PSYCHOPHARMACOLOGY Editor: Carl Salzman, MD
SAMe (S-adenosylmethionine)
John C. Echols, MD, Umadevi Naidoo, MD, and Carl Salzman, MD
S-adenosylmethionine (SAMe), already prescribed by physi-
cians in Europe for two decades for the treatment of arthritis
and depression, is now available in the United States with-
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out a prescription. It is currently widely marketed by stores
selling nutritional supplements and by internet vendors,
who are warding off government regulation by avoiding
therapeutic claims, saying only that the preparation pro-
motes “joint health” and “emotional well-being.” The usual
oral dosage for the treatment of depression is 200–800 mg
twice daily.1 A box of 20 200-mg SAMe tablets carrying the
Nature Made (Pharmavite) label costs $18.99 at one website,
which amounts to $228 for a month’s supply at 1600 mg per
Harv Rev Psychiatry 2000.8:84-90.
day. Despite its high cost, sales have been booming. SAMe
outsells the antidepressant Prozac in Italy, even though in-
surance does not reimburse for it, and it is currently used by
more than a million Europeans.2
Extensive studies have been done on SAMe as a treat-
ment for osteoarthritis, with more than 20,000 patients par-
ticipating in clinical trials.3 These trials have found the clini-
cal effectiveness of SAMe to be similar to that of nonsteroidal
antiinflammatory drugs, but with fewer adverse side effects.
In addition, SAMe stimulates the synthesis of proteoglycans
by articular chondrocytes, indicating some possible protec-
tive effects on cartilage.3 It has excellent gastric tolerability
and in fact has been shown to equal the prostaglandin E1 an-
alog misoprostol in its ability to protect the gastric mucosa
in rats against injury induced by ethanol, aspirin, or stress.4
SAMe is produced naturally in the central nervous sys-
tem from L-methionine and adenosine triphosphate. It is the
major source of methyl groups in the brain as a result of its
demethylation to S-adenosylhomocysteine (SAH). The ac-
tive methyl group of SAMe is transferred to a wide variety
of methyl acceptor molecules, including the catecholamines
norepinephrine and dopamine, as well as to fatty acids,
phospholipids, nucleic acids, polysaccharides, and porphy-
rins. Since these methyl groups are vital to a number of met-
abolic pathways, it is difficult to define the exact nature of
SAMe’s pharmacological action.5 Low levels of SAMe in the
central nervous system can occur due to inadequate activity
of methionine synthetase following deficiencies of its re-
Reprint requests: Carl Salzman, MD, Massachusetts Mental Health
Center, 74 Fenwood Rd., Boston MA 02115.
Harvard Rev Psychiatry 2000;8:84–90.
䉷 2000 President and Fellows of Harvard College
quired cofactors (vitamin B12 and folate), SAMe synthetase
(from ethanol), or SAH hydrolase.6 Folate and B12 deficien-
cies have been linked to depression and poor response to
antidepressant treatment;7 low levels of SAMe in cerebro-
spinal fluid (CSF) have also been correlated with depres-
sion.8 Decreased methylation as a result of low CSF SAMe
is therefore a possible mechanism of depression and SAMe’s
antidepressant effect. SAMe also has several effects on mem-
brane phospholipids and has been shown to normalize aged
membranes in rats by decreasing membrane microviscosity,
which has been suggested as an alternative mechanism for
its antidepressant effect.5 Although intriguing, neither of
these is a widely accepted model of depression, and SAMe’s
mechanism of action in this disorder remains unknown.
Research has shown a significant correlation between in-
crease in plasma SAMe levels and the degree of clinical im-
provement in depression.9 Parenterally or orally adminis-
tered SAMe crosses the blood-brain barrier, resulting in a
significant rise in CSF SAMe, as well as an increase in CSF
serotonin by an unknown mechanism.10 With a half-life after
intravenous injection of about 90 minutes in normal sub-
jects, SAMe is rapidly eliminated from the circulation. Due
to extensive first-pass metabolism in the liver, oral SAMe
must be given at much larger doses to raise CSF levels com-
parably.11
CONTROLLED TRIALS OF SAMe FOR DEPRESSION
An initial double-blind study of 30 depressed patients12 in
which 20 received 45 mg of SAMe intramuscularly and ten
received placebo was highly encouraging: 100% of the SAMe
group versus 30% of the placebo group showed improvement
in depressed mood; untoward side effects were not seen. Al-
though some subsequent studies13–15 have supported this ini-
tial observation that SAMe has antidepressant potential
with none of the side effects of standard medications, a
few16–18 have reported the development of side effects. How-
ever, limitations in the research design of many of these
studies (e.g., diagnostic heterogeneity, lack of a control
group, short duration of treatment) raise questions about
the validity of the published results. A summary of English-
language studies retrieved by a Medline search on “s-
adenosylmethionine” and “depression” is shown in Tables 1
(SAMe vs. placebo) and 2 (SAMe vs. various tricyclic anti-
depressants).
 Harvard Rev Psychiatry
Volume 8, Number 2 Echols, Naidoo, and Salzman 85

