Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionin
Bottiglieri T; Godfrey P; Flynn T; Carney MW; Toone BK; Reynolds EH
Department of Neurology, King's College Hospital, London,U.K.
J Neurol Neurosurg Psychiatry (ENG.) Dec 1990, 53 (12) p1096-8,

Cerebrospinal fluid (CSF) S-adenosylmethionine (SAM) levels were significantly lower in severely depressed patients than in a neurological control group. The administration of SAM either intravenously or orally is associated with a significant rise of CSF SAM, indicating that it crosses the blood-brain barrier in humans. These observations provide a rational basis for the antidepressant effect of SAM, which has been confirmed in several countries. CSF SAM levels were low in a group of patients with Alzheimer's dementia suggesting a possible disturbance of methylation in such patients and the need for trials of SAM treatment.

The antidepressant potential of oral S-adenosyl-l-methionine
Rosenbaum JF; Fava M; Falk WE; Pollack MH; Cohen LS; Cohen BM; Zubenko GS
Clinical Psychopharm. Unit, Mass. General Hospital, Boston 02114
Acta Psychiatr Scand (DENMARK) May 1990, 81 (5) p432-6

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.

Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial
Kagan BL; Sultzer DL; Rosenlicht N; Gerner RH
Department of Psychiatry, West Los Angeles VA Medical Center, CA.
Am J Psychiatry (UNITED STATES) May 1990, 147 (5) p591-5

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 trial for 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 patient with 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.

S-adenosylmethionine in the treatment of depression
Vahora SA; Malek-Ahmadi P
Texas Tech University, School of Medicine, Department of Psychiatry, Lubbock 79430
Neurosci Biobehav Rev (U.S.) Summer 1988, 12 (2) p139-41,

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. (38 Refs.)

S-adenosylmethionine treatment of depression: a controlled clinical trial
Bell KM; Plon L; Bunney WE Jr; Potkin SG
University of California, Irvine Medical Center, Orange 92668
Am J Psychiatry (UNITED STATES) Sep 1988, 145 (9) p1110-4,

The antidepressant properties of S-adenosylmethionine, an endogenous methyl donor, 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 14 days. 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.

S-Adenosylmethionine Treatment of Depression in patients with Parkinson's Disease: a double-blind crossover study versus placebo
Carrieri P.B.; Indaco A.; Gentile S.; Troisi E.; Campanella G.
Clinica Neurologica, Il Facolta di Medicina e Chirurgia,
Universita di Napoli, Napoli, Italy
Curr Ther Res Jul 1990, 48 (1) p164,

Depression is frequently observed in patients with Parkinson's Disease (PD). A double-blind, crossover study versus placebo was conducted in 21 patients with PD and depression treated with S-adenosylmethionine (SAMe), an endogenous methyl donor. Duration of the study was 30 days for each arm, with a washout period of two weeks between treatments. At each evaluation, the Webster Rating Scale, the Northwestern University Disablility Scale, the Hamilton Rating Scale for Depression, and the Beck Self Depression Inventory were used. SAMe was administered at a dose of 400 mg. BID orally plus 200 mg IM daily. SAMe improved depression in patients with PD to a statistically larger extent than did placebo, although Parkinson symptoms appeared to be unchanged. Side effects were moderate and of a brief duration.

Oral S-adenosyl-L-methionine in depression
Vanna M. DE; Rigamonti R.
University Psychiatric Department, University of Trieste, Trieste,
and Psychiatric Unit, Ospedale Civile, Gorizia, Italy
Curr Ther Res Sep 1992, 52 (3), p478,

The antidepressant activity of oral S-adenosyl-L-methionine (SAMe) was evaluated in a randomized, double-blind, imipramine-controlled trial in 30 patients with major depression. The results suggest that oral SAMe is a safe, effective antidepressant with negligible side effects and a rapid onset of action. Only one patient became hypomanic but did not drop out of the study. SAMe may be useful for patients who cannot tolerate other antidepressant agents of for patients with other risk factors. These findings suggest a role for methylation in the pathophysiology of depression.

