(S-Adenosylmethionine)t Clinical Studies
SAMe is used for depression, fibromyalgia, dementia, Alzheimer's disease, slowing the aging process, improving intellectual performance, Parkinson's disease, osteoarthritis and heart disease. Other uses include attention deficit-hyperactivity disorder (ADHD), multiple sclerosis, spinal cord injury, seizures, migraine headache and chronic lead poisoning.
Taking SAMe seems to reduce symptoms of major depression. S-adenosylmethionine (SAMe) is a naturally occurring molecule that is distributed throughout body tissues and fluids. Concentrations are highest in childhood and decrease with age. SAMe contributes to the synthesis, activation and/or metabolism of hormones, neurotransmitters, nucleic acids, proteins, phospholipids and some drugs. SAMe synthesis is linked to vitamin B12 and folate metabolism. Deficiencies of these vitamins can result in decreased SAMe concentrations in the central nervous system. Neuro-imaging studies indicate that SAMe affects the brain similarly to conventional antidepressants.
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Published Clinical Studiescl top
Abnormal hepatic methionine and glutathione metabolism in patients with alcoholic hepatitis.1
Lee TD, Sadda MR, Mendler MH, Bottiglieri T, Kanel G, Mato JM, Lu SC.
Division of Gastroenterology and Liver Diseases, University of Southern California Liver Disease Research Center, University of Southern California/University of California, USA.
BACKGROUND: Abnormal methionine metabolism occurs in animals fed ethanol and in end-stage cirrhotic patients. Expected consequences of these abnormalities include reduced hepatic S-adenosylmethionine and glutathione (GSH) levels, impaired transmethylation, and reduced homocysteine catabolism, resulting in the often-observed hyperhomocystinemia in cirrhotic patients. These parameters have not been examined simultaneously in patients with less advanced alcoholic liver disease. METHODS: Six patients hospitalized for alcoholic hepatitis were studied. Plasma was analyzed for homocysteine, methionine, and GSH levels. Liver biopsies diagnosed acute alcoholic hepatitis and underlying fibrosis. Liver specimens were processed for messenger RNA (mRNA) levels and various metabolites and were compared with those of six normal controls. RESULTS: Three patients had cirrhosis, and three had only portal fibrosis. Plasma levels of homocysteine and methionine were increased in two of the three patients with cirrhosis but not in the patients with fibrosis. All patients had markedly lower plasma GSH levels (mean +/- SD: 0.27 +/- 0.19 microM, which is at least 10-fold lower than the normal range). Hepatic S-adenosylmethionine levels were reduced by 50%, whereas methionine, GSH, and cysteine levels were reduced by 70-80%. The mRNA levels of most enzymes involved in methionine metabolism and GSH synthesis were decreased, whereas albumin expression was unchanged. Despite the well known induction of cytochrome P450 2E1 in chronic alcoholics, its mRNA levels were nearly 70% lower in these patients. CONCLUSIONS: In alcoholic hepatitis, abnormal hepatic gene expression in methionine and GSH metabolism occurs and often contributes to decreased hepatic methionine, S-adenosylmethionine, cysteine, and GSH levels. It may be important to replenish these thiols in patients hospitalized with alcoholic hepatitis.
PMID: 14745316 [PubMed - in process]
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2 S-adenosyl-L-methionine: effects on brain bioenergetic status and transverse relaxation time in healthy subjects.
Silveri MM, Parow AM, Villafuerte RA, Damico KE, Goren J, Stoll AL, Cohen BM, Renshaw PF.
Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
BACKGROUND: S-adenosyl-L-methionine is an effective treatment for clinical depression, although the mechanism underlying this effect is unclear. Presently, in vivo phosphorus magnetic resonance spectroscopy (31P MRS) and brain transverse relaxometry were employed to test if S-adenosyl-L-methionine supplementation alters brain bioenergetics and/or transverse relaxation time (T2RT) in a nondepressed cohort. If these magnetic resonance techniques are sensitive to S-adenosyl-L-methionine induced alterations in neurochemical processes, these methods may be used in cases of clinical depression to elucidate the mechanism underlying the antidepressant effect of S-adenosyl-L-methionine. METHODS: Twelve subjects self-administered 1600 mg of oral S-adenosyl-L-methionine daily. Phosphorus spectra and transverse relaxation time were acquired at baseline and after treatment using a 1.5 Tesla scanner. RESULTS: Phosphocreatine levels were significantly higher after treatment, whereas beta nucleoside triphosphate levels, predominantly adenosine triphosphate in brain, were significantly lower after treatment. A surprising gender difference in T2RT emerged after supplementation, with women exhibiting significantly lower T2RT than men. CONCLUSIONS: Alterations in phosphocreatine and beta nucleoside triphosphate are consistent with the report that S-adenosyl-L-methionine is involved in the production of creatine, which in turn is phosphorylated to phosphocreatine using adenosine triphosphate. These findings suggest that S-adenosyl-L-methionine alters parameters associated with cerebral bioenergetic status and that some effects of S-adenosyl-L-methionine (T2RT) occur in a gender-specific manner.
