SAMe (S-adenosyl-L-methionine)

Overview
SAMe is a substance naturally found in many of our body’s tissues and it is made up of the amino acid methionine (a sulfur containing amino acid) combined with adenosine. SAMe is used in a number of the body’s processes that require sulfur, especially the methylation reactions. There have been many favorable clinical studies on SAMe that indicate its potential as a therapy for osteoarthritis, depression and liver disease. SAMe’s general mechanism of action as a supplement is as a methyl donor for methylation reactions in our body’s natural processes. A deficiency of SAMe could be caused by a deficiency in the cofactors of its production, such as methionine, choline, and B vitamins. A defect in methylation may also cause a deficiency in SAMe. Overall, SAMe has been found to have anti-inflammatory, analgesic and anti-depressive effects.
One theory on depression and other neuropsychiatric disorders is that they are caused by a defect in our biochemical methylation process. Low levels of folate (used in methylation reactions) and serotonin have been linked to lower levels SAMe in depressed patients, and in clinical studies, the supplementation of SAMe has been shown to have an anti-depressant effect that also increases serotonin levels. The National Institute on Alcohol Abuse and Alcoholism and the Office of Dietary Supplements sponsored a conference examining the possible role of SAMe in treating alcoholic liver disease. Since oxidant stress is known to play a major role in the development of liver disease, and SAMe is involved in the manufacture of important liver antioxidant compounds (glutathione), it is being studied for its role in treatment of alcoholic liver disease. SAMe’s potential for osteoarthritis is based on its ability to support a higher production of proteoglycans, a substance that makes up cartilage.
Comments
SAMe seems to be a relatively safe and effective way of correcting our biochemical methylation process, what may be a route of cause for depression, osteoarthritis, liver disease, and other conditions. However, more clinical studies are needed for understanding exactly what kinds of depression SAMe works best for, more about its specific risks and therapeutic side effects, and its potential for other disease processes before it is an accepted treatment method for these and other conditions.
Scientific Support
Depression
A review of the published literature (from 1966 to 2001) on SAMe found that the majority of the clinical evidence for its use has been conducted on various depressive disorders, osteoarthritis, and fibromyalgia, and sample sizes and the dose used has varied widely. Several reviews and meta-analysis have been published all concluding that SAMe was better than placebo in treating depression, and equally as effective as the standard tricyclic antidepressants. However, the authors pointed out that even though SAMe seems well tolerated with most side effects being presented as gastrointestinal complaints, it may have the potential risk of psychiatric and cardiovascular adverse side effects. They concluded that until the side effects are more thoroughly researched, people should not be consuming it in an unmonitored fashion, and healthcare providers should be aware of the need for more research into the potential for adverse events (Fetrow and Avila, 2001; Bressa, 1994).
SAMe was tested in depressive patients and compared to imipramine in two multicenter studies. In one study (involving 143 patients over 6 weeks), 1600 mg of SAMe was given orally daily, and in the second study (involving 138 patients over 4 weeks) 400 mg of SAMe was given intramuscularly, and in both studies the SAMe treatment was compared (in 138 patients over 6 weeks) to the effects of 150 mg of imipramine given orally each day in a double-blind manner. The assessment measures were the Hamilton Depression Rating Scale (HAM-D) and the Clinical Global Impression at the endpoint. The authors stated that SAMe is the most important methyl donor in the central nervous system, and they concluded that both treatments of SAMe was as effective as 150 mg imipramine daily orally, but that SAMe was associated with significantly fewer adverse events (Delle Chiaie et al., 2002).
In one pilot study involving 13 depressed patients with Parkinson’s disease, for which no other previously tried antidepressant agents were effective (and were with intolerable side effects), SAMe was administered in doses of 800 to 3600 mg daily for 10 weeks. Ten of the eleven patients that completed the study showed at least a 50% improvement in the HAM-D score. One patient did not improve, and two dropped out due to increased anxiety. The only side effects noted in the others were mild nausea (in one patient) and mild and transient diarrhea (in two others). The authors concluded that this preliminary trial showed that SAMe is well tolerated and may be a safe alternative to current antidepressant agents used in Parkinson’s patients (DiRocco et al., 2000).