TABLE 1. Controlled Studies of SAMe vs. Placebo in Depression*

Outcome Authors’
Study n† Study design Subjects measure(s) conclusions Comments

Agnoli et al.12 30 Randomized, double- Patients with HAM-D Improvement in Only 1/3 received placebo
blind, placebo- depression 4–7 days in despite randomization;
controlled; 1-week 80% of authors tested
washout; patients patients; significance for each
hospitalized for considerable item of HAM-D at ␣
study; SAMe 45 improvement in level of 0.05 and did
mg/day IM or depressed mood not control for multiple
placebo for 2–15 in 100% of comparisons or show
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days (average, 6.6 SAMe patients total changes in the

days); no other and 30% of HAM-D in the
medications placebo analysis, leading to
allowed patients serious questions re
significance of results
Carney et al.16 32 Randomized, double- Inpatients with HAM-D, Significant 3 SAMe-treated patients
blind, placebo- severe BDI reductions in became very anxious
controlled; 1 week depression HAM-D scores during 2nd week and
washout; SAMe for both placebo were withdrawn from
Harv Rev Psychiatry 2000.8:84-90.

200 mg/day IV or (from 25.5 to study; reactions may

placebo for 14 22.5) and be evidence of an
days; SAMe (from activating effect of
benzodiazepines 26.5 to 20.1) SAMe (producing
permitted for groups but no mania or anxiety);
insomnia or significant SAMe increased in
marked anxiety difference CSF; SAMe causes
between groups increase in 5-HIAA
and HVA in CSF and
decrease in serum
prolactin
Caruso et al.13 60 Randomized, double- Outpatients with HAM-D SAMe better than No reported side effects;
blind, placebo- rheumatoid placebo; HAM- very high HAM-D
controlled; no arthritis and D scores scores even after
antidepressants depression reduced from treatment raises
allowed for 2 45.1 to 33.1 in question about validity
months prior to SAMe group, of diagnosis and
study; SAMe 200 and from 42.4 suggests that the data
mg/day IM or to 39.7 in are not relevant to
placebo for 21 placebo group psychiatric patients
days; antiarthritis with depression;
medications steroids may affect
(NSAIDs, mood by causing mania
chloroquine, or depression,26
steroids, D- potentially altering
penicillamine) HAM-D scores
permitted
De Leo14 40 Randomized, double- Outpatients with CGI, Zung SAMe better than Increased anxiety in 5
blind, placebo- depression placebo; Zung SAMe-treated patients;
controlled; 1-week scores dropped very high pretreatment
washout; SAMe from 53.42 to scores; posttreatment
200 mg/day 45.89 in SAMe scores reflect little
IV or placebo for group and from change and still
30 days; 55.22 to 52.82 indicate severe
benzodiazepines in placebo depression
permitted group
 Harvard Rev Psychiatry
86 Echols, Naidoo, and Salzman July/August 2000

TABLE 1. Controlled Studies of SAMe vs. Placebo in Depression (cont’d.)

