Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis

Editor - The Buscemi et al meta-analysis (1) concluded that there is
no evidence that melatonin is effective in treating sleep disorders.
Quite surprisingly, Buscemi et al (and, presumably, the British Medical
Journal’s editors and reviewers) ignored our similar, 2005 meta-analysis
(2) in their review. Our conclusions differed markedly from theirs: data
from 17 controlled clinical trials indicated that melatonin significantly
reduced sleep onset latency, and increased sleep efficiency and total
sleep duration.

Several additional comments:

1. The authors describe melatonin as a "popular complementary and
alternative treatment…". Melatonin is a hormone (secreted by the pineal
gland) and can no more be regarded as an “alternative therapy” than
estrogen for menopausal women or insulin for diabetics.

2. The authors dismiss as “clinically unimportant” their own finding
that melatonin produced a statistically significant increase (1.9%) in
sleep efficiency. Sleep efficiency, normally is 90–95%; small increases
usually reflect decreased number of awakenings during sleep or shortened
periods of wakefulness, both of which certainly are significant for
insomniacs (e.g., the FDA recently approved a new, melatonin-analog
hypnotic drug, ramelteon, which increases sleep efficiency by 2.5% and
total sleep time by 8-10 minutes).

3. Exogenous melatonin activates brain M1 and M2 receptors, thereby
promoting sleep onset and maintenance and providing time cues for
circadian rhythms. Large doses of melatonin (e.g., 3 mg, which raises its
plasma levels to 900-2500 pg/ml) down-regulate these receptors (3),
suppressing melatonin’s hypnotic and Zeitgeber effects (4). Almost all
the studies included in the Buscemi, et al meta-analysis used such
excessive doses. The correct, lower dose, which raises plasma melatonin
levels to what they would be in a young person at nighttime (i.e., about
150-250 pg/ml) are highly effective, both in melatonin-deficient older
people (5) and to treat jet lag or help shift workers.

REFERENCES

1. Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling
L, Vohra S, Klassen TP, and Baker G. Efficacy and safety of exogenous
melatonin for secondary sleep disorders and sleep disorders accompanying
sleep restriction: meta-analysis. BMJ 2006; 332: 385-393.

2. Brzezinski A, Vangel MG, Wurtman RJ, Norrie G, Zhdanova I, Ben-
Shushan A,Ford I. Effects of exogenous melatonin on sleep: a meta-
analysis. Sleep Med Rev. 2005 Feb; 9(1):41-50.

3. Dubocovich ML, Markowska M. Functional MT1 and MT2 melatonin
receptors in mammals. Endocrine. 2005; 27(2):101-110.

4. Lewy AJ, Emens JS, Sack RL, Hasler BP, Bernert RA. Low, but not
high, doses of melatonin entrained a free running blind person with a long
circadian rythm. Chronobiol Intl 2002; 19(3): 649-658.

5. Zhdanova V I, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU.
Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab
2001; 86(10): 4727—4730.

Competing interests:
Dr. Wurtman's university, MIT, owns a United States patent on the use of melatonin to promote sleep.