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LIKELY EFFECTIVE

• Osteoarthritis. Multiple studies show that oral SAMe can decrease symptoms and improve function in patients with osteoarthritis similarly to non-steroidal anti-inflammatory drugs (NSAIDs), although with a slower onset of action. Details: Multiple clinical trials show that taking SAMe orally, 400-1200 mg daily in up to 3 divided doses for up to 84 days, is superior to placebo and comparable to NSAIDs, including the COX-2 inhibitor celecoxib (Celebrex), for decreasing symptoms associated with osteoarthritis. SAMe is associated with fewer adverse effects than NSAIDs and is comparable in reducing pain and functional limitation (5188,5203,5204,5205,5206,5207,5208,5215,9111,12054,20202). Significant symptom relief with SAMe may require up to 30 days of treatment compared to only 15 days with NSAIDs. Some evidence suggests that intravenous loading doses of SAMe 400 mg daily for five days, followed by oral treatment, can speed symptom relief to 14 days (5188).

POSSIBLY EFFECTIVE

• Cholestasis. Clinical research suggests that oral or intravenous SAMe is similarly effective to ursodeoxycholic acid (ursodiol) for treatment of cholestasis. Details: Taking SAMe orally, 500 mg twice daily or 1600 mg daily for 2-8 weeks, or intravenously, 800 mg daily or 500 mg twice daily for 14-20 days, seems to be helpful for treating cholestasis associated with acute or chronic liver disease. Several clinical trials have shown that short-term SAMe therapy is superior to placebo in decreasing pruritus, fatigue, alkaline phosphatase levels, and total and conjugated bilirubin in patients with cholestasis (5219,5239,5240,20204,20229). However, SAMe does not appear to be significantly better than ursodeoxycholic acid (20207,20208,20210,20211).
• Depression. The available clinical research suggests that oral SAMe has a role in the treatment of depression when used as a second-line agent or in combination with conventional medications. Details: Clinical practice guidelines from the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) state that SAMe at doses of 800 mg per day is not currently recommended for monotherapy but is weakly recommended for adjunctive use in major depressive disorder when dosed 1600-3200 mg daily based on mixed evidence (110318). Practice guidelines from the American Psychiatric Association suggest that SAMe can be considered in patients with depression who prefer complementary and alternative therapies (17491). Several clinical studies in patients with depression show that taking SAMe monotherapy 800-1600 mg daily in divided doses for 4-12 weeks is more effective than placebo and as effective as tricyclic antidepressants (TCAs) (5189,5190,5192,5195,5196,9109). However, a 2016 meta-analysis of clinical research shows that although taking SAMe as monotherapy for depression is no more effective than placebo, it appears to be as effective as TCAs and escitalopram (95075). Reasons for these conflicting results include small study sizes, inconsistent diagnostic criteria, short treatment periods, and potentially flawed study designs (5189,90106,95075). Preliminary clinical research in patients who do not respond to conventional antidepressants shows that taking SAMe titrated to an oral dose of 1600 mg daily for 42 days does not improve depression symptom scores when compared with baseline in patients with major depressive disorder (20225). However, higher-quality clinical evidence shows that adding SAMe (SAMe Complete 400 mg, Nature Made) 400-800 mg twice daily to conventional treatment increases remission rates by about 14% after 6 weeks (17490). SAMe does not appear to improve depression in people with bipolar disorder that is resistant to treatment (90110). Administering SAMe intravenously or intramuscularly, 200-400 mg daily for 1-4 weeks, seems to improve symptoms of major depression. Several small clinical trials have shown that parenterally administered SAMe is superior to placebo and possibly as effective as intravenous or oral TCAs in studies lasting up to 30 days (5184,5189,5200,9109,20222). In some trials, the antidepressant effect occurred rapidly, within 1-2 weeks of initiation of treatment (5200). Parenteral SAMe has also been used successfully in combination with an oral TCA to speed the onset of antidepressant action (5193).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging. Although there is interest in using oral SAMe for aging, there is insufficient reliable information about the clinical effects of SAMe for this purpose.
