Overview
The objective of this report was to conduct a
search of the published literature on the use of S-adenosyl-L-methionine (SAMe) for the treatment
of osteoarthritis, depression, and liver disease;
and, on the basis of that search, to evaluate the
evidence for the efficacy of SAMe. A broad
search revealed sufficient literature to support a
detailed review of the use of SAMe for three
conditions: depression, osteoarthritis, and
cholestasis of pregnancy and intrahepatic
cholestasis associated with liver disease.
Depression will affect 10 to 25 percent of
women and 5 to 12 percent of men in the United
States during their lifetimes. Approximately 10 to
15 million people experience clinical depression
in any given year. The annual cost for treatment
and lost wages is estimated at $43.7 to $52.9
billion.
Osteoarthritis is the most common form of
arthritis. An estimated 15 percent of Americans
suffer from arthritis, and the annual cost to
society is estimated at $95 billion. It is the
second most common cause cited in claims for
Social Security disability benefits.
Intrahepatic cholestasis of pregnancy occurs in
1 in 500 to 1000 pregnancies and is associated
with an increased risk of premature delivery and
fetal death. Intrahepatic cholestasis is a relatively
common complication of a number of acute and
chronic liver diseases such as viral hepatitis,
alcoholic hepatitis, and autoimmune liver
diseases. In two series of chronic liver disease
patients, 35 percent had intrahepatic cholestasis
characterized by elevations of bilirubin and liver
enzymes. While an economic cost is difficult to
assign to cholestasis, pruritus causes significant
morbidity in affected patients.
Empirical evidence of the efficacy of SAMe for
the treatment of these three conditions would be
helpful to health care providers who manage them
and would be useful in identifying areas for future
research.
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Reporting the Evidence
Searches of the literature yielded 1,624 titles, of
which 294 were selected to review; the latter
included meta-analyses, clinical trials, and reports
that contained supplemental information on
SAMe. Ninety-nine articles, representing 102
individual studies, met the screening criteria.
They focused on SAMe treatment for depression,
osteoarthritis, or liver disease and presented data
from clinical trials on humans. Of these 102
studies, 47 focused on depression, 14 focused on
osteoarthritis, and 41 focused on liver disease (all
conditions).
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Methodology
A panel of technical experts representing
diverse disciplines was established to advise the
researchers throughout the research. In
consultation with the funding agencies and taking
into account the uses for which SAMe was
generally recommended, the use of SAMe to treat
depression, osteoarthritis, and liver disease was
selected as the focus of the report. The aim was
to perform a meta-analysis whenever the literature
was appropriate for such an analysis.
Search Strategy
Twenty-five biomedical databases were searched
through year 2000: MEDLINE®, HealthSTAR,
EMBASE, BIOSIS Previews®, MANTIS™,
Allied and Complementary Medicine,
Cochrane™ Library, CAB HEALTH, BIOBASE,
SciSearch®, PsychINFO, Mental Health
Abstracts, Health News Daily, PASCAL, TGG Health &
Wellness DB, and several pharmaceutical databases. The
researchers searched using the term SAMe and its many
pharmacological synonyms, the three focus disease states, study
design, and article type. They also searched the bibliographies
of review and meta-analysis articles and questioned experts to
identify additional citations. An additional 62 articles were
identified from these sources, particularly from review articles
and from citations suggested by the advisors.
Selection Criteria
Reports were included in the synthesis of evidence if they
focused on SAMe for one of the selected diseases and
presented the results of randomized clinical trials on human
subjects. Language of publication was not a barrier to
inclusion. About 25 percent of the selected studies were in
foreign languages, mainly Italian.
Data Collection and Analysis
All selected titles, abstracts, and articles, in all languages,
were reviewed independently by two reviewers who were fluent
in the appropriate language, and all disagreements were
resolved by consensus. Information was collected about
patient demographics, disease state, intervention, study design,
and outcomes. Sufficient numbers of homogeneous studies
existed to permit a meta-analysis of the efficacy of SAMe for
treatment of four conditions: depression versus placebo and
active (pharmacological) therapy, osteoarthritis versus placebo
and active (pharmacological) therapy, cholestasis of pregnancy
versus placebo and active therapy, and intrahepatic cholestasis
associated with liver disease versus placebo. The remainder of
the liver disease studies were too heterogeneous for pooled
analysis and were assessed qualitatively.
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Findings
Researchers identified 102 relevant studies in the three
selected areas: 47 studies for depression, 14 studies for
osteoarthritis, and 41 studies for liver disease. The majority of
the studies enrolled small numbers of patients, and the quality
of the studies varied greatly, as judged by the Jadad criteria.
Results are summarized in five evidence tables. After removal
of duplicate studies, the distribution of studies across the three
selected areas was as follows:
Out of 39 unique studies considered, 28 studies were
included in a meta-analysis of the efficacy of SAMe to decrease
symptoms of depression.