Results of treatment with S-adenosyl-L-methionine in patients with major depression and internal illnesses
Criconia AM; Araquistain JM; Daffina N; Navajas F; Bordino M
Department of Internal Medicine, Ospedale Cristo Re, Rome, Italy
Curr Ther Res June 1994, 55 (6), p666

Forty-eight patients with major depression associated with internal illnesses of various origins were enrolled for 4 weeks of treatment with S-adenosyl-L-methionine (SAMe). the medication was administered parenterally (400 mg daily either intravenously or intramuscularly) in inpatients and orally (800 mg daily) in outpatients. Evaluations were performed via Becks Depression Inventory (BDI) by comparing the scores on day 28 with baseline values. Statistically significant differences were observed (P < 0.01). Although minor adverse side effects were reported, they were not severe enough to withdraw medication. SAMe treatment proved to be effective and relatively safe in depressed patients with associated internal illnesses.

Clinical evaluation of S-adenosyl-L-methionine versus transcutaneous electrical nerve stimulation in primary fibromyalgia
Benedetto P Di; Iona LG; Zidarich V
Rehabilitation Center, Ospedale Santoro, Trieste, Italy
Curr Ther Res Feb 1993, 53 (2), p222,

The effects of S-adenosyl-L-methionine (SAMe) and transcutaneous electrical nerve stimulation (TENS) were evaluated in a 6-week controlled trial of 30 patients with primary fibromyalgia. Unlike TENS, SAMe significantly decreased the total number of tender points, had a significant beneficial effect on the subjective symptoms of pain and fatigue, and significantly reduced the scores on the Hamilton Depression and Anxiety Rating Scales and Zung's Self-Rating Scale for Depression. At the end of treatment, patients in the TENS group exhibited significantly reduced scores on the Hamilton Anxiety Scale only.

SAMe And Osteoarthritis
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.
Br J Rheumatol (ENGLAND) Jan 1997, 36 (1) p27-31

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 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 hours 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.

SAMe Impact on Hips And Knees
Glorioso S; Todesco S; Mazzi A; Marcolongo R; Giordano M;
Colombo B; Cherie-Ligniere G; Mattara L; Leardini G; Passeri M; et al.
Int J Clin Pharmacol Res (SWITZERLAND) 1985, 5 (1) p39-49

A randomized double-blind multicenter clinical trial was carried out to verify the effectiveness and tolerance of S-adenosylmethionine (SAMe) vs. ibuprofen in 150 patients with hip and/or knee osteoarthritis. Both drugs were given orally, 400 mg thrice daily for 30 days. SAMe exhibited a slightly more marked activity than the reference drug in the management of the various painful manifestations of the joint disease. Minor side-effects developed in five patients of the SAMe group, and in 16 patients of ibuprofen group. No drop-outs occurred. No changes were observed in the routine laboratory tests.

SAMe in Primary Fibromyalgia
Tavoni A; Vitali C; Bombardieri S; Pasero G Institute of Medical
Pathology I, University of Pisa, Italy.
Am J Med (UNITED STATES) Nov 20 1987, 83 (5A) p107-10

The effect of S-adenosylmethionine (SAMe) and placebo was evaluated in a short-term crossover study of 17 patients with primary fibromyalgia. Eleven of 17 patients had a significant depressive state as assessed by either the Hamilton Depression Rating Scale or the Scala di Autovalutazione per la Depressione (SAD) rating scale. The number of trigger points plus painful anatomic sites decreased after administration of SAMe (p less than 0.02) but not after placebo treatment. In addition, scores on both the Hamilton and SAD rating scales improved after SAMe administration (p less than 0.05 and p less than 0.005, respectively), whereas they did not significantly change after placebo treatment. In all the patients, there was a good correlation between scores on the Hamilton rating scale and the number of trigger points. Thus, this preliminary study confirms the close relationship between primary fibromyalgia and psychologic disturbances, particularly with regards to a depressive state. SAMe treatment, by improving the depressive state and reducing the number of trigger points, seems to be an effective and safe therapy in the management of primary fibromyalgia.

Oral SAMe And Primary Fibromyalgia
Jacobsen S; Danneskiold-Samsoe B; Andersen RB Department of
Rheumatology, Frederiksberg Hospital, Copenhagen, Denmark.
Scand J Rheumatol (SWEDEN) 1991, 20 (4) p294-302

S-adenosylmethionine is a relatively new anti-inflammatory drug with analgesic and anti-depressant effects. Efficacy of 800 mg orally administered s-adenosylmethionine daily vs. 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.

