Introduction

Sleep Disorders

Studies suggest that sleep disorders affect 50 to

70 million Americans, representing approximately

20 percent of the population.1 A sleep disorder

exists whenever a lower quality of sleep results in

impaired functioning or excessive sleepiness.2

Insomnia, literally “inability to sleep,” has various

etiologies and is the most common sleep disorder,

affecting between 6 to 12 percent of the adult

population.3 In addition to the adult population,

difficulties initiating and maintaining sleep are

very common in children, affecting about 15 to

25 percent of this population.1

Melatonin

Melatonin (N-acetyl-5-methoxytryptamine) is

a neurohormone that is primarily produced by

the pineal gland, located behind the third

ventricle in the brain.4 In the synthesis of

melatonin, tryptophan is hydroxylated to 5-

hydroxytryptophan, which in turn is

decarboxylated to 5-hydroxytryptamine

(serotonin). Serotonin is converted to the

melatonin precursor and metabolite Nacetylserotonin by the enzyme N-acetyl

transferase.5-7 N-acetylserotonin is methylated via

the enzyme hydroxyindole-o-methyltransferase to

produce melatonin.8 Approximately 90 percent

of melatonin is cleared in a single passage through

the liver. A small proportion of unmetabolized

melatonin is also excreted in the urine.8

Commercially available melatonin may be

isolated from the pineal glands of beef cattle9 or

chemically synthesized.

Methods

In this report, we review the use of melatonin

for the treatment of a number of categories of

sleep disorders, including primary sleep disorders,

secondary sleep disorders, and sleep restriction, in

a number of different populations. Moreover, we

review not only the safety and effectiveness of

melatonin for the treatment of sleep disorders,

but also the pharmacology of exogenous

melatonin and the physiology of endogenous

melatonin, to provide a comprehensive overview

of the state of research in this area. 

Literature Review

As a first step, a number of biomedical

databases were searched. Literature searches were

limited to English-language reports of studies on

human subjects, with no restrictions applied for

age, gender, or ethnicity. We searched for reports

of phase 1 and 2 clinical trials; phase 3 and 4

randomized clinical trials, quasi-randomized

controlled trials, prospective cohorts, case series,

registry data as well as narrative and systematic

reviews. Similar searches of MEDLINE® and

EMBASE were conducted periodically for more

recently published studies that were potentially

relevant to the review. Lastly, the reference lists of

relevant articles were reviewed and abstracts of the

Associated Professional Sleep Society (APSS)

covering 1999 to 2003 were hand-searched.

Inclusion Criteria

Specific inclusion criteria were developed for

each question of the review. In general, only

controlled clinical trials were included for each

Evidence Report/Technology Assessment

Number 108

Melatonin for Treatment of Sleep Disorders Summary

Authors: Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, 

Baker G, Vohra S, Klassen T

Agency for Healthcare Research and Quality

Advancing Excellence in Health Care • www.ahrq.gov

Agency for Healthcare Research and Quality Evidence-Based

Practice
2

question of the review, except for questions pertaining to the

pharmacology of exogenous melatonin and the basic

mechanism by which melatonin produces sleepiness. For the

latter questions, uncontrolled clinical trials, case-series, cohort,

cross-sectional, and case-control studies were also included. For

all questions of the review, the population of the study could

include individuals of any age, gender, ethnicity, and

socioeconomic status; however, these individuals were required

to be free of any type of sleep disorder in the case of the

question relating to the effect of melatonin on normal sleepers,

and to suffer from a sleep disorder in the case of the question

relating to the effect of melatonin on people with sleep

disorders. For questions pertaining to the administration of

exogenous melatonin to a study population, any formulation,

dosage, timing, frequency, and duration of melatonin

administration was acceptable; however, melatonin was

required to be the primary intervention, and in the case of

controlled trials, compared to placebo. In addition, a study was

included for a particular question of the review, if it analyzed at

least one of the predetermined outcomes relevant to that

question. Only English-language reports were included in the

review. 

Study Selection

The librarian removed all duplicates of the initial search

results. In the first stage of study selection, the titles and

abstracts of all potentially relevant articles were screened,

independently, by two reviewers and classified as “relevant,”

“clearly irrelevant,” and “unclear.” A given article was

considered “relevant” to the review if it was relevant to at least

one question of the review. The full text of all articles deemed

“relevant” or “unclear” by each reviewer was retrieved. In the

second stage of screening, the reviewers independently

appraised the manuscripts using predetermined inclusion

criteria for each question of the review. Only studies that met

all inclusion criteria for a given question of the review, as

determined by both reviewers, were considered relevant to that

question. Disagreements among reviewers were resolved by

discussion and consensus. 