• Alcohol-related liver disease. It is unclear if oral or intravenous SAMe is beneficial in patients with alcohol-related liver disease. Details: Some preliminary clinical research in patients with alcohol-related liver cirrhosis shows that administering SAMe orally, 400 mg three times daily for 2 years, decreases alanine transaminase (ALT) levels (1712). However, another small clinical study shows that administering SAMe orally at the same dose for 24 weeks does not significantly alter ALT or other measures of liver dysfunction, including international normalized ratio (INR), albumin, aspartate transaminase (AST), alkaline phosphatase (ALP), or total bilirubin levels (20230). SAMe also does not seem to reduce all-cause mortality, liver-related mortality, liver-related complications, transplant rates, or alcohol consumption (1712).
• Alzheimer disease. Although there is interest in using oral SAMe for Alzheimer disease, there is insufficient reliable information about the clinical effects of SAMe for this condition.
• Antidepressant-induced sexual dysfunction. Oral SAMe might improve sexual dysfunction in males taking antidepressants. Details: In males taking antidepressants for major depressive disorder who have subjective symptoms of sexual dysfunction, taking SAMe orally, 400 mg twice daily for 2 weeks, then 800 mg twice daily for 6 weeks, improves these symptoms when compared with placebo (20470).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear whether oral SAMe is beneficial in patients with ADHD. Details: A very small clinical study shows that taking SAMe orally 400 mg three times daily, titrated up to 800 mg three times daily for 4 weeks, might lessen ADHD symptoms in adults when compared with placebo (9981).
• Back pain. Although there is interest in using oral SAMe for back pain, there is insufficient reliable information about the clinical effects of SAMe for this condition.
• Cancer-related fatigue. It is unclear if oral SAMe is beneficial in patients with cancer-related fatigue. Details: A clinical study in patients with colon cancer receiving oxaliplatin-based chemotherapy in the adjuvant or metastatic setting shows that SAMe 400 mg twice daily during chemotherapy improves some cancer-related fatigue scores at 3 and 6 months when compared with no supplementation (106932). It is unclear if the improvement from baseline differed between groups.
• Chronic fatigue syndrome (CFS). Although there is interest in using oral SAMe for CFS, there is insufficient reliable information about the clinical effects of SAMe for this condition.
• Cirrhosis. It is unclear whether oral or intravenous SAMe is beneficial in patients with cirrhosis. Details: Preliminary clinical research shows that administering SAMe orally, 600 mg daily or 400 mg three times daily for 1 month, or intravenously, 800 mg once daily or 250-600 mg twice daily for 3-30 days, improves liver function parameters and pruritus in patients with chronic liver disease or liver cirrhosis (20214,20451,20460,20462). However, some conflicting evidence exists. Clinical research in patients with cirrhosis undergoing resection of hepatocellular carcinoma shows that intravenous postoperative administration of SAMe 1000 mg daily for 7 days does not reduce the frequency of postoperative liver insufficiency when compared with control (90111).
• Epilepsy. Although there has been interest in using oral SAMe for epilepsy, there is insufficient reliable information about the clinical effects of SAMe for this condition.