Two-Year Clinical SAMe Trial on Osteoarthritis
Konig B Institute of General Medicine, University of Mainz,
Federal Republic of Germany.
Am J Med (UNITED STATES) Nov 20 1987, 83 (5A) p89-94

In a long-term multicenter open trial involving 10 general practitioners, the efficacy and tolerance of S-adenosylmethionine (SAMe) were studied for 24 months in 108 patients with osteoarthritis of the knee, hip, and spine. At the end of the 24-month observation period, 97 of the patients were still in the study. The patients received 600 mg of SAMe daily (equivalent to three tablets of 200 mg each) for the first two weeks and thereafter 400 mg daily (equivalent to two tablets of 200 mg each) until the end of the 24th month of treatment. Separate evaluations were made for osteoarthritis of the knee, hip, cervical spine, and dorsal/lumbar spine. The severity of the clinical symptoms (morning stiffness, pain at rest, and pain on movement) was assessed using scoring before the start of the treatment, at the end of the first and second week of treatment, and then monthly until the end of the 24-month period. SAMe administration showed good clinical effectiveness and was well tolerated. The improvement of the clinical symptoms during therapy with SAMe was already evident after the first weeks of treatment and continued up to the end of the 24th month. Non-specific side effects occurred in 20 patients, but in no case did therapy have to be discontinued. Most side effects disappeared during the course of therapy. Moreover, during the last six months of treatment, no adverse effect was recorded. Detailed laboratory tests carried out at the start and after six, 12, 18, and 24 months of treatment showed no pathologic changes. SAMe administration also improved the depressive feelings often associated with osteoarthritis.

SAMe Vs. Ibuprofen
Muller-Fassbender H Rheumazentrum Bad Abbach, II Medizinische
Klinik, Bad Abbach, Federal Republic of Germany.
Am J Med (UNITED STATES) Nov 20 1987, 83 (5A) p81-3

Thirty-six subjects with osteoarthritis of the knee, the hip, and/or the spine were enrolled in a randomized double-blind study. Patients received a daily oral dose of 1,200 mg of S-adenosylmethionine (SAMe) or 1,200 mg of ibuprofen for four weeks. Morning stiffness, pain at rest, pain on motion, crepitus, swelling, and limitation of motion of the affected joints were assessed before and after treatment. The total score obtained by the evaluation of all the individual clinical parameters improved to the same extent in patients treated with SAMe or ibuprofen. Both treatments were well tolerated and no patient from either group withdrew from the study.

Clinical Studies: SAME And Osteoarthritis
Di Padova C Clinical Research Department, BioResearch S.p.A., Liscate-Milan, Italy.
Am J Med (UNITED STATES) Nov 20 1987, 83 (5A) p60-5

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.

Biochemistry of pharmacology of
S-adenosyl-L-methionine and rationale for its use in liver disease
DRUGS (New Zealand), 1990, 40/SUPPL. 3 (98-110)

The major biological functions of S-adenosyl-L-methionine (SAMe) include me thylation of various molecules (transmethylation) and synthesis of cysteine (trans-sulphuration). A stable double salt of SAMe has been found to be effective in intrahepatic cholestasis. The mechanism of its therapeutic effect is not fully understood but presumably involves methylation of phospholipids. Methylation of plasma membrane lipids may affect membrane fluidity and viscosity, which modulate the activities of a number of membrane-associated enzymes, for example, the activity of enzymes involved in Na+/Ca++ exchange (e.g. sarcolemmal vesicles), Na+/K+ adenosine triphosphatase (ATPase) (e.g. hepatocyte plasma membranes), and Na+/H+ exchange (e.g. plasma membranes of colonic cells). Recently, patients with cirrhosis were shown to have an acquired metabolic block in the hepatic conversion of methionine to SAMe. These patients, when administered conventional elemental diets, develop abnormally low plasma concentrations of cysteine and choline, 2 nonessential nutrients present in low concentrations in most elemental diets. These low concentrations probably reflect systemic deficiencies attributable to reduced endogenous syntheses of cysteine and choline caused by limited availability of hepatic SAMe. Such cirrhotic patients are often in negative nitrogen balance and have abnormal hepatic functions, which are corrected by cysteine and choline supplements. Noncirrhotic patients on parenteral elemental diets also become deficient in cysteine and choline. Consequently, these patients may require SAMe as an essential nutrient to normalise their overall hepatic transmethylation and trans-sulphuration activities.

