SAM-e Depression Research Studies
Psychiatry Res 1995
Apr 28;56(3):295-7
Rapidity of onset of the antidepressant effect of
parenteral S-adenosyl-L-methionine.
Fava M, Giannelli A, Rapisarda V, Patralia A,
Guaraldi GP
Depression Research Program, Massachusetts General
Hospital, Boston 02114, USA.
A possible method of reducing the delay in
antidepressant response is to use S-adenosyl-L-methionine
(SAM-e), 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 SAM-e, administered
parenterally, for 15 days. Depressive symptoms
remitted after both 7 and 15 days of treatment with
SAM-e, and no serious adverse events were reported.
Further studies with a double-blind design are
needed to confirm this preliminary indication that
SAM-e is a relatively safe and fast-acting
antidepressant.
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Acta Neurol Scand
Supply 1994;154:7-14
S-adenosyl-L-methionine (SAM-e) as antidepressant:
meta-analysis of clinical studies.
Bressa GM
Department of Psychiatry, University Cattolica Sacro
Cuore School of Medicine, Rome, Italy.
INTRODUCTION - S-adenosyl-L-methionine (SAM-e) 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 SAM-e 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 SAM-e when compared with placebo,
with a global effect size ranging from 17% to 38%
depending on the definition of response, and an
antidepressant effect comparable with that of
standard tricyclic antidepressants.
CONCLUSION - The efficacy of SAM-e in treating
depressive syndromes and disorders is superior with
that of placebo and comparable to that of standard
tricyclic antidepressants. Since SAM-e is a
naturally occurring compound with relatively few
side-effects, it is a potentially important
treatment for depression.
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Drugs 1994
Aug;48(2):137-52
The clinical potential of ademetionine (S-Adenosyl-Methionine)
in neurological disorders.
Bottiglieri T, Hyland K, Reynolds EH
Metabolic Disease Center, Baylor Research Institute,
Dallas, Texas.
This review focuses on the biochemical and clinical
aspects of methylation in neuropsychiatric disorders
and the clinical potential of their treatment with
ademetionine (S-Adenosyl-Methionine; SAM-e). SAM-e
is required in numerous transmethylation reactions
involving nucleic acids, proteins, phospholipids,
amines and other neurotransmitters. The synthesis of
SAM-e is intimately linked with folate and vitamin
B12 (cyanocobalamin) metabolism, and deficiencies of
both these vitamins have been found to reduce CNS
SAM-e concentrations. Both folate and vitamin B12
deficiency may cause similar neurological and
psychiatric disturbances including depression,
dementia, myelopathy and peripheral neuropathy.
SAM-e has a variety of pharmacological effects in
the CNS, especially on monoamine neurotransmitter
metabolism and receptor systems. SAM-e has
antidepressant properties, and preliminary studies
indicate that it may improve cognitive function in
patients with dementia. Treatment with methyl donors
(betaine, methionine and SAM-e) 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.
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Acta Neurol Scand
Supply 1994;154:15-8
S-Adenosyl-Methionine blood levels in major
depression: changes with drug treatment.
Bell KM, Potkin SG, Carreon D, Plon L
University of California, Irvine Medical Center,
Orange 92668.
INTRODUCTION - The relationship between plasma
levels of S-adenosylmethionine (SAM-e), 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 SAM-e 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 SAM-e 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 SAM-e concentration.
CONCLUSION - The significant correlation between
plasma SAM-e levels and the degree of clinical
improvement in depressed patients regardless of the
type of treatment suggests that SAM-e may play an
important role in regulating mood.
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Acta Neurol Scand
Suppl 1994;154:19-26
S-adenosylmethionine levels in psychiatric and
neurological disorders: a review.
Bottiglieri T, Hyland K
Metabolic Disease Center, Baylor Research Institute,
Dallas, TX 75226.
INTRODUCTION - S-adenosylmethionine (SAM-e) is an
important methyl donor in over 35 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
SAM-e in several psychological, neurological and
metabolic disorders.
RESULTS - Although studies have found no consistent
changes in whole blood SAM-e levels in psychiatric
patients, other investigators have found low
cerebrospinal fluid (CSF) SAM-e 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
SAM-e thus represents a possible treatment for these
neurological and metabolic disorders.
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J Psychiatry Neurosci
1993 Nov;18(5):235-44
The use of diet and dietary components in the study
of factors controlling affect in humans: a review.
Young SN
Department of Psychiatry, McGill University,
Montreal, Quebec, Canada.
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
in the literature that some depressed patients who
are folate deficient respond to folate
administration. Folate deficiency is known to lower
levels of S-Adenosyl-Methionine, and S-Adenosyl-Methionine
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-Adenosyl-Methionine.
They also suggest that the dietary intake and
psychopharmacological action of methionine, the
precursor of S-Adenosyl-Methionine, 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.