Outcome Authors’
Study n† Study design Subjects measure(s) conclusions Comments

Fava et al.19
39 Randomized, double- Outpatients with HAM-D No significant TRH test (IV TRH
blind, placebo- depression difference analog) used as a
controlled; 1-week between SAMe possible predictor of
washout; SAMe and placebo; antidepressant
1600 mg/day sample as a response; subjects with
orally or placebo whole improved more-abnormal TRH
for 6 weeks significantly, responses tended to
suggesting a improve more; since
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marked this was the first study

nonspecific to use an absolute
treatment measure of TSH
response deviation from the
norm to predict
treatment response, it
is not clear whether
data can be replicated
Kagan et al.17 15 Randomized, double- Inpatients with HAM-D Reduction in Small sample; 1 patient
Harv Rev Psychiatry 2000.8:84-90.

blind, placebo- depression HAM-D scores with no history of

controlled; 1-week from 26.6 to mania switched from
washout; SAMe 10.4 in SAMe depression to mania
1600 mg/day group and from
orally or placebo 31 to 23.7 in
for 21 days; no placebo group
other medications
permitted
Muscettola et al.18 20 Randomized, double- Outpatients with HAM-D, Posttreatment Small sample; 1 patient
blind, placebo- depression BPRS, scores not on SAMe showed sharp
controlled; 1-week (unipolar or CGI provided; graph increase in anxiety,
washout; SAMe bipolar) indicates HAM- insomnia, and hostility
150 mg/day IM or D scores during first 5 days of
placebo for 15 declined from treatment (no mention
days; 23 to 15 in of his diagnosis or how
benzodiazepines SAMe group he responded over the
permitted for but did not entire course)
sleep induction; 1 improve
patient taking significantly in
lithium placebo group
Salmaggi et al.15 80 Randomized, double- Outpatients with HAM-D SAMe better than 60 patients completed
blind, placebo- depression placebo; HAM- trial; side effects mild
controlled; 1-week D scores and transient
washout; SAMe dropped from
1600 mg/day 24.4 to 16.6 in
orally or placebo SAMe group
for 30 days; no and from 24.5
other medications to 23 in placebo
permitted group

BDI, Beck Depression Inventory; BPRS, Brief Psychiatric Rating Scale; CGI, Clinical Global Impressions scale; CSF, cerebrospinal fluid;
DSM-III-R, Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised; HAM-D, Hamilton Rating Scale for Depression; 5-
HIAA, 5-hydroxyindoleacetic acid; HVA, homovanillic acid; IM, intramuscularly; IV, intravenously; NSAIDs, nonsteroidal antiinflammatory
drugs; SAMe, S-adenosylmethionine; TRH, thyroid-releasing hormone; TSH, thyroid-stimulating hormone; Zung, Zung Self-Rating De-
pression Scale.
*Only studies published in English are included.
†Number of subjects at the outset of the study.
 Harvard Rev Psychiatry
Volume 8, Number 2 Echols, Naidoo, and Salzman 87

TABLE 2. Controlled Studies of SAMe vs. TCAs in Depression*

Outcome Authors’
Study n† Study design Subjects measure(s) conclusions Comments

Bell et al.21 22 Randomized, double- Inpatients with HAM-D, HAM-D scores Dose of imipramine and
blind, placebo- depression Somatic declined from duration of treatment
controlled; 2-day Symptom 40.0 to 14.6 in insufficient for full
washout; SAMe Checklist, SAMe group therapeutic response
400 mg/day IV BDI and from 39.0
plus placebo to 31.2 in
orally, or imipramine
imipramine 150 group
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mg/day orally plus

placebo IV, for 14
days; no other
medications
permitted
Bell et al.9 26 Randomized, double- In- or HAM-D 62% of patients HAM-D scores not given;
blind; 3-day outpatients taking SAMe improvement judged by
washout; SAMe with and 50% taking 50% reduction in
1600 mg/day depression desipramine pretreatment scores
Harv Rev Psychiatry 2000.8:84-90.