S-Adenosyl-L-methionine. A review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism
DRUGS (New Zealand), 1989, 38/3

S-Adenosyl-L-methionine (SAMe) is a naturally occurring molecule distributed to virtually all body tissues and fluids. It is of fundamental importance in a number 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 parenterallly, has been shown to restore normal hepatic function in the presence of various chronic liver diseases (including alcoholic and non-alcoholic cirrhosis, oestrogen-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.

Oral S-adenosylmethionine in primary fibromyalgia-Double-blind clinical evaluation
Scand J Rheumatol (SWEDEN) 1991, 20 (4) p294-302,

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.

Primary fibromyalgia is responsive to S-adenosyl-L-methionine
CURR. THER. RES. CLIN. EXP. (USA), 1994, 55/7 (797-806)

Forty-seven patients with primary fibromyalgia were treated with S-adenosyl-L-methionine (SAMe) 200 mg intramuscularly once daily, plus SAMe 400 mg orally twice daily, for 6 weeks. The treatment was preceded by a 7-day drug-free run-in washout period. SAMe significantly decreased tenderness of painful sites, significantly improved general well-being, and significantly reduced the mean scores (baseline vs day 42) for the Hamilton Rating Scale for Depression, the Zung Self-Rating Scale, the Hamilton Rating Scale for Anxiety, and Lorish and Maisiak's Face Scale. SAMe was well tolerated in all patients and no adverse side effects were reported.

S-adenosyl-L-methionine in Sjogren's syndrome and fibromyalgia
CURR. THER. RES. CLIN. EXP. (USA), 1994, 55/6 (699-706)

The subjects were 30 patients aged 25 to 60 years (mean, 51 years) with primary Sjogren's syndrome, both Sjogren's syndrome and primary fibromyalgia, or fibromyalgia only. Each patient received 200 mg of S-adenosyl-L-methionine (SAMe) by intramuscular injection daily. After 4 weeks of treatment, in the 10 patients with Sjogren's syndrome, disease symptoms and scores on Zung's Self-Rating Scale for Depression showed a nonsignificant decrease; a reduction in mean scores on Hamilton's Rating Scale for Depression, however, was statistically significant (P < 0.05). In the 10 patients with both Sjogren's syndrome and fibromyalgia, no significant changes in symptoms, depression scale scores, or scores on a pain-severity scale were found; however, the numbers of tender points and painful areas were reduced significantly (P < 0.01). In the 10 patients with fibromyalgia, symptoms of fibromyalgia, numbers of tender points and painful areas, pain severity scores, and scores on both depression scales were reduced significantly (P < 0.01). No adverse side effects were reported. The results indicate that SAMe can reduce the symptoms of fibromyalgia and improve mood; further studies are warranted.

Evaluation of S-adenosylmethionine in primary fibromyalgia. A double-blind crossover study
AM. J. MED. (USA), 1987, 83/5 A (107-110)

The effect of S-adenosylmethionine (SAMe) and placebo was evaluated in a short-term crossover study of 17 patients with primary fibromyalgia. Eleven of 17 patients had a significant depressive state as assessed by either the Hamilton Depression Rating Scale or the Scala di Autovalutazione per la Depressione (SAD) rating scale. The number of trigger points plus painful anatomic sites decreased after administration of SAMe (p < 0.02) but not after placebo treatment. In addition, scores on both the Hamilton and SAD rating scales improved after SAMe administration (p < 0.05 and p < 0.005, respectively), whereas they did not significantly change after placebo treatment. In all the patients, there was a good correlation between scores on the Hamilton rating scale and the number of trigger points. Thus, this preliminary study confirms the close relationship between primary fibromyalgia and psychologic disturbances, particularly with regards to a depressive state. SAMe treatment, by improving the depressive state and reducing the number of trigger points, seems to be an effective and safe therapy in the management of primary fibromyalgia.

