Evidence Report/Technology Assessment 

Number 108 

Melatonin for Treatment of Sleep Disorders 

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

540 Gaither Road 

Rockville, MD 20850 

www.ahrq.gov 

Contract No. 290-02-0023 

Prepared by: 

University of Alberta Evidence-based Practice Center, Edmonton, Alberta, Canada 

Nina Buscemi, PhD 

(Project Manager)

Ben Vandermeer, MSc 

Rena Pandya, MPH 

Nicola Hooton, BSc 

Lisa Tjosvold, MLIS 

Lisa Hartling, MSc 

Glen Baker, PhD, DSc 

(Co-Task Order Leader) 

Sunita Vohra, MD, MSc 

(Co-Task Order Leader) 

Terry Klassen, MD, MSc, FRCPC 

(EPC Director)

AHRQ Publication No. 05-E002-2 

November 2004 
This report may be used, in whole or in part, as the basis for development of clinical practice 

guidelines and other quality enhancement tools, or a basis for reimbursement and coverage 

policies. AHRQ or U.S. Department of Health and Human Services endorsement of such 

derivative products may not be stated or implied. 

AHRQ is the lead Federal agency charged with supporting research designed to improve the 

quality of health care, reduce its cost, address patient safety and medical errors, and broaden access 

to essential services. AHRQ sponsors and conducts research that provides evidence-based 

information on health care outcomes; quality; and cost, use, and access. The information helps 

health care decisionmakers—patients and clinicians, health system leaders, and policymakers—

make more informed decisions and improve the quality of health care services. 
This document is in the public domain and may be used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders. 

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. 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-E002-2. Rockville, MD: Agency 

for Healthcare Research and Quality. November 2004. 

ii
Preface 

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. This report was requested and funded by the National 

Center for Complementary and Alternative Medicine, National Institutes of Health (NIH). The 

reports and assessments provide organizations with comprehensive, science-based information 

on common, costly medical conditions and new health care technologies. The EPCs 

systematically review the relevant scientific literature on topics assigned to them by AHRQ and 

conduct additional analyses when appropriate prior to developing their reports and assessments. 

To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the healthcare system as a whole by 

providing important information to help improve health care quality. 

We welcome comments on this evidence report. They may be sent by mail to the Task Order 

Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, 

Rockville, MD 20850, or by email to epc@ahrq.gov. 

Jean Slutsky, P.A., M.S.P.H. 

Director, Center for Outcomes and 

Evidence 

Agency for Healthcare Research and Quality 

Carolyn M. Clancy, M.D. 

Director

Agency for Healthcare Research and Quality 

 

Stephen E. Straus, M.D. 

Director

National Center for Complementary and 

 Alternative Medicine, NIH 

Margaret Coopey, R.N., M.G.A., M.P.S. 

EPC Program Task Order Officer 

Agency for Healthcare Research and Quality 

Kenneth S. Fink, M.D., M.G.A., M.P.H. 

Director, EPC Program

Agency for Healthcare Research and Quality 

 

The authors of this report are responsible for its content. Statements in the report should 

not be construed as endorsement by the Agency for Healthcare Research and Quality or the 

U.S. Department of Health and Human Services of a particular drug, device, test, treatment, 

or other clinical service.

iii
Acknowledgments 

We are grateful to members of the technical expert panel for providing input on the direction 

and scope of the review. We thank Dr. Richard Nahin, Dr. Nancy Pearson and the National 

Center for Complementary and Alternative Medicine, National Institutes of Health, as well as 

Ms. Margaret Coopey and the Agency for Healthcare Research and Quality for insight and 

recommendations. We are also grateful to Ms. Michelle Tubman, Dr. Mia Lang, Ms. Maria 

Ospina, Mr. Victor Juorio and Ms. Ellen Crumley for their contribution to the systematic review 

process. 

Investigating authors acknowledge the following financial support: Dr. Sunita Vohra is 

supported by: Agency for Healthcare Research and Quality (USA); Canadian Institutes of Health 

Research; Change Foundation; Department of Pediatrics, Stollery Children’s Hospital; Natural 

Health Products Directorate, Health Canada; Ontario Mental Health Foundation; Stollery 

Children’s Hospital Foundation; The Hospital for Sick Children Foundation; and the University 

of Alberta. Dr. Glen Baker is supported by Canadian Institutes of Health Research, Canada 

Research Chairs Program and Zyprexa Research Foundation. 

iv
Structured Abstract 

Context. Sleep disorders affect 50 to 70 million Americans, representing approximately 20 per 

cent of the population. 

Objectives. To review the effectiveness of melatonin for the treatment of sleep disorders; the 

safety, pharmacology and mechanisms of action of exogenous melatonin; and the link between 

endogenous melatonin and circadian rhythms. 

Primary Data Sources. Studies were selected from the following electronic databases: 

MEDLINE®, PreMEDLINE®, EMBASE®, PubMed®, CAB Health®, CINAHL®, AMED®, 

Cochrane Central Register of Controlled Trials®, Cochrane Complementary Medicine Field 

Registry®, Science Citation Index®, Biological Abstracts®, International Pharmaceutical 

Abstracts®, NLM Gateway®, OCLC papers First and Proceedings First

®, TOXLINE®, Registry 

of Toxic Effects of Chemical Substances (RTECS) ®. Data were also obtained from register of 

ongoing trials. 

Study Selection. Studies were selected for particular questions of the review according to predetermined, question-specific inclusion criteria. Only English-language reports were included in 

the review. 

 

Quality Assessment. The quality of studies was assessed using either the Jadad Scale for 

Quality Assessment of Randomized-Controlled Trials or the Downs and Black Checklist for 

Quality Assessment of Non-Randomized Controlled Trials. Allocation concealment in the 

randomized controlled trials was also assessed. 

 

Data Analysis. Quantitative Analysis: Data were analyzed using a Random Effects Model. All 

results were reported with 95 per cent confidence intervals (95 per cent CI). Sources of 

heterogeneity were assessed using the I-squared statistic, and publication bias was assessed using 

the Funnel Plot approach, the Rank Correlation Test, the Graphical Test, and the Trim and Fill 

Method. Qualitative Analysis: Relevant information was summarized and synthesized. 

Main Results. Effectiveness of Exogenous Melatonin: People with a Primary Sleep 

Disorder: Melatonin decreased sleep onset latency; it was decreased greatly in people with 

delayed sleep phase syndrome and marginally in patients with insomnia. There was no evidence 

that melatonin had an effect on sleep efficiency. The magnitude of the effect of melatonin on 

sleep onset latency in people with delayed sleep phase syndrome, but not in people suffering 

from insomnia, appears to be clinically significant. People with a Secondary Sleep Disorder: 

There was no evidence that melatonin had an effect on sleep onset latency, but it increased sleep 

efficiency. The magnitude of the effect of melatonin on sleep efficiency in people with 

secondary sleep disorders appears to be clinically insignificant. People Suffering from Sleep 

Restriction: There was no evidence that melatonin had an effect on sleep onset latency or sleep 

efficiency. Safety of Exogenous Melatonin: There was no evidence of adverse effects of 

melatonin with short-term use. 

v
Main 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 shift-work disorder. 

• Evidence suggests that melatonin is safe with short-term use. 

vi
Contents 

Evidence Report ................................................................................................................. 1 

Chapter 1. Introduction ..................................................................................................... 3

 Sleep Disorders............................................................................................................. 3 

Classification of Sleep Disorders.................................................................................. 3 

Treatment of Sleep Disorders....................................................................................... 4 

 Chronotherapy........................................................................................................... 4 

 Pharmacotherapy....................................................................................................... 4 

 Melatonin ...................................................................................................................... 5

Discovery and History of Melatonin......................................................................... 5 

Physiology of Endogenous Melatonin ...................................................................... 6 

Effects of Exogenous Melatonin ............................................................................... 6 

 Melatonin Receptors ................................................................................................. 7 

Sleep Disorders and Melatonin..................................................................................... 7 

Clinical Trials of Melatonin for Sleep Disorders...................................................... 7 

Formulation and Dosage of Melatonin used in Clinical Trials................................. 8 

Adverse Effects of Melatonin ................................................................................... 9 

Systematic Reviews on the Use of Melatonin for the Treatment of Sleep Disorders... 9 

Melatonin Safety and Legal Status............................................................................... 9 

Status in the United States....................................................................................... 10 

Status in Canada ...................................................................................................... 10 

Status in Europe ...................................................................................................... 10 

Status in Australia ................................................................................................... 10 

Objectives of the Review............................................................................................ 10 

Questions of the Review............................................................................................. 11 

Chapter 2. Methods.......................................................................................................... 15

 Research Team............................................................................................................ 15 

Methods for the Systematic Review ........................................................................... 15 

 Overview ................................................................................................................. 15 

 Comprehensive Search............................................................................................ 16 

Development of Inclusion Criteria.......................................................................... 17 

Question-Specific Inclusion Criteria ................................................................. 17 

 Study Selection........................................................................................................ 21 

Assessment of Study Quality .................................................................................. 21 

 Data Extraction........................................................................................................ 21 

 Data Analysis .......................................................................................................... 22 

 Quantitative Analysis......................................................................................... 24 

 Qualitative Analysis........................................................................................... 25 

Chapter 3. Results............................................................................................................ 29 

 Literature Review........................................................................................................ 29 

Results of Quantitative Analysis................................................................................. 29 

Effect of Melatonin on Normal Sleepers................................................................. 29 

vii
Effect of Melatonin on People with Sleep Disorders.............................................. 32 

People with a Primary Sleep Disorder............................................................... 33 

People with a Secondary Sleep Disorder........................................................... 35 

People Suffering from Sleep Restriction ........................................................... 37 

Effectiveness of Melatonin Among Types of Sleep Disorders............................... 38 

Effectiveness of Melatonin Among Types of Populations...................................... 39 

Effectiveness of Melatonin with respect to Dosage ................................................ 40 

Effectiveness of Melatonin with respect to Timing ................................................ 41 

Effectiveness of Melatonin with respect to Formulation ........................................ 41 

Adverse Effects of Melatonin ................................................................................. 42 

Safety of Melatonin with respect to Formulation.................................................... 42 

Safety of Melatonin with respect to Patients Factors.............................................. 42 

Results of Qualitative Analysis................................................................................... 43 

Effectiveness and Safety of Melatonin.................................................................... 43 

Pharmacology of Melatonin .................................................................................... 43 

Endogenous Melatonin and the Sleep Cycle........................................................... 45 

 Intervention: manipulation of light/dark exposure ............................................ 45 

Intervention: manipulation of the sleep schedule .............................................. 48 

 Intervention: administration of a tryptophan-free mixture ................................ 49 

 Summary............................................................................................................ 49 

Mechanism of Action of Melatonin ........................................................................ 49 

Endogenous Melatonin and Circadian Rhythms..................................................... 51 

 Intervention: manipulation of light/dark exposure ............................................ 51 

Intervention: manipulation of body temperature ............................................... 53 

 Summary............................................................................................................ 53 

Melatonin and other Pharmacologic Treatments for Sleep Disorders........................ 54 

Overall Grade of Evidence on Effectiveness and Safety of Melatonin ...................... 55 

Chapter 4. Discussion .................................................................................................... 101 

Key Observations of the Literature Review.............................................................. 101 

Effectiveness of Exogenous Melatonin................................................................. 101 

Effectiveness of Exogenous Melatonin................................................................. 101 

Safety of Exogenous Melatonin ............................................................................ 103 

Formulations, Pharmacology and Mechanisms of Action of Exogenous 

 Melatonin ......................................................................................................... 103 

Endogenous Melatonin and Sleep and Temperature Rhythms ............................. 103 

Melatonin and other Pharmacologic Treatments for Sleep Disorders .................. 104 

Discussion of Key Observations of the Review ....................................................... 104 

Effectiveness of Melatonin.................................................................................... 104 

Effectiveness of Melatonin in the Treatment of Primary Sleep Disorders ........... 105 

Effectiveness of Melatonin in the Treatment of Secondary Sleep Disorders........ 106 

Effectiveness of Melatonin in the Treatment of Sleep Restriction Disorders....... 107 

Safety of Melatonin............................................................................................... 107 

Formulations and Pharmacology of Melatonin..................................................... 107 

Clinical Significance of Key Observations of this Review................................... 108 

Link Between Endogenous Melatonin and the Sleep Cycle ................................. 108 

viii
Link Between Endogenous Melatonin and the Temperature Rhythm .................. 109 

 Future Research ........................................................................................................ 109 

Limitations of the Review......................................................................................... 110 

 Conclusions............................................................................................................... 110 

References and Included Studies.................................................................................... 113 

List of Excluded Studies................................................................................................. 131 

 

Definitions of Terminology ........................................................................................... 153 

Flow Diagrams 

Flow Diagram 1: Analytic Framework ............................................................................ 12 

Flow Diagram 2: Flow Diagram of Study Retrieval and Selection for Melatonin and 

Sleep Disorders Review ............................................................................................. 56 

Figures

Figure 1: Meta-Graph: Sleep Onset Latency in Normal Sleepers .................................. 57 

Figure 2: Funnel Plot: Sleep Onset Latency in Normal Sleepers ................................... 58 

Figure 3: Meta-Graph: Sleep Efficiency in Normal Sleepers ......................................... 59 

Figure 4: Funnel Plot: Sleep Efficiency in Normal Sleepers .......................................... 60 

Figure 5: Meta-Graph: REM Latency in Normal Sleepers ............................................. 61 

Figure 6: Funnel Plot: REM Latency in Normal Sleepers .............................................. 62 

Figure 7: Meta-Graph: Sleep Onset Latency: Primary Sleep Disorder .......................... 63 

Figure 8: Funnel Plot: Sleep onset latency: Primary Sleep Disorder .............................. 64 

Figure 9: Meta-Graph: Sleep Efficiency in People with a Primary Sleep Disorder ....... 65 

Figure 10: Funnel Plot: Sleep Efficiency in People with a Primary Sleep Disorder ...... 66 

Figure 11: Meta-Graph: Sleep Onset Latency: Secondary Sleep Disorder .................... 67 

Figure 12: Meta-Graph: Sleep Efficiency: Secondary Sleep Disorder ........................... 68 

Figure 13: Meta-Graph: Sleep Onset Latency: Sleep Restriction ................................... 69 

Figure 14: Funnel Plot: Sleep Onset Latency: Sleep Restriction .................................... 70 

Figure 15: Meta-Graph: Sleep Efficiency: Sleep Restriction ........................................ 71 

Figure 16: Meta-Graph: Headaches ............................................................................... 72 

Figure 17: Meta-Graph: Dizziness Headaches .............................................................. 73 

Figure 18: Meta-Graph: Nausea .................................................................................... 74 

Figure 19: Meta-Graph: Drowsiness .............................................................................. 75 

Tables 

Table 1: Classification of Sleep Disorders according to ICSD......................................... 13 

Table 2: Biomedical Databases Searched ....................................................................... 26 

Table 3: Keywords and Subject Headings used in Searches ........................................... 27 

Table 4: Questions of the Review and Type of Analysis Applied to Data Relevant to 

these Questions .......................................................................................................... 27 

ix
Table 5: Number of Studies relevant to Individual Questions of the Review and Type of 

Analysis Applied to Data Relevant to these Questions ............................................. 77 

Table 6: Subgroup and Sensitivity Analysis: Sleep Onset Latency: Normal Sleepers ... 78 

Table 7: Subgroup and Sensitivity Analyses: Sleep Efficiency in Normal Sleepers ...... 80 

