S-adenosyl methionine

Common Names: SAMe, S-adenosyl-L-methionine, S-adenosylmethionine

Clinical Name: S-adenosyl Methionine

Summary

S-adenosyl methionine

chemical name: Sulfuradenosylmethionine, S-adenosyl-L-methionine

synonym: SAMe

overview of interactions:
• There are no known direct drug interactions with SAMe. However, due to SAMe's effects on the liver and its role in methylation reactions, it may enhance the elimination of various drugs from the body. The clinical significance of such possible actions are not yet understood.

• nutrient indirectly affected by drug: Vidarabine

chemistry:
• Methionine is an essential sulfur-containing amino acid that is converted in the liver into S-adenosyl methionine (SAMe), which is considered to be the activated form of methionine. This happens in the first step of the metabolism of methionine. This step requires energy in the form of ATP. In this activation of methionine, an adenosyl moiety is transferred from the ATP molecule. SAM synthesis is one of the most potent methyl donors and is involved in many methylation reactions. Its methyl group, which is attached in a sulfonium linkage with high-energy characteristics, may be donated to any of a large number of methyl-group acceptors in the presence of the appropriate enzyme.
• Once SAMe transfers its methyl group, homocysteine and adenosine are produced. In the presence of tetrahydrofolate (THF), vitamin B6, vitamin B12, magnesium and a source of methyl groups from either betaine, serine or dimethylglycine (DMG), homocysteine can be recycled back into methionine and subsequently to SAMe. This methyl transfer reaction can be done from betaine or from Me-THF in the presence of vitamin B12.
• Through a separate pathway, homocysteine can also be converted to cystathionine in a vitamin B6-dependent reaction. This pathway ends up removing methionine from the cycle and results in the production of cysteine, another sulfur-bearing amino acid. Cysteine can then be used to produce glutathione, an important antioxidant.
• SAMe is also involved in the biosynthesis of other sulfur-containing compounds, including the amino acids taurine and key components of connective tissue such as the glycosaminoglycans.
• SAMe is essential in the manufacture of brain neurotransmitters including dopamine, norepinephrine, epinephrine, and serotonin, as well as the phospholipids, phosphatidylcholine and phosphatidylserine. SAMe enhances the binding of the neurotransmitters to neural receptor sites, enhancing their activity. By methylating certain phospholipids in the cell membranes, SAMe can enhance cell membrane fluidity, thereby improving interneuronal communication.

function: SAMe plays an important role in detoxification processes and the synthesis of antioxidants. SAMe is intimately involved in the synthesis of brain chemicals, notably dopamine, and the compounds necessary for connective tissue and joint integrity.

dietary sources: SAMe is not a significant direct dietary component; rather it is derived from dietary sources of methionine. Dairy, fish and meat are considered the richest dietary sources of methionine. Sunflower seeds are also a good source of methionine. Soybeans are a poor source and soy-based infant formulas are generally low in methionine. Egg yolks are particularly high in sulfur. Methionine and cysteine make up 91% of the sulfur in the yolk. Average intake in the U.S.: 2.7 to 5 g per day. Bacteria in the gut may be able to synthesize significant amounts. However, high intake of methionine does not increase levels of SAMe, nor will it provide the same pharmacological activity as SAMe. In fact, high dosages of methionine have been associated with some degree of toxicity.

deficiency:
• Methionine deficiency is usually related to overall protein malnutrition.
• Deficiencies of B12, folate and methionine can cause a deficiency of SAMe.

known or potential therapeutic uses: Depression, detoxification and allergies, fibromyalgia, migraine headaches, improves brain function, infertility (male), liver disorders, migraine headaches, improvement of joint and connective tissue function, osteoarthritis, pain control, Parkinson's, post-concussion, radiation effects, schizophrenia, Wilson's disease.

maintenance dose: Dietary sources of methionine, the normal precursor to SAMe, are usually adequate so supplemental use is usually not considered necessary. Most healthcare professional experienced in nutritional therapies consider it inappropriate to supplement with SAMe without a specific therapeutic objective. Optimal levels of intake have not been established.

therapeutic dose: 400 to 1,600 mg per day, depending on the condition being
supported.

• Researchers studying the therapeutic efficacy of SAMe for a variety of conditions have often used significantly higher doses ranging from 800 mg per day for fibromyalgia and migraine headaches and 800-1200 mg per day for osteoarthritis to 1200 mg per day for liver disorders and 1,600 mg per day for depression.
• SAMe works best taken with its cofactors, vitamin B6 (50 mg), vitamin B12 (1000 mcg) and folic acid (800 mcg) to enhance production of the SAMe precursor, methionine. Failure to do so may convert SAMe into high levels of homocysteine, known for its dangers in causing cardiovascular disease.

product stability: The product imported by its European manufacturer, as a finished dose, is a relatively stable product in a pharmaceutical grade, enteric coated, dosage system. Specifications of the raw material state that it quickly degrades upon exposure to heat and/or moisture. Therefore, handling during manufacture must take place at relatively low humidity and at the recommended storage of less than 20°C (68°F), and not to exceed 25°C (77°F). At 35°C (95°F), SAMe remains stable only for 8-10 hours, quickly degrading thereafter.
(Czap A.)

side effects: SAMe is generally considered an extremely safe nutrient. No significant side effects have been reported with the oral intake of SAMe other than occasional nausea and gastrointestinal disturbances. When this occurs, the daily dosage should be broken down into a smaller serving size.

toxicity: Use caution if someone has bipolar depression (Manic-Depressive) as SAMe may precipitate the manic phase of the disorder. It is unclear if SAMe has the same problems with elevated levels of homocysteine as methionine does. In cases of strong family history of coronary heart disease, it is wise to check homocysteine levels before and during treatment.



Interactions

• There are no known direct drug interactions with SAMe. However, due to SAMe's effects on the liver and its role in methylation reactions, it may enhance the elimination of various drugs from the body. The clinical significance of such possible actions are not yet understood.

nutrient indirectly affected by drug: Vidarabine

• mechanism: Vidarabine is known to interfere with methionine synthesis. Methionine is converted into S-adenosyl methionine (SAMe), which is considered to be the activated form of methionine.
(Med Lett Drugs Ther 1977 May 20;19(10):42-43; Cantoni GL, et al. N Engl J Med 1982 Oct 21;307(17):1079.)

• nutritional concerns: Individuals taking vidarabine for an extended period of time should consult with their prescribing physician to discuss options for countering the potential adverse effects of this drug. Some nutritionally oriented physicians have found value in monitoring serum methionine in their patients taking vidarabine. Supplementation with methionine could be used to counter this adverse effect of vidarabine. Supplementation with SAMe has not been studied in this regard.

Please read the disclaimer concerning the intent and limitations of the information provided here.
Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.


References

[No author given] Vidarabine (Vira-A). Med Lett Drugs Ther 1977 May 20;19(10):42-43.