orally or improved
desipramine 250 significantly;
mg/day orally for all patients
4 weeks; no other with a ⱖ50%
medications improvement
permitted in HAM-D
score showed a
significant
increase in
SAMe blood
level
Janicak et al.20 20 Randomized, double- Patients with HAM-D Reduction in Small sample; only 7
blind comparison depression HAM-D scores patients on SAMe, 3 on
of SAMe, (unipolar or in SAMe group imipramine, and 3 on
imipramine, and bipolar) (from 33.6 to placebo completed
placebo; patients 21.2) study; 1 noncompleter
hospitalized for significantly on SAMe had psychotic
study; 2-week greater than in decompensation
washout; SAMe placebo-
400 mg/day IV, treated group
imipramine 150 (from 32.9 to
mg/day orally, or 30.5) and
placebo for 14 similar to
days (all patients imipramine
received IV group (33.3 to
infusions and 22.5)
capsules that
looked identical);
no other
medications
permitted
 Harvard Rev Psychiatry
88 Echols, Naidoo, and Salzman July/August 2000

TABLE 2. Controlled Studies of SAMe vs. TCAs in Depression (cont’d.)

Outcome Authors’
Study n† Study design Subjects measure(s) conclusions Comments

Küfferle & 18 Randomized, double- Inpatients with HAM-D, Statistically Actual HAM-D scores not
Grünberger22 blind; ⱖ 3-day depression Zung significant provided; data shown
washout; SAMe (unipolar or “moderate to in graph format; both
150 mg/day IV or bipolar) marked” graphs indicated
clomipramine improvement decline from 28 to 14
50 mg/day IV for in both groups;
18 days; no difference
benzodiazepines between groups
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permitted for
sleep induction
Miccoli et al.24 92 Randomized, double- Inpatients with HAM-D SAMe had More side effects in the
blind; patients depression antidepressant TCA group; mild
excluded if taking effect similar to anxiety in 6 patients in
antidepressants that of SAMe group; both
within 2 weeks clomipramine groups showed only
before study; and 50% improvement after
SAMe 200 mg/day amitriptyline 21 days, but study too
Harv Rev Psychiatry 2000.8:84-90.

IV, clomipramine but with faster short for optimal

100 mg/day IV, or onset of action response
amitriptyline 100 and no
mg/day IV for 21 significant side
days; no other effects
medications
permitted
Potkin et al.23 22 Randomized, double- Inpatients with HAM-D, 67% of SAMe Washout period
blind; 2-day depression BDI patients vs. insufficient and likely
washout; SAMe only 22% of to impact results;
400 mg/day IV or imipramine actual HAM-D scores
imipramine 150 patients not reported
mg/day orally for showed ⬎ 50%
14 days (all improvement
patients received on HAM-D at
IV infusions and day 14;
capsules that difference
looked identical); significant from
no other day 5
medications
permitted

BDI, Beck Depression Inventory; HAM-D, Hamilton Rating Scale for Depression; IM, intramuscularly; IV, intravenously; SAMe,
S-adenosylmethionine; TCA, tricyclic antidepressant; Zung, Zung Self-Rating Depression Scale.
*Only studies published in English are included.
†Number of subjects at the outset of the study.

