Ingredient review —SAMe (S-adenosylmethionine)
What is it?
Description
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)
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
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)
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
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
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
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
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
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)
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
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
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
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
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
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
Distribution
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)
References
- Bell, K. M., Plon, L., Bunney, W. E., Jr, & Potkin, S. G. (1988). S-adenosylmethionine treatment of depression: A controlled clinical trial. The American Journal of Psychiatry, 145(9), 1110–1114. ()
- Bell, K. M., Potkin, S. G., Carreon, D., & Plon, L. (1994). S-adenosylmethionine blood levels in major depression: Changes with drug treatment. Acta Neurologica Scandinavica. Supplementum, 154, 15–18. ()
- Berlanga, C., Ortega-Soto, H. A., Ontiveros, M., & Senties, H. (1992). Efficacy of S-adenosyl-L-methionine in speeding the onset of action of imipramine. Psychiatry Research, 44(3), 257–262. ()
- Binder, T., Salaj, P., Zima, T., & Vitek, L. (2006). [Ursodeoxycholic acid, S-adenosyl-L-methionine and their combinations in the treatment of gestational intrahepatic cholestasis (ICP)]. Ceska gynekologie / Ceska lekarska spolecnost J. Ev. Purkyne, 71(2), 92–98. ()
- Binder, T., Salaj, P., Zima, T., & Vítek, L. (2006). Randomized prospective comparative study of ursodeoxycholic acid and S-adenosyl-L-methionine in the treatment of intrahepatic cholestasis of pregnancy. Journal of Perinatal Medicine, 34(5), 383–391. ()
- Bottiglieri, T. (2002). S-Adenosyl-L-methionine (SAMe): From the bench to the bedside--molecular basis of a pleiotropic molecule. The American Journal of Clinical Nutrition, 76(5), 1151S – 7S. ()
- Bottiglieri, T., Godfrey, P., Flynn, T., Carney, M. W., Toone, B. K., & Reynolds, E. H. (1990). Cerebrospinal fluid S-adenosylmethionine in depression and dementia: Effects of treatment with parenteral and oral S-adenosylmethionine. Journal of Neurology, Neurosurgery, and Psychiatry, 53(12), 1096–1098. ()
- Bradley, J. D., Flusser, D., Katz, B. P., Schumacher, H. R., Jr, Brandt, K. D., Chambers, M. A., & Zonay, L. J. (1994). A randomized, double blind, placebo controlled trial of intravenous loading with S-adenosylmethionine (SAM) followed by oral SAM therapy in patients with knee osteoarthritis. The Journal of Rheumatology, 21(5), 905–911. ()
- Bressa, G. M. (1994). S-adenosyl-l-methionine (SAMe) as antidepressant: Meta-analysis of clinical studies. Acta Neurologica Scandinavica. Supplementum, 154, 7–14. ()
- Carney, M. W., Chary, T. K., Bottiglieri, T., & Reynolds, E. H. (1989). The switch mechanism and the bipolar/unipolar dichotomy. The British Journal of Psychiatry: The Journal of Mental Science, 154, 48–51. ()
- Caruso, I., & Pietrogrande, V. (1987). Italian double-blind multicenter study comparing S-adenosylmethionine, naproxen, and placebo in the treatment of degenerative joint disease. The American Journal of Medicine, 83(5A), 66–71. ()
- Cuomo, A., Beccarini Crescenzi, B., Bolognesi, S., Goracci, A., Koukouna, D., Rossi, R., & Fagiolini, A. (2020). S-Adenosylmethionine (SAMe) in major depressive disorder (MDD): A clinician-oriented systematic review. Annals of General Psychiatry, 19, 50. ()