Assessment of Study Quality

For the question pertaining to the effect of melatonin on

people with sleep disorders, only randomized controlled trials

were used as a source of evidence. Therefore, the Jadad Scale10

was used to assess the quality of studies relevant to this

question. The concealment of allocation in the randomizedcontrolled trials was assessed as “adequate,” “inadequate,” and

“unclear.”11 For all other questions of the review, which relied

on evidence from studies of other designs in addition to

randomized controlled trials, the Downs and Black Checklist12

was used to assess the quality of studies relevant to these

questions. Two reviewers assessed study quality, independently,

and disagreements were resolved by discussion and consensus.

The overall quality of the evidence regarding the safety and

effectiveness of melatonin in the treatment of sleep disorders

was assessed using the framework developed by the Oxford

Centre for Evidence-Based Medicine. 

Data Extraction

Data were extracted from all reports of studies that were

included in the review using a standardized Data Extraction

Form. The type of information extracted from reports

included details of study design and inclusion/exclusion criteria;

details of the population such as gender, age, ethnicity, and type

of sleep disorder; the number of individuals that were eligible

for, and enrolled in, the study; the number of comparison

groups and participants allocated to each group; the number of

participants who withdrew from the study; details of the

intervention such as the formulation, dosage, timing, frequency

and duration of melatonin administration as well as the type

and frequency of usage of concurrent medication; and results

obtained for predetermined, question-specific outcomes.

Additional information that was extracted from reports

included the source of funding for the study and whether an

intention-to-treat analysis was planned or performed. A trained

reviewer extracted relevant data from a given report and a

second reviewer verified the data that were extracted for that

article for accuracy and completeness. Disagreements between

reviewers were resolved by discussion and consensus. 

Data Analysis

Data were analyzed using a Random Effects Model.

Calculations included: Relative Risk (RR) for dichotomous

data and Weighted Mean Difference (WMD) or Standardized

Mean Difference (SMD) for continuous data.13 All results were

reported with 95-percent confidence intervals (CIs). Sources of

heterogeneity were assessed using the I-squared statistic, and

publication bias was assessed by visual inspection of a funnel

plot, the Rank Correlation Test,14 the Graphical Test,15 and the

Trim and Fill Method.16
Results

The following is an outline of the key observations of the

literature review.

Effectiveness of Exogenous Melatonin in

Normal Sleepers

Normal Sleepers

• Melatonin decreased sleep onset latency (SOL) in normal

sleepers (weighted mean difference (WMD): -3.9 min; 95-

percent CI: -5.3 min., -2.6 min.). The magnitude of this

effect appears to be clinically insignificant. There was

evidence of possible publication bias in the selection of

studies that were analyzed; we found a greater number of

studies reporting positive results compared to negative

results. 

• Melatonin increased sleep efficiency in normal sleepers

(WMD: 2.3 percent; 95-percent CI: 0.7 percent, 3.9

percent), and this effect was dependent on the timing of

sleep, such that the effect of melatonin was greater in

daytime sleepers (daytime sleep: WMD: 8.0 percent; 95-

percent CI: 1.0 percent, 15.0 percent; night-time sleep:

WMD: 1.2 percent; 95-percent CI: 0 percent, 2.4

percent). The magnitude of this effect appears to be

clinically insignificant. There was considerable evidence of

possible publication bias in the selection of studies

analyzed; we found a greater number of studies reporting

positive results compared to negative results. 

• Overall, melatonin did not have an effect on REM latency

in normal sleepers, although doses of 1 mg to 3 mg

produced a significant increase in REM latency compared

to placebo (WMD: 12.7 min.; 95-percent CI: 6.8 min.,

18.6 min.), while both higher and lower doses did not

show this effect. 

• Generally, these studies were of low-to-moderate quality.

Effectiveness of Exogenous Melatonin in

People with Sleep Disorders

People with a Primary Sleep Disorder

• Melatonin decreased sleep onset latency in people with a

primary sleep disorder (WMD: -10.7 min.; 95-percent

CI: -17.6 min., -3.7 min.). SOL was decreased greatly in

people with delayed sleep phase syndrome (WMD: -38.8

min.; 95-percent CI: -50.3 min., -27.3 min.). The

magnitude of this effect appears to be clinically significant.