Alarcon RD, Tolbert LC, Monti JA, Morere DA, Walter-Ryan WG, Kemp B, Smythies JR. One-carbon metabolism disturbances in affective disorders. A preliminary report. J Affect Disord 1985 Nov;9(3):297-301.
Methionine adenosyltransferase (MAT) activity (Vmax) and the relative amount of phosphatidylcholine (% PC) were measured in erythrocytes of up to 30 DSM-III diagnosed manic, 17 unipolar depressed patients, and 28 normal controls. Manic subjects had significantly higher and depressed subjects significantly lower MAT Vmax than normals. The relative amount of PC was in the low range for the depressives, and in the high range for the manics. Depressive patients present, in these tests, similar abnormalities to those seen previously in schizophrenic patients. Clinical and diagnostic implications of these findings are discussed.

Angelico M, Gandin C, Nistri A, Baiocchi L, Capocaccia L. Oral S-adenosyl-L-methionine (SAMe) administration enhances bile salt conjugation with taurine in patients with liver cirrhosis. Scand J Clin Lab Invest 1994 Oct;54(6):459-464.
Abstract: We investigated whether the oral administration of SAMe influences the hepatic availability of sulphur amino acids and the extent of bile salt amidation with taurine in liver cirrhosis. Ten patients with cirrhosis (eight Child-Pugh A and 2 B, aged 48-65 years), were studied before and 2 months after oral SAMe administration (800 mg per day). Bile was obtained using a string-test device (Entero-test), after gall-bladder contraction with caerulein. No significant changes were found in the per cent composition of biliary amino acids, except for an increase in glutamic acid (from 3.7 +/- 0.6% before to 6.1 +/- 1.1% after SAMe, p = 0.003) and taurine from 2.2 +/- 2.3% (range 0.4-6.8) to 7.2 +/- 9.2% (range 0.5-28.1), (NS). HPLC analysis showed a trend towards increased per cent tauroconjugation of all individual bile salts, with a significant rise in taurochenodeoxycholic acid (from 15.0 +/- 9.4% to 25.3 +/- 9.7%, p = 0.05) and a drop in glycocholic acid (from 39.1 +/- 15.3% to 25.3 +/- 9.8%, p = 0.05). These data suggest that in the cirrhotic liver exogenous SAMe is partially metabolized to taurine, which is used for bile salt amidation.

Baldessarini RJ. Neuropharmacology of S-adenosyl-L-methionine. Am J Med 1987 Nov 20;83(5A):95-103.
The metabolite S-adenosyl-L-methionine (SAMe), when prepared as the stable p-toluene-sulfonate complex of its sulfate salt and given parenterally in high doses, appears to have mood-elevating effects in depressed adults. The material is remarkably well tolerated when given by injection or intravenous infusion for this purpose, even in elderly or demented patients. Assuming that the toluene sulfonate component is inert, SAMe appears to have central neuropharmacologic effects after systemic injection in high doses. Nevertheless, the functional consequences of these remain unclear and, indeed, the ability of exogenous SAMe to reach the brain, and especially neuronal cytoplasm, is limited. SAMe has small effects on monoamine metabolism and, after injection, appears to have effects on the microviscosity of cell membranes that may be related to stimulation of phospholipid synthesis. The recent introduction of an orally administered form of SAMe for use in the treatment of osteoarthritis promises to stimulate further study of SAMe in disease-associated depression, major depressive disorder, and other neuropsychiatric conditions.

Ballerini FB, Anguera AL, Alcaraz P, et al. SAM in the management of postconcussional syndrome. Med Clin (Barc) 1983;80:161-164.

Bell KM, Potkin SG, Carreon D, Plon L. S-adenosylmethionine blood levels in major depression: Changes with drug treatment. Acta Neurol Scand 1994;154(suppl):15-18.
Abstract: INTRODUCTION--The relationship between plasma levels of S-adenosylmethionine (SAMe), an endogenous methyl donor, and clinical response were studied inpatients with a DSM-III-R diagnosis of major depression. MATERIAL ANDMETHODS--A double-blind randomized protocol comparing oral SAMe with oral desipramine, involving a total of 26 patients, was employed. RESULTS--At the end of the 4-week trial, 62% of the patients treated with SAMe and 50% of thepatients treated with desipramine had significantly improved. Regardless of thetype of treatment, patients with a 50% decrease in their Hamilton Depression Scale (HAM-D) score showed a significant increase in plasma SAMe concentration. CONCLUSION--The significant correlation between plasma SAMe levels and thedegree of clinical improvement in depressed patients regardless of the type of treatment suggests that SAMe may play an important role in regulating mood.

Bell KM, Plon L, Bunney WE Jr, Potkin SG.S-adenosylmethionine treatment of depression: a controlled clinical trial. Am J Psychiatry 1988 Sep;145(9):1110-1114.
Abstract: The antidepressant properties of S-adenosylmethionine, an endogenous methyldonor, were studied in inpatients who met the DSM-III criteria for major depression. Nine patients given intravenous S-adenosylmethionine and nine given low oral doses of imipramine were compared in a double-blind design for 14days. The S-adenosylmethionine produced superior results by the end of the first week of treatment. By the end of the second week, 66% of the S-adenosylmethionine patients had a clinically significant improvement in depressive symptoms, compared to 22% of the imipramine patients. Side effects appeared to be fewer with S-adenosylmethionine than with imipramine during the last 5 days of the study.

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):257-262.
A double-blind clinical trial was carried out to evaluate the efficacy of S-adenosyl-L-methionine (SAMe) in speeding the onset of action of imipramine(IMI). SAMe is a naturally occurring substance that has been shown to possess antidepressant activity with a rapid mode of onset and minimal side effects. Sixty-three outpatients with moderate to severe depression were included in the study. After an initial 1-week placebo period, only 40 patients entered the active treatment phase. During the first 2 weeks of the trial, half of these patients received 200 mg/day of SAMe intramuscularly, while the other half received placebo. Simultaneously, oral IMI was administered to all patients at a fixed dose of 150 mg/day. The onset of clinical response was determined by evaluating patients every second day. By the end of week 2, the parenteral treatment was suppressed and IMI was adjusted according to individual needs. Depressive symptoms decreased earlier in the patients who were receiving the SAMe-IMI combination than in those who were receiving the placebo-IMI combination.

Bombardieri G, et al. Effects of S-adenosyl-L-methionine (SAMe) in the treatment of Gilbert’s syndrome. Curr Ther Res 1985;37:580-585.

Bombardieri G, Pappalardo G, Bernardi L, Barra D, Di Palma A, Castrini G. Intestinal absorption of S-adenosyl-L-methionine in humans. Int J Clin Pharmacol Ther Toxicol. 1983 Apr;21(4):186-188.
Abstract: S-adenosyl-L-methionine (SAM) has proven to be fairly stable in gastric and duodenal juices as well as in bile. It was, therefore, administered orally to six healthy subjects. No increase in SAM levels was observed in the systemic blood. SAM was then directly injected into a jejunal loop of nine patients undergoing cholecystectomy. SAM concentrations increased significantly in venous mesenteric and systemic blood. Infusions of methionine directly into the jejunum by the same method used for SAM did not induce any increase in SAM concentrations in the mesenteric or systemic blood.