- De Berardis, D., Orsolini, L., Serroni, N., Girinelli, G., Iasevoli, F., Tomasetti, C., de Bartolomeis, A., Mazza, M., Valchera, A., Fornaro, M., Perna, G., Piersanti, M., Di Nicola, M., Cavuto, M., Martinotti, G., & Di Giannantonio, M. (2016). A comprehensive review on the efficacy of S-Adenosyl-L-methionine in Major Depressive Disorder. CNS & Neurological Disorders Drug Targets, 15(1), 35–44. ()
- De Silva, V., El-Metwally, A., Ernst, E., Lewith, G., Macfarlane, G. J., & Arthritis Research UK Working Group on Complementary and Alternative Medicines. (2011). Evidence for the efficacy of complementary and alternative medicines in the management of osteoarthritis: A systematic review. Rheumatology, 50(5), 911–920. ()
- Delle Chiaie, R., Pancheri, P., & Scapicchio, P. (2002). Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: Comparison with imipramine in 2 multicenter studies. The American Journal of Clinical Nutrition, 76(5), 1172S – 6S. ()
- Di Benedetto, P., Iona, L. G., & Zidarich, V. (1993). Clinical evaluation of S-adenosyl-L-methionine versus transcutaneous electrical nerve stimulation in primary fibromyalgia. Current Therapeutic Research, Clinical and Experimental, 53(2), 222–229. ()
- Domljan, Z., Vrhovac, B., Dürrigl, T., & Pucar, I. (1989). A double-blind trial of ademetionine vs naproxen in activated gonarthrosis. International Journal of Clinical Pharmacology, Therapy, and Toxicology, 27(7), 329–333. ()
- Dording, C. M., Mischoulon, D., Shyu, I., Alpert, J. E., & Papakostas, G. I. (2012). SAMe and sexual functioning. European Psychiatry: The Journal of the Association of European Psychiatrists, 27(6), 451–454. ()
- Frezza, M. (1993). [A meta-analysis of therapeutic trials with ademetionine in the treatment of intrahepatic cholestasis]. Annali italiani di medicina interna: organo ufficiale della Societa italiana di medicina interna, 8 Suppl, 48S – 51S. ()
- Frezza, M., Centini, G., Cammareri, G., Le Grazie, C., & Di Padova, C. (1990). S-adenosylmethionine for the treatment of intrahepatic cholestasis of pregnancy. Results of a controlled clinical trial. Hepato-Gastroenterology, 37 Suppl 2, 122–125. ()
- Frezza, M., Pozzato, G., Chiesa, L., Stramentinoli, G., & di Padova, C. (1984). Reversal of intrahepatic cholestasis of pregnancy in women after high dose S-adenosyl-L-methionine administration. Hepatology , 4(2), 274–278. ()
- Frezza, M., Surrenti, C., Manzillo, G., Fiaccadori, F., Bortolini, M., & Di Padova, C. (1990). Oral S-adenosylmethionine in the symptomatic treatment of intrahepatic cholestasis. A double-blind, placebo-controlled study. Gastroenterology, 99(1), 211–215. ()
- Galizia, I., Oldani, L., Macritchie, K., Amari, E., Dougall, D., Jones, T. N., Lam, R. W., Massei, G. J., Yatham, L. N., & Young, A. H. (2016). S-adenosyl methionine (SAMe) for depression in adults. Cochrane Database of Systematic Reviews, 10, CD011286. ()
- Giulidori, P., Cortellaro, M., Moreo, G., & Stramentinoli, G. (1984). Pharmacokinetics of S-adenosyl-L-methionine in healthy volunteers. European Journal of Clinical Pharmacology, 27(1), 119–121. ()
- Glorioso, S., Todesco, S., Mazzi, A., Marcolongo, R., Giordano, M., Colombo, B., Cherie-Ligniere, G., Mattara, L., Leardini, G., & Passeri, M. (1985). Double-blind multicentre study of the activity of S-adenosylmethionine in hip and knee osteoarthritis. International Journal of Clinical Pharmacology Research, 5(1), 39–49. ()
- Green, T., Steingart, L., Frisch, A., Zarchi, O., Weizman, A., & Gothelf, D. (2012). The feasibility and safety of S-adenosyl-L-methionine (SAMe) for the treatment of neuropsychiatric symptoms in 22q11.2 deletion syndrome: A double-blind placebo-controlled trial. Journal of Neural Transmission, 119(11), 1417–1423. ()
- Guo, T., Chang, L., Xiao, Y., & Liu, Q. (2015). S-adenosyl-L-methionine for the treatment of chronic liver disease: A systematic review and meta-analysis. PloS One, 10(3), e0122124. ()
- Hardy, M., Coulter, I., Morton, S. C., Favreau, J., Venuturupalli, S., Chiappelli, F., Rossi, F., Orshansky, G., Jungvig, L. K., Roth, E. A., Suttorp, M. J., & Shekelle, P. (2002). S-Adenosyl-L-methionine for treatment of depression, osteoarthritis, and liver disease. Centre for Reviews and Dissemination (UK). ()