S-adenosylmethionine blood levels in major depression: Changes with drug treatment
ACTA NEUROL. SCAND. SUPPL. (Denmark), 1994, 89/154 (15-18)

Introduction - The relationship between plasma levels of S-adenosylmethionine (SAMe), an endogenous methyl donor, and clinical response were studied in patients with a DSM-III-R diagnosis of major depression. Material and methods - 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 the patients treated with desipramine had significantly improved. Regardless of the type 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 the degree of clinical improvement in depressed patients regardless of the type of treatment suggests that SAMe may play an important role in regulating mood.

Psychological distress during puerperium: A novel therapeutic approach using S-adenosylmethionine
CURR. THER. RES. CLIN. EXP. (USA), 1993, 53/6 (707-716)

A study was undertaken to assess postpartum psychological distress and to evaluate a novel approach to treatment. Kellner's Symptom Questionnaire proved to be a valuable predictive tool for anxiety, depression, somatic symptoms, and hostility in 190 women during puerperium. This epidemiologic investigation was followed by a two-phase comparative clinical study. The first phase was a double-blind trial of oral S-adenosylmethionine (SAMe) 1600 mg/day versus placebo for 30 days administered to two groups of 30 patients each. Compared with the patients receiving placebo, patients receiving SAMe exhibited improved symptom questionnaire total scores and depression and anxiety scores by day 10 of treatment. Progressive improvement was observed throughout the duration of the study. The second phase of the study was an open trial comparing 40 SAMe-treated patients with the epidemiologic group of patients as controls. After 30 days of treatment, the patients receiving SAMe showed a significant improvement in both total scores and depression and anxiety items compared with the control group. We conclude that SAMe is an effective treatment for reducing or relieving the signs and symptoms of psychological distress during puerperium.

Double blind, placebo-controlled study of S-adenosyl-L-methionine in depressed postmenopausal women
PSYCHOTHER. PSYCHOSOM. (Switzerland), 1993, 59/1 (34-40)

S-adenosyl-L-methionine (SAMe) is a naturally occurring substance which is a major source of methyl groups in the brain and has been found in previous studies to be an effective antidepressant. The aim of this study was to assess the efficacy of oral SAMe in the treatment of depressed postmenopausal women in a 30-day double-blind placebo-controlled randomized trial. During the course of the study, 80 women, between the ages of 45 and 59, who were diagnosed as having DSM-III-R major depressive disorder or dysthymia between 6 and 36 months following either natural menopause or hysterectomy, underwent 1 week of single-blind placebo washout, followed by 30 days of double-blind treatment with either SAMe 1,600mg/day or placebo. There was a significantly greater improvement in depressive symptoms in the group treated with SAMe compared to the placebo group from day 10 of the study. Side effects were mild and transient.

Treatment of depression in rheumatoid arthritic patients. A comparison of S-adenosylmethionine (Samyr) and placebo in a double-blind study
CLIN. TRIALS J. (UK), 1987, 24/4 (305-310)

A double-blind study to compare the efficacy and tolerability of S-adenosylmethionine (SAMe), Samyr, with that of placebo in the treatment of depression in rheumatoid arthritic (RA) patients was made. SAMe showed a significant improvement in the depression in RA patients and there was a significant difference between SAMe and placebo in all variables measured. No side-effects were ref S-adenosylmethionine for treatment of depression

Monitoring S-adenosyl-methionine blood levels and antidepressant effect
ACTA NEUROL. (ITALY), 1980, 35/6 (488-495)

Seven depressed inpatients, classified according to the Multi-Aspect Classification Model, were treated with S-adenosyl-methionine (SAMe), 200 mg pro die i.v. for three weeks, in a single blind trial. Blood SAMe levels were determined in samples collected in a basal condition and after drug administration on the 7th, 14th and 21st day of the treatment. Computerized spectral frequency analysis of bioelectric brain activity has been performed before and after the treatment using some geometrical spectral parameters. The Hamilton Rating Scale for Depression (HRS), Comprehensive Psychopathological Rating Scale and Zung's Scale were rated before, during and after the treatment on the days of blood collection. At the end of the treatment, the improvement, according to HRS total scores, varied from 12.8 to 42.8 per cent (mean + or - SD: 21.8 + or - 4). No side effects were noted. A negative linear correlation was found between HRS total scores and blood SAMe levels (r = -0.3641; p<0.05). EEG spectral computerized analysis shows some differences after the treatment, which might indicate that SAMe interacts with brain tissues. Further studies are required to clarify the relationship between blood SAMe levels, therapeutic response and EEG recordings.

