo.34

Clinical data

Meta-analyses, primarily involving trials in Italy, have been published describing the efficacy of SAMe in reducing pain and improving function compared with nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, aspirin, ibuprofen, sulindac, piroxicam, celecoxib).3, 32, 33, 35, 36 A Cochrane systematic review examining evidence for the use of SAMe in osteoarthritis of the hip or knee was inconclusive given the small trials of questionable quality.37 A randomized, double-blind, 8-week trial in Koreans with knee OA published after the Cochrane review found no significant difference between SAMe and nabumetone for pain reduction, patient- and physician-rated treatment response, and use of acetaminophen rescue use.85

In some studies, the recommended dosage of 1,200 mg/day was exceeded for 2 weeks and was followed by a maintenance dosage of 400 mg/day.38 Oral administration of 400 mg/day for 7 days resulted in increases in synovial SAMe concentrations.3 However, a trial of SAMe versus celecoxib reported a slower onset of action for SAMe, with at least 30 days of treatment required for the onset of efficacy.33 A systematic review reported that SAMe had the lowest dropout rates from clinical trials compared with those of NSAIDs and placebo.39


Animal/In vitro data

In a study of human umbilical vein endothelial cells in a tumor environment, SAMe inhibited angiogenesis, a process necessary for tumor growth and metastasis.40

SAMe and its metabolite 5-methylthioadenosine reduced tumor load by 43% and 40%, respectively, in mice with inflammation-induced colon cancer. Induction of genes playing a role in the pathogenesis of colon cancer was reduced with both treatments except for the expression of tumor necrosis factor-alpha and inducible nitric oxide synthase.41

SAMe was also found to prevent hepatocellular carcinoma in rats; however, it was not effective in treating established carcinoma. Its preventive effects may be associated with its pro-apopotic action and inhibition of angiogenesis.42

Clinical data

There are no clinical data to support the use of SAMe for the treatment of cancer.

Alzheimer disease

In Alzheimer disease, there appears to be a reduction in glutathione S-transferaseactivity and an increase in S-adenosylhomocysteine when there is a lack of folate. SAMe may be beneficial in Alzheimer disease because of its effects on glutathione S-transferase activity.43

Animal data

In a study of mice with vitamin B12 deficiency, supplementation with SAMe was found to decrease the production of amyloids, enhance spatial memory, and influence gene expression caused by vitamin B12 deficiency. The spreading of plaques was also reduced with supplementation.44

Clinical data

A nutraceutical formulation containing SAMe 400 mg, vitamin E, folic acid, vitamin B12, N-acetyl cysteine, and acetyl-L-carnitine improved Dementia Rating Scale (DRS) score and clock-drawing tests in patients with early-stage Alzheimer disease. Improvements were also noted by caregivers on domains of the Neuropsychiatric Inventory (NPI) and performance in the Alzheimer's Disease Cooperative Study—Activities of Daily Living. The improvements noted on the NPI at 3 and 6 months were similar to those seen with donepezil and better than those with galantamine.45 This formulation was also tested in 12 institutionalized patients with moderate- to late-stage Alzheimer disease who subsequently experienced a delay in the decline of the DRS score and clock-drawing test. Caregivers within the institution reported about a 30% improvement in the NPI, which remained elevated for at least 9 months.46

Other uses

The role of SAMe in the management of remyelination in diseases of the spinal cord has been studied.3

Decreased concentrations of SAMe in the cerebrospinal fluid of HIV-infected patients may play a role in HIV-related myelopathy.3 However, a trial among HIV-patients found L-methionine 6 g/day ineffective in reducing symptoms of myelopathy.49

A small study investigated the effects of SAMe in 44 patients with fibromyalgia. A dosage of SAMe 800 mg/day for 6 weeks improved clinical disease activity (P = 0.04), pain occurring during the last week (P = 0.002), fatigue (P = 0.02), morning stiffness (P = 0.03), and mood (P = 0.006), but tender-point scores were not impacted.50 The European League Against Rheumatism revised recommendations for the management of fibromyalgia (2016) does not recommend the use of SAMe due to limited data from small sample studies (weak recommendation against, 93% agreement).90

A meta-analysis assessing effects of antidepressants as long-term (at least 6 months) aids to smoking cessation identified 1 trial that evaluated 2 daily doses of SAMe (1,600 mg vs 800 mg). Lower quit rates were documented with SAMe versus placebo, and outcomes were similar for the 2 doses; however, the difference was not significant enough to warrant futher studies.86

Older trials have explored the potential for SAMe in migraines, aging, and sleep modulation.51, 52, 53, 54

A phase 2 trial (n = 43) assessed the efficacy of SAMe to treat hot flashes in women 18 years and older with at least 14 hot flashes per week for at least a month and sufficient enough in severity for them to seek treatment. SAMe was initiated at 400 mg once daily for 7 days on an empty stomach 30 minutes prior to breakfast, then increased to 400 mg twice daily prior to breakfast and evening meal for 5 more weeks. The primary outcome was not met, which was a target reduction in hot flash activity of at least 50%, which would be considered significantly better than the documented placebo-induced reduction of 25% to 35% in noncancer patients. Secondary quality of life outcomes identified 9 symptoms that improved and 5 that worsened. Abnormal sweating, trouble sleeping, fatigue, and muscle or joint aches and pains showed significant improvement on one scale while total mood disturbance, fatigue, mood, sleep, and concentration improved significantly on 2 other scales. SAMe was well tolerated with 1 incident of grade 3 insomnia possibly related to treatment.89