- Jacobsen, S., Danneskiold-Samsøe, B., & Andersen, R. B. (1991). Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. Scandinavian Journal of Rheumatology, 20(4), 294–302. ()
- Kagan, B. L., Sultzer, D. L., Rosenlicht, N., & Gerner, R. H. (1990). Oral S-adenosylmethionine in depression: A randomized, double-blind, placebo-controlled trial. The American Journal of Psychiatry, 147(5), 591–595. ()
- Kim, J., Lee, E. Y., Koh, E.-M., Cha, H.-S., Yoo, B., Lee, C. K., Lee, Y. J., Ryu, H., Lee, K. H., & Song, Y. W. (2009). Comparative clinical trial of S-adenosylmethionine versus nabumetone for the treatment of knee osteoarthritis: An 8-week, multicenter, randomized, double-blind, double-dummy, phase IV study in Korean patients. Clinical Therapeutics, 31(12), 2860–2872. ()
- Levkovitz, Y., Alpert, J. E., Brintz, C. E., Mischoulon, D., & Papakostas, G. I. (2012). Effects of S-adenosylmethionine augmentation of serotonin-reuptake inhibitor antidepressants on cognitive symptoms of major depressive disorder. Journal of Affective Disorders, 136(3), 1174–1178. ()
- Lieber, C. S., & Packer, L. (2002). S-Adenosylmethionine: molecular, biological, and clinical aspects--an introduction. The American Journal of Clinical Nutrition, 76(5), 1148S – 50S. ()
- Loehrer, F. M., Schwab, R., Angst, C. P., Haefeli, W. E., & Fowler, B. (1997). Influence of oral S-adenosylmethionine on plasma 5-methyltetrahydrofolate, S-adenosylhomocysteine, homocysteine and methionine in healthy humans. The Journal of Pharmacology and Experimental Therapeutics, 282(2), 845–850. ()
- Loenen, W. A. M. (2006). S-adenosylmethionine: Jack of all trades and master of everything? Biochemical Society Transactions, 34(Pt 2), 330–333. ()
- Lu, S. C. (2000). S-Adenosylmethionine. The International Journal of Biochemistry & Cell Biology, 32(4), 391–395. ()
- Maccagno, A., Di Giorgio, E. E., Caston, O. L., & Sagasta, C. L. (1987). Double-blind controlled clinical trial of oral S-adenosylmethionine versus piroxicam in knee osteoarthritis. The American Journal of Medicine, 83(5A), 72–77. ()
- Mantero, M., Pastorino, P., Carolei, A., & Agnoli, A. (1975). [Controlled double-blind study (SAMe-imipramine) in depressive syndromes]. Minerva medica, 66(78), 4098–4101. ()
- Manzillo, G., Piccinino, F., Surrenti, C., Frezza, M., Giudici, G. A., & Le Grazie, C. (1992). Multicentre double-blind placebo-controlled study of intravenous and oral S-adenosyl-L-methionine (SAMe) in cholestatic patients with liver disease. Drug Investigation, 4(4), 90–100. ()
- Mato, J. M., Cámara, J., Fernández de Paz, J., Caballería, L., Coll, S., Caballero, A., García-Buey, L., Beltrán, J., Benita, V., Caballería, J., Solà, R., Moreno-Otero, R., Barrao, F., Martín-Duce, A., Correa, J. A., Parés, A., Barrao, E., García-Magaz, I., Puerta, J. L., … Rodés, J. (1999). S-adenosylmethionine in alcoholic liver cirrhosis: A randomized, placebo-controlled, double-blind, multicenter clinical trial. Journal of Hepatology, 30(6), 1081–1089. ()
- Mato, J. M., Martínez-Chantar, M. L., & Lu, S. C. (2013). S-adenosylmethionine metabolism and liver disease. Annals of Hepatology, 12(2), 183–189. ()
- McMillan, J. M., Walle, U. K., & Walle, T. (2005). S-adenosyl-L-methionine: transcellular transport and uptake by Caco-2 cells and hepatocytes. The Journal of Pharmacy and Pharmacology, 57(5), 599–605. ()
- Mischoulon, D., Alpert, J. E., Arning, E., Bottiglieri, T., Fava, M., & Papakostas, G. I. (2012). Bioavailability of S-adenosyl methionine and impact on response in a randomized, double-blind, placebo-controlled trial in major depressive disorder. The Journal of Clinical Psychiatry, 73(6), 843–848. ()
- Mischoulon, D., Price, L. H., Carpenter, L. L., Tyrka, A. R., Papakostas, G. I., Baer, L., Dording, C. M., Clain, A. J., Durham, K., Walker, R., Ludington, E., & Fava, M. (2014). A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-L-methionine (SAMe) versus escitalopram in major depressive disorder. The Journal of Clinical Psychiatry, 75(4), 370–376. ()