Table 8: Subgroup and Sensitivity Analyses: REM Latency in Normal Sleepers .......... 81 

Table 9: Subgroup and Sensitivity Analyses: Sleep Onset Latency in People with a 

Primary Sleep Disorder .............................................................................................. 82 

Table 10: Subgroup and Sensitivity Analyses: Sleep Efficiency in People with a Primary 

Sleep Disorder ............................................................................................................ 83 

Table 11: Subgroup and Sensitivity Analyses: Sleep Onset Latency in People with a 

Secondary Sleep Disorder........................................................................................... 84 

Table 12: Sensitivity and Subgroup Analyses: Sleep Efficiency in People with a 

Secondary Sleep Disorder .......................................................................................... 85 

Table 13: Subgroup and Sensitivity Analyses: Sleep Onset Latency in People Suffering 

from Sleep Restriction ............................................................................................... 86 

Table 14: Subgroup and Sensitivity Analyses: Sleep Efficiency in People Suffering from

Sleep Restriction ........................................................................................................ 87 

Table 15: Subgroup Analysis: Headaches ...................................................................... 88 

Table 16: Subgroup Analysis: Dizziness ....................................................................... 89 

Table 17: Subgroup Analysis: Nausea ............................................................................ 90 

Table 18: Subgroup Analysis: Drowsiness .................................................................... 91 

Table 19: Effect of Manipulation of Light/Dark Exposure on Endogenous Melatonin and 

the Sleep Cycle in Normal Sleepers: Manipulation during Evening or Night ......... 92 

Table 20: Effect of Manipulation of Light/Dark Exposure on Endogenous Melatonin and 

the Sleep Cycle: Normal Sleepers: Manipulation During Morning or Daytime ..... 93 

Table 21: Effect of Manipulation of Light/Dark Exposure on Endogenous Melatonin and 

the Sleep Cycle in Normal Sleepers: Manipulation Involves Unique Conditions..... 94 

Table 22: Effect of Manipulation of Light/Dark Exposure on Endogenous Melatonin and 

the Sleep Cycle in People with Sleep Disorders ....................................................... 95 

Table 23: Effect of Manipulation of Light/Dark Exposure on Endogenous Melatonin and 

the Sleep Cycle in People with a Disorder that may or may not be Accompanied by a 

Sleep Disorder .......................................................................................................... 96 

Table 24: Effect of Manipulation of Light/Dark Exposure on Endogenous Melatonin and 

the Sleep Cycle in Normal Sleepers: Manipulation During Evening or Night ........ 97 

Table 25: Effect of Manipulation of Light/Dark Exposure on Endogenous Melatonin and 

the Sleep Cycle: Normal Sleepers: Manipulation Involved Unique Conditions ..... 98 

Table 26: Effect of Manipulation of Light/Dark Exposure on Endogenous Melatonin and 

the Sleep Cycle in People with a Sleep Disorder ...................................................... 99 

Table 27: Oxford Centre for Evidence-based Medicine Levels of Evidence .............. 100 

Table 28: Summary of the Evidence Surrounding the Effect of Melatonin on Sleep in 

Various Populations ................................................................................................. 111 

x
Appendixes 

Appendix A: Exact Search Strings 

Appendix B: Quality Assessment and Data Extraction Forms 

Appendix C: Evidence Tables 

Appendix D: Technical Expert Panel 

The Appendixes and Evidence Tables cited in this report are provided electronically 

at http://www.ahrq.gov/clinic/tp/melatntp.htm. 

xi
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
Evidence Report
2
Chapter 1. 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 Sleep disorders can also be associated with other conditions. For example, 

psychiatric conditions are the most common cause of insomnia and insomnia is often associated 

with subsequent development of a psychiatric disorder.1

 Similarly, many neurological 

conditions are strongly associated with sleep disorders, with prevalence of sleep disorders up to 

80 percent in people with severe mental retardation.1

Sleep disorders place a tremendous burden on society due to their association with 

psychiatric disorders, negative impact on quality of life, safety, productivity and high health care 

utilization. The National Institutes of Health (NIH) has identified many areas of sleep disorder 

research that require greater attention, such as the neurobiology of sleep disorders, the effects of 

sleep disorders and deprivation on performance, and treatment of sleep disorders, including 

complementary and alternative therapy. 

Generally, one of two approaches is used to treat sleep disorders. These approaches are 

designed to improve performance during waking hours by either improving the amount and 

quality of sleep, or improving alertness during waking hours. A range of therapies are employed 

for the treatment of sleep disorders, from behavioral therapy to light therapy to pharmacotherapy. 

Complementary and alternative therapy is increasingly utilized in the management of sleep 

disorders. Complementary and alternative medicine (CAM) may be defined as a broad area of 

healing resources distinct from those intrinsic to the politically dominant health system of a 

particular society at a given time.4

 This review will focus on the use of melatonin, a popular 

therapy within CAM, for the treatment of sleep disorders. 

Classification of Sleep Disorders 

Sleep disorders have been classified in various ways (Diagnostic and Statistical Manual 

of Mental Disorders, 4th Edition, Text Revision [DSM-IV-TR]; International Classification of 

Diseases, 9th Revision, Clinical Modification [ICD-9-CM]; International Classification of Sleep 

Disorders [ICSD]). The most recent and detailed classification is the revised version of the 

International Classification of Sleep Disorders (1990), published by the American Academy of 

Sleep Medicine.5

 This document classifies sleep disorders according to four broad categories: 

dyssomnias, which are characterized by poor sleep; parasomnias, which are characterized by the 

occurrence of unusual events during sleep; sleep disorders associated with mental, neurological, 

or medical disorders; and proposed sleep disorders. Dyssomnias, disturbances of the normal 

sleep or rhythm pattern, are further subdivided into intrinsic (internally-caused), extrinsic 

(environmentally-caused) and circadian rhythm disorders. Circadian rhythm disorders may also 

3
have an intrinsic cause, such as the inability to entrain the sleep-wake cycle to a 24-hour day in 

non-24-hour sleep wake syndrome, or an extrinsic cause in which the internal circadian 

apparatus is normal, but the demands of the external environment override it, such as in shiftwork disorder or jet lag. Parasomnias involve dysfunctions occurring during sleep, such as 

nightmares, sleep paralysis or sleepwalking. Sleep disorders often occur in conjunction with 

mental disorders such as psychoses or mood and anxiety disorders; neurological disorders such 

as fatal familial insomnia, dementia, and Parkinsonism; and medical disorders such as chronic 

obstructive pulmonary disease and nocturnal cardiac ischemia (Table 1).

5

Treatment of Sleep Disorders 

The specific treatment used for a given sleep disorder depends on the type and etiology of 

the disorder.6

 Generally, the first line of treatment for sleep disorders involves improving sleep 

hygiene, which may consist of such strategies as strict adherence to a consistent routine seven 

days per week, a quiet and comfortable sleep environment, wind-down time before bed, stimulus 

control, avoidance of alcohol and caffeine before sleep and properly-timed exercise.6

 The 

American Academy of Sleep Medicine endorses the use of sleep hygiene and stimulus control, 

but other behavioral treatments, such as biofeedback, sleep restriction, relaxation training and 

cognitive therapy, may also be used. 

Chronotherapy

Chronotherapy may be used for delayed or advanced sleep phase syndrome and usually 

involves application of a series of consecutive shifted 24-hour days, thus phase-delaying the 

sleep cycle three hours per sleep-wake cycle, until the desired bedtime is reached.7

 Light therapy 

may be used alone or in conjunction with chronotherapy and is often a treatment of choice for 

circadian rhythm disorders, since light is the principal synchronizer of circadian timing.8

 For 

delayed sleep phase syndrome, bright light exposure in the morning will lead to a phase advance, 

leading to an earlier time of rising,9

 while for advanced sleep phase syndrome, bright light 

exposure in the evening is effective in re-synchronizing the circadian rhythm.

10 11 

Light can shift the timing of the melatonin rhythm in a dose-response manner, with early 

night exposure resulting in phase delays and late night exposures resulting in phase advances. 12 

13 Light can also suppress endogenous melatonin levels in a dose-response manner.

12

 

Pharmacotherapy 

Pharmacotherapy with sedative/hypnotic drugs is also widely used in the treatment of sleep 

disorders. Hypnotics promote drowsiness and facilitate the onset of sleep, while sedatives induce 

a calming effect. Ideally, a hypnotic should be rapidly absorbed into the bloodstream, display 

specific receptor binding, and induce sleep quickly, without causing side effects, buildup of 

tolerance, physical dependence, and respiratory or central nervous system depression.14 

However, no hypnotic is perfect. Benzodiazepines are the most commonly prescribed hypnotics 

and act on the inhibitory neurotransmitter receptors that are directly activated by the amino acid 

gamma-aminobutyric acid. Drugs of this class can be effective in treating transient insomnia 

and, due to anxiolytic as well as sedative/hypnotic properties, may be useful in the management 

of insomnia associated with select psychiatric disorders.6

 Although there are several chemical 

4
classes of benzodiazepines, some benzodiazepines are metabolized in the body to Ndesmethyldiazepam (nordiazepam), an active metabolite with a long elimination half-life and 

sedative effects. Unwanted effects of the benzodiazepines include daytime sedation, respiratory 

depression, dependence, and rebound insomnia.6

 Non-benzodiazepine hypnotics include 

zolpidem and zaleplon. Drugs of this class are more specific, display more rapid onset and 

shorter duration of action as well as fewer negative effects on memory and motor coordination, 

and are less likely to result in rebound insomnia, compared to benzodiazepines.6

 Antidepressants 

such as tricyclic antidepressants, trazodone and mirtazapine may also have sedative/hypnotic 

properties. Alternatives to traditional hypnotics include herbal and “natural” products such as St. 

John’s Wort, valerian, kava kava, and melatonin.15 These products have been reported to be 

effective, however, the methodological quality of studies on effectiveness of these products as 

well as their inconsistent findings, necessitate further research in this area. 

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.16 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 

N-acetylserotonin by the enzyme N-acetyl transferase.17-19 N-acetylserotonin is methylated via 

the enzyme hydroxyindole-o-methyltransferase to produce melatonin.20 Approximately 90 

percent of melatonin is cleared in a single passage through the liver. Microsomal enzymes of 

hepatic cells metabolize melatonin to 6-hydroxymelatonin.20 The majority of the latter 

compound is subsequently conjugated with sulphate to produce 6-sulfoxymelatonin, while a 

smaller proportion is conjugated to glucuronide, prior to excretion in the urine. A small 

proportion of unmetabolized melatonin is also excreted in the urine.20 Commercially available 

melatonin may be isolated from the pineal glands of beef cattle21 or chemically synthesized. 

Discovery and History of Melatonin 

Melatonin was discovered as a result of the observation that bovine pineal extracts caused 

blanching of the skin of tadpoles when it was added to swimming water.22 Aaron Lerner, an 

American dermatologist, isolated and characterized the hormone from beef pineal extracts in 

1958, naming it melatonin based on its ability to lighten melanocytes.23 

Melatonin is present in a number of organisms such as bacteria, algae, fungi, plants, insects 

and vertebrates, including humans.24 Melatonin is also found in foodstuffs such as vegetables, 

fruits, rice, wheat and herbal medicines.24

 Early research involving melatonin was conducted on animals and examined its effects on 

gonadal maturation and circadian systems. These early animal experiments provided evidence 

for chronobiologic and sleep-inducing effects of melatonin,22 suggesting a role for this hormone 

in sleep and behavior in humans. The first experiments of melatonin on humans were conducted 

in the early 1970s, which provided evidence of a sleep inducing effect of melatonin in humans.25 

26 The first study involving administration of chronic small doses of melatonin in human 

volunteers was conducted in 1984 and this study found that melatonin increased self-rated 

tiredness.27 Sedative-hypnotic effects of melatonin were also noted in a study examining the 

behavioral effects of melatonin.28 In 1984, melatonin was tested for its ability to alleviate the 

5
symptoms of jet lag,27 and this stimulated further trials of melatonin for the treatment of sleep 

disorders. 

Physiology of Endogenous Melatonin 

Melatonin secretion follows a circadian rhythm and is entrained to the light/dark cycle; light 

suppresses the production of melatonin, and with the onset of darkness, melatonin is produced 

and secreted from pinealocytes.29 Light input is transmitted from the photic receptors in the 

retina through the retinohypothalamic tract to the suprachiasmatic nucleus (SCN), which is 

located in the anterior hypothalamus and functions as the central circadian pacemaker of the 

body.30 During the dark period, the SCN stimulates the release of norepinephrine from the 

superior cervical ganglion; activation of pinealocyctes by norepinephrine results in production 

and release of melatonin.31

Melatonin is not stored in the pineal gland, but is secreted upon production. The hormone is 

likely secreted into the bloodstream before entering the cerebrospinal fluid (CSF) of the third 

ventricle, although it may also be secreted directly into cerebrospinal fluid.32 Evidence for direct 

secretion of melatonin into CSF has been provided by findings that melatonin levels in CSF are 

substantially higher than in plasma.

33 Melatonin can also be measured in saliva, where levels are 

about 70 percent of plasma levels. The onset of melatonin secretion occurs at approximately 

2200-2300 hours and maximal plasma concentrations occur at about 0300-0400 hours for a 

regular sleep cycle.34 The offset of melatonin secretion occurs at approximately 0700-0900 

hours.34 The levels of metabolite in urine correlate positively with plasma levels of the 

hormone29 and provide a non-invasive method of measuring melatonin levels in the body.35 

Although melatonin is present in plasma of newborns, the circadian rhythm of melatonin 

does not exist at birth, but appears at 9-12 weeks of age and is fully established by 5-6 months of 

age.35 Melatonin reaches high values at 1-3 years of age, with plasma levels peaking at 

approximately 250 pg/ml. Melatonin levels in plasma begin to decrease just prior to puberty to 

peak values of less than 100 pg/ml in adulthood.36 There are, however, marked individual 

differences in the levels of melatonin that are produced by the pineal gland.29 

 

Effects of Exogenous Melatonin 

Melatonin has several effects on the body. It is best known as an entrainer of the circadian 

rhythm.

37 In mammals, removal of the pineal gland abolishes melatonin secretion.19 Exogenous 

melatonin will cause a phase advance of the melatonin rhythm if given at dusk, and a phase delay 

if given in the morning.38 The constant lag time between the onset of melatonin secretion and 

the onset of sleep suggests that exogenous melatonin could promote sleep.39 Administration of 

exogenous melatonin to healthy volunteers has been shown to increase sleep propensity, reduce 

sleep onset latency and decrease REM sleep latency.40 

The secretion of melatonin is also associated with the thermoregulatory cycle. The circadian 

rhythm of melatonin inversely correlates with the temperature rhythm in humans; melatonin 

levels in blood increase as core body temperature decreases.41 Administration of pharmacologic, 

as opposed to physiologic, doses of exogenous melatonin, has been reported to cause a reduction 

in core body temperature.42 43

The secretion of melatonin secretion is also associated with the reproductive rhythm. In 

humans, melatonin secretion is inversely correlated with gonadal development; peak melatonin 

6
levels fall just prior to the onset of puberty.44 In addition, higher levels of plasma melatonin 

have been noted in women with amenorrhea.45 Taken together, these findings suggest an 

inhibitory effect of melatonin on the reproductive rhythm. 