SOL was decreased marginally in patients with insomnia

(WMD: -4.3min.; 95-percent CI: - 8.4 min., -0.1 min.).

The magnitude of this effect appears to be clinically

insignificant. SOL was reduced more in children (less

than age 17 years) (WMD: -17.0 min., 95-percent CI: -

33.5 min, -0.5 min.) than in adults (age 18-65 years)

(WMD: -11.2; 95-percent CI: -27.7 min, 5.4 min.) or

elderly patients (greater than age 65 years) (WMD: -7.8

min.; 95-percent CI: -17.4 min., 1.7 min.). The effects of

melatonin did not vary with dose or duration of

treatment. If the analysis is approached using the Fixed

Effects Model, melatonin does not have any effect on

sleep onset latency in people with primary insomnia.

• Melatonin did not have an effect on sleep efficiency in

people with primary sleep disorders; the effects of

melatonin did not vary by age, type of primary sleep

disorder, dose, or duration of treatment. 

• Melatonin did not have an effect on sleep quality,

wakefulness after sleep onset (WASO), total sleep time, or

percent time spent in REM sleep.

• Generally, these studies were of moderate-to-high quality.

People with a Secondary Sleep Disorder

• Melatonin did not have an effect on sleep onset latency in

people with a secondary sleep disorder; the effects of

melatonin did not differ between children and adults; the

effect of melatonin did not vary with dose or duration of

treatment. 

• Melatonin increased sleep efficiency in people with a

secondary sleep disorder (WMD: 1.9 percent; 95-percent

CI: 0.5 percent, 3.3 percent); the effect of melatonin did

not vary by age, dose or duration of treatment. The

magnitude of this effect appears to be clinically

insignificant.

• Melatonin did not have an effect on WASO or percent

time spent in REM sleep in people with a secondary sleep

disorder, but increased total sleep time in this population

• Generally, these studies were of moderate-to-high quality.

People Suffering from Sleep Restriction

• Melatonin did not have an effect on sleep onset latency in

people suffering from sleep restriction; the effect of

melatonin did not vary by dose or type of sleep restriction

disorder i.e. shift-work and jet lag

• Melatonin did not have an effect on sleep efficiency in

people suffering from sleep restriction; the effect of

melatonin did not vary by dose

• Melatonin did not have an effect on sleep quality, WASO

and percent time spent in REM sleep in people suffering

from sleep restriction, but significantly increased total

sleep time in this population

• Generally, these studies were of moderate-to-high quality.

3
4

Safety of Exogenous Melatonin

• The most commonly reported adverse effects of melatonin

were nausea (incidence: ~ 1.5 percent), headache

(incidence: ~ 7.8 percent), dizziness (incidence: 4.0

percent), and drowsiness (incidence: 20.33 percent);

however, these effects were not significant compared to

placebo. This result did not change by dose, the presence

or absence of a sleep disorder, type of sleep disorder,

duration of treatment, gender, age, formulation of

melatonin, use of concurrent medication, study design,

quality score, and allocation concealment score.

• Generally, these studies were of moderate-to-high quality.

Formulations, Pharmacology, and Mechanism

of Action of Exogenous Melatonin

• A number of different formulations of melatonin have

been used in clinical trials on humans; it is unclear how

these formulations differ in terms of content, quality, and

effectiveness in treating sleep disorders.

• The half-life of melatonin ranged from 0.54h to 2h. The

peak circulating concentration of melatonin ranged from

14.75 pg/ml to 64 730 pg/ml, reflecting a dose range of

0.003mg to 75mg. The time required to reach peak

values ranged from 0.25h to 13h. There is evidence from

one study that exogenous melatonin penetrates the bloodbrain-barrier.

• The basic mechanism by which melatonin produces

sleepiness in humans is unclear, although three main

hypotheses have been proposed; the mechanism may

involve a phase-shift of the endogenous circadian

pacemaker, a reduction in core body temperature and/or a

direct action on somnogenic structures of the brain.

Melatonin and Other Pharmacological

Treatments for Sleep Disorders

• There are no differences in the effects of melatonin and

triazolam on normal sleepers; zopiclone reduced SOL to a

greater extent than melatonin during particular periods of

investigation of normal sleepers in one study; there were

no differences in the effect of melatonin and zolpidem on

alleviation of jet lag in one study; however, there were

more reports of adverse effects with zolpidem than with

melatonin.