- Montrone, F., Fumagalli, M., Sarzi Puttini, P., Boccassini, L., Santandrea, S., Volpato, R., Locati, M., & Caruso, I. (1985). Double-blind study of S-adenosyl-methionine versus placebo in hip and knee arthrosis. Clinical Rheumatology, 4(4), 484–485. ()
- Müller-Fassbender, H. (1987). Double-blind clinical trial of S-adenosylmethionine versus ibuprofen in the treatment of osteoarthritis. The American Journal of Medicine, 83(5A), 81–83. ()
- Murphy, B. L., Babb, S. M., Ravichandran, C., & Cohen, B. M. (2014). Oral SAMe in persistent treatment-refractory bipolar depression: A double-blind, randomized clinical trial. Journal of Clinical Psychopharmacology, 34(3), 413–416. ()
- Najm, W. I., Reinsch, S., Hoehler, F., Tobis, J. S., & Harvey, P. W. (2004). S-adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: A double-blind cross-over trial. [ISRCTN36233495]. BMC Musculoskeletal Disorders, 5, 6. ()
- Nelson, J. C. (2010). S-adenosyl methionine (SAMe) augmentation in major depressive disorder [Review of S-adenosyl methionine (SAMe) augmentation in major depressive disorder]. The American Journal of Psychiatry, 167(8), 889–891. ()
- Noureddin, M., Sander-Struckmeier, S., & Mato, J. M. (2020). Early treatment efficacy of S-adenosylmethionine in patients with intrahepatic cholestasis: A systematic review. World Journal of Hepatology, 12(2), 46–63. ()
- Pancheri, P., Scapicchio, P., & Chiaie, R. D. (2002). A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder. The International Journal of Neuropsychopharmacology, 5(4), 287–294. ()
- Papakostas, G. I., Mischoulon, D., Shyu, I., Alpert, J. E., & Fava, M. (2010). S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: A double-blind, randomized clinical trial. The American Journal of Psychiatry, 167(8), 942–948. ()
- Raikhelson, K. L., & Kondrashina, E. A. (2019). Аdеmethionine in the treatment of fatigue in liver diseases: A systematic review. Terapevticheskii Arkhiv, 91(2), 134–142. ()
- Roncaglia, N., Locatelli, A., Arreghini, A., Assi, F., Cameroni, I., Pezzullo, J. C., & Ghidini, A. (2004). A randomised controlled trial of ursodeoxycholic acid and S-adenosyl-l-methionine in the treatment of gestational cholestasis. BJOG: An International Journal of Obstetrics and Gynaecology, 111(1), 17–21. ()
- Rutjes, A. W., Nüesch, E., Reichenbach, S., & Jüni, P. (2009). S-Adenosylmethionine for osteoarthritis of the knee or hip. Cochrane Database of Systematic Reviews, 4, CD007321. ()
- Salmaggi, P., Bressa, G. M., Nicchia, G., Coniglio, M., La Greca, P., & Le Grazie, C. (1993). Double-blind, placebo-controlled study of S-adenosyl-L-methionine in depressed postmenopausal women. Psychotherapy and Psychosomatics, 59(1), 34–40. ()
- Sarris, J., Murphy, J., Mischoulon, D., Papakostas, G. I., Fava, M., Berk, M., & Ng, C. H. (2016). Adjunctive nutraceuticals for depression: A systematic review and meta-analyses. The American Journal of Psychiatry, 173(6), 575–587. ()
- Sarris, J., Papakostas, G. I., Vitolo, O., Fava, M., & Mischoulon, D. (2014). S-adenosyl methionine (SAMe) versus escitalopram and placebo in major depression RCT: Efficacy and effects of histamine and carnitine as moderators of response. Journal of Affective Disorders, 164, 76–81. ()
- Sarris, J., Price, L. H., Carpenter, L. L., Tyrka, A. R., Ng, C. H., Papakostas, G. I., Jaeger, A., Fava, M., & Mischoulon, D. (2015). Is S-adenosyl methionine (SAMe) for depression only effective in males? A re-analysis of data from a randomized clinical trial. Pharmacopsychiatry, 48(4-5), 141–144. ()
- Sharma, A., Gerbarg, P., Bottiglieri, T., Massoumi, L., Carpenter, L. L., Lavretsky, H., Muskin, P. R., Brown, R. P., Mischoulon, D., & as Work Group of the American Psychiatric Association Council on Research. (2017). S-Adenosylmethionine (SAMe) for neuropsychiatric disorders: A clinician-oriented review of research. The Journal of Clinical Psychiatry, 78(6), e656–e667. ()