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PMID: 14550683 [PubMed - indexed for MEDLINE]
Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence.3
Mischoulon D, Fava M.
Harvard Medical School, Depression Clinical and Research Program, Massachusetts General Hospital, Boston 02114, USA. dmischoulon@partners.org
Major depression remains difficult to treat, despite the wide array of registered antidepressants available. In recent years there has been a surge in the popularity of natural or alternative medications. Despite this growing popularity, there is limited evidence for the effectiveness of many of these natural treatments. S-adenosyl-L-methionine (SAMe) is one of the better studied of the natural remedies. SAMe is a methyl donor and is involved in the synthesis of various neurotransmitters in the brain. Derived from the amino acid L-methionine through a metabolic pathway called the one-carbon cycle, SAMe has been postulated to have antidepressant properties. A small number of clinical trials with parenteral or oral SAMe have shown that, at doses of 200-1600 mg/d, SAMe is superior to placebo and is as effective as tricyclic antidepressants in alleviating depression, although some individuals may require higher doses. SAMe may have a faster onset of action than do conventional antidepressants and may potentiate the effect of tricyclic antidepressants. SAMe may also protect against the deleterious effects of Alzheimer disease. SAMe is well tolerated and relatively free of adverse effects, although some cases of mania have been reported in bipolar patients. Overall, SAMe appears to be safe and effective in the treatment of depression, but more research is needed to determine optimal doses. Head-to-head comparisons with newer antidepressants should help to clarify SAMe's place in the psychopharmacologic armamentarium.
PMID: 12420702 [PubMed - indexed for MEDLINE]
4 S-Adenosyl-L-methionine (SAMe): from the bench to the bedside--molecular basis of a pleiotrophic molecule.
Bottiglieri T.
Baylor University Medical Center, Institute of Metabolic Disease, Dallas, TX 75226, USA. teodorob@baylorhealth.edu
S-Adenosyl-L-methionine (SAMe), a metabolite present in all living cells, plays a central role in cellular biochemistry as a precursor to methylation, aminopropylation, and transsulfuration pathways. As such, SAMe has been studied extensively since its chemical structure was first described in 1952. Decades of research on the biochemical and molecular roles of SAMe in cellular metabolism have provided an extensive foundation for its use in clinical studies, including those on depression, dementia, vacuolar myelopathy, liver disease, and osteoarthritis. This article provides an overview of the biochemical, molecular, and therapeutic effects of this pleiotrophic molecule.
PMID: 12418493 [PubMed - indexed for MEDLINE]
S-adenosylmethionine and depression.5
Nguyen M, Gregan A.
BACKGROUND: Depression is one on the most common psychological problems encountered in medical practice. Conventional antidepressants, although effective, have many side effects and there is a need for effective medications with fewer side effects. OBJECTIVE: To present all the available clinical evidence on the supplement, S-adenosylmethionine (SAMe) in the treatment of depressive symptoms as well as its safety. DISCUSSION: Recent clinical studies have revealed that SAMe, a naturally occurring molecule, is safe and effective in the treatment of mild and moderate depression. Although further research is required to clarify SAMe's role as a potential first line treatment for depression, physicians should be aware of the safety and efficacy of SAMe in order to advise patients on its appropriate use as complementary or as an alternative to traditional therapy for depression.
PMID: 12043126 [PubMed - indexed for MEDLINE]
Sulfur in human nutrition and applications in medicine.6
Parcell S.