In an open, multi-center study involving 195 patients, 400 mg of SAMe was given parentally for 15 days. Depressive symptoms were found to decrease after days 7 and 15 of treatment with no serious adverse events reported. The authors concluded that further double-blind studies are need to confirm the findings that SAMe is not only a safe and effective anti-depressant, but that it is fast-acting, and could be a possible method for reducing the delay in antidepressant response (Fava et al., 1995).
The anti-depressive effect of SAMe was compared to desipramine in a double-blind randomized clinical study involving 26 patients. In the SAMe group, 62% showed significant improvement compared to 50% in the desipramine group. Regardless of the treatment group, the plasma SAMe concentration was shown to have been significantly improved in all patients that showed a 50% decrease in their HAM-D assessment. The authors concluded that this ladder finding showed that SAMe played a major role in regulating mood (Bell et al.,1994).
Another study examined the effect of SAMe in depressed postmenopausal women in a 30 day double-blind, placebo-controlled randomized design. Eighty women who were diagnosed with DSM-III-R major depressive disorder or dysthymia 6-36 months subsequent to menopause (either natural or through hysterectomy) were given 1,600 mg daily SAMe or placebo. A significant improvement was found in depressive symptoms compared to placebo starting day 10 of the study, and side effects were mild and transient (Salmaggi et al., 1993).
In an effort to study the effect of speeding up the onset of action of the antidepressant imipramine, SAMe was given to 40 patients in a double-blind manner alongside imipramine at 150 mg daily. The SAMe was administered at 200 mg daily intramuscularly. SAMe was concluded to effectively increase the onset of antidepressive action of imipramine (Berlanga et al., 1992).
In one earlier study, SAMe was administered both orally and intravenously and levels of SAMe were found to significantly rise in the cerebrospinal fluid, indicating that it crossed the blood-brain barrier. The authors also pointed out that SAMe levels were low in a group of Alzheimer’s patients, and that this suggested a problem in methylation in the disease that the possible use of SAMe as treatment (Bottiglieri et al., 1990).
Osteoarthritis
A meta-analysis of randomized controlled clinical trials was conducted on the use of SAMe compared to nonsteroidal anti-inflammatory drugs (NSAIDs) for osteoarthritis. SAMe was found to be as effective as NSAIDs as reducing pain and functional limitation of osteoarthritis but without the side effects associated with NSAIDs (Soeken et al., 2002).
In another meta-analysis of the use of SAMe in osteoarthritis, all randomized clinical trials on SAMe and oxaceprol were reviewed for their efficacy in osteoarthritis. Assessments of clinical trials were based mostly on pain scores and pain and function scores. Because there were only a few trials that had a mixture of results, the authors cautioned that the results of the meta-analysis had to be interpreted very carefully, but that overall there was not enough evidence to recommend using SAMe and oxaceprol for the treatment of osteoarthritis, but that there was a comparable effect of them to NSAIDs (Witte et al., 2002).
SAMe was tested in a bicentric, randomized, double-blind, placebo-controlled study on its effectiveness for treatment on 81 patients with osteoarthritis. After a 7-day washout period, patients were administered either 400 mg boluses of SAMe i.v. for 5 days followed by 200 mg three times daily for 23 days or a matching placebo regimen. The major outcome measures were the Stanford Health Assessment Questionnaire disability and pain scales, and supplemental visual analog scales for rest and walking pain. In one center, where the patients tended to have a milder baseline of osteoarthritis, the SAMe showed a significantly greater effect in reducing overall pain and resting pain than placebo. In the other center, the baseline osteoarthritis was much more severe, and there was no difference between treatment groups in outcome measures. The authors concluded SAMe to be beneficial to the treatment of osteoarthritis in some patients, and that intravenous loading of SAMe may be an more effective strategy to beginning oral treatment (Bradley et al., 1994).
Fibromyalgia
In one study of SAMe for fibromyalgia, 34 patients were given 600 mg i.v. or placebo for 10 days in a double blind cross-over trial. The primary outcome measure was the tender point change between the treatment groups, and there was no significant difference between the two found, even though there was a trend towards the SAMe group showing significantly improved measures of perception of pain (Volkmann et al., 1997).
