Overview

The objective of this report was to conduct a

search of the published literature on the use of Sadenosyl-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. 

Reporting the Evidence

Searches of the literature yielded 1624 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). 

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®, MANTISTM,

Allied and Complementary Medicine,

CochraneTM Library, CAB HEALTH, BIOBASE,

SciSearch®, PsychINFO, Mental Health

Evidence Report/Technology Assessment

Number 64

S-Adenosyl-L-Methionine for Treatment of

Depression, Osteoarthritis, and Liver Disease

Summary

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service

Agency for Healthcare Research and Quality • www.ahrq.gov
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.

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% 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% 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% CI [-0.39, - 0.02]) compared

to placebo, thus demonstrating a decrease in the pain of

osteoarthritis.

• Compared to treatment with nonsteroidal antiinflammatory medication, treatment with SAMe was not

associated with a statistically significant difference in

outcomes (effect size 0.11; 95% 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% CI [-1.45, -0.45]) for decrease in pruritus and of over

one and one-third standard deviations (-1.32; 95% 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% CI

[0.37, 0.58]).

2
• 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.

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.

Availability of Full Report

The full evidence report from which this summary was

derived was prepared for AHRQ by the Southern California

Evidence-Based Practice Center under contract number 290-

97-0001. It is expected to be available in mid-2002. At that

time, printed copies may be obtained free of charge from the

AHRQ Publications Clearinghouse by calling 800-358-9295.

Requestors should ask for Evidence Report/Technology

Assessment No. 64, S-Adenosyl-L-Methionine for Treatment of

Depression, Osteoarthritis, and Liver Disease. Internet users will

be able to access the report online through AHRQ’s Web site

at: www.ahrq.gov.

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www.ahrq.gov

AHRQ Pub. No. 02-E033

August 2002

ISSN 1530-440X