Bottiglieri T, Godfrey P, Flynn T, et al. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: Effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol, Neurosurg Psychiat 1990;53:1096-1098.

Bottiglieri T, Hyland K, Reynolds EH. The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs 1994;48:137-152. (Review)
Abstract: This review focuses on the biochemical and clinical aspects of methylation inneuropsychiatric disorders and the clinical potential of their treatment with ademetionine (S-adenosylmethionine; SAMe). SAMe is required in numeroustransmethylation reactions involving nucleic acids, proteins, phospholipids,amines and other neurotransmitters. The synthesis of SAMe is intimately linkedwith folate and vitamin B12 (cyanocobalamin) metabolism, and deficiencies of both these vitamins have been found to reduce CNS SAMe concentrations. Bothfolate and vitamin B12 deficiency may cause similar neurological andpsychiatric disturbances including depression, dementia, myelopathy andperipheral neuropathy. SAMe has a variety of pharmacological effects in the CNS, especially on monoamine neurotransmitter metabolism and receptor systems.SAMe has antidepressant properties, and preliminary studies indicate that it may improve cognitive function in patients with dementia. Treatment with methyl donors (betaine, methionine and SAMe) is associated with remyelination inpatients with inborn errors of folate and C-1 (one-carbon) metabolism. These studies support a current theory that impaired methylation may occur by different mechanisms in several neurological and psychiatric disorders.

Bottiglieri T, Hyland K. S-adenosylmethionine levels in psychiatric and neurological disorders: a review. Acta Neurol Scand Suppl 1994;154:19-26.
INTRODUCTION--S-adenosylmethionine (SAMe) is an important methyl donor in over35 methylation reactions involving DNA, proteins, phospholipids and catechol- and indole- amines. MATERIAL AND METHODS--This article reviews the studies that have examined brain and blood levels of SAMe in several psychological, neurological and metabolic disorders. RESULTS--Although studies have found no consistent changes in whole blood SAMe levels in psychiatric patients, other investigators have found low cerebrospinal fluid (CSF) SAMe levels in patients with neurological disorders such as Alzheimer's dementia, subacute combined degeneration of the spinal cord (SACD), and HIV-related neuropathies, as well as in patients with metabolic disorders such as 5, 10-CH2-H4 folate reductase deficiency. CONCLUSION-- Intravenous or oral administration of SAMe thus represents a possible treatment for these neurological and metabolic disorders.

Bressa GM. S-adenosyl-l-methionine (SAMe) as antidepressant: Meta-analysis of clinical studies. Acta Neurol Scand 1994;154(suppl):7-14.
Abstract: INTRODUCTION--S-adenosyl-l-methionine (SAMe) is a naturally-occurring substancewhich is a major source of methyl groups in the brain. MATERIAL AND METHODS--We conducted a meta-analysis of the studies on SAMe to assess the efficacy of thiscompound in the treatment of depression compared with placebo and standardtricyclic antidepressants. RESULTS--Our meta-analysis showed a greater responserate with SAMe when compared with placebo, with a global effect size rangingfrom 17% to 38% depending on the definition of response, and an antidepressanteffect comparable with that of standard tricyclic antidepressants. CONCLUSION--The efficacy of SAMe in treating depressive syndromes and disordersis superior with that of placebo and comparable to that of standard tricyclic antidepressants. Since SAMe is a naturally occurring compound with relatively few side-effects, it is a potentially important treatment for depression.

Cantoni L, Budillon G, Cuomo R, Rodino S, Le Grazie C, Di Padova C, Rizzardini M. Protective effect of S-adenosyl-L-methionine in hepatic uroporphyria. Evaluation in an experimental model. Scand J Gastroenterol. 1990 Oct;25(10):1034-1040.

Cantoni GL, Aksamit RR, Kim IK Methionine biosynthesis and vidarabine therapy. N Engl J Med 1982 Oct 21;307(17):1079. (Letter)

Carney MW, Edeh J, Bottiglieri T, Reynolds EM, Toone BK. Affective illness and S-adenosyl methionine: a preliminary report. Clin Neuropharmacol 1986;9(4):379-385.
S-Adenosyl methionine may well have an antidepressant action beyond a placebo effect but this is virtually confined to endogenous depression. This should be subjected to further study. Our own double-blind placebo-controlled study is still incomplete. The indications are that SAM specifically affects folate, dopamine, and serotonin metabolism as well as activating and switching brain mechanisms. This suggests exciting prospects for further investigations. SAM is a nontoxic physiological metabolite virtually free of side effects.

Carney MW, Toone BK, Reynolds EH. S-adenosylmethionine and affective disorder. Am J Med 1987 Nov 20;83(5A):104-106.
Abstract: Several open and double-blind studies suggest that SAMe may have an anti-depressant effect, and further studies are indicated. SAMe may exert a beneficial effect selectively on endogenous rather than neurotic depression. SAMe crosses the blood-brain barrier. SAMe is involved in several central enzyme pathways relating to transmethylation and folate and monoamine metabolism as well as in membrane function and neuro-transmission. The neuropharmacology of SAMe's effect on mood and the switch mechanism has yet to be fully explored. The actions of SAMe on the dopaminergic system are as yet unclear. SAMe is a physiologic substance that is non-toxic and relatively free of severe side effects (with the exception of mania, which may be a manifestation of the basic mood disorder.

Carney MW, Chary TK, Bottiglieri T, Reynolds EH. The switch mechanism and the bipolar/unipolar dichotomy. Br J Psychiatr 1989 Jan;154:48-51.
Abstract: During open trials of intravenous and oral S-adenosyl methionine (SAM) and a placebo-controlled trial of intravenous SAM in 29 patients, 25 patients had SAM and four had placebo (27 courses of SAM, two of the patients receiving two trials a piece). Nine of 11 bipolar patients (all SAM-treated) switched into elevated mood state (hypomania, mania and euphoria) and two did not respond. Six endogenous unipolar patients improved and five did not. No non-endogenous patient or placebo patient responded for more than 14 days. No unipolar patient switched into elated mood. In eleven (38%) trials and nine (33%) patients there was a switch from depression to elation. Biochemical data from the cerebrospinal fluid of eight patients suggested that the role of the dopaminergic system should be further explored.

Carney MW, Chary TK, Bottiglieri T, Reynolds EH. Switch and S-adenosyl-methionine. Alabama J Med Sci 1988 Jul;25(3):316-319.