Melatonin is also involved in immune function, and evidence suggests an immunoenhancing 

function for melatonin, via stimulation of natural killer cell activity, regulation of cytokine 

expression and inhibition of apoptosis in immune cells.46 In support of such a function, high 

affinity melatonin receptors have been detected in human T lymphocytes.47 Melatonin has also 

been shown to have oncostatic effects; it reduces tumor growth in animals and humans,

48 49 may

reduce angiogenesis, protects DNA from mutation, and may also decrease tumor initiation.29 

Melatonin Receptors 

Melatonin has endocrine, autocrine and paracrine actions,29 and some of these actions are 

receptor-mediated, while others are direct. There are three classes of melatonin receptors, MT1, 

MT2, and MT3.50 In mammalian tissues, the distribution of melatonin receptors appears to be 

widespread.29 The receptors are most consistently found in the SCN and the pars tuberalis of the 

adenophysis, although current research suggests that few tissues are devoid of melatonin 

receptors.29 MT1 receptors are high affinity receptors that fall into the G-protein coupled 

receptor superfamily, and binding of melatonin to these receptors results in inhibition of 

adenylate cyclase activity in target cells.51 There are two subgroups of the ML1 receptors, ML1a 

receptors and ML1b receptors.52 The ML1 receptors are likely involved in regulation of retinal 

function, circadian rhythms and reproduction.31 The ML2 receptors are low affinity receptors 

that are coupled to phosphoinositol hydrolysis.31 Activation of MT3 receptors inhibits 

leukotriene B4-induced leukocyte adhesion and decreases intraocular pressure.50 

Sleep Disorders and Melatonin 

Clinical Trials of Melatonin for Sleep Disorders 

The circadian phase modulating effects of melatonin point to its potential use in the treatment 

of circadian rhythm disorders, while the hypnotic/soporific effects of melatonin suggest its 

potential use in the treatment of insomnia. The use of melatonin in the elderly is considered a 

potential treatment for sleep disturbances in this population. Similarly, sleep disorders secondary 

to other medical conditions, such as depression or neurological disorders, may involve circadian 

rhythm abnormality, and thus could be mitigated by melatonin. A number of randomized 

controlled trials have been conducted to examine the effect of melatonin in the treatment of 

various types of insomnia

53-58 such as sleep maintenance insomnia,37 terminal insomnia,57 sleep 

onset insomnia,59 psychophysiological insomnia60 as well as circadian rhythm disorders such as 

time zone change (jet lag) syndrome,61-65 shift work sleep disorder,66-70 delayed sleep phase 

syndrome,71-75 and non-24-hour sleep wake disorder (associated with blindness).73 76 77 

Randomized controlled trials have also been conducted to examine the effect of melatonin in the 

treatment of sleep disorders secondary to neurological conditions such as dementia,78

Alzheimer’s syndrome,79 Rett syndrome,80 tuberous sclerosis81 and various other developmental 

disabilities82 as well as disorders secondary to psychiatric conditions such as depression, bipolar 

disorder83 and seasonal affective disorder.84 85 Many case studies have also been conducted, 

particularly in children, on the use of melatonin for sleep difficulties secondary to neurological 

7
syndromes such as Rett syndrome,86 Smith-Magenis syndrome,87 Angelman syndrome,88

autism82 and epilepsy.

83 Randomized controlled trials have also been conducted to examine the 

effect of melatonin in the treatment of parasomnias and REM sleep behavior disorder.89 

Formulation and Dosage of Melatonin Used in Clinical Trials 

The trials on melatonin for the treatment of sleep disorders vary in the formulation, timing of 

administration, frequency and duration of melatonin administration. The providers of melatonin 

for the various clinical trials on melatonin are diverse; Nestle, Sigma, Neurim, and Regis 

formulations are common providers. Melatonin products vary from fast-release to sustained 

release formulations. The formulation of melatonin used in the treatment of sleep disorders may 

have an effect on sleep outcomes, for example, in one trial, constant-release melatonin improved 

sleep quality in elderly insomniacs,90 but in another trial, fast-release melatonin did not improve 

sleep quality in elderly insomniacs.91 By far the most common method of melatonin 

administration is orally by capsule; the capsule usually consists of melatonin and lactose in a 

gelatin capsule. However, melatonin has also been administered by a sublingual tablet route, in 

patch format, and has also been tested intravenously. Commercially available agents are even 

more variable; melatonin products available include capsule, tablet (oral or sublingual), lozenge, 

liquid or spray forms. In trials of melatonin, the hormone has been administered orally or by 

transbuccal patch in dosages between 0.1 and 10 mg. The duration of melatonin administration in 

these trials varied from a single, one-time dose of melatonin92 to multiple doses of melatonin 

administered for several months.86 In most studies, melatonin is administered thirty minutes to 

two hours before usual bedtime or desired sleep time. The sleep outcomes analyzed in these 

studies include such measures as sleep onset latency, total sleep time, sleep duration, quality of 

sleep, number of awakenings, wake time after sleep onset, sleep efficiency as well as alertness, 

mood and performance. Some of these studies have found a positive effect of melatonin on these 

outcomes in people with sleep disorders, whereas some have shown no benefit of melatonin 

administration, that is, no improvement in sleep quality. 

Adverse Effects of Melatonin 

Compared to some pharmacological treatments for sleep disorders, melatonin has a very 

short half-life and its effects are short-lived.93 There have been some side effects of melatonin 

reported, such as drowsiness and headache.65 94 95 In general, most trials have not reported any 

hangover effects of melatonin, although some trials have reported adverse effects of melatonin 

on performance.96 Melatonin administration in epileptic children has been associated with 

increased seizure activity.97 Melatonin has also been associated with deterioration of mood in 

depression,83 98 and has been reported to be associated with development of autoimmune 

hepatitis in one case.99

8
Systematic Reviews on the Use of Melatonin for the 

Treatment of Sleep Disorders 

A small number of systematic reviews have been conducted on the use of melatonin for the 

treatment of sleep disorders. One systematic review of the effectiveness of melatonin in the 

treatment of jet lag, which included ten randomized controlled trials with a total of 953 patients, 

found melatonin to be effective in decreasing subjective ratings of symptoms of jet lag.100 The 

timing of melatonin administration was found to be important for positive effects of the 

hormone; melatonin must be taken close to the target bedtime at the destination in order to 

alleviate the symptoms of jet lag. A second systematic review on the effect of melatonin in the 

treatment of elderly insomniacs found that the administration of exogenous melatonin reduced 

sleep onset latency and improved sleep quality, as measured by increased sleep efficiency and 

total sleep time, in elderly people with insomnia, who were characterized with benzodiazepine 

use and low circulating levels of melatonin.101 This review included six small randomized 

controlled trials with 95 patients. In another review of the effectiveness of melatonin in the 

treatment of sleep disorders,102 evidence was provided that melatonin may have modest 

effectiveness in treating insomnia, jet lag, and sleep disorders in neurologically impaired 

patients. This study was based on four trials involving the use of melatonin for the treatment of 

jet lag, two trials involving the use of melatonin for the treatment of shift work disorder and six 

trials of melatonin for the treatment of insomnia, all of which were indexed in MEDLINE®. 

Finally, a review of the effectiveness of melatonin in treating children with neurodevelopmental 

disability and severe sleep problems found very little good quality evidence for the effectiveness 

of melatonin in this population, due to small study sizes and difficulties with objective 

assessments of outcomes, and the authors proposed that melatonin may be more effective in the 

treatment of sleep onset difficulties rather than fragmented sleep or early morning awakening.103 

This review included six trials and the report highlighted a lack of significant evidence for the 

long-term safety of melatonin; one of the included studies reported a notable increase in seizures 

with melatonin administration.97

Although a few systematic reviews have been conducted on the use of melatonin for the 

treatment of sleep disorders, many focus on the treatment of a particular category of sleep 

disorders in a specific population. In this systematic review, we broaden the focus to include a 

review of 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. 

Melatonin Safety and Legal Status 

Melatonin has sometimes been considered a “safe” substance, since it has been shown to 

have low toxicity in animal studies104 and to result in minor and infrequent adverse events in 

humans (see above). However, its safety has not, in fact, been definitively established; the safety

of melatonin products is still under review and these products are regulated differently in various 

9
countries. Rigorous safety evaluations of melatonin in humans have not been conducted and 

clear standards have not been developed for the quality of melatonin formulations. 

Status in the United States 

Currently, melatonin falls under the Food and Drug Administration’s (FDA’s) Dietary 

Supplement Health and Education Act

105 in the category “other dietary supplements”. Melatonin 

is not considered a drug, since it is a naturally occurring substance106 and it is designated 

“generally recognized as safe” (GRAS). Recognizing the lack of a common framework for 

evaluating the safety of dietary supplements, the Institute of Medicine Food and Nutrition Board 

has proposed a framework accompanied by six prototype monographs for the evaluation of 

various dietary supplements, including melatonin.107

 

Status in Canada 

The Natural Health Products Directorate (NHP) of Health Canada has been re-evaluating 

natural health products such as melatonin. New NHP regulations have come into effect as of 

January 1st, 2004, which permit natural health products to be sold in Canada if they meet 

specific licensing, manufacturing, labelling, and safety standards. Melatonin is now available for 

sale in Canada.108

 

Status in Europe 

In the European Union, melatonin is not considered as a foodstuff but rather a medicine or 

hormone. It is available by prescription only.109 

Status in Australia 

Melatonin is an unregistered good under the Therapeutic Goods administration. However, it 

can be imported for use under the Personal Import Scheme with a prescription.110

Objectives of the Review 

The primary objective of this Evidence Report is to provide the details of a comprehensive 

literature review and synthesis of evidence on the use of melatonin for the treatment of sleep 

disorders, including not only the safety and effectiveness of melatonin for the treatment of sleep 

disorders, but also, the pharmacology of exogenous melatonin as well as the physiology of 

endogenous melatonin. Specifically, we sought to synthesize evidence related to four topic 

areas, including the physiology and pharmacology of melatonin; the populations that would 

benefit most from melatonin treatment; the effectiveness of melatonin treatment; and the safety 

of melatonin treatment. 

10
Questions of the Review 

The specific questions addressed in this Evidence Report are as follows: 

Topic Area 1: Physiology and Pharmacology of Melatonin 

1. What are the various formulations of melatonin? How are the formulations different in 

terms of content and quality as well as safety and effectiveness? What is the clinical

importance of any observed differences?

2. What is the pharmacology of exogenous melatonin (including pharmacokinetics and 

pharmacodynamics)? How is it absorbed, distributed, metabolized and excreted? What 

blood levels are achieved? Does it penetrate the blood/brain barrier?

3. What is the evidence linking endogenous melatonin to sleep cycles? 

4. What are the basic mechanisms by which melatonin produces sleepiness?

5. What is the effect of exogenous melatonin on sleep latency, sleep efficiency, and REM 

latency in normal sleepers?

6. How is endogenous melatonin involved in circadian rhythms? 

Topic Area 2: Population at Risk 

7. Which sleep disorders would be most effectively managed by treatment with melatonin?

8. Which populations, based on gender, age, ethnicity, genetic factors and co-morbid 

conditions, would benefit most from treatment with melatonin?

Topic Area 3: Effectiveness of Melatonin 

9. What is the effect of exogenous melatonin on people with sleep disorders? 

10. What is the appropriate dosage/duration of melatonin for the treatment of sleep disorders? 

Does the appropriate dosage depend on patients’ gender, age, and/or ethnicity?

11. What is the timing of melatonin administration during the sleep/wake cycle that would 

produce optimum treatment effects?

Topic Area 4: Safety of Melatonin 

12. What are the adverse effects of short and long-term use of exogenous melatonin?

13. How do the benefits and harms of exogenous melatonin vary based on dose, timing of 

administration, and patient factors such as gender, age and ethnicity?

14. How do the benefits and harms of melatonin compare to those of other approved 

pharmacological treatments for sleep disorders? 

11
Flow Diagram 1: Analytic Framework 

Basic

science

Population Screening for

 treatment Treatment

Morbidity of 

treatment

Intermediate and

surrogate outcomes Medical

benefits

14

1

13

2

3

6 

4

9 10 11

12

5

at risk

 7 8

12
Table 1: Classification of Sleep Disorders according to ICSD 

 Dyssomnias 

Intrinsic Sleep 

Disorders 

Extrinsic Sleep Disorders Circadian Rhythm Sleep

Disorders 

Parasomnias 

Arousal disorders Sleep-wake transitional 

disorders 

Parasomnias usually

associated with REM 

sleep 

Other parasomnias 

Sleep disorders associated with mental, neurologic, and other medical disorders

Associated with mental 

disorders 

Associated with

neurological disorders 

Associated with other 

medical disorders 

Proposed Sleep Disorders 

Short sleeper 

Sleep hyperhidrosis 

Sleep-related 

neurogenic tachypnea 

Long sleeper 

Menstrual-associated

sleep disorder 

Sleep-related 

laryngospasm 

Subwakefulness 

syndrome

Pregnancy-associated

sleep disorder 

Sleep choking syndrome

Fragmentary 

myoclonus 

Terrifying hypnagogic 

hallucinations 

Abbreviations: ICSD = International Classification of Sleep Disorders 

13
14
Chapter 2. Methods 

Research Team 

The research team designated to this Task Order was selected to represent the diverse areas 

of expertise required to properly elucidate the topic of the review and has both basic and 

clinical science expertise. The areas of expertise encompassed by the research team include 

melatonin and pineal cell biology, sleep, complementary and alternative medicine (CAM), 

neurochemistry, pharmacology, physiology, as well as systematic review methodology. The 

research team consists of a Core Research Team, which has been involved in the day-to-day 

operations required to fulfill the Task Order, as well as a Technical Expert Panel (TEP), which 

has functioned in an advisory capacity. The Core Team consists of two Task Order Leaders 

with expertise in clinical pharmacology, clinical epidemiology, pediatrics and CAM (Dr. Sunita 

Vohra) and pharmacology/neurochemistry (Dr. Glen Baker); the Evidence-based Practice 

Centre (EPC) Director (Dr. Terry Klassen), Associate Director (Dr. Brian Rowe) and 

Administrative Director (Ms. Lisa Hartling) with expertise in systematic review methodology; 

and a Project Manager (Dr. Nina Buscemi) and Staff. The Core Team has met on a regular 

basis to plan the approach for fulfilling the Task Order and to ensure that project activities were 

conducted in an appropriate and timely manner. 

The TEP is multi-disciplinary in nature and has provided the breadth of expertise required 

to produce a comprehensive Evidence Report on the use of melatonin for the treatment of sleep 

disorders. During the course of the project, a total of 15 individuals have joined the TEP. 

Members of the TEP have been consulted during the course of the project, as required, for 

specific input and guidance, according their particular area of expertise. See Appendix D∗

 for 

affiliations and areas of expertise of TEP members. 

In addition to the individuals mentioned above, the Core Research Team maintained regular 

communication and dialogue with representatives of the National Center of Complementary 

and Alternative Medicine (NCCAM) as well as the Task Order Officer of the Agency for 

Healthcare Research and Quality (AHRQ). 

Methods for the Systematic Review 

Overview 

The methods of the University of Alberta Evidence-based Practice Centre (UAEPC) were 

used to conduct a systematic review and synthesis of evidence relevant to the questions of the 

review. A number of steps were followed in producing this Evidence Report: 

• Comprehensive Search 

• Development of Inclusion Criteria 

• Study Selection 

• Assessment of Study Quality 

 

∗ The Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gov/clinic/tp/melatntp.htm.