• Fibromyalgia. Limited evidence shows that oral or intramuscular SAMe might modestly improve some symptoms of fibromyalgia. Details: Clinical research of SAMe has demonstrated modest improvement in some symptoms of fibromyalgia when compared with placebo, or when compared with transcutaneous electrical nerve stimulation (TENS) therapy (5211,5241,20228). Doses used include 200 mg intramuscularly daily for 21 days, 800 mg orally daily in 2 divided doses for 6 weeks (5241), or 400 mg orally daily in 2 divided doses for 6 weeks, plus 200 mg daily by IM injection (20228). There is conflicting evidence for the use of SAMe intravenously for fibromyalgia. Some clinical research shows that SAMe 600 mg intravenously once daily for 10 days does not improve symptoms of fibromyalgia (5221). However, other clinical research shows that 400 mg intravenously once daily for 15 days reduces pain, the number of tender points, and depression scores when compared with baseline (20227).
• Gilbert syndrome. It is unclear if oral SAMe is beneficial in patients with this condition. Details: Preliminary clinical research shows that taking SAMe orally, 1200 mg daily, or intravenously, 200-800 mg daily, both for 10 days, improves total and conjugated serum bilirubin levels when compared with placebo or no treatment in patients with Gilbert syndrome (20215,20461).
• Hepatitis C. It is unclear if oral SAMe is beneficial in patients with hepatitis C. Details: Taking SAMe 1600 mg daily orally for 2 weeks in between courses of peginterferon and ribavirin seems to improve the early viral response in patients with hepatitis C who previously did not respond to conventional therapy (20466). In other clinical research in patients with a previously poor response to the same conventional therapy, adding SAMe 400 mg three times daily orally and betaine 3 grams twice daily orally increases the percentage of patients with an early viral response from 14% to 59%. However, a sustained viral response was seen in only 10% of patients (20465).
• Lead toxicity. Although there has been interest in using oral or intravenous SAMe for lead toxicity, there is insufficient reliable information about the clinical effects of SAMe for this purpose.
• Menopausal symptoms. It is unclear if oral SAMe is beneficial for menopausal hot flashes. Details: Preliminary clinical research in patients with frequent menopausal hot flashes shows that taking SAMe (SAM-e Complete, Nature Made Nutritional Products) 400 mg orally once daily for one week, then 400 mg twice daily for another 5 weeks, does not significantly decrease the frequency or severity of hot flashes when compared with an historical placebo control (95076).
• Migraine headache. Although there is interest in using oral SAMe for migraine, there is insufficient reliable information about the clinical effects of SAMe for this purpose.
• Multiple sclerosis (MS). Although there is interest in using oral SAMe for MS, there is insufficient reliable information about the clinical effects of SAMe for this condition.
• Premenstrual syndrome (PMS). Although there is interest in using oral SAMe for PMS, there is insufficient reliable information about the clinical effects of SAMe for this condition.
• Schizophrenia. It is unclear if oral SAMe is beneficial in patients with schizophrenia. Details: A very small clinical study in adults with schizophrenia shows that taking SAMe 400 mg daily orally in divided doses for one week, followed by 800 mg daily in divided doses for 7 weeks, modestly reduces aggressive behavior when compared with placebo (20468).
• Smoking cessation. A small clinical study suggests that oral SAMe does not improve abstinence rates in cigarette smokers. Details: Preliminary clinical research in cigarette smokers shows that SAMe (Nature Made, Pharmavite LLC) 400 mg or 800 mg twice daily for 8 weeks does not improve abstinence rates when compared with placebo (20471). More evidence is needed to rate SAMe for these uses.