Caruso I, Pietrogrande V. Italian double-blind multicenter study comparing S-adenosylmethionine, naproxen, and placebo in the treatment of degenerative joint disease. Am J Med Nov 20;83(5A):66-71.
Abstract: In a double-blind study, the efficacy and tolerability of S-adenosylmethionine (SAMe) were evaluated in comparison with those of placebo and naproxen in the treatment of osteoarthritis of the hip, knee, spine, and hand. Thirty-three centers, 18 rheumatologic and 15 orthopedic, participated in this study. A total of 734 subjects, including 582 with coxarthrosis (hip osteoarthritis) or gonarthrosis (knee osteoarthritis), were enrolled. SAMe administered orally at a dose of 1,200 mg daily was shown to exert the same analgesic activity as naproxen at a dose of 750 mg daily. Both drugs were more effective than placebo (p less than 0.01). Tolerability of SAMe was significantly better than that of naproxen, both in terms of physicians' (p less than 0.025) and patients' (p less than 0.01) judgments and in terms of the number of patients with side effects (p less than 0.05). There was no difference between SAMe and placebo in the number of side effects. Ten patients in the SAMe group and 13 in the placebo group withdrew from the study because of intolerance to the drug.

Cass H. SAMe: A Supplement for the 21st Century. Natural Pharmacy, Dec 1999.

Cerutti R, et al. Psychological distress during peurperium: A novel therapeutic approach using S-adenosyl-methionine. Curr Ther Res 1993;53:707-717.

Chiang PK, Gordon RK, Tal J, Zeng GC, Doctor BP, Pardhasaradhi K, McCann PP. S-Adenosylmethionine and methylation. FASEB J 1996 Mar;10(4):471-480. (Review)
Abstract: S-Adenosylmethionine (AdoMet or SAM) plays a pivotal role as a methyl donor in a myriad of biological and biochemical events. Although it has been claimed that AdoMet itself has therapeutic benefits, it remains to be established whether it can be taken up intact by cells. S-Adenosylhomocysteine (AdoHcy), formed after donation of the methyl group of AdoMet to a methyl acceptor, is then hydrolyzed to adenosine and homocysteine by AdoHcy hydrolase. This enzyme has long been a target for inhibition as its blockade can affect methylation of phospholipids, proteins, DNA, RNA, and other small molecules. Protein carboxymethylation may be involved in repair functions of aging proteins, and heat shock proteins are methylated in response to stress. Bacterial chemotaxis involves carboxymethylation and demethylation in receptor-transducer proteins, although a similar role in mammalian cells is unclear. The precise role of phospholipid methylation remains open. DNA methylation is related to mammalian gene activities, somatic inheritance, and cellular differentiation. Activation of some genes has been ascribed to the demethylation of critical mCpG loci, and silencing of some genes may be related to the methylation of specific CpG loci. Viral DNA genomes exist in cells as extrachromosomal units and are generally not methylated, although once integrated into host chromosomes, different patterns of methylation are correlated with altered paradigms of transcriptional activity. Some viral latency may be related to DNA methylation. Cellular factors have been found to interact with methylated DNA sequences. Methylation of mammalian ribosomal RNAs occurs soon after the synthesis of its 47S precursor RNA in the nucleolus before cleavage to smaller fragments. Inhibition of the methylation of rRNA affects its processing to mature 18S and 28S rRNAs. The methylation of 5'-terminal cap plays an important role in mRNA export from the nucleus, efficient translation, and protection of the integrity of mRNAs. Another important function of AdoMet is that it serves as the sole donor of an aminopropyl group that is conjugated with putrescine to form, first, the polyamine spermidine, and then spermine.

Czap A. Beware the Son of SAMe. http://www.thorne.com/altmedrev/editorial4-2.html.

Czyrak A, Rogoz Z, Skuza G, Zajaczkowski W, Maj J. Antidepressant activity of S-adenosyl-L-methionine in mice and rats. J Basic Clin Physiol Pharmacol 1992 Jan-Mar;3(1):1-17.
S-Adenosyl-L-methionine (SAM), main methyl donor, was tested in mice and rats in several models which are predictive of possible antidepressant activity. In the forced swimming test in rats the effect of SAM was compared with that of the tricyclic antidepressant amitriptyline. SAM decreased dose-dependently immobility time in the forced swimming test in mice and rats, these effects being antagonized by haloperidol and prazosin (the latter only in rats). Locomotor or exploratory activity in mice and rats was not increased by SAM. D-Amphetamine-induced locomotor hyper-activity in rats was increased by repeated (14 days, twice daily) treatment with SAM. Behavioral stimulation induced by D-amphetamine or L-dopa (given with benserazide) in mice was not changed by a single dose of SAM. The drug reduced hypothermia induced by apomorphine in mice. Hypothermia induced by reserpine or clonidine in mice was not antagonized. SAM increased the amplitude of the acoustic startle reflex. The above results indicate that the psychopharmacological profile of SAM resembles that of antidepressants in only some tests. The mechanism by which SAM produces its antidepressant effect needs further investigation.

De Vanna M, Rigamonti R. Oral S-adenosyl-L-methionine in depression. Curr Ther Res 1992;52:478-485.

Di Benedetto P, Iona LG, Zidarich V. Clinical evaluation of S-adenosyl-L-methionine versus transcutaneous nerve stimulation in primary fibromyalgia. Curr Ther Res 1993;53, 222-229.

Di Padova C. S-adenosyl-methionine in the treatment of osteoarthritis: Review of the clinical studies. Am J Med 1987;Nov 20;83(5A):60-64.
Abstract: S-Adenosylmethionine (SAMe), a physiologic compound that ranks with ATP as a pivotal molecule in biology, offers physicians an innovative approach to the treatment of osteoarthritis. Experimental investigations suggest that the administration of SAMe exerts analgesic and antiphlogistic activities and stimulates the synthesis of proteoglycans by articular chondrocytes with minimal or absent side effects on the gastrointestinal tract and other organs. The results of extensive clinical trials, which have enrolled about 22,000 patients with osteoarthritis in the last five years, support the clinical effectiveness and the optimal tolerability of SAMe administration. The intensity of therapeutic activity of SAMe against osteoarthritis is similar to that exerted by nonsteroidal anti-inflammatory drugs, but its tolerability is higher. Based on these findings, SAMe is proposed as the prototype of a new class of safe drugs for the treatment of osteoarthritis.

Domljan Z, Vrhovac B, Durrigl T, Pucar I. A double-blind trial of ademetionine vs naproxen in activated gonarthrosis. Int J Clin Pharmacol Ther Toxicol 1989 Jul;27(7):329-333.