- Compared to placebo, treatment with SAMe was associated
with an improvement of approximately 6 points in the score
of the Hamilton Rating Scale for Depression measured at 3
weeks (95 percent CI [2.2, 9.0]). This degree of improvement is
statistically as well as clinically significant and is equivalent
to a partial response to treatment. Too few studies were
available for which a risk ratio could be calculated for either
a 25 percent or 50 percent improvement in the Hamilton
Rating Scale for Depression. Therefore a pooled analysis
could not be done, but the results generally favored SAMe
compared to placebo.
- Compared to treatment with conventional antidepressant
pharmacology, treatment with SAMe was not associated
with a statistically significant difference in outcomes (risk
ratios for a 25 and for a 50 percent decrease in the
Hamilton Rating score for depression were 0.99 and 0.93,
respectively; effect size for the Hamilton Rating score for
depression measured continuously was 0.08 (95 percent CI [-0.17,
-0.32])).
Out of 13 unique studies considered, 10 studies were
included in a meta-analysis of the efficacy of SAMe to decrease
pain of osteoarthritis.
- One large randomized clinical trial showed an effect size in
favor of SAMe of 0.20 (95 percent CI [-0.39, -0.02]) compared
to placebo, thus demonstrating a decrease in the pain of
osteoarthritis.
- Compared to treatment with nonsteroidal anti-inflammatory
medication, treatment with SAMe was not
associated with a statistically significant difference in
outcomes (effect size 0.11; 95 percent CI [0.56, 0.35]).
Eight unique studies were included in a meta-analysis of the
efficacy of SAMe to relieve pruritus and decrease elevated
serum bilirubin levels associated with cholestasis of pregnancy.
- Compared to placebo, treatment with SAMe was associated
with an effect size of nearly a full standard deviation (-0.95;
95 percent CI [-1.45, -0.45]) for decrease in pruritus and of over
one and one-third standard deviations (-1.32; 95 percent CI
[-1.76, -0.88]) for decrease in serum bilirubin levels.
- In two clinical trials that were not pooled, conventional
therapy (ursodeoxycholic acid) was favored over SAMe for
the treatment of pruritus. One of them was statistically
significant. For serum bilirubin, the results of three small
trials varied, and no conclusion could be drawn.
Out of 10 unique studies considered, six studies were
included in a meta-analysis of the efficacy of SAMe to relieve
pruritus and decrease elevated bilirubin levels associated with
intrahepatic cholestasis caused by a variety of liver diseases.
- Compared to placebo, treatment with SAMe for pruritus
was associated with a risk ratio of 0.45, meaning that
patients treated with SAMe were twice as likely as placebo
treated patients to have a reduction in pruritus (95 percent CI
[0.37, 0.58]).
- Studies that compared SAMe to active therapy were
insufficient in number to permit pooled analysis.
Twenty remaining studies were too heterogeneous with
respect to both diagnosis (a wide variety of liver conditions)
and outcomes to permit pooled analysis. They were assessed
qualitatively.
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Future Research
The review has identified a number of promising areas for
future research. These areas are discussed briefly.
A need exists for additional review studies, studies
elucidating the pharmacology of SAMe, and clinical trials. A
better understanding of the risk benefit ratio of SAMe
compared to conventional therapy, especially for depression
and osteoarthritis, is very important. To that end, additional
analysis of existing data could be done, but it would likely be
more productive to support new definitive clinical studies to
address this issue.
Good dose-escalation studies have not been performed
using the oral formulation of SAMe for depression,
osteoarthritis, or liver disease. Once efficacy of the most
effective oral dose of SAMe has been demonstrated, larger
clinical trials are indicated for the use of SAMe for depression,
osteoarthritis, and cholestasis. Such trials would need to enroll
large numbers of patients with homogeneous diagnoses, and
focus on significant clinical outcomes. Ideally, they would
compare SAMe to both placebo and standard care.
Information on side effects and adverse events should be
systematically collected in these trials.
For liver conditions other than cholestasis, additional
smaller trials should be conducted to ascertain which patient
populations would benefit most from SAMe, and what
interventions (dose and route of administration) are most
effective. Additional smaller clinical trials of an exploratory
nature should be conducted to investigate uses of SAMe to
decrease the latency of effectiveness of conventional
antidepressants and to treat of postpartum depression.
Additional Resources:
- For related articles on Complementary and Alternative Medicine on the Web, click on: “Sphere: Related
Content” located at the bottom of this blog post.
- For related books or blog
posts with related content in Dr. Jeff’s and Dr. Tanya’s Blog, click on
the “Treatments: Alternative” category at the bottom of the post or type
in keywords “Complementary and Alternative Medicine” into “Google Search”
located in the sidebar.
- For related articles from
Psychology Today, click on the “Psychology Today” banner in the side bar
and type in Key words, “Complementary and Alternative Medicine” into the
Psychology Today “Search”.
- For more books with related
content, click any hyperlinked key word in the blog or type in key words,
“Complementary and Alternative Medicine“ into “Amazon Search” on the
Amazon banner located in the side bar.
Source: The National Center for Complementary and Alternative Medicine (NCCAM), See also blog posts in: Treatments: Alternative
Dr. Tanya Korkosz
Dr. Jeffrey Speller
Psychopharmacology Associates of New England
www.psychopharmassociates.com