Doses of 200 to 1,600 mg/day have typically been used in depression trials, but doses of up to 3,200 mg/day have been administered.81 One dosing strategy is to start with 400 mg/day, increasing every 5 to 7 days up to 800 mg twice daily. Due to its antidepressant effects, SAMe should ideally be taken earlier in the day (ie, before 4 PM) to prevent insomnia.8 In osteoarthritis trials, 1,200 mg/day has been used, with a maintenance dose of 400 mg/day (recommended).38 Doses of 800 to 1,000 mg/day intramuscularly, IV, and orally have been used in trials investigating liver disease and gestational cholestasis.20, 25, 26

Pregnancy / Lactation

Trials conducted in pregnant women documented no harmful effects.25 Infants naturally have SAMe levels that are 3 to 7 times higher than adults during brain development.19


Agents with Antiplatelet Properties: Herbs (Anticoagulant/Antiplatelet Properties) may enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Consider therapy modification.55, 56, 57, 58

Amphetamines: Amphetamines may enhance the adverse/toxic effect of Serotonin Modulators. The risk of serotonin syndrome may be increased. Monitor therapy.59, 60, 61

Anticoagulants: Herbs (Anticoagulant/Antiplatelet Properties) may enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Consider therapy modification.55, 56, 57, 58

Antiemetics: Antiemetics (5HT3 antagonists) may enhance the serotonergic effect of serotonin modulators. This could result in serotonin syndrome. Monitor therapy.91, 92, 93, 94, 95, 96, 97, 98, 99

Antipsychotics: Serotonin modulators may enhance the adverse/toxic effect of antipsychotic agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of serotonin modulators. This could result in serotonin syndrome.Monitor therapy.62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75

Daptomycin: Dapoxetine may enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination.76, 77, 100, 101

Herbs (anticoagulant/antiplatelet properties): Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of other herbs (anticoagulant/antiplatelet properties). Bleeding may occur. Consider therapy modification.55, 56, 57, 58

Linezolid: Linezolid may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Consider therapy modification.102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125

Metaxalone: Metaxalone may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy.126, 127, 128, 129

Methylene Blue: Methylene Blue may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination.97, 98, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157

Methylphenidate: Methylphenidate may enhance the adverse/toxic effect of Serotonin Modulators. Specifically, the risk of serotonin syndrome or serotonin toxicity may be increased. Monitor therapy.158, 159, 160, 161

Metoclopramide: Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Monitor therapy.62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 162

Monoamine Oxidase Inhibitor: Anti-Parkinson Agents (Monoamine Oxidase Inhibitor) may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Transdermal selegiline product labeling states that use with any serotonin modulator is contraindicated. Labeling for other selegiline products, rasagiline, and safinamide state that their use with certain serotonin modulators is contraindicated (meperidine, tramadol, methadone, St. John’s wort, cyclobenzaprine, dextromethorphan, and any other monoamine oxidase inhibitor) while caution is advised when combined with others. Consider therapy modification.163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186

Opioid Analgesics: Opioid Analgesics may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy.95, 140, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242

Nonsteroidal Anti-Inflammatory Agents: Herbs (Anticoagulant/Antiplatelet Properties) may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Bleeding may occur. Consider therapy modification.55, 56, 57, 58

Salicylates: Herbs (Anticoagulant/Antiplatelet Properties) may enhance the adverse/toxic effect of Salicylates. Bleeding may occur. Consider therapy modification.57, 58

Serotonin Modulators: Serotonin modulators may enhance the adverse/toxic effect of other serotonin modulators. The development of serotonin syndrome may occur. Monitor therapy.76, 77

Tedizolid: Tedizolid may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy.92, 104, 105, 110, 111, 124, 243, 244

Thrombolytic Agents: Herbs (Anticoagulant/Antiplatelet Properties) may enhance the adverse/toxic effect of Thrombolytic Agents. Bleeding may occur. Consider therapy modification.55, 56, 57, 58

Tramadol: Serotonin Modulators may enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy.187, 197, 198, 203, 207, 208, 212, 214, 216, 217, 218, 219, 221, 222, 224, 227, 230, 236, 237, 239, 241, 242, 245, 246, 247

Adverse Reactions

Available data indicate nausea, diarrhea, constipation, mild insomnia, dizziness, irritability, anxiety, and sweating to be the most commonly reported adverse reactions associated with the use of SAMe. No serious adverse reactions have been reported.4, 5, 9, 15, 38, 49

Data from long-term use of SAMe are lacking. SAMe should not be used in people with bipolar disorder due to reports of increased anxiety and mania.9


Toxicological studies concluded that SAMe is safe even at the highest doses. Mutagenicity and carcinogenicity studies conducted in the 1980s and 1990s resulted in no safety concerns.2 More recent studies are lacking.


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