American Institute for Biosocial and Medical Research (AIBMR), Tacoma, WA, USA. steveparcell@attbi.com
Because the role of elemental sulfur in human nutrition has not been studied extensively, it is the purpose of this article to emphasize the importance of this element in humans and discuss the therapeutic applications of sulfur compounds in medicine. Sulfur is the sixth most abundant macromineral in breast milk and the third most abundant mineral based on percentage of total body weight. The sulfur-containing amino acids (SAAs) are methionine, cysteine, cystine, homocysteine, homocystine, and taurine. Dietary SAA analysis and protein supplementation may be indicated for vegan athletes, children, or patients with HIV, because of an increased risk for SAA deficiency in these groups. Methylsulfonylmethane (MSM), a volatile component in the sulfur cycle, is another source of sulfur found in the human diet. Increases in serum sulfate may explain some of the therapeutic effects of MSM, DMSO, and glucosamine sulfate. Organic sulfur, as SAAs, can be used to increase synthesis of S-adenosylmethionine (SAMe), glutathione (GSH), taurine, and N-acetylcysteine (NAC). MSM may be effective for the treatment of allergy, pain syndromes, athletic injuries, and bladder disorders. Other sulfur compounds such as SAMe, dimethylsulfoxide (DMSO), taurine, glucosamine or chondroitin sulfate, and reduced glutathione may also have clinical applications in the treatment of a number of conditions such as depression, fibromyalgia, arthritis, interstitial cystitis, athletic injuries, congestive heart failure, diabetes, cancer, and AIDS. Dosages, mechanisms of action, and rationales for use are discussed. The low toxicological profiles of these sulfur compounds, combined with promising therapeutic effects, warrant continued human clinical trails.
PMID: 11896744 [PubMed - indexed for MEDLINE]
7 Influence of SAMe on the modifications of brain polyamine levels in an animal model of depression.
Genedani S, Saltini S, Benelli A, Filaferro M, Bertolini A.
Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Via G. Campi 287, 41100 Modena, Italy.
The mechanism(s) of the antidepressant activity of S-adenosyl-L-methionine (SAMe) have not yet been elucidated. SAMe is essential for the synthesis of polyamines, which have a key role in protein synthesis, cell proliferation, and neuronal plasticity. On the other hand, accumulating data indicate that depression is associated with a reduction in regional brain volume and that antidepressants increase neurogenesis in defined brain regions and also influence neuronal plasticity. Here we show that in a validated rat model of depression (chronic unpredictable mild stress-induced anhedonia) there is a significant reduction of putrescine, spermidine and spermine in the hippocampus, and of only putrescine in the nucleus accumbens septi. SAMe, at a fully antidepressant dose (300 mg/kg i.m., daily for 7 days), completely restores the levels of putrescine in the nucleus accumbens, and restores in part the levels of both spermidine and spermine in the hippocampus. These results may suggest (i) a role for brain polyamines in depression and in reward processes, and (ii) that the antidepressant effect of SAMe may be due, at least in part, to a normalization of putrescine levels in the nucleus accumbens septi.
PMID: 11742215 [PubMed - indexed for MEDLINE]
8 SAMe restores the changes in the proliferation and in the synthesis of fibronectin and proteoglycans induced by tumour necrosis factor alpha on cultured rabbit synovial cells.
Gutierrez S, Palacios I, Sanchez-Pernaute O, Hernandez P, Moreno J, Egido J, Herrero-Beaumont G.
Research Laboratory, Fundacion Jimenez Diaz, Universidad Autonoma, Madrid, Spain.
S-Adenosyl-L-methionine (SAMe) is a naturally occurring compound involved in transmethylation and trans-sulphuration reactions. The administration of SAMe to patients with osteoarthritis (OA) seems to have a protective effect, although the mechanisms of its action are largely unknown. We have studied the effect of SAMe as a protective agent against the modifications induced by tumour necrosis factor alpha (TNF alpha) on synovial cell proliferation and extracellular matrix protein synthesis, two important hallmarks of progressive articular diseases. The stimulation of cells with 100 U/ml TNF alpha for 24 h decreased the proliferative rate (58 +/- 14% with TNF alpha vs basal 100%, P < 0.05), fibronectin (FN) mRNA expression (36 +/- 14% vs basal, P < 0.05) and FN synthesis (79 +/- 20% vs basal, P > 0.05). By contrast, TNF alpha raised total protein and proteoglycan synthesis (127 +/- 12% vs basal and 239 +/- 40% vs basal, respectively, P < 0.05). The addition of increasing concentrations of SAMe (10(-10)-10(-6) M) to synoviocytes incubated with TNF alpha reversed the effects induced by the cytokine, while SAMe alone did not modify significantly the metabolic processes studied. These results indicate that, in cultured synovial cells, SAMe restores basal conditions after cell damage elicited by TNF alpha stimulation.
PMID: 9117169 [PubMed - indexed for MEDLINE]
9 A randomized, double blind, placebo controlled trial of intravenous loading with S-adenosylmethionine (SAM) followed by oral SAM therapy in patients with knee osteoarthritis.
Bradley JD, Flusser D, Katz BP, Schumacher HR Jr, Brandt KD, Chambers MA, Zonay LJ.