Fava M, Rosenbaum JF, MacLaughlin R, Falk WE, Pollack MH, Cohen LS, Jones L,Pill L. Neuroendocrine effects of S-adenosyl-L-methionine, a novel putativeantidepressant. J Psychiatr Res 1990;24(2):177-184.
Abstract: S-adenosyl-L-methionine (SAMe), a putative antidepressant, is a naturally occurring substance whose mechanism of action is still a matter of speculation. It has been recently postulated that SAMe may increase the dopaminergic tone in depressed patients. Since dopamine inhibits both thyrotropin (TSH) and prolactin secretion, we investigated the effects of treatment with SAMe on the TSH and prolactin response to thyrotropin-releasing-hormone (TRH) stimulation in 7 depressed outpatient women (mean age: 46.1 +/- 7.2 years) and 10 depressed outpatient men (mean age: 38.0 +/- 10.0 years) participating in a six-week open study of oral SAMe in the treatment of major depression. At the end of the study, there was a significant reduction after treatment with SAMe in the response of both prolactin and TSH to TRH stimulation in the group of depressed men compared to pre-treatment values. On the other hand, in the group of depressed women, the posttreatment prolactin response to TRH did not appear to change when compared to pre-treatment and the TSH response to TRH challenge tended even to augment slightly after treatment with SAMe. Our results, at least in depressed men, seem to support the hypothesis of a stimulating effect of SAMe on the dopaminergic system.

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):295-297.
Abstract: A possible method of reducing the delay in antidepressant response is to useS-adenosyl-L-methionine (SAMe), a naturally occurring compound that appears tohave a rapid onset of effect in the treatment of depression. In this open,multicenter study, 195 patients were given 400 mg of SAMe, administeredparenterally, for 15 days. Depressive symptoms remitted after both 7 and 15 days of treatment with SAMe, and no serious adverse events were reported.Further studies with a double-blind design are needed to confirm thispreliminary indication that SAMe is a relatively safe and fast-acting antidepressant.

Fava M, Rosenbaum JF, MacLaughlin R, Falk WE, Pollack MH, Cohen LS, Jones L, Pill L. Neuroendocrine effects of S-adenosyl-L-methionine, a novel putative antidepressant.J Psychiatr Res. 1990;24(2):177-184.
Abstract: S-adenosyl-L-methionine (SAMe), a putative antidepressant, is a naturally occurring substance whose mechanism of action is still a matter of speculation. It has been recently postulated that SAMe may increase the dopaminergic tone in depressed patients. Since dopamine inhibits both thyrotropin (TSH) and prolactin secretion, we investigated the effects of treatment with SAMe on the TSH and prolactin response to thyrotropin-releasing-hormone (TRH) stimulation in 7 depressed outpatient women (mean age: 46.1 +/- 7.2 years) and 10 depressed outpatient men (mean age: 38.0 +/- 10.0 years) participating in a six-week open study of oral SAMe in the treatment of major depression. At the end of the study, there was a significant reduction after treatment with SAMe in the response of both prolactin and TSH to TRH stimulation in the group of depressed men compared to pre-treatment values. On the other hand, in the group of depressed women, the posttreatment prolactin response to TRH did not appear to change when compared to pre-treatment and the TSH response to TRH challenge tended even to augment slightly after treatment with SAMe. Our results, at least in depressed men, seem to support the hypothesis of a stimulating effect of SAMe on the dopaminergic system.

Fava M, Rosenbaum JF, Birnbaum R, et al. The thyrotropin-releasing hormone as a predictor of response to treatment in depressed outpatients. Acta Psychiatr Scand 1992;86:42-45.

Frezza M, Surrenti C, Manzillo G, Fiaccadori F, Bortolini M, Di Padova C. Oral S-adenosyl-methionine in the symptomatic treatment of intrahepatic cholestasis: A double-blind, placebo-controlled study. Gastroenterology 1990 Jul;99(1):211-215.
Abstract: Parenteral S-adenosylmethionine proved to be effective in reversing intrahepatic cholestasis in pregnant women. Based on these findings, a prospective multicenter, double-blind, placebo-controlled trial was planned to assess whether oral S-adenosylmethionine is effective in cholestatic patients with chronic liver disease. Accordingly, 220 inpatients (26% chronic active hepatitis, 68% cirrhosis, 6% primary biliary cirrhosis) with stable (1 month or more) at least twofold increases in serum total and conjugated bilirubin and alkaline phosphatase volunteered for the trial. Serum markers of cholestasis significantly (P less than 0.01) decreased after oral S-adenosylmethionine administration (1600 mg/day), and their values were significantly (P less than 0.01) lower than the corresponding values in the placebo group. S-adenosylmethionine significantly (P less than 0.01) improved subjective symptoms such as pruritus, fatigue, and feeling of being unwell, whereas placebo was ineffective. Two patients in the S-adenosylmethionine group and 9 controls (P less than 0.05) withdrew from the trial for reduced compliance because of inefficacy of treatment. Oral S-adenosylmethionine was tolerated to the same extent as placebo. In conclusion, short-term administration of oral S-adenosylmethionine is more effective than placebo in improving clinical and laboratory measures of intrahepatic cholestasis and offers a new therapeutic modality for the symptomatic management of this syndrome.

Frezza M, Tritapepe R, Pozzato G, Di Padova C. Prevention of S-adenosylmethionine of estrogen-induced hepatobiliary toxicity in susceptible women. Am J Gastroenterol. 1988 Oct;83(10):1098-1102.
Abstract: Women with past histories of intrahepatic cholestasis of pregnancy (ICP) exhibit a congenital exaggerated sensitivity to estrogens, which may express as abnormal hepatic reactivity to oral contraceptive intake and increased risk of developing gallbladder disease. Since previous investigations have shown that S-adenosylmethionine (SAMe) is effective in antagonizing ICP, we wondered whether its administration to subjects with previous ICP could 1) protect them from a challenge with ethynylestradiol (EE) or 2) normalize the cholesterol saturation index (CSI). To test the first hypothesis, six women volunteered to receive EE (0.1 mg/day orally for 1 wk) and, after 3 months, the same EE dose plus oral SAMe (800 mg/day for 1 wk). EE significantly increased serum values of transaminases, conjugated bilirubin, and total bile acids with respect to basal values. In the rechallenge with EE plus SAMe, liver function tests did not differ from basal levels and were significantly lower than the values obtained after EE. In the second experiment, we gave oral SAMe (800 mg/day for 2 wk) to seven women with previous ICP who exhibited cholesterol supersaturation of duodenal bile. Both subjects were nonpregnant and nonobese and had cholecystograms negative for gallstones. Bile CSI decreased from a basal value of 1.35 +/- 0.07 to 0.98 +/- 0.08 after SAMe (p less than 0.01). These findings indicate that SAMe protects women with previous ICP from EE-induced liver toxicity and normalizes bile CSI in the same subjects who secrete lithogenic bile. The data support the belief that SAMe acts as a physiological antidote against estrogen hepatobiliary toxicity in susceptible women.