Evaluation of S-adenosylmethionine (SAMe) effectiveness on depression
CURR. THER. RES., CLIN. EXP. (USA), 1980, 27/6II (908-918)

The therapeutic effect of S-adenosylmethionine (SAMe) was investigated in 39 patients affected with depressive illness. The study was not controlled by use of a placebo or another drug. The finding of a greater effect exerted by this drug on the symptoms of depression core than on those of anxiety, the good improvement in the mental state probably obtained through physiological mechanisms, the short latency of action and the absence of side effects suggest that SAMe may be an active drug for the treatment of the depressive illness.

Rapidity of onset of the antidepressant effect of parenteral S-adenosyl-L-methionine
Psychiatry Research (Ireland), 1995, 56/3

A possible method of reducing the delay in antidepressant response is to use S-adenosyl-L-methionine (SAMe), a naturally occurring compound that appears to have a rapid onset of effect in the treatment of depression. In this open, multicenter study, 195 patients were given 400 mg of SAMe, and no serious adverse events were reported. Further studies with a double-blind design are needed to confirm this preliminary indication that SAMe is a relatively safe and fast-acting antidepressant.

The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders
DRUGS (New Zealand), 1994, 48/2 (137-152)

This review focuses on the biochemical and clinical aspects of methylation in neuropsychiatric disorders and the clinical potential of their treatment with ademetionine (S-adenosylmethionine; SAMe). SAMe is required in numerous transmethylation reactions involving nucleic acids, proteins, phospholipids, amines and other neurotransmitters. The synthesis of SAMe is intimately linked with folate and vitamin B12 (cyanocobalamin) metabolism, and deficiencies of both these vitamins have been found to reduce CNS SAMe concentrations. Both folate and vitamin B12 deficiency may cause similar neurological and psychiatric disturbances including depression, dementia, myelopathy and peripheral 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 in patients 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.

Effects of S-adenosyl-L-methionine on cognitive and vigilance functions in the elderly
CURR. THER. RES. CLIN. EXP. (USA), 1994, 55/6

Forty elderly patients with impaired cognition and vigilance functions associated with primary or secondary organic brain syndrome were treated with S-adenosyl-L-methionine (SAMe) for 2 months. Patients scoring 17 or higher on Hamilton's Rating Scale for Depression (HRSD) were excluded from the study. The SAMe dosing schedule was 400 mg intravenously during the first 20 days, and 200 mg intramuscularly plus 400 mg orally twice daily for another 40 days. Examinations were performed using the Mini-Mental State Examination (MMSE) and the Sandoz Clinical Assessment Geriatric Scale (SCAG) at time 0 (baseline) and on days 20 and 60 of treatment. Statistically significant differences (P < 0.01) were observed in MMSE and SCAG total scores on day 60 versus baseline. Significant improvements were observed in 4 out of 19 items on the SCAG versus baseline on day 20, and in 13 out of 19 items versus baseline on day 60. No adverse side effects were reported.

S-adenosyl-l-methionine (SAMe) as antidepressant: Meta-analysis of clinical studies
ACTA NEUROL. SCAND. SUPPL. (Denmark), 1994, 89/154

Introduction - S-adenosyl-l-methionine (SAMe) is a naturally-occurring substance which 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 this compound in the treatment of depression compared with placebo and standard tricyclic antidepressants. Results - Our meta-analysis showed a greater response rate with SAMe when compared with placebo, with a global effect size ranging from 27% to 38% depending on the definition of response, and an antidepressant effect comparable with that of standard tricyclic antidepressants. Conclusion - The efficacy of SAMe in treating depressive syndromes and disorders is 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.

S-adenosyl-L-methionine in the treatment of major depression complicating chronic alcoholism
CURR. THER. RES. CLIN. EXP. (USA), 1994, 55/1

S-adenosyl-L-methionine (SAMe) is a methyl donor endowed with both antidepressant and detoxifying activity. In a 4-week trial, 40 alcoholic patients with major depression received 200 mg of SAMe daily administered intravenously and 400 mg BID administered orally. After a 1-week placebo period during which placebo responders were eliminated, patients were evaluated with the Hamilton Rating Scale for Depression, the Zung Self- Rating Scale for depression, the Hamilton Rating Scale for Anxiety, and the Lorish and Maisiak face scale at baseline and at days 7, 14, 21, and 28. Standard laboratory values were measured at baseline and at the completion of the trial. Significant improvements were seen in most psychometric scores beginning on day 14 and continuing through the end of the study. Baseline values for gamma-glutamyltranspeptidase, alkaline phosphatase, bilirubin, and mean corpuscular volume dropped dramatically and, in some cases, returned to normal. No adverse reactions were reported. Although standard antidepressant therapy has very often been unsuccessful in treating depression in these patients, SAMe proved to be well tolerated at the study dosage and was effective in reducing depression.