Specialized Center of Research in Osteoarthritis, Indiana University School of Medicine, Indianapolis 46202.
OBJECTIVE. We evaluated the effectiveness and rapidity of onset of S-adenosylmethionine (SAM), administered as daily intravenous boluses of 400 mg for 5 days, followed by oral tablets, 200 mg thrice daily for 23 days, versus a matching placebo regimen, in the treatment of 81 patients with symptomatic knee osteoarthritis (OA). METHODS. The study was bicentric, randomized, double blinded, and placebo controlled. Patients underwent a 7-day washout of arthritis medications prior to initiation of this study treatment. Major outcome measures were the Stanford Health Assessment Questionnaire disability and pain scales, and supplemental visual analog scales for rest and walking pain. RESULTS. At one site, patients had milder OA, the baseline characteristics of the treatment groups were well matched, and the SAM treated group showed significantly greater reduction in overall pain and rest pain (p < 0.05) than the placebo treated group. At the other site, the patients had more severe OA, randomization yielded markedly different treatment groups, and the response to treatment did not differ between groups. Onset of SAM effect was seen as early as 14 days after the start of treatment. CONCLUSION. SAM may be an effective treatment for some patients with symptomatic knee OA, and merits further study. Intravenous loading before oral maintenance therapy may be advantageous.
PMID: 8064733 [PubMed - indexed for MEDLINE]
[Experimental osteoarthritis and its course when treated with S-adenosyl-L-methionine]10
Barcelo HA, Wiemeyer JC, Sagasta CL, Macias M, Barreira JC.
Instituto de Docencia e Investigaciones Biologicas, S.A. Buenos Aires, Argentina.
Degenerative arthropathy was experimentally induced in the right knee of 24 rabbits. The animals were randomly divided in 3 groups of 8 rabbits each. S-Adenosyl-L-Methionine (SAMe) was administered intramuscularly to 2 groups. One group received 30 and 60 mg/kg/day i.m. The remaining group was a control and received only a diluent. After 12 weeks of therapy rabbits were sacrificed and tibial and femoral cartilage specimens of both knees were taken. The latter was stained with hematoxylin -eosine, Masson's trichromic and Safranine 0 stains and was microscopically studied. The thickness and cell density of the lesioned cartilages were significantly greater in both groups treated with SAMe than the group control (p less than 0.001). Statistical differences (p less than 0.05) were found within 60 and 30 mg/kg/day of SAMe. A greater concentration of proteoglycans in the cartilage matrix was found in animals treated were as, a severe reduction was found in controls. The severity of the lesions, based on the histologic-histochemical analysis, was significantly lower in rabbits receiving SAMe (p less than 0.0005). These differences were correlated with the administration of SAMe and the possible mechanisms of action are discussed.
PMID: 2244062 [PubMed - indexed for MEDLINE]
Alzheimer's disease revisited.11
Newman PE.
Paris, France.
In a previous paper, it was suggested that a relative deficiency of essential fatty acids might play a role in the etiology of sporadic or non-familial Alzheimer's disease. A recent article regarding dementia in the Rotterdam Study reinforces this suggestion. It is also hypothesized that this relative deficiency could facilitate passage of aluminum into the brain, aluminum being increasingly suggested as one of the possible pathogenic factors in AD. It is further suggested that hypomethylation caused by a deficiency of S-adenosylmethionine might also play a role in the etiology of this disease and perhaps even of Parkinson's disease. Copyright 2000 Harcourt Publishers Ltd.
PMID: 10859685 [PubMed - indexed for MEDLINE]
Brain hydrogen sulfide is severely decreased in Alzheimer's disease.12
Eto K, Asada T, Arima K, Makifuchi T, Kimura H.
National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan.
Although hydrogen sulfide (H2S) is generally thought of in terms of a poisonous gas, it is endogenously produced in the brain from cysteine by cystathionine beta-synthase (CBS). H2S functions as a neuromodulator as well as a smooth muscle relaxant. Here we show that the levels of H2S are severely decreased in the brains of Alzheimer's disease (AD) patients compared with the brains of the age matched normal individuals. In addition to H2S production CBS also catalyzes another metabolic pathway in which cystathionine is produced from the substrate homocysteine. Previous findings, which showed that S-adenosyl-l-methionine (SAM), a CBS activator, is much reduced in AD brain and that homocysteine accumulates in the serum of AD patients, were confirmed. These observations suggest that CBS activity is reduced in AD brains and the decrease in H2S may be involved in some aspects of the cognitive decline in AD.
PMID: 12054683 [PubMed - indexed for MEDLINE]