15
• Data Extraction 

• Data Analysis 

Comprehensive Search 

As a first step, a number of biomedical databases were searched. Given the subject area of 

the review, there was a possibility that these databases would not provide accurate 

representation of the breadth of research in this area. Thus, our intention was to conduct 

preliminary searches of these databases, assess publication bias, and if it were found across 

studies relevant to the questions of the review pertaining to the effectiveness of melatonin in 

the treatment of sleep disorders, we would expand our search accordingly. Table 2 outlines the 

electronic databases that were searched and Table 3 outlines the keywords and subject headings 

that were used in the searches. See Appendix A∗

 for a detailed description of the search 

strategy. 

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. In addition to these initial searches, similar searches of MEDLINE® and EMBASE 

were conducted periodically for more recently published studies that were potentially relevant 

to the review. 

In addition to the electronic searches described above, the reference lists of a random

sample of reports, encompassing half of all studies included in the review, were reviewed. The 

reference lists of narrative and systematic reviews related to melatonin and sleep disorders were 

also reviewed. We also reviewed the reference list of a Health Canada document on the use of 

melatonin for the treatment of various disorders as well the reference list of a document from

Natural Standard Research Collaboration on the use of melatonin for the treatment of sleep 

disorders. Lastly, we hand-searched Associated Professional Sleep Society (APSS) Abstracts 

of 1999 to 2003. 

As mentioned above, searches were limited to English-language reports. We sought to 

avoid the inclusion of non-English language reports in the review, unless deemed necessary, as 

a means of containing resource requirements for this review, which was already large in scope. 

The Core Team, in consultation with NCCAM and AHRQ, devised a strategy for inclusion of 

non-English language reports in the review. Our approach was to evaluate the presence of 

publication bias across studies relevant to the question of the review pertaining to the 

effectiveness of melatonin in the treatment of sleep disorders. If publication bias were found, 

we would expand our search to include non-English language data. We would also expand our 

search to include non-mainstream data sources. Publication bias refers to a bias in the literature 

whereby the publication of research is dependent upon the results of research. In Western 

medical journals, this phenomenon is reflected in the fact that results indicating no effect of an 

intervention are less likely to be published.111 The problem is reversed for CAM-related 

research, such that studies with negative results are more likely to be published in mainstream

Western medical journals (e.g. “MEDLINE®”), and CAM studies with positive results are 

 

∗ The Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gov/clinic/tp/melatntp.htm.

16
more likely to be published in smaller journals that may not be accessible on usual search 

engines.112 Thus, it was necessary to assess this bias across studies related to the effectiveness 

of melatonin included in this review. We considered the use of non-English language reports 

and expansion of data sources only for the latter question of the review, since this question 

related to the main thesis of the report. 

Development of Inclusion Criteria

Specific inclusion criteria were developed for each question of the review. In general, only 

controlled clinical trials were included for each 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 pre-determined 

outcomes relevant to that question. Only English-language reports were included in the review. 

Question-Specific Inclusion Criteria 

What are the various formulations of melatonin? How are the formulations different in terms 

of content, quality as well as safety and effectiveness? 

A study was considered relevant to the portion of this question that pertains to the 

differences in the safety of various formulations of melatonin if it met inclusion criteria for the 

question relating to the safety of melatonin, and the formulation of melatonin used in the study 

was specified in the report. A study was considered relevant to all other portions of this 

question if it met inclusion criteria for the question relating to the effectiveness of melatonin, 

and the formulation of melatonin used in the study was specified in the report. 

What is the pharmacology of exogenous melatonin, including pharmacokinetics and 

pharmacodynamics? How is it absorbed, distributed, metabolized and excreted? What blood 

levels are achieved? What is its half-life? Does it penetrate the blood-brain barrier? 

A study was considered relevant to this question of the review if it met the following 

inclusion criteria: 

• it involved human participants 

• melatonin was administered to a group of participants 

17
• at least one of the following outcomes was assessed in participants’ serum/plasma/blood 

within hours of melatonin administration and a value was ascribed to it in the text of the 

report: 

− half-life of melatonin (t1/2) 

− time to reach peak concentration of melatonin (Tmax) 

− peak concentration of melatonin (Cmax) 

− area under the melatonin versus time curve (AUC) 

What is the evidence linking endogenous melatonin to sleep cycles?

A study was considered relevant to this question of the review if it met the following 

inclusion criteria: 

• it was a controlled clinical trial 

• it involved human participants 

• it involved an intervention that altered either endogenous melatonin or the sleep cycle, 

such as manipulation of light/dark exposure or manipulation of the sleep schedule, 

respectively. If the intervention involved light administration, a lower intensity light 

condition was required as a control. If the intervention involved manipulation of the 

sleep schedule, a normal sleep schedule condition was required as a control. 

• it involved only one intervention; a constant routine was not considered a secondary 

intervention if it was applied to both the experimental and control groups. 

• it assessed the levels of melatonin and/or the phase of the melatonin rhythm in 

participants’ blood, urine, saliva or cerebrospinal fluid in the case where the 

intervention altered the sleep cycle, or it assessed an aspect of participants’ sleep cycle 

in the case where the intervention altered endogenous melatonin. 

What are the basic mechanisms by which melatonin produces sleepiness? 

Initially, a study was considered relevant to this question of the review if it met the 

following inclusion criteria: 

• it involved human participants 

• it involved administration of exogenous melatonin or an intervention that manipulated 

endogenous melatonin levels 

• it characterized a mechanism by which alterations in endogenous melatonin levels 

affect sleep propensity 

Given the lack of studies that met these inclusion criteria, the latter criteria were revised. A 

study was considered relevant to this question of the review if it met the inclusion criteria of the 

question relating to the effectiveness of melatonin in normal sleepers or the question relating to 

the effectiveness of melatonin in people with a sleep disorder, and the report provided a 

proposed mechanism by which melatonin produces sleepiness based on findings of the study. 

18
What is the effect of exogenous melatonin on sleep latency, sleep efficiency and REM latency in 

normal sleepers? 

A study was considered relevant to this question of the review if it met the following 

inclusion criteria: 

• it was a controlled clinical trial 

• it involved participants that did not have a sleep disorder 

• melatonin was administered to a group of participants and placebo was administered to 

a group of participants 

• at least one of the following outcomes was assessed: 

• sleep onset latency 

• sleep efficiency 

• REM latency 

How is endogenous melatonin involved in circadian rhythms?

The scope of this question was limited to an analysis of how endogenous melatonin is 

involved in the temperature rhythm. A study was considered relevant to this question of the 

review if it met the following inclusion criteria: 

• it was a controlled clinical trial 

• it involved human participants 

• it involved an intervention that altered endogenous melatonin or the temperature 

rhythm, such as manipulation of light/dark exposure or temperature exposure, 

respectively. If the intervention involved light administration, a lower intensity light 

condition was required as a control. If the intervention involved manipulation of the 

temperature rhythm, a normal temperature condition was required as a control. 

• it involved only one intervention; a constant routine was not considered a secondary 

intervention if it was applied to both the experimental and control groups. 

• it assessed the levels of melatonin and/or the phase of the melatonin rhythm in 

participants’ blood, urine, saliva or cerebrospinal fluid in the case where the 

intervention altered the temperature rhythm, or it assessed an aspect of participants’ 

temperature rhythm in the case where the intervention altered endogenous melatonin. 

What is the effect of exogenous melatonin on people with sleep disorders? 

A study was considered relevant to this question of the review if it met the following 

inclusion criteria: 

• it was a randomized controlled clinical trial 

• it involved human participants who suffer from a sleep disorder and this condition was 

explicitly mentioned in the report 

• melatonin was administered to a group of participants and placebo was administered to 

a group of participants 

• at least one of the following outcomes was assessed: 

− sleep onset latency 

− sleep efficiency 

− sleep quality 

19
− wakefulness after sleep onset 

− total sleep time

− percent time in REM sleep 

Which sleep disorders would be most effectively managed by treatment with melatonin? Which 

populations based on gender, age, ethnicity, genetic factors and co-morbid conditions, would 

benefit most from treatment with melatonin? 

What is the appropriate dosage/duration of melatonin for the treatment of sleep disorders? 

Does the appropriate dosage depend on patients’ gender, age, and/or ethnicity? What is the 

timing of melatonin administration during the sleep/wake cycle that would produce optimal 

treatment effects? 

A study was considered relevant to these questions of the review if it met the inclusion 

criteria for the question relating to the effectiveness of melatonin in people with sleep 

disorders, and the report provided the information necessary for the study to be incorporated 

into a subgroup analysis related to at least one variable specified in the question. 

What are the adverse effects of short and long-term use of exogenous melatonin? 

A study was considered relevant to this question of the review if it met the following 

inclusion criteria: 

• it included human participants 

• melatonin was administered to a group of participants and placebo was administered to 

a group of participants 

• it reported on adverse events and/or adverse effects of the interventions 

For this question of the review, short-term melatonin use was defined as less than three 

months duration and long-term melatonin use was defined as three months or greater duration. 

How do the benefits and harms of exogenous melatonin vary based on dose, timing of 

administration, and patient factors such as gender, age and ethnicity? 

A study was considered relevant to this question of the review if it met the inclusion criteria 

for the question relating to the safety of melatonin, and the report provided the information 

necessary for the study to be incorporated into a subgroup analysis related to at least one 

variable specified in the question. 

How do the benefits and harms of melatonin compare to those of other approved 

pharmacological treatments for sleep disorders? 

A study was considered relevant to this question of the review if it met the inclusion criteria 

for the question relating to the effectiveness of melatonin in normal sleepers and the question 

relating to the effectiveness of melatonin in people with sleep disorders, except that melatonin 

and another pharmacological treatment for sleep disorders, instead of placebo, were 

administered to groups of participants. 

20
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 key 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 pre-determined inclusion criteria for each key 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 Scale113

was used to assess the quality of studies relevant to this question. The Jadad Scale assigns 

studies a quality score of zero to five, with a score of five indicating high quality. The scale 

assesses the components of randomization, blinding and reporting of dropouts and withdrawals. 

To our knowledge, neither this scale nor any other has been validated for the quality assessment 

of crossover trials. However, this scale has been validated for the quality assessment of

randomized-controlled trials, and thus, was considered an appropriate quality assessment tool 

for this review. The concealment of allocation in the randomized-controlled trials was assessed 

as “adequate”, “inadequate” and “unclear”.114 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 Checklist115 was used to assess the quality of studies relevant to these 

questions. This checklist is partially validated and assesses a number of design components 

including reporting, internal and external validity, and the statistical power of a study to detect 

a clinically important difference. 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. 

See Appendix B∗

 for Quality Assessment Forms. 

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 

 

∗ The Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gov/clinic/tp/melatntp.htm.

21
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 name of the first author 

of the report and year of publication of the report; the country where the study took place; the 

source of funding for the study; authors’ objectives and conclusions; and whether an intentionto-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 completion. Disagreements between reviewers were resolved by discussion and 

consensus. See Appendix B∗

 for the Data Extraction Form. 

Data Analysis

Table 4 outlines the keywords associated with the questions of the review and the type of 

analysis that was applied to data relevant to these questions. Data relevant to questions relating 

to the pharmacology of melatonin, the link between endogenous melatonin and the sleep and 

temperature rhythms, the mechanism of action of melatonin and the benefits and harms of 

melatonin compared to other pharmacological treatments for sleep disorders were analyzed 

qualitatively. All components of the question relating to the formulation of melatonin, except 

for the portion pertaining to the differences in the safety and effectiveness of melatonin 

formulations, were analyzed qualitatively. Data relevant to questions relating to the 

effectiveness, safety, and appropriate timing and duration of melatonin treatment were analyzed 

quantitatively. 

Quantitative Analysis 

For all continuous outcomes (e.g. sleep onset latency, sleep efficiency) studies were 

combined using a Weighted Mean Difference (WMD) with the exception of sleep quality 

where studies were combined using a Standardized Mean Difference (SMD). Due to the large 

number of studies with a crossover design, the Inverse Variance Method116 was used to weight 

the studies. An effectiveness estimate with corresponding 95 percent confidence interval was 

computed for each outcome. 

We were usually able to calculate the effectiveness estimates for each study exactly (i.e. 

weighted mean difference, standardized mean difference, risk difference), but occasionally, 

estimates had to be made by extracting from graphs or using medians. Standard errors of the 

differences were calculated exactly from available data (i.e. individual patient data or exact pvalues) whenever possible. For studies with a parallel design, this calculation was usually 

accomplished with the standard formula for variance of difference of independent variables:

var(A-B) = var(A) + var(B). For studies with a crossover design, the standard error was 

estimated using the formula for variance of difference of dependant variables: var(A-B) = 

var(A) + var(B) -2ρ(var(A)var(B))1⁄2 and using a correlation estimate of 0.5. In cases where this 

calculation could not be done, standard errors were estimated using conservative p-values (i.e. 

 

∗ The Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gov/clinic/tp/melatntp.htm.

22
p < 0.05), inter-quartile ranges, and extracting from graphs. As a last resort, an average of 

standard deviations of other studies was used to impute standard deviations of a study. 

For studies with a parallel design, change from baseline data was used if available, 

otherwise final data were used. For studies with a crossover design, final data were always 

used. 

When continuous data were presented for multiple conditions, which we wished to 

combine, a new mean and standard deviation were computed. If the study had a parallel 

design, the new mean and standard deviation could be computed exactly using the formula: 

= ∑ i x

g

y

1 1

[( 1) ] 2 2 2

−

− + − = ∑

N

n s n x Ny

s

i i i i

y 

where y is the mean of the newly formed combined arm, g is the number of groups 

combined, i x are the means of each group (i may take the value of 1 through g), sy is the 

standard deviation of the newly formed combined arm, ni are the sample sizes of each group, si

are the standard deviations of each group and N is the total new sample size (the sum of the ni). 

If the study had a crossover design, we treated the data as we would a repeated measures 

experiment. The formula for the mean was the same, but the following formula was used for 

the standard deviation with the within subject correlation (ρ) being estimated as 0.5. 

g

s s s

s

i j

i ij i j

y

∑ ∑<

+

=

2ρ 2

Dichotomous outcomes (i.e. safety outcomes) were combined using a Risk Difference with 

corresponding 95 percent confidence interval. Many studies stated that there were no reported 

adverse events. These were included in the analysis, but a sensitivity analysis excluding them

was also performed, since the lack of reporting on adverse events does not necessarily indicate 

that they did not occur in the study. 

All meta-analyses were performed using a Random Effects Model. Bailey117 suggests that 

the Random Effects Model is more appropriate when making recommendations for 

management and treatment of the next given patient. Fixed effects were considered in a 

sensitivity analysis. 

All estimates of effectiveness (weighted mean differences, standardized mean differences, 

and risk differences) were assessed for heterogeneity using the I-squared statistic.118 Based on 

this statistic, heterogeneity for each outcome was classified as negligible (I2 = 0 percent), 

minimal (I

2 < 20 percent), moderate (20 percent < I2 < 50 percent), or substantial (I2 > 50 

percent). For our primary outcomes, heterogeneity was explored in subgroup analyses using a 

number of variables. These variables were: age, gender, ethnicity, use of concurrent 

medication, formulation, dosage, duration of study, method of measurement, study design, and 

study quality. For patients with sleep disorders, we also examined type of disorder and 

allocation concealment, while for subjects with normal sleep patterns, we also examined patient 

description, time of sleep, and use of multiple sleep onset techniques. Deeks’ chi-square 

statistic119 was used to test for significant heterogeneity reduction in partitioned subgroups. 

We tested for publication bias visually using the Funnel Plot and quantitatively using the 

Rank Correlation Test,120 the Graphical Test,

121 and the Trim and Fill Method.122 

23
Qualitative Analysis 

What are the various formulations of melatonin? How are the formulations different in terms 

of content, quality as well as safety and effectiveness? What is the clinical importance of any 

observed differences? 