- Soeken, K. L., Lee, W.-L., Bausell, R. B., Agelli, M., & Berman, B. M. (2002). Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis. The Journal of Family Practice, 51(5), 425–430. ()
- Sood, A., Prasad, K., Croghan, I. T., Schroeder, D. R., Ehlers, S. L., & Ebbert, J. O. (2012). S-adenosyl-L-methionine (SAMe) for smoking abstinence: A randomized clinical trial. Journal of Alternative and Complementary Medicine, 18(9), 854–859. ()
- Stramentinoli, G., Gualano, M., & Galli-Kienle, M. (1979). Intestinal absorption of S-adenosyl-L-methionine. The Journal of Pharmacology and Experimental Therapeutics, 209(3), 323–326. ()
- Strous, R. D., Ritsner, M. S., Adler, S., Ratner, Y., Maayan, R., Kotler, M., Lachman, H., & Weizman, A. (2009). Improvement of aggressive behavior and quality of life impairment following S-adenosyl-methionine (SAM-e) augmentation in schizophrenia. European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology, 19(1), 14–22. ()
- Sun, Q.-F., Ding, J.-G., Wang, X.-F., Fu, R.-Q., Yang, J.-X., Hong, L., Xu, X.-J., Wang, J.-R., Wu, J.-G., & Xu, D.-Z. (2010). Efficacy and safety of intravenous stronger neo-minophagen C and S-adenosyl-L-methionine in treatment of pregnant woman with chronic hepatitis B: A pilot study. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, 16(8), PR9–PR14. ()
- Thompson, M. A., Bauer, B. A., Loehrer, L. L., Cha, S. S., Mandrekar, J. N., Sood, A., & Wahner-Roedler, D. L. (2009). Dietary supplement S-adenosyl-L-methionine (AdoMet) effects on plasma homocysteine levels in healthy human subjects: A double-blind, placebo-controlled, randomized clinical trial. Journal of Alternative and Complementary Medicine, 15(5), 523–529. ()
- Vendemiale, G., Altomare, E., Trizio, T., Le Grazie, C., Di Padova, C., Salerno, M. T., Carrieri, V., & Albano, O. (1989). Effects of oral S-adenosyl-L-methionine on hepatic glutathione in patients with liver disease. Scandinavian Journal of Gastroenterology, 24(4), 407–415. ()
- Vetter, G. (1987). Double-blind comparative clinical trial with S-adenosylmethionine and indomethacin in the treatment of osteoarthritis. The American Journal of Medicine, 83(5A), 78–80. ()
- Walker, K. F., Chappell, L. C., Hague, W. M., Middleton, P., & Thornton, J. G. (2020). Pharmacological interventions for treating intrahepatic cholestasis of pregnancy. Cochrane Database of Systematic Reviews, 7, CD000493. ()
- Williams, A.-L., Girard, C., Jui, D., Sabina, A., & Katz, D. L. (2005). S-adenosylmethionine (SAMe) as treatment for depression:Aa systematic review. Clinical and Investigative Medicine, 28(3), 132–139. ()
- Witte, S., Lasek, R., & Victor, N. (2002). [Meta-analysis of the efficacy of adenosylmethionine and oxaceprol in the treatment of osteoarthritis]. Der Orthopade, 31(11), 1058–1065. ()
- Yang, J., He, Y., Du, Y.-X., Tang, L.-L., Wang, G.-J., & Fawcett, J. P. (2009). Pharmacokinetic properties of S-adenosylmethionine after oral and intravenous administration of its tosylate disulfate salt: A multiple-dose, open-label, parallel-group study in healthy Chinese volunteers. Clinical Therapeutics, 31(2), 311–320. ()
- Zhang, L., Liu, X.-H., Qi, H.-B., Li, Z., Fu, X.-D., Chen, L., & Shao, Y. (2015). Ursodeoxycholic acid and S-adenosylmethionine in the treatment of intrahepatic cholestasis of pregnancy: A multi-centered randomized controlled trial. European Review for Medical and Pharmacological Sciences, 19(19), 3770–3776. ()
- Zhou F., Gao B., Wang X., & Li J. (2014). [Meta-analysis of ursodeoxycholic acid and S-adenosylmethionine for improving the outcomes of intrahepatic cholestasis of pregnancy]. Chinese journal of hepatology, 22(4), 299–304. ()
- Zhu S.-S., Dong Y., Gan Y., Tang H.-M., Xu Z.-Q., Chen D.-W., Jia W.-Z., Wang L.-M., & Zhang H.-F. (2010). [Efficacy and safety of ademetionine for treatment of drug-induced liver disease in children]. Chinese journal of experimental and clinical virology, 24(2), 136–138. ()