S-Adenosyl-methionine (SAMe) as antidepressant
NEW TRENDS CLIN. NEUROPHARMACOL. (Italy), 1992, 6/1-4

In 1971 S-Adenosylmethionine (SAMe) entered in clinical research. The clinical trial as well as an extensive clinical practice in Europe and more recently in the United States have shown that SAMe, related to depressive syndromes, is effective as tricyclic, but it has some characteristics which distinguish it from other antidepressant drugs. They are: - absence of side effects particularly at liver level; - rapid effect and therefore short period of latency between administration and therapeutic activity.

Efficacy of S-adenosyl-L-methionine in speeding the onset of action of imipramine
PSYCHIATRY RES. (Ireland), 1992, 44/3

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.

Neuroendocrine effects of S-adenosyl-(L)-methionine, a novel putative antidepressant
J. PSYCHIATR. RES. (United Kingdom), 1990, 24/2

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 plus or minus7.2 years) and 10 depressed outpatient men (mean age: 38.0 plus or minus 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 derpressed 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.

Antidepressants: A Comparative review of the clinical pharmacology and therapeutic use of the 'newer' versus the 'older' drugs
DRUGS (New Zealand), 1989, 37/5 (713-738)

Supplementing but not supplanting the original series of tricyclic and monoamine oxidase (MAO) inhibitor compounds, a new generation of antidepressant medications has been developed and marketed throughout the past decade. Constituting a more diverse group of drugs than the standard agents, the newer drugs in general have more selective acute biochemical actions (reuptake blockade of a single neurotransmitter, inhibition of 1 subtype of MAO), enabling more precise targeting of symptoms and avoiding common antidepressant-associated side effects, especially anticholinergic and cardiovascular effects. Moreover, a number of recent additions to this group, such as bupropion and ademetionine (S-adenosyl-methionine), incorporate novel mechanisms of action, challenging previous concepts of how antidepressants work, and offering opportunities for research into the pathophysiology of mood disorders. Caution in prescribing the newer antidepressants must be applied, however, as recent experience, e.g. with nomifensine, suggests that unforeseen toxicities may not appear until a medication has been in use for several years.

Neuropharmacology of S-adenosyl-L-methionine
AM. J. MED. (USA), 1987, 83/5 A (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.

S-adenosyl-L-methionine (SAMe) in clinical practice: Preliminary report on 75 minor depressives
CURR. THER. RES., CLIN. EXP. (USA), 1985, 37/4

An open trial was performed on a population of 75 patients suffering from minor depression. The subjects were administered 100 mg/die of S-adenosyl-L-methionine intramuscularly for 30 days. Modifications occurring were evaluated with the Zung Self-Rating Depression Scale and with the Clinical Global Impression and Patient Global Impression. The trial showed SAMe to have good clinical efficacy and to be virtually devoid of side effects.

S-Adenosyl-L-Methionine (SAMe) treatment in psychogeriatry: a controlled clinical trial in depressed patients
G.GERONTOL. (ITALY), 1977, 25/3

The authors report some results obtained by treatment with S-Adenosyl-L-Methionine (135 mg/day given intramuscularly for 15 days) in senile depressed patients (17 subjects). The evaluation was performed using the Hamilton Rating Scale for depression (HRS) and the scale by Overall and Gorham (BPRS). The items considering the depressive state improved significantly by treatment.