Endogenous Melatonin and Sleep and

Temperature Rhythms

• There is evidence linking endogenous melatonin to the

sleep cycle; manipulation of endogenous melatonin was

often accompanied by changes in the sleep cycle and vice

versa; an analysis of the correlation between changes in the

two variables was often not conducted, and in cases where

it was conducted, the results were mixed.

• There is evidence linking endogenous melatonin to the

temperature rhythm. Manipulation of endogenous

melatonin was often accompanied by changes in the

temperature rhythm; manipulation of the temperature

rhythm was accompanied by changes in endogenous

melatonin in one out of two studies. An analysis of the

correlation between changes in the two variables was often

not conducted, and in cases where it was conducted, the

results were mixed.

Discussion

Effectiveness of Melatonin in People with

Primary Sleep Disorders

Our literature review indicated that melatonin reduced sleep

onset latency to a greater extent in people with delayed sleep

phase syndrome than in people with insomnia. This finding

may indicate that the effects of melatonin on people with

primary sleep disorders are mediated by a direct re-setting of

the endogenous circadian pacemaker rather than via a direct

action on somnogenic structures of the brain, given that

individuals with delayed sleep phase syndrome are

distinguished from individuals with insomnia by the presence

of a circadian abnormality. It is also possible that melatonin

may initially act on somnogenic structures of the brain to

promote sleep; the reduction in sleep onset latency would

decrease evening light exposure, which would in turn promote

a phase-advance of the endogenous melatonin rhythm and a resetting of the endogenous clock. The finding that melatonin

had an effect on sleep onset latency, but not on sleep efficiency,

in people with primary sleep disorders supports the hypothesis

that melatonin exerts its effects on this population by acting as

a phase re-setter rather than as a hypnotic.

Effectiveness of Melatonin in People with

Secondary Sleep Disorders

Our literature review indicated that melatonin had no effect

on sleep onset latency, while increasing sleep efficiency, in

people with a secondary sleep disorder. However, these

summary estimates are markedly influenced by the results of a

study by Shamir et al.17 The study was unique in that

polysomnography, rather than actigraphy or questionnaire/sleep

diaries, was used to assess sleep outcomes, and the method of

concealing treatment allocation was reported and was adequate.

Additional studies that use polysomnography to assess sleep

outcomes are required before it can be concluded that
melatonin does not affect sleep onset latency or that melatonin

increases sleep efficiency in people with secondary sleep

disorders. 

Effectiveness of Melatonin in People Suffering

from Sleep Restriction

Two other systematic reviews examining the use of

melatonin for the alleviation of jet lag concluded that

melatonin is effective in alleviating the symptoms of jet lag.18 ,19

The results of the current review suggest that melatonin does

not affect either sleep onset latency or sleep efficiency in jet lag

sufferers or people suffering from shift-work disorder. Taken

together, the findings of the current review and those of

previous reviews suggest that the effectiveness of melatonin in

alleviating jet lag may not involve alleviation of the sleep

disturbance, but rather, the daytime fatigue associated with jet

lag. 

Safety of Melatonin

The findings of this review suggest that exogenous melatonin

is a relatively safe substance when used in the short term, over a

period of days or weeks, and is safe at relatively high doses and

in various formulations. However, the safety of exogenous

melatonin when used in the long-term, over months and years,

remains unclear.

Melatonin and Other Pharmacological

Treatments for Sleep Disorders

It appears that there are no major differences in the

effectiveness of melatonin and triazolam, and melatonin and

zopiclone, in normal sleepers, and in the effectiveness of

melatonin and zolpidem in people suffering from jet lag,

although zolpidem may have more adverse effects. The adverse

events associated with these treatments were not addressed in

most reports, such that their relative safety is unclear. 

Clinical Significance of Observations of this

Review Related to the Effectiveness of

Melatonin

One cannot draw firm conclusions regarding the

effectiveness of melatonin in normal sleepers due to the

presence of heterogeneity and evidence of possible publication

bias in the studies relevant to this area. Similarly, the presence

of heterogeneity across studies related to people with primary

or secondary sleep disorders prevents one from drawing firm

conclusions regarding the effectiveness of melatonin in

alleviating these disorders. 

Despite the inability to draw firm conclusions regarding the

effectiveness of melatonin in normal sleepers and people with

sleep disorders, one may comment on the clinical significance

of the findings of this review based on the current evidence.