Friedel HA, Goa KL, Benfield. S-adenosyl-L-methionine. A review of its pharmacological properties andtherapeutic potential in liver dysfunction and affective disorders in relationto its physiological role in cell metabolism. Drugs 1989 Sep;38(3):389-416.
S-Adenosyl-L-methionine (SAMe) is a naturally occurring molecule distributed to virtually all body tissues and fluids. It is of fundamental importance in anumber of biochemical reactions involving enzymatic transmethylation, contributing to the synthesis, activation and/or metabolism of such compounds as hormones, neurotransmitters, nucleic acids, proteins, phospholipids and certain drugs. The administration of a stable salt of SAMe, either orally or parenterally, has been shown to restore normal hepatic function in the presence of various chronic liver diseases (including alcoholic and non-alcoholic cirrhosis, estrogen-induced and other forms of cholestasis), to prevent or reverse hepatotoxicity due to several drugs and chemicals such as alcohol, paracetamol (acetaminophen), steroids and lead, and to have antidepressant properties. In all of these studies SAMe has been very well tolerated, a finding of great potential benefit given the well-known adverse effects of tricyclic antidepressants with which it has been compared in a few trials. Thus, with its novel mechanisms of action and good tolerability, SAMe is an interesting new therapeutic agent in several diverse disease conditions, but its relative value remains to be determined in appropriate comparisons with other treatment modalities in current use.

Gatto G et al. Analgesizing effect of a methyl donor (S-adenosylmethionine) in migraine: an open clinical trial. Int J Clin Pharmacol Res 1986;6:15-17.

Glorioso S, Todesco S, Mazzi A, Marcolongo R, Giordano M, Colombo B, Cherie-Ligniere G, Mattara L, Leardini G, Passeri M, et al. Double-blind multicentre study of the activity of S-adenosylmethionine in hip and knee osteoarthritis. Int J Clin Pharmacol Res 1985;5(1):39-49.

Harmand MF, Vilamitjana J, Maloche E, Duphil R, Ducassou D. Effects of S-adenosylmethionine on human articular chondrocyte differentiation: An in vitro study. Am J Med 1987 Nov 20;83(5A):48-54.
Abstract: The effect of S-adenosyl-L-methionine (SAMe) on human articular osteoarthritic chondrocytes was studied using a thick-layer culture model. Three SAMe concentrations were tested (1, 10, and 100 micrograms/ml). For 10 micrograms/ml, the most efficient dose, a significant rise in the incorporation levels of 35S-sulfate and 3H-serine was observed, as was as an increase in the hexuronic acid content. All the parameters seem to express a more active protein synthesis, particularly for proteoglycans. Under the same conditions, the proliferation rate of chondrocytes does not undergo important variations. These results point to a direct action on the cell metabolism but little is known concerning the mechanism involved.

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.
Abstract: S-adenosylmethionine is a relatively new anti-inflammatory drug with analgesic and anti-depressant effects. Efficacy of 800 mg orally administered s-adenosylmethionine daily versus placebo for six weeks was investigated in 44 patients with primary fibromyalgia in double-blind settings. Tender point score, isokinetic muscle strength, disease activity, subjective symptoms (visual analog scale), mood parameters and side effects were evaluated. Improvements were seen for clinical disease activity (P = 0.04), pain experienced during the last week (P = 0.002), fatigue (P = 0.02), morning stiffness (P = 0.03) and mood evaluated by Face Scale (P = 0.006) in the actively treated group compared to placebo. The tender point score, isokinetic muscle strength, mood evaluated by Beck Depression Inventory and side effects did not differ in the two treatment groups. S-adenosylmethionine has some beneficial effects on primary fibromyalgia and could be an important option in the treatment hereof.

Janicak PG, Lipinski J, Davis JM, Altman E, Sharma RP. Parenteral S-adenosyl-methionine (SAMe) in depression: literature review and preliminary data. Psychopharmacol Bull 1989;25(2):238-242.

Kagan BL, Sultzer DL, Rosenlicht N, Gerner RH. Oral S-adenosylmethionine in depression: a randomized, double-blind,placebo-controlled trial. Am J Psychiatry 1990 May;147(5):591-595.
Abstract: Methylation has been implicated in the etiology of psychiatric illness. Parenteral S-adenosylmethionine, a methyl group donor, has been shown to be an effective antidepressant. The authors studied the antidepressant effect of oral S-adenosylmethionine in a randomized, double-blind, placebo-controlled trialfor 15 inpatients with major depression. The results suggest that oral S-adenosylmethionine is a safe, effective antidepressant with few side effects and a rapid onset of action. S-Adenosylmethionine induced mania in a patientwith no history of mania. S-Adenosylmethionine may be useful for patients who cannot tolerate tricyclic anti-depressants. These findings support a role for methylation in the pathophysiology of depression.

Konig H, Stahl H, Sieper J, Wolf KJ. [ Magnetic resonance tomography of finger polyarthritis: Morphology and cartilage signals after ademetionine therapy.] Aktuelle Radiol 1995 Jan;5(1):36-40. [Article in German]
Abstract: This report deals with a prospective study of 21 patients with finger osteoarthritis treated over a period of three months with either Ademetionin (therapy group: 14/21) or without (control group: 7/21). MR-Imaging was carried out before and after treatment using spin-echo and 3D-Flash sequences. Morphological parameters and signal intensity changes of the hyaline cartilage were evaluated. The increase of the cartilage signal intensity was significant in the therapy group, this can be interpreted as an structural improvement. Also a decrease of the cartilage signal intensity with age was found. The morphological parameters showed no significant changes in the therapy and control groups.

Lieber CS. Herman Award lecture, 1993: a personal perspective on alcohol, nutrition, and the liver. Am J Clin Nutr 1993;58:430-442. (Review)

Lipinski JF, Cohen BM, Frankenburg F, Tohen M, Waternaux C, Altesman R, Jones B, Harris P. Open trial of S-adenosylmethionine for treatment of depression. Am J Psychiatry 1984 Mar;141(3):448-450.
Nine depressed inpatients completed trials with S-adenosylmethionine. Seven showed improvement or remission of their symptoms. As in European studies, no side effects were seen except the apparent induction of mania in two patients with bipolar disorder.

Loehrer FM, Schwab R, Angst CP, Haefeli WE, Fowler B. Influence of oral S-adenosylmethionine on plasma 5-methyltetrahydrofolate, S-adenosylhomocysteine, homocysteine and methionine in healthy humans. J Pharmacol Exp Ther. 1997 Aug;282(2):845-850.
Abstract: Elevated plasma homocysteine concentration is an independent risk factor for vascular disease in humans. In addition to nutritional and genetic factors, an interruption of the coordinate regulatory function of S-adenosylmethionine has been proposed to be involved in the occurrence of hyperhomocysteinemia. The effect of oral S-adenosylmethionine on homocysteine metabolism in humans is unknown. We investigated the effect of oral S-adenosylmethionine (400 mg) on plasma levels of 5-methyltetrahydrofolate, which is the active form of folate in the remethylation of homocysteine to methionine, S-adenosylhomocysteine, the demethylated product of S-adenosylmethionine, homocysteine and methionine over 24 hr in 14 healthy subjects. After oral administration, S-adenosylmethionine increased from 38.0 +/- 13.4 to 361.8 +/- 66.4 nmol/liter (mean +/- S.E., P < .001) and returned to base-line values with a half-life of 1.7 +/- 0.3 hr. Both S-adenosylhomocysteine and 5-methyltetrahydrofolate showed a significant transient increase (from 29.9 +/- 3.7 to 51.7 +/- 7.1 nmol/liter, and from 25.1 +/- 2.5 to 36.2 +/- 3.5 nmol/liter, respectively, P < .001), although homocysteine and methionine did not change over the time of measurement. These changes were not found in subjects without previous S-adenosylmethionine administration. The observed metabolic changes suggest that S-adenosylmethionine, at least in concentrations obtained in this study, does not inhibit 5,10-methylenetetrahydrofolate reductase, the 5-methyltetrahydrofolate forming enzyme. Rather they indicate a positive effect on 5-methyltetrahydrofolate, a key cofactor in homocysteine metabolism, which should be considered in homocysteine lowering strategies for the prevention of vascular disease.