A methyl donor, adenosylmethionine, in depression
FOLIA NEUROPSYCHIAT.(LECCE) (ITALY), 1973, 16/4

Because of the excellent results obtained by Fazio et al. in depressive syndromes with S adenosyl L methionine (SAM), the same drug was administered in the present trial. It was given intravenously in doses of 45 mg per day, for periods of 10 to 20 days to 8 patients suffering from depressive syndromes. Five patients (62%) were cured. Normalization occurred rapidly (in 5 days) and appeared to be lasting (still good at followup 5 months after the end of the treatment). Since SAM readily gives off methyl groups and since it passes the blood brain barrier, it probably influences the biochemistry of the brain, especially its catecholamine metabolism which is probably subnormal in depressive psychoses. Consequently, it may be regarded as a highly useful drug in the treatment of hypothermic syndromes; further trials on a larger scale are advocated.

Therapeutic effects and mechanism of action of S adenosyl l methionine in depressive syndromes
MINERVA MED. (ITALY), 1973, 64/29 (1515-1529)

S adenosyl methionine (SAM) is physiologically synthesised in the CNS and present in various concentrations in the different areas of the brain. The donor substance is activated by methyls and is involved in neurotransmitter synthesis and catabolism process. SAM injected into the systemic circulation rapidly crosses the blood brain barrier and is thus a potential nerve drug in the management of depression in the present crisis surrounding neuropharmacological theory. An open and double blind clinical trial was run on 49 patients. The drug manifested a rapid and intense antidepressive action, with positive results in over 80% of cases. A specific rating scale (Hamilton's scale) for depression was used in evaluating the experiment and the effect of the drug on certain target symptoms is discussed.

Clinic and psychometric effects of S adenosyl methionine on chronically L Dopa treated parkinsonians
ACTA NEUROL. (NAPOLI) (ITALY), 1977, 32/2 (204-217)

S adenosyl methionine was administered for 15 days i.v. by glucose, at a daily dosage of 60 mg, to 15 subjects affected by idiopathic parkinsonism in chronic treatment with L-Dopa. SAM: favors the remission of akinesia; has an antidepressive effect; increases the anxious valencies; is a manageable drug, well tolerated with secondary side effects of minute importance.

Effect of S-adenosyl-L-methionine administration on red blood cell cysteine and glutathione levels in alcoholic patients with and without liver disease.
Alcohol Alcohol (ENGLAND) Sep 1994, 29 (5) p597-604

We measured glutathione and cysteine concentrations in erythrocytes of chronic alcohol misusers with (20 subjects) and without liver cirrhosis (20 subjects). Glutathione levels were decreased, whereas those of cysteine were increased in all patients. Parenteral treatment with S-adenosylmethionine (SAME); (2 g daily in 250 ml 0.15 M NaCl for 15 days) corrected the erythrocyte thiol alterations. We conclude that parenteral treatment with SAME affects the metabolism of SH compounds in erythrocytes of alcoholic patients.

"S-Adenosylmethionine and the Liver"
The Liver: Biology and Pathobiology, 3rd Edition, 1994; 27:461-470

In the adult 6 to 8 gm of S-adenosylmethionine (SAM) is produced daily. Most of it is produced in the liver where it is utilized. The methionine cycle and trans-sulfuration pathways are impaired in human liver disease. One or more of these abnormalities may be responsible for some of the clinical manifestations of liver cirrhosis. The increased breakdown in methionine at the expense of methylation reactions is generated by a need to synthesize hepatic GSH to offset the damaging oxidant effects of ethanol. Paracetamol (acetaminophen) can result in fetal liver damage in overdosed individuals. Two forms of cytochrome P450 convert paracetamol into a reactive metabolite that depletes liver reduced glutathione. Reduced glutathione is a tripeptide containing glycine, glutamic acid and cysteine. It is the most important cellular thiol. N- acetylcysteine, in an hepatic toxic condition resulting from paracetamol overdose can, if given in time, improve survival and reduce liver damage. Different studies have shown SAM to be effective in symptomatic treatment of intrahepatic cholestasis of the liver and of pregnancy. SAM has also been reported to improve liver function in various chronic liver diseases including alcoholic and nonalcoholic cirrhosis. This article also notes that the trans-sulfuration pathway, which can lead to homocystinuria/homocysteinemia, is dependent on enzymes that are cofactors with vitamin B12, folic acid, B6, choline and betaine hydrochloride. Homocysteine is believed to be an independent risk factor for the development of coronary artery disease in man. The molecular basis for homocysteine playing a role in cardiovascular function is not known, but it may be related to its interference with cross-linking of collagen.