In another study on fibromyalgia treatment using SAMe, 800 mg of SAMe was administered orally daily or placebo for 6 weeks in a double-blind, placebo controlled study. The outcome parameters measured that showed improvement vs. placebo were clinical disease activity, subjective symptoms (visual analog scale) of pain experienced during the last week, fatigue, and morning stiffness, and mood parameters evaluated by the Face Scale. Parameters for which there was no improvement found were tender point score, isokinetic muscle strength, and mood evaluated by Beck Depression Inventory. The authors noted that there were no differences in side effects between treatment and placebo groups, and concluded SAMe to be beneficial to primary fibromyalgia (Jacobsen et al., 1991).
Liver Disease
A review of clinical and preclinical science on SAMe was performed in order to give relevance to new findings of the role of SAMe in liver growth, differentiation and injury. Through genome sequence analysis, it was revealed that all organisms make SAMe, and a large percentage of all genes are SAMe dependent methyltransferases. Since most methylation reactions occur in the liver and a large percentage of methionine metabolism occurs in the liver, the authors contended that the liver is essential in the regulation of blood methionine. They added that SAMe is not only an intermediate in methionine catabolism, but that it is a control switch that works intracellularly to regulate liver regeneration, differentiation and protection (Mato et al., 2002).
A systematic review of the clinical studies on the use of SAMe in alcoholic liver disease was performed. Once the clinical studies were compiled, the methodology of each one was assessed using the components of quality and the Jadad-score. In the review, there were 8 placebo-controlled randomized clinical trials found, and of these, only one of them (involving 123 patients) used the adequate methodology and reported with clarity on mortality and liver transplantation. The authors found no significant effect of SAMe on mortality, liver related mortality, liver transplantation or liver complications, and therefore did not recommend it for alcoholic liver disease outside clinical trials (Rambaldi and Gluud, 2001; Mato et al. 1999).
SAMe was tested in a randomized placebo-controlled study involving 32 women with intrahepatic cholestasis of pregnancy. The study groups were divided into those who were treated with (a) ursodeoxycholic acid, (b) SAMe, (c) both drugs, or (d) a placebo. The authors found the combination treatment, group (c) to be significantly more effective than placebo or than either drug alone (groups a, b or d) (Nicastri et al., 1998).
In another study comparing SAMe treatment to ursodeoxycholic acid for intrahepatic cholestasis of pregnancy, 20 women were treated with either SAMe (1000 mg/day i.m.) or ursodeoxycholic acid (450 mg/day) from the last trimester of pregnancy until time of delivery. Ursodeoxycholic acid was shown to be more effective at treating pruritus and total bile acids than SAMe, and was recommended for further testing in this indication (Floreani et al., 1996). Earlier studies on the use of SAMe for intrahepatic cholestasis of pregnancy have likewise given mixed results (Ribalta et al., 1991; Frezza et al.,
1990).
Parkinson’s Disease
See DiRocco et al., 2000 in the section above on Depression.
Safety / Dosage
Experimental studies have found that SAMe does not cause the same side effects as other non-steroidal anti-inflammatory agents, such as aspirin, on the gastric irritation, or by interfering with blood clotting mechanisms, or inhibition of prostaglandins. In clinical studies the side effects noted have been mostly mild and transient, especially gastrointestinal discomfort.
SAMe appears to be well absorbed through intravenous and intramuscular routes, and through oral administration if an enteric-coated capsule is used. In clinical studies, the amounts taken ranged from 600 to 1,600 mg a day for osteoarthritis. For depression, higher amounts of SAMe are recommended, starting with a high dosage of 1,600 mg daily (divided into two or four doses per day) for two to three weeks, and then to reduce the dosage to a maintenance level depending on the individuals’ depressive symptoms (such as 800 mg or 400 mg daily). Preclinical studies suggest that SAMe functions when folate and vitamin B12 levels are normal (not low) (Grazi and Costa, 1999).
References
1.Bell KM, Potkin SG, Carreon D, Plon L. S-adenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand Suppl. 1994;154:15-8.
2.Berlanga C, Ortega-Soto HA, Ontiveros M, Senties H. Efficacy of S-adenosyl-L-methionine in speeding the onset of action of imipramine. Psychiatry Res. 1992 Dec;44(3):257-62.
3.Bottiglieri T, Godfrey P, Flynn T, Carney MW, Toone BK, Reynolds EH. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg Psychiatry. 1990 Dec;53(12):1096-8.