The tables suggest that the methodology of the clinical
trials was generally lacking in rigor, that in most studies ac-
tual reduction in depression scores was modest in SAMe re-
cipients, and that differences between drug and placebo
were also modest. One study19 showed no difference between
placebo and SAMe, with a large response in both groups. In
one investigation13 the initial Hamilton Depression Scale
scores were extremely high, raising questions about diag-
nostic validity. Some studies9,17,18,20–23 had too few subjects to
have much statistical weight. Investigations comparing
SAMe with standard antidepressants20–24 were also limited
by their short duration (2–3 weeks), since 3–6 weeks are of-
ten necessary for standard antidepressants to take effect.
Trials of 8 weeks or longer would be much more convincing.
 Harvard Rev Psychiatry
Volume 8, Number 2
One study25 showed a significant decrease in depressive
symptoms in a group of patients receiving SAMe together
with imipramine compared with patients receiving a
placebo-imipramine combination, suggesting that SAMe
may be a useful adjunct or augmenting agent. Side effects
were few in SAMe recipients, but activation or switch into
hypomania was apparent in several of the studies.
RECOMMENDATIONS
Based on these published reports, it is premature to consider
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SAMe to be a reliable and clinically significant antidepress-
ant agent. The substance appears to be active, and its use
seems to be associated with modest reductions in scores on
depression rating scales. Whether these effects are truly
therapeutic, and whether SAMe is equal to currently avail-
able antidepressants for all patients with major depression
or only for selected patients with mild or modest depression,
are not yet clear. SAMe’s potential for causing a switch to hy-
pomania should be considered a potentially serious side ef-
Harv Rev Psychiatry 2000.8:84-90.
fect—albeit one that does speak to an antidepressant effect.
If a patient is to use SAMe, determining the starting and
therapeutic doses is difficult since little is currently known
about the oral bioavailability of this agent. The usual oral
dose recommended for the treatment of depression is 200–
800 mg twice daily. This information is entirely anecdotal,
however, and caution is advised with this new medication
since little is known about its therapeutic range or any toxic-
ity associated with it. As with other dietary supplements, the
potency and purity of SAMe preparations sold in the United
States are uncertain.1 No studies have been conducted to ex-
amine the combination of SAMe and a monoamine-oxidase
inhibitor, and as with other antidepressants, a washout is
probably advisable before starting SAMe after use of a medi-
cation in this class.
REFERENCES
1. Anonymous. SAMe for depression. Med Lett 1999;41:107.
2. Brown R, Bottiglieri T, Colman C. Stop depression now:
SAM-e. New York: Putnam, 1999.
3. Di Padova CD. S-adenosylmethionine in the treatment of os-
teoarthritis: review of the clinical studies. Am J Med 1987;
83(suppl 5A):60–5.
4. Laudanno OM. Cytoprotective effect of S-adenosylmethionine
compared with that of misoprostol against ethanol-, aspirin-,
and stress-induced gastric damage. Am J Med 1987;83(suppl
5A):43–7.
5. Baldessarini RJ. Neuropharmacology of S-adenosyl-L-
methionine. Am J Med 1987;83(suppl 5A):95–103.
6. Scott JM, Molloy AM, Kennedy DG, Kennedy S, Weir DG. Ef-
Echols, Naidoo, and Salzman 89
fects of the disruption of transmethylation in the central ner-
vous system: an animal model. Acta Neurol Scand 1994;
89(suppl 154):27–31.