Loehrer FM, Angst CP, Haefeli WE, Jordan PP, Ritz R, Fowler B. Low whole-blood S-adenosylmethionine and correlation between 5-methyltetrahydrofolate and homocysteine in coronary artery disease. Arterioscler Thromb Vasc Biol 1996 Jun;16(6):727-733.

Maccagno A, Di Giorgio EE, Caston OL, Sagasta CL. Double-blind controlled clinical trial of oral S-adenosylmethionine versus piroxicam in knee osteoarthritis. Am J Med 1987;83(suppl 5A):72-77.
Abstract: A double-blind, randomized, 84-day controlled clinical trial was carried out to compare orally administered S-adenosylmethionine (SAMe) (1,200 mg per day) with oral piroxicam therapy (20 mg per day) in the management of unilateral knee osteoarthritis. The ability of each drug to maintain the results achieved at the end of the treatment period was also evaluated during a 56-day follow-up period. Forty-five patients completed the study, 22 in the SAMe group and 23 in the piroxicam group. Both SAMe and piroxicam proved effective in inducing a significant improvement in the total pain score after 28 days of treatment. With regard to the other clinical parameters (i.e., morning stiffness, the distance walked before the onset of pain, active and passive motility), improvement started from about Day 56 in both groups. No significant difference was found between the two treatments in terms of efficacy and tolerability. Patients treated with SAMe maintained clinical improvement achieved at the end of treatment longer than did patients receiving piroxicam.

Mantero M, Pastorino P, Carolei A, Agnoli A. [Controlled double-blind study (SAMe-imipramine) in depressive syndromes.] Minerva Med 1975 Nov 17;66(78):4098-4101.[Article in Italian]
Thirty one patients were treated with either S-Adenosylmethionine or Imipraminein a double-blind clinical trial comparing S-Adenosylmethionine (25 mg i.m. three times daily) with Imipramine (25 mg i.m. three times daily) administered for a period of three weeks. Hamilton Rating scores showed no significant differences between treatments, but such slight differences as were observed favored S-Adenosylmethionine.

Marcolongo R, Giordano N, Colombo B, et al. Double-blind multicentre study of the activity of s-adenosyl-methionine in hip and knee osteoarthritis. Curr Ther Res 1985;37:82-94.

Montrone F, Fumagalli M, Sarzi Puttini P, et al. Double-blind study of S-adenosyl-methionine versus placebo in hip and knee arthrosis. Clin Rheumatol 1985;4:484-485.

Muller-Fassbender H. Double-blind clinical trial of S-adenosylmethionine in versus ibuprofen in the treatment of osteoarthritis. Am J Med 1987;83(suppl 5A):81-83.

Ortiz P. [S-Adenosyl-L-methionine. Latest results on its efficacy as an antidepressiveagent]. Actas Luso Esp Neurol Psiquiatr Cienc Afines 1988 May-Jun;16(3):201-203. [Article in Spanish]

Osman E, Owen JS, Burroughs AK. S-adenosyl-L-methionineæ a new therapeutic agent in liver disease? Aliment Pharmacol Ther 1993;7:21-28. (Review)

Piacentino R, Malara D, Zaccheo F, et al. Preliminary study of the use of s. adenosyl methionine in the management of male sterility. Minerva Ginecologica 1991;43:191-193. [Article in Italian]

Potkin SG, Bell K, Plon L, Bunney WE Jr. Rapid antidepressant response with SAMe. A double-blind study. Ala J Med Sci 1988 Jul;25(3):313-316. Published erratum appears in Ala J Med Sci 1988 Oct;25(4):496.

Reynolds EH, Carney MW, Toone BK. Methylation and mood. Lancet 1984 Jul 28;2(8396):196-198.
Abstract: S-adenosylmethionine (SAM) has antidepressant properties. The commonest neuropsychiatric complication of severe folate deficiency is depression. These independent observations suggest that methylation in the nervous system may underlie the expression of mood and related processes and may be implicated in some affective disorders; suggest new biological approaches to the understanding and treatment of some affective disorders; and may explain why methionine sometimes aggravates schizophrenia.

Rosenbaum JF, Fava M, Falk WE, Pollack MH, Cohen LS, Cohen BM, Zubenko GS. The antidepressant potential of oral S-adenosyl-l-methionine. Acta Psychiatr Scand 1990 May;81(5):432-436.
S-adenosyl-l-methionine (SAMe), a naturally occurring brain metabolite, has previously been found to be effective and tolerated well in parenteral form as a treatment of major depression. To explore the antidepressant potential of oral SAMe, we conducted an open trial in 20 outpatients with major depression, including those with (n = 9) and without (n = 11) prior history of antidepressant nonresponse. The group as a whole significantly improved with oral SAMe: 7 of 11 non-treatment-resistant and 2 of 9 treatment-resistant patients experienced full antidepressant response. Side effects were mild and transient.

Salmaggi P, Bressa GM, Nicchia G, et al. Double-blind, placebo-controlled study of s-adenosyl-methionine in depressed post-menopausal women. Psychotherapy and Psychosomatics 1993;59:34-40.

Schumacher HR. Osteoarthritis: The clinical picture, pathogenesis, and management with studies on a new therapeutic agent, S-adenosylmethionine. Am J Med 1987;83(suppl 5A):1-4. (Review)

Smythies JR, Alarcon RD, Morere D, Monti JA, Steele M, Tolbert LC, Walter-Ryan WG. Abnormalities of one-carbon metabolism in psychiatric disorders: study of methionine adenosyltransferase kinetics and lipid composition of erythrocyte membranes. Biol Psychiatry 1986 Dec;21(14):1391-1398.
Two independent lines of inquiry have implicated some disturbance of one-carboncycle metabolism in affective disorders. Folic acid deficiency commonly leadsto depression, and S-adenosylmethionine has been reported to have antidepressant properties. Methionine adenosyltransferase has been reported to be underactive in depression and schizophrenia and overactive in mania. This study reports the effects on erythrocyte methionine adenosyltransferase (MAT)kinetics (Vmax) of a 2-week treatment in a population of patients housed on a psychiatric research ward. The drug-free schizophrenic patients and depressives had, upon admission, low Vmax values, and the drug-free manic patients had high Vmax values on admission. After 2 weeks of appropriate treatment, the values for all three patient samples showed significant normalization (i.e., the levels rose in schizophrenics and depressives and fell in manics). We have further shown that pretreatment low levels of erythrocyte membrane phosphatidylcholine in depressives and high levels in manics show statistically significant normalization following 2 weeks of pharmacotherapy. The significance of these results is discussed.