In order to obtain more detailed information regarding the content and quality of the 

melatonin formulations that were used in the studies relevant to this question of the review, the 

corresponding authors of these studies were contacted and asked to respond to a short 

questionnaire. The following is a list of questions that were posed: 

1. What are the constituents of the formulation and the relative proportion of each 

constituent?

2. Was the melatonin component natural or synthetic and what was the purity of this 

component? 

3. Do you have information on the pharmacology of this formulation in humans?

The information provided by corresponding authors was used to supplement information 

that was provided in the report of these studies. It was used to answer the portion of the 

question regarding the differences in the content and quality of melatonin formulations that 

have been used in relevant studies. 

What is the pharmacology of exogenous melatonin, including pharmacokinetics and 

pharmacodynamics? How is it absorbed, distributed, metabolized, excreted? What blood 

levels are achieved? What is its half-life? Does it penetrate the blood brain barrier? 

A detailed Evidence Table was created outlining the design details and results of studies 

relevant to this question of the review. The results of the studies were also summarized in a 

Summary Table. The key elements of these tables were summarised. 

What is the evidence linking endogenous melatonin to sleep cycles? AND How is endogenous 

melatonin involved in circadian rhythms? 

The studies relevant to these questions of the review were categorized according to details 

of study design. First, studies were categorized according the type of intervention that was 

employed; in the case of the question relating to the link between endogenous melatonin and 

the sleep cycle, these interventions were either alterations in lighting, alterations in the sleep 

schedule or exposure to another intervention that altered either endogenous melatonin or the 

sleep cycle; in the case of the question relating to the link between endogenous melatonin and 

the temperature rhythm, these interventions were either alterations in lighting or temperature. 

The studies were further subdivided into studies involving participants with or without a sleep 

disorder or with a disorder other than a sleep disorder. Each of these categories of studies was 

further categorized according to timing of the intervention. The analysis of data pertaining to 

these sub-categories of studies began with a summary of the conditions of the intervention and 

characteristics of the population and continued with a synthesis of the results of each study as 

they pertain to the question being addressed. 

24
What are the basic mechanisms by which melatonin produces sleepiness? 

 

The studies relevant to this question of the review were categorized as involving 

participants with or without a sleep disorder and further grouped according to the proposed 

mechanism by which melatonin produces sleepiness. The findings upon which the proposed 

mechanisms were based were described for each category of studies. 

How do the benefits and harms of melatonin compare to those of other approved 

pharmacological treatments for sleep disorders? 

The studies relevant to this question of the review were categorized as involving 

participants with or without a sleep disorder and the effects of melatonin and another 

pharmacological treatment for sleep disorders were compared in terms of their effects on one or 

more of the following outcomes: sleep onset latency, sleep efficiency, sleep quality, 

wakefulness after sleep onset, total sleep time and percent time in REM sleep. The adverse 

events accompanying both treatments were also compared. 

25
Table 2: Biomedical Databases Searched 

Database Platform Dates of Search

MEDLINE® Ovid 1966 to June, Week 3, 2003 

PreMEDLINE Ovid June 30 and July 4, 2003 

EMBASE Ovid 1988 to Week 26, 2003 

PubMed® N/A July 9, 2002

CAB Health SilverPlatter version 4.3 July 8, 2003 

CINAHL® Ovid 1982 to June Week 4, 2003 

Cochrane Central Register of Controlled 

Trials 

Ovid 3rd Quarter, 2003 

Science Citation Index ISI Web of Knowledge July 4, 2003 

Biological Abstracts SilverPlatter version 4.3 July 4, 2003 

International Pharmaceutical Abstracts OVID 1970 to August, 2003 

NLM® Gateway http://gateway.nlm.nih.gov/gw/Cmd August 13, 2003

OCLC Papers First and Proceedings First OCLC FirstSearch July 11, 2003 

TOXLINE CSA Internet Database Service July 4, 2003 

26
Table 3: Keywords and Subject Headings used in Searches 

melatonin restless legs syndrome

melatonine nocturnal eating (drinking) syndrome 

5-methoxy-N-acetyltryptamine time-zone change syndrome

N-(2-(5-methoxy-1H-indol-3-yl)ethyl)acetamide Jet lag

N-acetyl-5-methoxytryptamine parasomnias

3-(2-acetamidoethyl)-5-methoxyindole confusional arousals

Acetamide, N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-(9CI) rhythmic movement disorder 

Acetamide, N-(2-(5-methoxyindol-3-yl)ethyl)-, N-(2-(5-

methoxyindol-3-eyl)ethyl)acetamide, CAS Reg No: 73-

31-4 

nocturnal leg cramps 

luzindole nightmares

sleep nocturnal paroxysmal dystonia

sleep disorders sudden unexplained nocturnal death syndrome 

dyssomnias snoring

insomnia congenital central hypoventilation syndrome 

narcolepsy sudden infant death syndrome

hypersomnia subwakefulness syndrome

central alveolar hypoventilation syndrome fragmentary myoclonus 

periodic limb movement disorder terrifying hypnagogic hallucinations 

circadian

Table 4: Questions of the Review and Type of Analysis Applied to Data Relevant to these Questions

 

Questions Type of Analysis Applied to Data Relevant to 

Question

Formulations of melatonin Qualitative and Quantitative 

Pharmacology of melatonin Qualitative 

Endogenous melatonin and the sleep cycle Qualitative 

Mechanism of action of melatonin Qualitative

Effect of melatonin on normal sleepers Quantitative 

Endogenous melatonin and circadian rhythms Qualitative 

Effectiveness of melatonin among types of sleep 

disorders 

Quantitative 

Effectiveness of melatonin among types of populations Quantitative 

Effect of melatonin on people with sleep disorders Quantitative 

Appropriate dosage of melatonin for treatment of sleep 

disorders 

Quantitative 

Appropriate timing of melatonin administration for 

treatment of sleep disorders 

Quantitative 

Adverse effects of melatonin Quantitative

Adverse effects of melatonin as a function of dose, 

timing, and patient factors 

Quantitative 

Melatonin and other pharmacological treatments for 

sleep disorders

Qualitative 

27
28
29

Chapter 3. Results 

Literature Review

The database searches yielded 1884 references of potentially relevant articles. An initial 

screening of titles and abstracts of articles identified from database searches, as well as from 

hand-searching, yielded 935 studies to which specific inclusion criteria were applied. Of these 

935 studies, 796 studies were excluded from the review and 139 studies were included in the 

review. Of the 796 studies that were excluded from the review, the majority were excluded 

because they were reviews (n=328). Other reasons for exclusion included inappropriate study 

topic (n=36), design (n=272), population (n=7), intervention (n=21) and outcomes (n=101). 

Three studies were not included in the review because of inadequate reporting. The reports of 25 

studies were unobtainable at the time of this writing and two were realized upon completion of 

the final report. The rate of disagreement for study inclusion was approximately 20 percent. 

These disagreements were usually due to oversight of particular details of study design, and were 

easily resolved with discussion. In many cases, a given study was relevant to more than one 

question of the review (Flow Diagram 2). Table 5 outlines the number of studies relevant to 

each question of the review and the type of analysis that was applied to data relevant to these 

questions. 

Results of Quantitative Analysis 

What is the effect of exogenous melatonin on sleep latency, sleep efficiency, and REM latency in 

healthy people? 

Twenty-one studies were relevant to this question of the review. The quality of these studies 

was assessed using the Downs and Black Checklist.115 The overall quality of studies ranged 

from 11 to 25 on a 29-point scale; most studies had a score between 16 and 20; four studies had a 

score between 10 and 15;78 123-125 and one study had a score of 25.126 The quality of reporting 

ranged from 4 to 11 on an 11-point scale; most studies had a score between seven and nine, three 

studies had a score between four and six78 124 125 and two studies had a score of 10 or 11.126 127 

The external validity of studies ranged from zero to three on a three-point scale; most studies had 

a score of zero, five studies had a score of one124 127-130 and one study had a score of three.126 

The internal validity of studies ranged from seven to 11 on a 13-point scale; approximately half 

of the studies had a score of 10 or 11; five studies had a score of nine;78 127 131-133 and six studies 

had a score of seven or eight.123-125 134-136 None of the studies reported a power calculation for 

the primary outcome and, therefore, it was unclear whether the study had sufficient power to 

detect a clinically important effect where the probability value for a difference being due to 

chance is less than 5 percent. In general, these studies were of relatively low quality. Although 

all studies involved a placebo control, many studies did not involve random allocation of 

participants to interventions. For studies in which participants were randomly allocated to 

intervention groups, it was often unclear whether allocation concealment was maintained or 

whether participants were blinded as to the intervention they received. See Evidence Table C-1 
30

for a description of design characteristics and overall quality scores of studies relevant to this 

question of the review. 

The following three outcomes were examined with respect to effectiveness of melatonin in 

normal sleepers, the first two being the primary outcomes: 

• Sleep Onset Latency: Defined as the amount of time between the subject laying down to 

sleep and the onset of stage one sleep. 

• Sleep Efficiency: Defined as the amount of time the subject spent asleep expressed as a 

percentage of the total time spent in bed. 

• REM Latency: Defined as the amount of time required to begin REM sleep after sleep 

onset. 

Sleep Onset Latency 

Primary Analysis 

There were a total of twenty studies with data on sleep onset latency for normal sleepers. 

The combined estimate comparing melatonin to placebo showed that melatonin caused a 

statistically significantly reduction in sleep onset latency (weighted mean difference (WMD): -

3.9 minutes (min.); 95 percent confidence interval (CI): -5.3 min, -2.6 min). This effect appears 

to be clinically insignificant. Heterogeneity among the studies was moderate (I2: 47.1 percent). 

Nineteen of the twenty studies had a point estimate that favoured melatonin (Figure 3-1). 

Subgroup and Sensitivity Analyses 

The results of all the subgroup and sensitivity analyses are summarized in Table 6. 

Subgroups that could not be analyzed for sleep onset latency included age (all studies involved 

adult participants), ethnicity (not specified in any study), and formulation of melatonin (all 

studies used fast-release melatonin). 

As can be seen from Table 6, none of the subgroups produced markedly different results 

from those obtained from the primary analysis. All of the subgroup point estimates favoured 

melatonin and this result was significant in most cases; the only exceptions were cases with only 

a small number of studies. Four of the partitions showed a significant Deeks’ chi-square value, 

indicating that heterogeneity was significantly reduced by the partition. Method of measurement 

of sleep outcomes and timing of melatonin administration had the largest effect. Method of 

measurement of sleep outcomes showed the questionnaire group to have a larger effect than the 

other methods, but this could be due to the smaller sample size of only two studies. For all other 

subgroup analyses, the subgroups had overlapping confidence intervals. 

Using the Fixed Effects Model instead of the Random Effects Model tightened the 

confidence interval but did not greatly change the point estimate (WMD: -3.2; 95 percent CI: -

4.0, -2.5). 

Assessment of Publication Bias 

There was evidence of asymmetry in the funnel plot, indicating possible publication bias 

(Figure 3-2). In the numerical tests, the results of Egger’s Graphical Test showed a p-value that 

was borderline significance, indicating possible bias (p-value: 0.049). Begg’s Test (Kendall’s 

S=-39 giving a p-value of 0.217 for 20 studies) and Duvall’s Trim and Fill Test did not indicate 

publication bias. 
31

Sleep Efficiency 

Primary Analysis 

There were a total of thirteen studies with data on sleep efficiency for normal sleepers. A 

statistically significant increase in sleep efficiency with melatonin was calculated when 

comparing melatonin to placebo (WMD: 2.3 percent; 95 percent CI: 0.7 percent, 3.9 percent). 

This effect appears to be clinically insignificant. Heterogeneity among the studies was 

substantial (I2: 53.9 percent). Eleven of the thirteen studies showed a point estimate indicating 

increased sleep efficiency with melatonin, one study indicated neutrality between melatonin and 

placebo, and one study indicated increased sleep efficiency with placebo (Figure 3-3). 

Subgroup and Sensitivity Analyses 

The same subgroups that were analysed for sleep onset latency were also analysed for this 

outcome except for the use of the multiple sleep onset latency test (there were no studies 

employing this test) and study design (all studies had a crossover design). The results are 

summarized in Table 7. 

While most of the subgroups produced estimates there were not markedly different from the 

primary analysis, some differences are noteworthy. The most striking difference was in time of 

sleep; the efficiency effect of melatonin was much more prominent in the daytime sleepers. 

Timing of melatonin administration was the only partitioned result that showed a significant 

reduction in heterogeneity, but the confidence intervals of the two groups overlapped. 

Using the Fixed Effects Model in place of the Random Effects Model gave a slightly lower 

effectiveness estimate of sleep efficiency but remained significant (WMD: 1.38; 95 percent CI: 

0.5, 2.3). 

Assessment of Publication Bias 

All four tests of asymmetry indicated the possible presence of publication bias (Figure 3-4). 

The funnel plot showed a marked asymmetry that was confirmed by both Begg’s Rank 

Correlation Test (Kendall’s S=41—with 13 studies giving a continuity corrected p-value of 

0.014) and Egger’s Regression Test (bias p-value of 0.005). Duval’s Trim and Fill Algorithm 

added 5 studies to the analysis and gave a modified estimate that was not significant (WMD: 0.9; 

95 percent CI: -0.8, 2.7). 

REM Latency 

Primary Analysis 

Eleven studies had data on REM latency for normal sleepers. The point estimate showed that 

REM latency was slightly higher with melatonin but the difference was not significant (WMD: 

2.6 min.; 95 percent CI: -4.1 min, 9.2 min). Heterogeneity among the studies was substantial (I2: 

55.2 percent). Six of the 11 studies had a point estimate that showed an increase in REM latency 

for melatonin, while five studies showed a decrease (Figure 3-5). 

 

Sensitivity and Subgroup Analysis 

The subgroups analysed for REM latency in normal sleepers were the same as those analysed 

for sleep onset latency with the exception of method of measurement (all studies used 
32

polysomnography to measure sleep outcomes) and study design (all studies had a crossover 

design). The results are summarized in Table 8. 

All of the subgroup point estimates, except one, showed a non-significant difference in REM 

latency between melatonin and placebo; the 1-3 mg dosage subgroup, showed increased REM 

latency compared to both higher and lower doses. Although three of the partitioned subgroups 

indicated significant reduction in heterogeneity, besides the group already mentioned, there was 

no indication that REM latency is affected by melatonin. 

The point estimate using the Fixed Effects Model in place of the Random Effects Model 

favoured placebo rather than melatonin, but was not statistically significant (WMD: -0.4, 95 

percent CI: -3.9, 3.1). 

Assessment of Publication Bias 

While a visual inspection of the funnel plot seems to indicate some minor asymmetries 

(Figure 3-6), there was no evidence of publication bias in any of the quantitative tests. Begg’s 

Test (Kendall’s S=2; with 11 studies this is a p-value of 0.938), Egger’s Test (bias p-value: 

0.257) and Duval’s Trim and Fill test (no studies added) did not give any indication of any 

asymmetry in the funnel plot. 

What is the effect of exogenous melatonin on people with sleep disorders? 