7. Abou-Saleh MT, Coppen A. The biology of folate in depression:
implications for nutritional hypotheses of the psychoses. J
Psychiatr Res 1986;20:91–101.
8. Bottiglieri T, Godfrey P, Flynn T, Carney MWP, Toone BK,
Reynolds EH. Cerebrospinal fluid S-adenosylmethionine in
depression and dementia: effects of treatment with parenteral
and oral S-adenosylmethionine. J Neurol Neurosurg Psychia-
try 1990;53:1096–8.
9. Bell KM, Potkin SG, Carreon D, Plon L. S-adenosyl-
methionine blood levels in major depression: changes with
drug treatment. Acta Neurol Scand 1994;89(suppl 154):15–8.
10. Bottiglieri T, Laundy M, Martin R, Carney MW, Nissenbaum
H, Toone BK, et al. S-adenosylmethionine influences mono-
amine metabolism [Letter]. Lancet 1984;2:224.
11. Giulidori P, Cortellaro M, Moreo G, Stramentinoli G. Pharma-
cokinetics of S-adenosyl-L-methionine in healthy volunteers.
Eur J Clin Pharmacol 1984;27:119–21.
12. Agnoli A, Andreoli V, Casacchia M, Cerbo R. Effect of S-
adenosyl-L-methionine (SAMe) upon depressive symptoms. J
Psychiatr Res 1976;13:43–54.
13. Caruso I, Fumagalli M, Boccassini L, Puttini PS, Santandrea
S, Ciniselli G, et al. Treatment of depression in rheumatoid
arthritic patients. Clin Trials J 1987;24:305–10.
14. De Leo D. S-adenosylmethionine as an antidepressant: a
double blind trial versus placebo. Curr Ther Res 1987;41:
865–70.
15. Salmaggi P, Bressa GM, Nicchia G, Coniglio M, La Greca P,
Le Grazie C. Double-blind, placebo-controlled study of S-
adenosyl-L-methionine in depressed postmenopausal women.
Psychother Psychosom 1993;59:34–40.
16. Carney MWP, Edeh J, Bottiglieri T, Reynolds EH, Toone BK.
Affective illness and S-adenosyl methionine: a preliminary re-
port. Clin Neuropharmacol 1986;9:379–85.
17. Kagan BL, Sultzer DL, Rosenlicht N, Gerner RH. Oral S-
adenosylmethionine in depression: a randomized, double-
blind, placebo-controlled trial. Am J Psychiatry 1990;147:
591–5.
18. Muscettola G, Galzenati M, Balbi A. SAMe versus placebo: a
double blind comparison in major depressive disorders. In:
Costa E, Racagni G, eds. Typical and atypical antidepressants:
clinical practice. New York: Raven, 1982:151–6.
19. Fava M, Rosenbaum JF, Birnbaum R, Kelly K, Otto MW,
MacLaughlin R. The thyrotropin response to thyrotropin-
releasing hormone as a predictor of response to treatment in
depressed outpatients. Acta Psychiatr Scand 1992;86:42–5.
20. Janicak PG, Lipinski J, Davis JM, Comaty JE, Waternaux C,
Cohen B, et al. S-adenosylmethionine in depression: a litera-
ture review and preliminary report. Ala J Med Sci 1988;25:
306–13.
21. Bell KM, Plon L, Bunney WE Jr, Potkin SG. S-
adenosylmethionine treatment of depression: a controlled clin-
ical trial. Am J Psychiatry 1988;145:1110–4.
22. Küfferle B, Grünberger J. Early clinical double-blind study
with S-adenosyl-L-methionine: a new potential antidepress-

90 Echols, Naidoo, and Salzman
ant. In: Costa E, Racagni G, ed. Typical and atypical anti-
depressants: clinical practice. New York: Raven, 1982:175–80.
23. Potkin SG, Bell K, Plon L, Bunney WE Jr. Rapid antidepress-
ant response with SAMe: a double-blind study. Ala J Med Sci
1988;25:313–6.
24. Miccoli L, Porro V, Bertolino A. Comparison between the anti-
depressant activity of S-adenosylmethionine (SAMe) and that
of some tricyclic drugs. Acta Neurol 1978;33:243–55.
Downloaded from informahealthcare.com by CDL-UC Davis on 01/31/15. For personal use only.
Harv Rev Psychiatry 2000.8:84-90.
Harvard Rev Psychiatry
July/August 2000
25. 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;44:257–62.
26. Sadock BJ, Sadock VA, eds. Kaplan and Sadock’s comprehen-
sive textbook of psychiatry. 7th ed. Philadelphia: Lippincott
Williams & Wilkins, 2000.