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Psychotherapy
Psychosom 1993;59(1):34-40
Double-blind, placebo-controlled study of S-adenosyl-L-methionine
in depressed postmenopausal women.
Salmaggi P, Bressa GM, Nicchia G, Coniglio M, La
Greca P, Le Grazie C
Obstetrics and Gynecology Department, University La
Sapienza School of Medicine, Rome, Italy.
S-adenosyl-L-methionine (SAM-e) 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 SAM-e 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 SAM-e 1,600 mg/day or placebo.
There was a significantly greater improvement in
depressive symptoms in the group treated with SAM-e
compared to the placebo group from day 10 of the
study. Side effects were mild and transient.
J Basic Clin
Physiology Pharmacology 1992 Jan-Mar;3(1):1-17
Antidepressant activity of S-adenosyl-L-methionine
in mice and rats.
Czyrak A, Rogoz Z, Skuza G, Zajaczkowski W, Maj J
Institute of Pharmacology, Polish Academy of
Sciences, Krakow.
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.
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Psychiatry Res 1992
Dec;44(3):257-62
Efficacy of S-adenosyl-L-methionine in speeding the
onset of action of
imipramine.
Berlanga C, Ortega-Soto HA, Ontiveros M, Senties H
Special Studies Clinic, Mexican Institute of
Psychiatry, Tlalpan.
A double-blind clinical trial was carried out to
evaluate the efficacy of S-adenosyl-L-methionine
(SAM-e) in speeding the onset of action of
imipramine (IMI). SAM-e 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 SAM-e
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 SAM-e-IMI
combination than in those who were receiving the
placebo-IMI combination.
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Am J Psychiatry 1990
May;147(5):591-5
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.
Methylation has been implicated in the etiology of
psychiatric illness. Parenteral S-Adenosyl-Methionine,
a methyl group donor, has been shown to be an
effective antidepressant. The authors studied the
antidepressant effect of oral S-Adenosyl-Methionine
in a randomized, double-blind, placebo-controlled
trial for 15 inpatients with major depression. The
results suggest that oral S-Adenosyl-Methionine is a
safe, effective antidepressant with few side effects
and a rapid onset of action. S-Adenosyl-Methionine
induced mania in a patient with no history of mania.
S-Adenosyl-Methionine may be useful for patients who
cannot tolerate tricyclic anti-depressants. These
findings support a role for methylation in the
pathophysiology of depression.
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Acta Psychiatry Scand
1990 May;81(5):432-6
The antidepressant potential of oral S-adenosyl-l-methionine.
Rosenbaum JF, Fava M, Falk WE, Pollack MH, Cohen LS,
Cohen BM, Zubenko GS
Clinical Psychopharmacology Unit, Massachusetts
General Hospital, Boston 02114.
S-adenosyl-l-methionine (SAM-e), 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
SAM-e, 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 SAM-e: 7 of 11
non-treatment-resistant and 2 of 9
treatment-resistant patients experienced full
antidepressant response. Side effects were mild and
transient.
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J Psychiatry Res
1990;24(2):177-84
Neuroendocrine effects of S-adenosyl-L-methionine, a
novel putative antidepressant.
Fava M, Rosenbaum JF, MacLaughlin R, Falk WE,
Pollack MH, Cohen LS, Jones L, Pill L
Clinical Psychopharmacology Unit, Massachusetts
General Hospital, Harvard Medical School, Boston
02114.
S-adenosyl-L-methionine (SAM-e), a putative
antidepressant, is a naturally occurring substance
whose mechanism of action is still a matter of
speculation. It has been recently postulated that
SAM-e may increase the dopaminergic tone in
depressed patients. Since dopamine inhibits both
thyrotropin (TSH) and prolactin secretion, we
investigated the effects of treatment with SAM-e 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 SAM-e
in the treatment of major depression. At the end of
the study, there was a significant reduction after
treatment with SAM-e 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 SAM-e. Our
results, at least in depressed men, seem to support
the hypothesis of a stimulating effect of SAM-e on
the dopaminergic system.
Drugs 1989
Sep;38(3):389-416
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.
Friedel HA, Goa KL, Benfield P
ADIS Drug Information Services, Auckland, New
Zealand.
S-Adenosyl-L-methionine (SAM-e) 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 SAM-e, 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 SAM-e 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, SAM-e 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.
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Encephale 1988
May-Jun;14(3):113-8
[Therapeutic indications of S-adenosyl methionine in
neuropsychiatry].
[Article in French]
Tramoni AV, Azorin JM
Clinique de Psychiatrie et de Psychologie Medicale,
C.H.U. Timone, Marseille.
Studies conducted by Italian and Anglo-saxon authors
underline the thymoanaleptic properties of a
transmethylant biological substance, the S-adenosyl
methionine (SAM-e). The authors discuss a review of
literature concerning the use of SAM-e in neuro-psychiatry,
particularly in the treatment of affective
disorders. The many physiopathological implications
are subtended by the biological inter-relations of
SAM-e 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.
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