Indeed, the magnitude of the effects of melatonin appear to be

of no clinical significance in all populations studied in this

review, except for people suffering from delayed sleep phase

syndrome. However, even for the latter population, one cannot

definitively conclude that melatonin is effective in alleviating

the sleep disturbance, since the observation of melatonin

effectiveness in this population was based on only two studies

with less that 25 participants. Therefore, there is evidence to

suggest that melatonin is not effective in treating most primary

and secondary sleep disorders, although there is some evidence

to suggest that melatonin is effective in treating delayed sleep

phase syndrome. Moreover, there is no evidence to suggest that

melatonin is effective in alleviating the sleep disturbance aspect

of jet lag and shift-work disorder.

A rigorous comparison of the effectiveness of melatonin and

all other treatments for sleep disorders was beyond the scope of

this review, and a systematic approach is required to determine

how the effects of melatonin compare to other treatments for

sleep disorders. However, our literature review revealed a

paucity of evidence related to how melatonin compares with

other pharmacological agents for sleep disorders in its

effectiveness in normal sleepers and people with sleep disorders,

and in its safety.

Future Research

In light of the substantial amount of heterogeneity across

studies of melatonin for the treatment of primary and

secondary sleep disorders, more studies are necessary in this

area. It is necessary that the conditions of these studies be

clearly defined, especially with respect to the formulation and

pharmacology of the melatonin product used in these studies.

For studies involving melatonin administration to normal

sleepers, the presence of substantial heterogeneity and evidence

of publication bias necessitates more research in this area.

In addition to the areas outlined earlier in this report,

research is required in various areas within the field of

melatonin and sleep disorders research. There were some

aspects of some questions of this review that could not be

answered by the review, due to a lack of relevant information.

For example, it remains unclear how the effects of melatonin

vary by age, gender, ethnicity, and co-morbid conditions of the

population, as well as formulation, timing, and duration of

melatonin administration. Moreover, the long-term effects of

melatonin on people with primary and secondary sleep

disorders, beyond 4 weeks, remains to be determined. The

short- and long-term effects of melatonin on people with sleep

apnea also need to be determined. The safety of melatonin in

5
6

people of different ethnicities and with different timing of

administration needs to be determined, as well as the effects of

long-term use of melatonin.

The mechanism by which melatonin produces sleepiness in

humans is unclear as are the mechanisms by which melatonin is

absorbed, distributed, metabolized, and excreted in humans,

and research is in this area is required. Very few studies

compare the benefits and harms of melatonin and other

pharmacological treatments for sleep disorders, and more

research in this area is necessary. 

Limitations of the Review

The presence of substantial heterogeneity in the conduct of

and results across studies involving administration of melatonin

to people with either primary or secondary sleep disorders

limits one from drawing any firm conclusions regarding the

effectiveness of melatonin in these populations. Similarly, the

presence of substantial heterogeneity and evidence of possible

publication bias across studies involving normal sleepers

prevents one from drawing any firm conclusions on

effectiveness of melatonin in this population. The studies did

not provide any evidence surrounding the safety of long-term

use of melatonin, which prevents one from drawing any

conclusions regarding this aspect of its safety. Moreover, one

cannot draw any firm conclusions with respect to how

melatonin compares with other pharmacological agents for

sleep disorders in its effectiveness and safety.

A number of gaps were identified in the area of melatonin

and sleep disorders research, which prevented us from

addressing certain aspects and/or entire questions of the review.

Major shortcomings of the studies included in the analysis of

the effectiveness of melatonin for the treatment of sleep

disorders and its safety were the quality of reporting with

respect to the formulation and pharmacology of the melatonin

product used in the study, the details of the sleep disorder

suffered by participants and the funding sources for the studies. 

Conclusions

• Evidence suggests that melatonin is not effective in

treating most primary sleep disorders with short-term use,

although there is some evidence to suggest that melatonin

is effective in treating delayed sleep phase syndrome with

short-term use. 

• Evidence suggests that melatonin is not effective in

treating most secondary sleep disorders with short-term

use.

• No evidence suggests that melatonin is effective in

alleviating the sleep disturbance aspect of jet lag and shiftwork disorder.

• Evidence suggests that melatonin is safe with short-term

use.

• Evidence suggests that exogenous melatonin has a short

half-life and it penetrates the blood-brain-barrier.