4.Bradley JD, Flusser D, Katz BP, Schumacher HR Jr, Brandt KD, Chambers MA, Zonay LJ. A randomized, double blind, placebo controlled trial of intravenous loading with S-adenosylmethionine (SAM) followed by oral SAM therapy in patients with knee osteoarthritis. J Rheumatol. 1994 May;21(5):905-11.
5.Bressa GM. S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurol Scand Suppl. 1994;154:7-14.
6.Delle Chiaie R, Pancheri P, Scapicchio P. 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. Am J Clin Nutr. 2002 Nov;76(5):1172S-6S.
7.Di Rocco A, Rogers JD, Brown R, Werner P, Bottiglieri T. S-Adenosyl-Methionine improves depression in patients with Parkinson's disease in an open-label clinical trial. Mov Disord. 2000 Nov;15(6):1225-9.
8.Jacobsen S, Danneskiold-Samsoe B, Andersen RB. Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. Scand J Rheumatol. 1991;20(4):294-302.
9.Fava M, Giannelli A, Rapisarda V, Patralia A, Guaraldi GP. Rapidity of onset of the antidepressant effect of parenteral S-adenosyl-L-methionine. Psychiatry Res. 1995 Apr 28;56(3):295-7.
10.Fetrow CW, Avila JR. Efficacy of the dietary supplement. S-adenosyl-L-methionine. Ann Pharmacother. 2001 Nov;35(11):1414-25.
11.Floreani A, Paternoster D, Melis A, Grella PV. S-adenosylmethionine versus ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy: preliminary results of a controlled trial. Eur J Obstet Gynecol Reprod Biol. 1996 Aug;67(2):109-13.
12.Grazi, S. and Costa, M. The European Arthritis and Depression Breakthrough: SAMe. 1999. Prima Health: Rocklin, CA. 248 pp.
13.Mato JM, Camara J, Fernandez de Paz J, Caballeria L, Coll S, Caballero A, Garcia-Buey L, Beltran J, Benita V, Caballeria J, Sola R, Moreno-Otero R, Barrao F, Martin-Duce A, Correa JA, Pares A, Barrao E, Garcia-Magaz I, Puerta JL, Moreno J, Boissard G, Ortiz P, Rodes J. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial J Hepatol. 1999 Jun;30(6):1081-9.
14.Mato JM, Corrales FJ, Lu SC, Avila MA. S-Adenosylmethionine: a control switch that regulates liver function. FASEB J. 2002 Jan;16(1):15-26.
15.Nicastri PL, Diaferia A, Tartagni M, Loizzi P, Fanelli M. A randomised placebo-controlled trial of ursodeoxycholic acid and S-adenosylmethionine in the treatment of intrahepatic cholestasis of pregnancy. Br J Obstet Gynaecol. 1998 Nov;105(11):1205-7.
16.Rambaldi A, Gluud C. S-adenosyl-L-methionine for alcoholic liver diseases. Cochrane Database Syst Rev. 2001;(4):CD002235.
17.Ribalta J, Reyes H, Gonzalez MC, Iglesias J, Arrese M, Poniachik J, Molina C, Segovia N. S-adenosyl-L-methionine in the treatment of patients with intrahepatic cholestasis of pregnancy: a randomized, double-blind, placebo-controlled study with negative results. Hepatology. 1991 Jun;13(6):1084-9.
18.Salmaggi P, Bressa GM, Nicchia G, Coniglio M, La Greca P, Le Grazie C. Double-blind, placebo-controlled study of S-adenosyl-L-methionine in depressed postmenopausal women. Psychother Psychosom. 1993;59(1):34-40.
19.Soeken KL, Lee WL, Bausell RB, Agelli M, Berman BM. Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis. J Fam Pract. 2002 May;51(5):425-30.
20.Volkmann H, Norregaard J, Jacobsen S, Danneskiold-Samsoe B, Knoke G, Nehrdich D. Double-blind, placebo-controlled cross-over study of intravenous S-adenosyl-L-methionine in patients with fibromyalgia. Scand J Rheumatol. 1997;26(3):206-11.
21.Witte S, Lasek R, Victor N. Meta-analysis of the efficacy of adenosylmethionine and oxaceprol in the treatment of osteoarthritis. Orthopade. 2002 Nov;31(11):1058-65.
EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.