Thirty randomized controlled trials were relevant to this question. The quality of relevant 

studies was assessed using the Jadad Scale.113 The overall quality scores ranged from two to five 

on a five-point scale. Three studies had a quality score of two,125 137 138 eight studies had a 

quality score of three,66 70 80 132 139-142 12 studies had a quality score of four54 60 63 69 71 73 74 81 82 90 131 

135 and seven studies had a quality score of five.57 61 67 68 78 91 143 It was unclear whether there was 

adequate concealment of treatment allocation in all studies except six.67-69 78 90 143 All studies 

were described as randomized and double-blind and a description of withdrawals and dropouts 

was provided in all reports except six.80 125 137-139 141 The method of randomization was described 

and was appropriate in nine studies,57 61 63 67 68 78 91 135 143 while the method of randomization was 

not described in all other studies. All reports except 1160 63 66 70 125 132 135 137 138 140 142 provided a 

description of an appropriate method of double-blinding; the method of double-blinding was not 

described in all other reports. These studies differed from studies involving normal sleepers 

mentioned above in that participants were randomized to intervention groups. However, other 

aspects of study design such as allocation concealment and blinding were similar to studies 

involving normal sleepers. See Evidence Table C-2 for a description of design characteristics 

and overall quality scores of studies relevant to this question of the review. 

The following six outcomes were examined with respect to effectiveness of melatonin in 

people with sleep disorders, the first two being the primary outcomes: 

• Sleep Onset Latency: Defined as the amount of time between the subject laying down to 

sleep, and the onset of stage 1 sleep. 

• Sleep Efficiency: Defined as the amount of time the subject spent asleep as a percentage 

of the total time spent in bed. 

• Sleep Quality: Defined as the overall quality of sleep attained. This outcome was 

measured differently across studies and was thus combined using a Standardized Mean 

Difference. 
33

• Wakefulness After Sleep Onset (WASO): This is the amount of time spent awake in 

bed following the first attainment of stage one sleep. 

• Total Sleep Time: Defined as the total time spent asleep while in bed. 

• Percentage Time in REM Sleep: Defined as the total time spent in REM sleep as a 

percentage of total sleep time. 

People with a Primary Sleep Disorder 

Sleep Onset Latency 

Primary Analysis. There were 12 studies that examined sleep onset latency in patients with a 

primary sleep disorder. The combined weighted mean difference (WMD) of the studies showed 

that those in the melatonin group had a statistically significant shorter sleep onset latency period 

than those in the placebo group (WMD: -10.7 min.; 95 percent CI: -17.6 min., -3.7 min.), 

although there was substantial heterogeneity among the studies (I2: 81.5 percent). This effect 

appears to be clinically insignificant. Nine of the 12 studies showed a difference that favoured 

melatonin (Figure 3-7). These results are based on trials of four weeks or less in duration. 

 Sensitivity and Subgroup Analysis. Table 9 summarizes the results of the subgroup and 

sensitivity analyses of sleep onset latency in patients with a primary sleep disorder. Subdivision 

by gender was not possible as all studies were mixed gender. Only two studies specified 

ethnicity—both were Caucasian. For use of concurrent medications, all but two studies either 

did not specify or had a mixture of patients on and off medications. For dosage, three studies 

used multiple doses and were included in two or more groups, while two studies were excluded 

since they did not specify dosage. 

Many of these sub groupings significantly reduced heterogeneity despite retaining a 

substantial heterogeneity statistic in at least one subgroup. The one subgroup that is noteworthy 

is that of primary diagnosis, which substantially reduced the heterogeneity and is the only sub 

grouping that gave results with non-overlapping confidence intervals. This variable appears to 

explain much of the heterogeneity in the primary analysis. 

Using the Fixed Effects Model rather than Random Effects Model greatly changes the results 

of the primary analysis as well as the conclusion. One study91 received nearly 92 percent of the 

weight and the new difference was not significant (WMD = -0.32; 95 percent CI –1.3, 0.6). 

Assessment of Publication Bias. Assessment of publication bias for sleep onset latency of 

patients with primary sleep disorders was performed. No obvious asymmetry was evident in the 

funnel plot (Figure 3-8). Begg’s test gave a Kendal’s score of S=6—with 12 studies, this 

constitutes a continuity corrected p-value of 0.732 indicating no publication bias. Performing 

Duval’s Trim and Fill Method, no studies were added to the meta-analysis, and the final results 

were identical to the primary analysis. The only test that showed any indication of publication 

bias was Egger’s Graphical test, which had a p-value of 0.027 on the bias of the funnel plot.

Sleep Efficiency 

Primary Analysis. Nine trials were included in the analysis of sleep efficiency for people 

with primary sleep disorders. Although the WMD did favour melatonin, the difference was not 

significant (WMD: 1.5 percent; 95 percent CI: -0.7 percent, 3.6 percent) and the heterogeneity 

among the studies was substantial (I2: 62.8 percent). Six out of the nine studies showed a point 

estimate that favoured melatonin (Figure 3-9). These results are based on trials of four weeks or 

less in duration. 
34

Sensitivity and Subgroup Analysis. Table 10 summarizes the results of the subgroup analysis 

of sleep efficiency in patients with a primary sleep disorder. Subdivision by gender and ethnicity 

was not possible since all studies were of mixed gender and none of the studies specified 

ethnicity. For use of concurrent medications, all studies either did not specify or had a mixture 

of patients on and off medications. For subdivision by dosage, three studies used multiple doses 

and were in multiple groups; one study was excluded, as it did not specify dosage. 

The only sub-grouping that is noteworthy is that of allocation concealment. Removing the 

study by Garfinkel et al.,90 which was considered to have adequate allocation concealment, 

removed the vast majority of the heterogeneity from the analysis and the result based on this 

study was significant. This finding is likely due to chance, since allocation concealment has 

been associated with smaller, rather than larger, effect sizes.114 The remaining eight studies 

showed no effect. The only other sub grouping that significantly reduced heterogeneity was age, 

but the resulting confidence intervals were non-overlapping and non-significant. 

If we use a fixed effects model instead of a random effects model in our analysis, our point 

estimate decreases slightly and our confidence interval tightens, but the result is still nonsignificant (WMD: 0.8; 95 percent CI: -0.3, 1.8). 

Assessment of Publication Bias. The funnel plot showed some asymmetry (Figure 3-10), 

however all other tests did not indicate publication bias. Begg’s test gave a Kendal’s score of 

S=7—with nine studies, this constitutes a continuity corrected p-value of 0.529. Egger’s 

Graphical Test had a p-value of 0.441 on the bias of the funnel plot. Finally, Duval’s Trim and 

Fill Method had no studies added to the meta-analysis, and the final results were identical to the 

primary analysis. 

Sleep Quality 

Sleep quality for patients with a primary sleep disorder was recorded in only two studies57 140

and measured on different scales. The results were combined using a Standardized Mean 

Difference (SMD); this outcome is slightly more difficult to interpret since it appears in units of 

standard deviation. The SMD favoured melatonin over placebo, but the result was not 

significant (SMD: 0.5; 95 percent CI: -0.1, 1.1). Heterogeneity between the two studies was 

negligible (I2

: 0 percent). Both studies had a point estimate that favoured melatonin. 

Wakefulness After Sleep Onset 

WASO was reported in five studies involving administration of melatonin to individuals with 

primary sleep disorders. Combining them with a WMD showed virtually no difference between 

placebo and melatonin (WMD: -1.4 min.; 95 percent CI: -21.8 min., 19.0 min.). The 

heterogeneity among the studies was substantial (I2

: 84.0 percent). Three of the studies had point 

estimates that favoured placebo, one study had a point estimate that favoured neither melatonin 

nor placebo, and one study had a point estimate that favoured melatonin. 

Total Sleep Time 

Eleven studies had data on total sleep time for patients with a primary sleep disorder. Their 

combined estimate comparing total sleep time between placebo and melatonin using a WMD 

favoured melatonin but was not significant (WMD: 4.0 min.; 95 percent CI: -10.5 min., 18.5 

min.). The studies showed substantial heterogeneity (I2

: 67.6 percent). Only five of the 11 

studies had a point estimate that favoured melatonin. 
35

Percentage Time Spent in REM Sleep 

Three studies involving melatonin administration to individuals suffering from a primary 

sleep disorder reported on percentage time spent in REM sleep. Using a WMD to combine the 

studies gave an estimate that marginally favoured melatonin but was not significant (WMD: 0.4 

min.; 95 percent CI: -1.2 min., 2.0 min.). Heterogeneity in the estimate was negligible (I2

: 0 

percent). Two of the three studies had a point estimate that favoured melatonin. 

People with a Secondary Sleep Disorder 

Sleep Onset Latency 

Primary Analysis. There were six trials involving melatonin administration to individuals 

with a secondary sleep disorder that reported on sleep onset latency. Their combined estimate 

favoured melatonin but was non-significant (WMD: -13.2 min.; 95 percent CI: -27.3 min., 0.9 

min.). Heterogeneity among the studies was substantial (I2: 79.2 percent) due primarily to one 

study132 that had a very small standard deviation and an estimate very different from the other 

five studies. This study had a point estimate that favoured placebo, while the other five studies 

had point estimates that favoured melatonin (Figure 3-11). These results are based on trials of 

four weeks or less in duration.

Sensitivity and Subgroup Analysis. Table 11 summarizes the results of the subgroup and 

sensitivity analyses of sleep onset latency for patients with a secondary sleep disorder. 

Subgroups not analysed below were ethnicity (not specified in any study), concurrent 

medications (all patients taking additional medications in all studies), and Jadad score (same for 

all studies). For gender, all study populations were mixed except for a study by McArthur et 

al.,80 which was all female. For dosage, only four studies are listed since one study did not 

specify dosage,82 and another gave varying doses based on weight.80 Primary disorder was 

different for all studies except for two studies that both examined patients with schizophrenia.131 

132

One study by Shamir et al.132 completely dictated the results of the subgroup analysis. 

Subgroups that omitted this study, showed a significant result in favour of melatonin with 

negligible heterogeneity, while subgroups that did include this study were non-significant with 

substantial heterogeneity. The two sub groupings in which this study stood alone do not shed 

much light on the reason for the difference. The Shamir et al. study132 was the only study that 

used polysomnography to measure sleep outcomes and also the only study that was considered to 

have adequate allocation concealment. 

Using the Fixed Effects Method instead of the Random Effects Method drastically changed 

the results due to the vast majority of the weight being assigned to the study by Shamir et al.132 

The point estimate for sleep onset latency favoured placebo and was non-significant (WMD: 3.0; 

95 percent CI: -0.1, 6.1). 

Assessment of Publication Bias. With only six studies analysing sleep onset latency in 

patients with a secondary sleep disorder, the number of studies was deemed too few to do any 

meaningful tests for publication bias. 

Sleep Efficiency 

Primary Analysis. There were six trials for which data were available for comparing 

melatonin to placebo in sleep efficiency. The WMD of the six studies showed a statistically 

significant effect that favoured melatonin (WMD: 1.9 percent; 95 percent CI: 0.5 percent, 3.3 
36

percent). This effect appears to be clinically insignificant. Heterogeneity among the studies was 

negligible (I2: 0 percent). Five of the six studies had point estimates that favoured melatonin 

while one study had a point estimate that favoured neither melatonin nor placebo (Figure 3-12). 

These results are based on trials of four weeks or less in duration. 

Sensitivity and Subgroup Analysis. Table 12 summarizes the results of the subgroup analysis 

of sleep efficiency on patients with a secondary sleep disorder. Subgroups that were not possible 

were gender, ethnicity, timing, and Jadad score. Only three studies could be classified by use of 

concurrent medications (others were mixed or not specified). For dosage, one study was 

excluded since it gave varying doses based on weight and another gave multiple doses and was 

included in multiple categories. Primary disorder was different for all studies except for two 

studies that both examined patients with schizophrenia. 

The only study that did not show a positive effect for sleep efficiency used polysomnography 

instead of actigraphy as its method to measure sleep outcomes. The two studies considered to 

have adequate allocation concealment had the lowest sleep efficiency estimates. However, the 

differences were not enough to significantly reduce heterogeneity in either of the subgroups. 

Due to the negligible amount of heterogeneity, using the Fixed Effects Model instead of the 

Random Effects Model did not change the estimate in the primary analysis. The WMD and 

confidence interval were identical. 

Assessment of Publication Bias. With only six included studies analysing sleep efficiency in 

patients with a secondary sleep disorder, the number of studies was deemed too few to do any 

meaningful tests for publication bias.

Sleep Quality 

There were no studies involving individuals with a secondary sleep disorder that examined 

sleep quality. 

Wakefulness After Sleep Onset 

Three studies involving individuals with secondary sleep disorders had data on WASO. The 

combined estimate showed a difference between melatonin and placebo that favoured melatonin 

but the difference was non-significant (WMD: -6.3 min.; 95 percent CI: -16.6 min, 3.9 min.). 

Heterogeneity among the studies was moderate (I2

: 35.3 percent). Two of the three studies had a 

point estimate that favoured melatonin. 

Total Sleep Time 

There were a total of nine studies that analyzed total sleep time for patients with secondary 

sleep disorders. The studies showed a combined estimate that significantly favoured melatonin 

(WMD: 15.6 min.; 95 percent CI: 7.2 min., 24.0 min.). Heterogeneity was negligible (I2

: 0 

percent). Eight out of the nine studies had a point estimate that favoured melatonin. 

Percentage Time in REM Sleep 

There was only one study involving individuals with a secondary sleep disorder that provided 

data on percent time spent in REM sleep. The WMD favoured placebo but was not significant 

(WMD: -1.5 percent; 95 percent CI: -4.4 percent, 1.4 percent). 
37

People Suffering from Sleep Restriction 

Sleep Onset Latency 

Primary Analysis. There were a total of nine studies that provided data on sleep onset latency 

for patients suffering from sleep restriction. Despite a tight confidence interval, the nine studies 

did not show a significant effect for melatonin on sleep onset latency (WMD: -1.0 min.; 95 

percent CI: -2.3 min., 0.3 min.). Heterogeneity among the studies was minimal (I2: 4.0 percent). 

Six of the nine studies had a point estimate that favoured melatonin (Figure 3-13). 

Sensitivity and Subgroup Analyses. Many of the planned subgroup analyses of sleep onset 

latency in patients suffering from sleep restriction could not be performed. The subgroups 

include gender (all studies involved both males and females and did not provide a breakdown by 

gender), age (subjects’ age was similar across studies), ethnicity (not specified in any study), 

timing (all patients took melatonin before bed), and duration (the duration of melatonin 

administration was similar across studies). The results of the subgroup analyses that could be 

performed are summarized in Table 13. Note that only two studies could be classified in terms 

of concurrent medication use. 

Using the Fixed Effect Model in place of the Random Effects Model does not change the 

conclusions. The point estimate and confidence interval (WMD: -1.0; 95 percent CI: -2.1, 0.1) 

are comparable to the random effects estimate. 

Assessment of Publication Bias. The funnel plot showed no obvious signs of asymmetry 

(Figure 3-14). There were also no indications of publication bias by any of the tests conducted. 

Begg’s Test gives a Kendall’s score of –10, which gives a continuity corrected p-value of 0.348 

with nine studies. Egger’s Test has a p-value of 0.479 on the bias of the funnel plot. Duval’s 

Trim and Fill Method added no new studies and thus had the same effectiveness estimate. 

Sleep Efficiency 

Primary Analysis. Data on sleep efficiency were available for only five studies that examined 

patients suffering from sleep restriction. The combined estimate of the studies showed no 

significant difference between melatonin and placebo with respect to sleep efficiency (WMD: 

0.5 percent; 95 percent CI: -0.6 percent, 1.6 percent). Heterogeneity among the studies was 

moderate (I2

: 20.9 percent). Four of the five studies had point estimates that favoured melatonin 

(Figure 3-15). 