• Evidence suggests a link between endogenous melatonin

and the sleep cycle.

• Evidence suggests a link between endogenous melatonin

and the temperature rhythm. 

Availability of the Full Report

The full evidence report from which this summary was taken

was prepared for the Agency for Healthcare Research and

Quality (AHRQ) by the University of Alberta Evidence-based

Practice Center, under Contract No. 290-02-0023. It is

expected to be available in November 2004. At that time,

printed copies may be obtained free of charge from the AHRQ

Publications Clearinghouse by calling 800-358-9295.

Requesters should ask for Evidence Report/Technology

Assessment No. 108, Melatonin for Treatment of Sleep Disorders.

In addition, Internet users will be able to access the report and

this summary online through AHRQ's Web site at

www.ahrq.gov.

Suggested Citation

Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold

L, Hartling L, Baker G, Vohra S, Klassen T. Melatonin for

Treatment of Sleep Disorders. Summary, Evidence

Report/Technology Assessment No. 108. (Prepared by the

University of Alberta Evidence-based Practice Center, under

Contract No. 290-02-0023.) AHRQ Publication No. 05-E002-

1. Rockville, MD: Agency for Healthcare Research and Quality.

November 2004.

References

1. National Institutes of Health. National Institutes of Health. National

Center on Sleep Disorder Research. 2003.

www.nhlbi.nih.gov/health/prof/sleep/res_plan/sleep-rplan.pdf

2. Roller L. Treating sleep disorders. 83. 2002:443-7. 

3. Grustein R. Insomnia. Diagnosis and management. Austr Fam Phys

2002; 31(11):995-1000.

4. Gordon N. The therapeutics of melatonin: a paediatric perspective

Brain Dev 2000 Jun; 22(4):213-7. 

5. Leone RM, Silman RE. Melatonin can be differentially metabolized in

the rat to produce N-acetylserotonin in addition to 6-hydroxymelatoni. Endocrinology 1984; 114(5):1825-32.
6. Young IM, Leone RM , Francis P , Stovell P , Silman RE. Melatonin

is metabolized to N-acetyl serotonin and 6-hydroxymelatonin in man.

J Clin Endocrinol Metab 1985 Jan; 60(1):114-19.

7. Melatonin and the mammalian pineal gland. London: Chapman and

Hall, 1885. 

8. Vijayalaxmi, Thomas Jr CR, Reiter RJ, Herman TS. Melatonin: from

basic research to cancer treatment clinics. J Clin Oncol 2002: May 15;

20(10):2575-601.

9. The Merck Index, 10th ed. Rahway, New Jersey: Merck and Co,

1983. 

10. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports

of randomized clinical trials: is blinding necessary? Controlled Clin

Trials 1996; 17:1-12.

11. Schulz KF, Chalmers I, Hayes RJ, Altman D. Empirical evidence of

bias. Dimensions of methodological quality associated with estimates

of treatment effects in controlled trials. J Am Med Assoc 1995; 273

(5):408-12.

12. Downs SH, Black N. The feasibility of creating a checklist for the

assessment of the methodological quality both of randomized and

non-randomized studies of health care interventions. J Epidemiol

Commun Health 1998; 52:377-84.

13. Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for

examining heterogeneity and combining results from several studies in

meta-analysis. Systematic Reviews in Health Care 2001; 300.

14. Begg CB, Mazumdar M. Operating characteristics of a rank

correlation test for publication bias. Biometrics 1994; 50:1088-101.

15. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis

detected by a single graphical test. Br Med J 1997; 315:629-34.

16. Duval S, Tweedie R. A nonparametric "trim and fill" method of

accounting for publication bias in meta-analysis. J Am Med Assoc

2000; 95(449):89-98.

17. Shamir E, Rotenberg VS, Laudon M, Zisapel N, Elizur A. First-night

effect of melatonin treatment in patients with chronic schizophrenia.

J Clin Psychopharmacol 2000 Dec;20(6):691-4. 

18. Herxheimer A, Petrie KJ. Melatonin for preventing and treating jet

lag. Cochrane Database Syst Rev 2002;(2):CD001520. Review. 

19. Chase JE, Gidal BE. Melatonin: therapeutic use in sleep disorders.

Ann Pharmacother 1997 Oct; 31(10):1218-26. 

7
www.ahrq.gov

AHRQ Pub. No. 05-E002-1

November 2004

ISSN 1530-440X