Solomon L, Drug induced arthropathy and necrosis of the femoral head. J Bone Joint Surg 1973;55B, 246-251.

Tavoni A, Vitali C, Bombardieri S, et al. Evaluation of S-adenosylmethionine in primary fibromyalgia: A double-blind crossover study. Am J Med 1987;83(suppl 5A):107-110.

Thomas CS, Bottiglieri T, Edeh J, Carney MW, Reynolds EH, Toone BK. The influence of S-adenosylmethionine (SAM) on prolactin in depressed patients. Int Clin Psychopharmacol 1987 Apr;2(2):97-102.
Twenty subjects entered a double-blind placebo-controlled trial of SAM in depression. Prolactin concentrations were measured before and after 14 days' treatment. There was a highly significant fall in prolactin concentrations in the SAM-treated group.

Tramoni AV, Azorin JM. [Therapeutic indications of S-adenosyl methionine in neuropsychiatry.] Encephale 1988 May-Jun;14(3):113-118.[Article in French]
Abstract: Studies conducted by Italian and Anglo-saxon authors underline the thymoanaleptic properties of a transmethylant biological substance, the S-adenosyl methionine (SAMe). The authors discuss a review of literature concerning the use of SAMe in neuro-psychiatry, particularly in the treatment of affective disorders. The many physiopathological implications are subtended by the biological inter-relations of SAMe with other biological substances. Some hypotheses are proposed on the role played by phospholipid methylation, the folate metabolism and the purinergic transmission in mental diseases.

Vahora SA, Malek-Ahmadi P. S-adenosylmethionine in the treatment of depression. Neurosci Biobehav Rev 1988 Summer;12(2):139-141.
The antidepressant property of S-adenosylmethionine (SAMe) has been supported by several uncontrolled and controlled studies. Compared to standard antidepressant agents, SAMe has fewer side-effects and shorter lag period. Future studies to delineate SAMe-responsive depression are warranted.

Vendemiale G, Altomare E, Trizio T, Le Grazie C, Di Padova C, Salerno MT, Carrieri V, Albano O. Effects of oral S-adenosyl-L-methionine on hepatic glutathione in patients with liver disease. Scand J Gastroenterol. 1989 May;24(4):407-415.
Abstract: S-Adenosyl-L-methionine (SAMe) is a physiologic precursor of thiols and sulfurated compounds, which are known to be decreased in patients with liver disease. The effect of its administration on the hepatic glutathione content of liver patients was investigated. Four groups of subjects were selected: a) 9 patients with alcoholic liver disease treated with SAMe (1.2 g/day orally for 6 months); b) 7 patients with non-alcoholic liver disease treated as above; c) 8 placebo-treated patients with alcoholic liver disease; and d) 15 normal subjects as a control group. Total and oxidized glutathione were assayed by high-performance liquid chromatography of liver biopsy specimens before and after the treatment period. In all patients pre-treatment hepatic glutathione was significantly decreased as compared with controls. SAMe therapy resulted in a significant increase of hepatic glutathione levels both in patients with alcoholic and in those with non-alcoholic liver diseases as compared with placebo-treated patients. SAMe may therefore exert an important role in reversing hepatic glutathione depletion in patients with liver disease.
Vetter G. Double-blind comparative clinical trial with S-adenosylmethionine and indomethacin in the treatment of osteoarthritis. Am J Med 1987;83(suppl 5A):78-80.

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):206-211.
Abstract: The objective of this study was to test the efficacy of intravenously administered S-adenosyl-L-methionine (SAMe) in patients with fibromyalgia (FM). Thirty-four out-patients with fibromyalgia symptoms received SAMe 600 mg i.v. or placebo daily for 10 days in a cross-over trial. There was no significant difference in improvement in the primary outcome: tender point change between the two treatment groups. There was a tendency towards statistical significance in favour of SAMe on subjective perception of pain at rest (p = 0.08), pain on movement (p = 0.11), and overall well-being (p = 0.17) and slight improvement only on fatigue, quality of sleep, morning stiffness, and on the Fibromyalgia Impact Questionnaire for pain. No effect could be observed on isokinetic muscle strength, Zerrsen self-assessment questionnaire, and the face scale. No effect of SAMe in patients with FM was found in this short term study.

Young SN. The use of diet and dietary components in the study of factors controlling affect in humans: a review. J Psychiatry Neurosci 1993 Nov;18(5):235-244.
Abstract: Although one of the first biological treatments of a major psychiatric disorder was the dietary treatment of pellagra, the use of diet and dietary components in the study of psychopathology has not aroused much interest. This article reviews three areas in which the dietary approach has provided interesting information. The tryptophan depletion strategy uses a mixture of amino acids devoid of tryptophan to lower brain tryptophan in order to study the symptoms that can be elicited. One effect of tryptophan depletion is a lowering of mood,the magnitude of which seems to depend on the baseline state of the subject. Therefore, recovered depressed patients often undergo an acute relapse, while normal subjects show more moderate changes of mood. Totally euthymic subjects show no lowering of mood, but subjects with high normal depression scale scores or subjects with a family history of depression show a moderate lowering of mood. These data indicate that low serotonin levels alone cannot cause depression. However, serotonin does have a direct effect on mood, and low levels of serotonin contribute to the etiology of depression in some depressed patients. Folic acid deficiency causes a lowering of brain serotonin in rats, and of cerebrospinal fluid 5-hydroxyindoleacetic acid in humans. There is a high incidence of folate deficiency in depression, and there are indications inthe literature that some depressed patients who are folate deficient respond to folate administration. Folate deficiency is known to lower levels of S-adenosylmethionine, and S-adenosylmethionine is an antidepressant that raises brain serotonin levels. These data suggest that low levels of serotonin in some depressed patients may be a secondary consequence of low levels of S-adenosylmethionine. They also suggest that the dietary intake and psychopharmacological action of methionine, the precursor ofS-adenosylmethionine, should be studied in patients with depression. Normal meals have definite effects on mood and performance in humans. The composition of the meal, in terms of protein and carbohydrate content, can influence these behaviors. Because protein and carbohydrate meals can influence brain serotonin in rats, these effects in humans have usually been interpreted in terms of altered serotonin functioning. However, the current balance of evidence is against the involvement of serotonin in the acute effects of protein and carbohydrate meals in humans. The underlying mechanisms involved are unknown, but there are a variety of possibilities.