Sensitivity and Subgroup Analyses. Many subgroup analyses could not be performed, 

including gender (all studies involved both males and females and did not provide a breakdown 

by gender), age (subjects’ age was similar across studies), ethnicity (not specified in any study), 

timing (all patients took melatonin before bed), duration (the duration of melatonin 

administration was similar across studies), use of concurrent medication (not stated in any of the 

studies) and dosage (different across studies). The partitions that could be performed are 

outlined in Table 14. 

Interestingly, all four subdivisions above gave negligible heterogeneity in all of their 

respective subgroups, although it was never a significant reduction in overall heterogeneity. 

Using the Fixed Effects Model in place of the Random Effects Model to obtain the estimate 

of sleep efficiency for patients suffering from sleep restriction did not differ substantially from 

the primary analysis. The effectiveness estimate slightly favoured melatonin but was nonsignificant (WMD: 0.2; 95 percent CI: -0.6, 0.9). 
38

Assessment of Publication Bias. There were an insufficient number of studies that involved 

subjects suffering from sleep restriction that examined sleep efficiency to justify performing tests 

for publication bias. 

Sleep Quality 

Five studies contained data on sleep quality. The standardized mean difference showed an 

effectiveness estimate that favoured melatonin but was not significant (SMD: 0.24; 95 percent 

CI: -0.17, 0.64). Heterogeneity among the studies was substantial (I2

: 58.5 percent). Four out of 

the five studies had a point estimate that favoured melatonin. 

Wakefulness After Sleep Onset 

Two studies involving individuals suffering from sleep restriction provided data on WASO. 

Their combined estimate favoured melatonin but was not significant (WMD: -10.4 min; 95 

percent CI: -21.0, 0.2). Heterogeneity between the studies was negligible (I2

: 0 percent). Both 

studies’ point estimates favoured melatonin. 

Total Sleep Time 

Seven studies involving patients suffering from sleep restriction compared total sleep time 

between placebo and melatonin; a significant effect that favoured melatonin was observed 

among the seven studies (WMD: 18.2 min; 95 percent CI: 8.1 min, 28.3 min). Heterogeneity 

among the studies was negligible (I2

: 0 percent). Five of the seven studies showed a point 

estimate that favoured melatonin, one study had a point estimate that neither favoured melatonin 

or placebo, and one study had a point estimate that favoured placebo. 

Percentage Time in REM Sleep 

Only one study138 presented data on percentage time spent in REM sleep. The effectiveness 

estimate favoured placebo and was non-significant (WMD: -3.6 percent; 95 percent CI: -7.3, 

0.1). 

Which sleep disorders would be most effectively managed by treatment with melatonin? 

As can be seen by the results above, the effect of melatonin on the various sleep disorders 

varies by outcome. 

Sleep Onset Latency 

For patients with primary sleep disorders, there was too much statistical heterogeneity among 

the studies to make a valid conclusion about the effect of melatonin on sleep onset latency in a 

broad sense. However, the heterogeneity largely disappears when we subdivide by type of sleep 

disorder. We then find that sleep onset latency is reduced substantially (by nearly 39 minutes) 

by melatonin in patients with delayed sleep phase syndrome, and marginally (by about 4 

minutes) in patients with insomnia. Both results are statistically significant, however, the effect 

of melatonin on sleep onset latency in people with insomnia appears to be clinically 

insignificant. The reduced heterogeneity lends support to these conclusions. 

The results for patients with secondary sleep disorders are also unclear as there was too much 

statistical heterogeneity in the data to make a firm conclusion. The removal of the study by 

Shamir et al.132 would lead to conclusions that melatonin significantly reduces sleep onset 
39

latency, but there are no grounds for its exclusion as it is clinically similar to the other studies in 

all aspects except for method of measurement and a clear method of allocation concealment. 

Thus, we can give no real statement as to the effect of melatonin on sleep onset latency for these 

patients. 

Sleep onset latency did not significantly change with melatonin in patients suffering from 

sleep restriction. This conclusion does not change when we analyze the data by type of sleep 

restriction (i.e. jet lag or shift work). 

Sleep Efficiency 

There was no significant difference in sleep efficiency between patients with a primary sleep 

disorder taking either melatonin or placebo. Unlike sleep onset latency, sleep efficiency did not 

change when we partitioned the studies into sleep phase syndrome patients and patients with 

insomnia. With heterogeneity substantial in both cases, we can say that there is no evidence that 

sleep efficiency is changed by melatonin in these patients. 

Melatonin had the strongest effect on sleep efficiency among patients with secondary sleep 

disorders; our results show a statistically significant increase in sleep efficiency with melatonin 

(about 1.9 percent), however, this effect appears to be clinically insignificant. 

There was no effect of melatonin on sleep efficiency in patients suffering from sleep 

restriction. 

Other Outcomes 

There was no evidence that melatonin affects sleep quality, wakefulness after sleep onset 

(WASO), or percentage time spent in REM sleep for any of the three sleep disorder groups. 

There is evidence that total sleep time is increased with melatonin in individuals suffering 

from a secondary sleep disorder and those suffering from sleep restriction. There was, however, 

no evidence of any change in total sleep time in patients with primary sleep disorders. 

Which populations based on gender, age, ethnicity, and co-morbid conditions would benefit most 

from treatment with melatonin? 

Gender 

No information could be obtained regarding the effect of melatonin on sleep disorder patients 

by gender. All studies but one were a mixed population and a breakdown of data by gender was 

not available in any of them. The one exception80 was an all female study of children with Rett 

syndrome and the results of this one study were non-significant with respect to both sleep onset 

latency and sleep efficiency. 

Age 

For patients with primary sleep disorders, there is some evidence that sleep onset latency is 

reduced more in children (up to 17 years) than in adults (18-65 years) or elderly patients (greater 

than 65 years). The one study involving children showed a significant reduction in sleep onset 

latency with melatonin while the studies involving adults and the elderly did not show this 

overall reduction, despite the presence of studies showing a highly significant reduction of sleep 

onset latency in this latter category. In terms of sleep efficiency, however, both the studies 

involving adults and the elderly showed non-significant differences between melatonin and 

placebo (there were no studies involving children that examined sleep efficiency). 
40

There is no evidence that sleep onset latency is reduced more in children than in adults in 

studies involving individuals with secondary sleep disorders; none of the studies involving 

elderly with secondary sleep disorders examined sleep onset latency. Although the three studies 

involving children showed a significant reduction in sleep onset latency while the three studies 

involving adults did not, the confidence intervals are fully overlapping. In terms of sleep 

efficiency, there was no evidence of any differences among the three groups. Although the two 

studies involving elderly subjects showed a significant difference, they actually had the smallest 

point estimate. Similar to sleep onset latency, the three confidence intervals are fully 

overlapping. 

No comparisons could be made by age for patients suffering from sleep restriction since all 

studies examined adult subjects. 

Ethnicity 

Ethnicity was generally not mentioned in any of the studies. Only two studies stated that 

their patients were all Caucasian. These two studies both involved individuals with primary 

sleep disorders and did show a significant reduction in sleep onset latency. 

Co-Morbid Conditions 

Regarding the studies involving subjects with secondary sleep disorders, the only co-morbid 

condition reported in more than one study was schizophrenia, which was present in two 

studies.131 132 The other studies involved patients with different conditions: Rett syndrome,80

tuberous sclerosis,81 developmental disabilities,82 depression,125 dementia,78 and Alzheimer’s 

disease;135 the first three studies involved children, the study by Serfaty et al. 125 involved adults, 

while the last two studies involved the elderly (the two studies by Shamir involved adults). 

Based on these other differences, it is difficult to discern the effects of melatonin solely by comorbid condition. We can say that the study that involved children with tuberous sclerosis did 

show a significant reduction in sleep onset latency with melatonin (WMD: -23.4 min; 95 percent 

CI: --45.2, -1.6) and the study that involved elderly patients with Alzheimer’s showed a 

significant increase in sleep efficiency with melatonin (WMD: 2.0 percent; 95 percent CI: 0.1, 

3.9). It is difficult, however, to draw any conclusions from these results. 

What is the appropriate dosage/duration of administration of melatonin for the treatment of 

sleep disorders? Does the appropriate dosage depend on patients’ gender, age, and/or 

ethnicity? 

Dosage 

We categorized dosage according to the following levels: <1 mg, 1-3 mg, 4-5 mg, 6-10 mg, 

>10 mg. Among patients with a primary sleep disorder, there was no obvious effect of dose on 

the outcome of sleep onset latency or sleep efficiency. The point estimate of difference in sleep 

onset latency increased in magnitude with increasing dosage, while the point estimate of sleep 

efficiency decreased in magnitude with increasing dosage, but all confidence intervals for both 

outcomes were overlapping and non-significant. 

The breakdown by dosage for patients with a secondary sleep disorder is also inconclusive; 

all confidence intervals were overlapping and non-significant for both sleep onset latency and 

sleep efficiency. With only two dosage groups for each outcome, no trends were detectable. 
41

The breakdown of the studies involving sleep restriction also showed no discernable effect of 

dosage; all confidence intervals were overlapping and non-significant and no trend was 

detectable. There was no evidence of a dose effect on sleep onset latency or sleep efficiency for 

subjects suffering from sleep restriction. 

A further subdivision by age, gender, or ethnicity was not possible in any of the sleep 

disorder subgroups due to lack of data. 

Duration of Administration 

 When studies involving sleep disorders were subdivided by duration of administration (i.e., 

<1 week, 1-2 weeks, 3-4 weeks), there was no apparent melatonin effect with respect to either 

sleep onset latency or sleep efficiency. The results were generally the same (i.e. overlapping 

confidence intervals) regardless of the duration. 

There were no data for subjects suffering from sleep restriction, as all studies were 

approximately the same duration. 

What is the timing of melatonin administration during the sleep/wake cycle that would produce 

optimal treatment effects? 

Without exception, every sleep disorder study administered melatonin to its patients just 

before they went to bed. As a result there is no information on effect of timing of melatonin 

administration. 

How do different formulations of melatonin differ with respect to effectiveness? 

There was insufficient information on melatonin formulations in the sleep disorder studies to 

allow us to do any subgroup analysis by formulation. 

What are the adverse effects of short and long-term use of melatonin? 

Thirty-four studies were relevant to this question of the review. The overall quality of these 

studies was assessed using the Downs and Black Checklist.115 The overall quality of studies 

ranged from 12 to 26 on a 29-point scale; one study had a score of 12,144 13 studies had a score 

between 16 and 20,27 60 61 63-65 81 92 94 124 145-147 19 studies had a score between 21 and 2554 66 68 69 71 

74 76 78 80 82 90 95 129 130 143 148-151 and one study had a score of 26.67 The quality of reporting ranged 

from five to 11 on an 11-point scale; two studies had a score of five or six,63 144 15 studies had a 

score between seven and nine27 61 64-66 68 76 80-82 92 94 145-147 and 17 studies had a score between 10 

and 11.54 60 67 69 71 74 78 90 95 124 129 130 143 148-151 The external validity of studies ranged from zero to 

three; most studies had a score of one, eight studies had a score of two,63 66 74 80 82 130 145 151 four 

studies had a score of three,54 67 90 143 and six studies had a score of zero.78 94 95 146 147 149 The 

quality of internal validity ranged from five to 12 on a 13-point scale; most studies had a score 

between nine and 11; one study had a score of five,144 one study had a score of eight,27 one study 

had a score of 10,151 and two studies had a score of 12.54 130 A power calculation for the primary 

outcome was reported for eight studies;66-68 76 78 82 143 150 four of these had sufficient power to 

detect a clinically important effect where the probability value for a difference being due to 

chance is less than 5 percent,66-68 150 while four others did not.76 78 82 143 A power calculation was 

not provided for one study, but it had sufficient power to detect a clinically important effect 
42

where the probability value for a difference being due to chance is less than 5 percent.63 See 

Evidence Table C-3 for a description of design characteristics and overall quality scores of 

studies relevant to this question of the review. 

Primary Analysis. There were few reports of adverse events accompanying melatonin 

administration. The most common adverse events reported were headaches, dizziness, nausea 

and drowsiness. In all cases there was no significant differences found between melatonin and 

placebo despite tight confidence intervals. 

There were a total of 33 studies with information on headaches. There was no difference 

between placebo and melatonin (Risk Difference: 0.00; 95 percent CI: -0.02, 0.02) and 

heterogeneity was minimal (I2: 0 percent) (Figure 3-16). The results were similar for dizziness 

(32 studies; RD: 0.00; 95 percent CI: -0.02, 0.02; I2: 0 percent) (Figure 3-17), nausea (33 studies; 

RD: 0.00; 95 percent CI: -0.02, 0.01; I2

: 0 percent) (Figure 3-18) and drowsiness (34 studies; 

RD: 0.00; 95 percent CI: -0.01, 0.02; I2: 0 percent) (Figure 3-19). 

Subgroup and Sensitivity Analyses. Analyses were performed on the safety outcomes for the 

following subgroups: gender, age, use of concurrent medications, dosage, duration, patient 

category, study design, quality score, and allocation concealment score. The homogeneity of the 

comparisons made all of these analyses irrelevant. For all outcome measures, the calculated risk 

difference was not significant and the point estimate was never more than a few percentage 

points from zero. Thus, no change was observed between melatonin and placebo in terms of 

headaches, dizziness, nausea or drowsiness for different doses of melatonin, type of sleep 

disorder (or lack thereof), duration of melatonin treatment, or for any other subgroup mentioned 

above. 

Using the Fixed Effect Model in place of the Random Effects Model did not change any of 

the results due to the homogeneity of studies for all four outcomes. 

A sensitivity analysis using only the studies where the specific outcome was mentioned was 

also performed, and still none of the results were significant. The point estimate for risk 

difference of headaches between melatonin and placebo included 14 studies and was just a 

fraction above zero and not significant (RD: 0.00; 95 percent CI: -0.04, 0.05). This estimate had 

moderate heterogeneity (I2

: 33.9 percent). For dizziness, only four studies were included, and 

again the results were just above zero and non-significant (RD: 0.03; 95 percent CI: -0.03, 0.09) 

with moderate heterogeneity (I2

: 36.8 percent). The nausea estimate included five studies and 

actually favoured melatonin (RD: -0.02; 95 percent CI: -0.05, 0.02), but was also not significant; 

the heterogeneity was negligible (I2

: 0 percent). Finally, the drowsiness estimate included nine 

studies with non-significant results that favoured placebo (RD: 0.03; 95 percent CI: -0.05, 0.11). 

The heterogeneity for this last estimate was substantial (I2

: 57.0 percent). 

How do the harms of exogenous melatonin vary based on dose, timing of administration, and 

patient factors such as gender, age, and ethnicity? How do different formulations of melatonin 

differ with respect to safety? 

There was insufficient information to answer this question in terms of timing of melatonin 

administration (all studies involved melatonin administration just before bed) and ethnicity (no 

studies reported information on ethnicity). The sub groupings for dose, gender, age, and 

formulation are provided in Tables 3-11, 3-12, 3-13 and 3-14 below. It is clear from these tables 

that there is no evidence that the adverse effects of melatonin change by gender, age, dose or 
43

formulation. This was to be expected as the primary analysis showed that the adverse effects of 

melatonin were quite minimal. 

Results of Qualitative Analysis 

What are the various formulations of melatonin? How are the formulations different in terms of 

content, quality as well as safety and effectiveness? What is the clinical importance of any 

observed differences? 