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LIKELY SAFE ...when used orally, intravenously, or intramuscularly and appropriately. Serious adverse effects have not been reported in multiple clinical studies involving more than 22,000 patients and lasting from a few days to 2 years (5189,5201,5202,5219,5231,5232,12231,17490,95075,95076).

PREGNANCY: POSSIBLY SAFE
when used intravenously short-term during the third trimester of pregnancy. In two small-scale trials, SAMe 800 mg daily was used intravenously for 14-20 days during the third trimester of pregnancy for cholestasis. No adverse effects were observed (5219,5231,5240). However, use of SAMe in pregnancy should only be considered when benefits clearly outweigh the potential risks. There is insufficient reliable information available about the use of SAMe at higher doses, for extended periods of time, or during the earlier trimesters of pregnancy.

LACTATION:
Insufficient reliable information available; avoid using.

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LEVODOPA Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D SAMe might reduce the effectiveness of levodopa.  Details SAMe methylates levodopa, which might reduce its effectiveness for treating Parkinson disease (10466).

SEROTONERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Taking SAMe with serotonergic drugs might increase the risk of serotonin syndrome and other serotonergic side effects.  Details SAMe has serotonergic effects (3521,5196,5232,5193). Theoretically, combining serotonergic drugs with SAMe might increase the risk of serotonergic side effects, including serotonin syndrome and cerebral vasoconstrictive disorders (8056). In one case report, SAMe 100 mg intramuscularly was given daily with clomipramine (Anafranil) 25 mg per day. When the clomipramine dose was increased to 75 mg per day the patient experienced serotonin syndrome about 48-72 hours later, requiring hospitalization (3521).

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General ...Orally, SAMe is generally well tolerated when used in typical doses. Side effects are more common with higher doses.
Most Common Adverse Effects:
Orally: Anorexia, constipation, diarrhea, dizziness, dry mouth, flatulence, headache, insomnia, nausea, nervousness, sweating, vomiting.

Cardiovascular ...There has been some concern that SAMe might increase homocysteine levels. SAMe is metabolized to s-adenosylhomocysteine, which can be metabolized to homocysteine (5232). Elevated levels of homocysteine have been linked to cardiovascular and kidney disease (1698). However, in a study lasting 4 weeks, administration of SAMe orally in doses titrated up to 1600 mg daily was not associated with a significant increase in homocysteine levels (12231). In another study, there also was no difference in cardiovascular mortality in people with cirrhosis taking SAMe 1200 mg daily for 2 years (1712).
Intravenously, SAMe infusions may cause phlebitis (20204). Also, a case of tachycardia has been reported in a patient treated with intravenous SAMe (72988).

Dermatologic ...Orally, SAMe may cause rash and itching, transient hair loss, sweating, and night sweats (5196,5199,5203,20202,20230,73035).
Intravenously, SAMe may cause rash and sweating (20204,72996,73038).

Gastrointestinal ...When taken orally or given intravenously, SAMe may cause increased salivation, bloating, flatulence, nausea, vomiting, diarrhea, stomach ache, heartburn, constipation, hunger, thirst, anorexia, blood in the stool, and dry mouth (1712,5188,5196,5200,5203,5208,5221,5241,9113,9981,12054,20202,20218,73035,95075,95076).

Genitourinary ...Orally, rare adverse effects associated with SAMe include increased urinary frequency (5196).

Neurologic/CNS ...Orally, SAMe may cause vertigo, headache, insomnia, fatigue, tremors, agitation, dizziness, vivid dreams, and anxiety (5188,5195,5196,5203,5241,9981,12054,17123,20203,20218,20225,20230,20468,20471,72942,73001,95076).
Intramuscularly, SAMe may cause insomnia , anxiety, hostility, dizziness and drowsiness, and headache, although these events are rare (5188,20218,73002).
Intravenously, side effects rarely associated with SAMe include insomnia, anxiety, and psychomotor agitation (20204,72978,72988,73038).

Ocular/Otic ...Orally, rare side effects associated with SAMe include blurred vision, and a hot sensation and itchiness of the ear (5195,5196,9981,20225).

Psychiatric ...Orally, anxiety and tiredness have been reported in patients with depression (5231,14841). Rare adverse effects associated with SAMe include hypermania (5196). Hypomania has occurred with a combination of intramuscular and oral SAMe (20218). Cases of mania with suicidal ideation have also been reported in otherwise healthy patients (5195,12231). A crawling sensation on the skin has been reported in a clinical trial (5195). In a case report, a patient with depression self-medicated with oral SAMe and attempted suicide four days later (72965).
When used as an injection, rarely SAMe has caused both hypermania and hypomania in people with bipolar disorder or depression (5216,5231,17122,72978). Two suicide attempts occurred in a clinical trial of intramuscular SAMe in patients with major depression (20222).

Pulmonary/Respiratory ...Orally, congestion has occurred rarely in clinical trials of SAMe (5196,20225,72981).

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