Eight studies were relevant to this question of the review. Three studies were relevant to the 

question relating to the effectiveness of melatonin in people with sleep disorders,58 139 152 six 

studies were relevant to the question relating to the safety of melatonin,63 78 80 90 130 143 and one 

study was relevant to both questions.90 See Evidence Table C-4 for a description of study design 

characteristics and quality scores of studies relevant to this question of the review. 

An immediate-release formulation was used in one study,80 a fast-release formulation was 

used in one study,143 a slow-release formulation was used in two studies,57 78 and a controlledrelease formulation was used in two studies.90 130 Haimov et al. 139 compared slow-release and 

fast-release formulations and Suhner et al.63 compared fast-release and controlled-release 

formulations. The content and quality of the formulations used in the studies were not 

adequately described in the reports of these studies. Thus, the corresponding authors of these 

studies were contacted for additional information regarding the content and quality of the 

formulations. To summarize the information that is available, the controlled-release formulation 

used by Garfinkel et al. 90 was reported to be synthetic and 100 percent pure and the slow-release 

formulation used by Serfaty et al. 78 was also synthetic. The pharmacokinetics of the slowrelease formulation used by Almeida-Montes et al.57 was also provided: melatonin concentrations 

in plasma begin to rise 30 minutes following its administration, attain maximal levels 60 minutes 

following its administration and reach a stable concentration 6 hours following its 

administration; release is sustained for 8 hours.57 Smits et al. (2003)143 and McArthur et al. 

(1998)80 reported that the formulations used in their studies contained carboxymethylcellulose 

and lactose filler, respectively. Given the paucity of information available to us regarding the 

details of the melatonin formulations used in the various studies relevant to this question of the 

review, an in-depth comparison of the content and quality of the various formulations that have 

been used to assess its effectiveness and safety is not possible. 

As mentioned in the “Results of Quantitative Analysis” section above, there was insufficient 

information on the melatonin formulations used in studies involving individuals with sleep 

disorders to allow a subgroup analysis of the effect of formulation on the effectiveness of 

melatonin in the treatment of sleep disorders. However, a subgroup analysis of the effect of 

formulation on the safety of melatonin reveals a lack of evidence showing that the adverse 

effects of melatonin vary by formulation. 

What is the pharmacology of exogenous melatonin, including pharmacokinetics and 

pharmacodynamics? How is it absorbed, distributed, metabolized, excreted? What blood levels 

are achieved? What is its half-life? Does it penetrate the blood brain barrier? 

Twenty-six studies were relevant to this question of the review. The quality of these studies 

was assessed using the Downs and Black Checklist115 with the exception that the power of the 
44

studies to detect a clinically important difference was not assessed. The overall quality score 

ranged from eight to 21 on a 29-point scale; one study had a score of eight,153 10 studies had a 

score between 10 and 15,133 134 154-161 14 studies had a score between 16 and 20,94 127 162-173 and 

one study had a score of 21.137 The quality of reporting ranged from five to nine on an 11-point 

scale; most studies had a score between seven and nine and six studies had a score of five or 

six.133 134 153 156 159 164 Most studies had a score of zero on a three-point scale for external validity 

and two studies had a score of two.137 170 The internal validity of studies ranged from three to 11 

on a 13-point scale; most studies had a score between seven and nine; five studies had a score 

between three and six,133 134 153 158 159 and six studies had a score of 10 or 11.64 137 162 167 168 170 See 

Evidence Table C-5 for a description of design characteristics, overall quality scores, and results 

of studies relevant to this question of the review. 

Regarding the pharmacology of exogenous melatonin, the formulation used in the studies 

was often not reported. Melatonin was administered orally in most studies. The timing of 

melatonin administration varied across studies, although in many cases, melatonin was 

administered in the morning. The use of co-medication by study participants was often not 

specified, and in some cases, participants suffered from a sleep disorder (Evidence Table C-5). 

Thus, the conditions of the intervention, the characteristics of the population, and the quality of 

reporting varied across studies relevant to this question of the review, which precluded 

quantitative pooling of results. Thus, we provide a qualitative synthesis of the evidence 

pertaining to the pharmacokinetics of exogenous melatonin. The half-life of exogenous 

melatonin ranged from 0.54 hours (h) to 2h and most studies reported a value between 0.54h and 

0.8h. The peak concentration of melatonin achieved in the blood ranged from 14.75pg/ml to 64 

730 pg/ml, which reflected a dose range of 0.003mg to 75mg. The time required to reach peak 

values ranged from 0.25h to 13h and most studies reported a value between 0.5h and 1.0h. The 

period over which the area under the melatonin versus time curve was calculated varied across 

studies, precluding both a quantitative and qualitative synthesis of the evidence pertaining to this 

outcome. 

Of the studies that met eligibility criteria for any of the questions of the review involving 

administration of exogenous melatonin to study participants, none provided a thorough 

examination of the dose-response relationship of exogenous melatonin with respect to the sleeprelated outcomes analyzed in this review. Thus, information on the pharmacodynamics of 

exogenous melatonin was not available. 

Only one study155 was identified which examined pharmacokinetic characteristics of 

exogenous melatonin in cerebrospinal fluid (CSF). In this study, a patient with an external CSF 

drainage device was examined; drainage was required due to a shunt infection. Five milligrams 

of melatonin was administered at 20:00h. A rapid rise in melatonin levels in the CSF was 

evident beginning 10 minutes after its administration and melatonin concentrations in CSF 

peaked within 80 minutes following its administration. The levels of melatonin in CSF declined 

rapidly over a period of 5 hours.155 This study provides evidence that exogenous melatonin 

penetrates the blood-brain-barrier. 

The mechanism by which melatonin is absorbed, distributed, metabolized, and excreted in 

man was not described in the studies that met inclusion criteria for this question of the review. 
45

What is the evidence linking endogenous melatonin to sleep cycles? 

A study was considered relevant to this question of the review if it involved an intervention 

that altered endogenous melatonin levels or the sleep cycle, such as a manipulation of light/dark 

exposure or the sleep schedule, and it examined either melatonin levels in blood, urine, saliva or 

CSF or an aspect of the sleep cycle, depending on which intervention was used. That is, if the 

study intervention was designed to manipulate endogenous melatonin, then it was necessary that 

the study examine the effect of this manipulation on an aspect of the sleep cycle, and vice-versa. 

These criteria allow for an understanding of the relationship between endogenous melatonin and 

the sleep cycle via an assessment of the effect of manipulation of one variable on the other. 

Forty-four studies were relevant to this question of the review. The overall quality scores, 

according to the Down’s and Black Checklist, ranged from eight to 23 on a 29-point scale; most 

studies had a score between 16 and 20, one study had a score of eight,174 13 studies had a score 

between 10 and 15175-187 and one study had a score of 23.188 The quality of reporting ranged 

from three to nine on an 11- point scale; most studies had a score between eight and nine 

inclusive, three studies had a score between three and five174 176 180 and 17 studies had a score 

between six and seven.175 178 181-187 189-196 The internal validity of the studies ranged from zero to 

three on a three-point scale; most studies had a score of zero, seven studies had a score of one,128 

191 194 197-200 one study had a score of two188 and one study had a score of three.189 The internal 

validity of studies ranged from five to 12 on a 13-point scale; most studies had a score between 

seven and nine; three studies had a score of five or six;174 177 180 three studies had a score of 10 or 

11195 201 202 and one study had a score of 12.188 For most studies, a power calculation was not 

reported, however, for one study, a power calculation was reported and the study had sufficient 

power to detect a statistically significant effect where the probability value for a difference being 

due to chance was less than 5 percent.203 See Evidence Table C-6 for a description of design 

characteristics and overall quality scores of studies relevant to this question of the review. 

One of three types of interventions was employed in the studies relevant to this question of 

the review: manipulation of light/dark exposure, manipulation of the sleep schedule and 

administration of a tryptophan-free mixture. Here, we provide the results of a qualitative 

analysis of evidence surrounding the relationship between endogenous melatonin and the sleep 

cycle according to the various interventions that have been used to manipulate one of the 

variables of this relationship. 

Intervention: manipulation of light/dark exposure 

Manipulation of light/dark exposure is designed to alter endogenous melatonin levels. The 

studies that employed this intervention can be categorized as those involving normal sleepers, 

people with a sleep disorder and people with a disorder that may or may not be accompanied by 

a sleep disorder. For most studies, a comparison was made between the effects of light of 

different intensities on endogenous melatonin and the sleep cycle, with the light of lower 

intensity serving as a control. The levels of light intensity varied widely across studies, such that 

a comparison of “bright” and “dim” light involved very different light levels across studies. 

Here, we use “brighter” to denote the light of higher intensity and “dimmer” to denote the light 

of lower intensity, for studies in which a comparison was made between the effects of light of 

different intensities, in order to highlight the fact that these light levels were relative and do not 

necessarily indicate “bright” or “dim” light in absolute terms. 
46

Normal sleepers. The nature, magnitude, duration and timing of the light stimulus 

intervention varied across studies. Most studies involved direct application of light of different 

intensities,128 176 183 191 194 199 204-209 while others involved application of these signals within the 

context of a workstation,192 dawn simulation179 or video display terminal.182 Most studies 

compared the effect of brighter light to the effect of dimmer light,128 176 179 182 183 191 192 194 199 204-

209while one study compared the effect of light exposure of long duration (16h) to light exposure 

of short duration (10h),187 and another compared the effect of evening versus morning brighter 

light administration.199 The magnitude of the light stimuli ranged from 0.1 lux to 300 lux for the 

dimmer light condition and 45 lux to 11000 lux for the brighter light condition, and the duration 

of light stimuli application ranged from three hours to 36 hours, over hours to weeks. The timing 

of light administration varied from early morning to late night. Most studies involved ocular 

light administration, while one study involved extra-ocular light administration applied to the 

bend of the knee.128 Some studies involved application of light stimuli under conditions of 

prolonged sleep deprivation.183 192 194 204 206 209 (Evidence Table C-6) 

In the case of studies in which ocular light stimuli were administered in the evening or night, 

brighter light (BL) tended to suppress endogenous melatonin levels,176 182 183 191 192 194 205 206

relative to dimmer light (DL) and one study found a delay in the phase of the melatonin 

rhythm.204 The reduction in endogenous melatonin levels with BL was accompanied by no 

change in194 or increased205 sleep onset latency, a smaller and delayed accumulation of REM 

sleep176 and increased REM latency176 and NREM period length,176 without a change in REM 

cycle and REM period length.176 The suppression of endogenous melatonin levels was also 

accompanied by increased alertness and performance in some studies,183 191 206 while others 

found no effect of BL on these variables.182 192 194 In some studies, the suppression of 

endogenous melatonin levels and/or the alerting response in the presence of BL only occurred in 

the early night.183 206 In the study in which bright light resulted in a delay of the melatonin 

rhythm, sleep onset was delayed as well.204 (Table 19) 

Three studies involved ocular BL administration during the morning or daytime.179 207 208 

Ocular BL resulted in a phase advance of the melatonin rhythm179 207 and a suppression of 

endogenous melatonin levels, 179 208 relative to DL. In a study by Dijk et al., the advance in the 

melatonin rhythm was accompanied by a reduction in sleep duration and REM sleep, relative to 

DL;207 REM latency, percent time spent in the various sleep stages and sleep quality were 

unaffected by BL, relative to DL.207 In two studies, the suppression of endogenous melatonin 

levels with BL was accompanied by increased alertness, relative to DL.179 208 (Table 20) 

In a study by Gordijn et al. in which the effects of morning and evening ocular light exposure 

were compared, evening light exposure resulted in suppression of endogenous melatonin levels 

compared to morning light exposure, although the phase of endogenous melatonin was not 

affected.199 The changes in endogenous melatonin with evening light exposure were 

accompanied by greater “movement time”, shorter duration of the first REM episode, later time 

of sleep termination and no change in sleep latency and REM latency, compared to morning BL 

exposure.199 In a study by Wehr et al., exposure to a longer photoperiod resulted in a reduction 

in the duration of the nocturnal endogenous melatonin rhythm, duration of the sleep period and 

the nocturnal phase of increasing sleepiness, compared to exposure to a shorter photoperiod.187 

Similarly in a study by Daurat et al., light exposure or a light/dark cycle were administered for 

36 hours during sleep deprivation and no difference was found in endogenous melatonin levels 

or in total sleep time, REM latency, WASO and REM sleep.209 In a study by Lushington et al. in 
47

which light stimuli were administered behind the knee, BL did not affect endogenous melatonin, 

however, it resulted in increased wakefulness, relative to DL.128 (Table 13-17) 

Five of the studies included in this analysis conducted an analysis of the correlation between 

endogenous melatonin and the sleep cycle.179 191 194 204 207 In the study by Kubota et al., no 

correlation was found between change in phase of the melatonin rhythm and change in sleep 

onset with BL administration,204 while in the study by Cajochen et al., the alerting response to 

BL was positively correlated with the degree of suppression of endogenous melatonin levels by 

BL.191 Similarly, in the study by Danilenko et al.,179 the phase of the melatonin rhythm was 

correlated to sleepiness and midpoint of sleep, while in the study by Dijk et al., no correlation 

was found between phase of the melatonin rhythm and sleep duration.207 Lastly, in the study by 

Lavoie et al., none of the vigilance variables were found to correlate to endogenous melatonin 

levels.194 (Tables 3-15, 3-16, 3-17) 

People with a Sleep Disorder 

A number of studies in this category examined the relationship of endogenous melatonin and 

the sleep cycle and these differed in many aspects of study design. Many studies involved shift 

workers,174 178 190 193 195 210 211 while others involved people with delayed sleep phase syndrome188 

189 or people who suffer from jet-lag.197 Most studies involving night-shift workers employed 

light stimuli during the night-shift,174 178 190 193 210 211 although one study employed the stimuli, 

after the night-shift.195 While most studies involved application of light stimuli while 

participants were awake, one study involved administration of light stimuli during sleep, through 

closed eyelids.188 All studies involved direct application of brighter or dimmer/control light 

stimuli, and while most studies compared brighter versus dimmer light effects on endogenous 

melatonin and the sleep cycle,174 178 188-190 193 195 197 210 one study examined the effect of the 

frequency of light stimulation on these variables.211 The intensity of the light stimuli ranged 

from 0.1 lux to 1500 lux for dimmer/control light administration and 660 lux to 12 000 lux for 

BL administration. The duration of application of light stimuli ranged from two to 12 hours, 

over hours to weeks. (Evidence Table C-6) 

In the case of studies involving administration of light stimuli to night-shift workers during 

the night shift and comparing BL to DL/control, many studies found that BL resulted in a greater 

phase delay in endogenous melatonin from baseline measurements compared to dimmer 

light/control.174 193 210 While one study found a suppression of endogenous melatonin levels with 

BL administration, compared to DL administration,190 another study found no change in 

endogenous melatonin levels following BL administration, compared to DL administration.178 

Of the studies that reported alterations in endogenous melatonin with BL administration, the 

effects of BL on the sleep cycle were varied. While one study reported no effect of BL on sleep 

start time and sleep wake time,193 another reported no effect of BL on total sleep time,190 and yet 

another study reported greater sleep time and sleep continuity and no change in sleep latency 

with BL administration.210 While most studies found that BL increased alertness and 

performance,174 190 193 210 another did not find such an effect.178 In a study by Ross et al., light 

stimuli were administered for 2h daily for one week after night shift work; the DL group 

readapted slightly, but faster than the BL group after the night shift. Moreover, the BL exposure 

resulted in a reduction in sleep latency but had no effect on sleep duration, sleep quality, night 

awakenings or mood, compared to DL exposure.190 In a study by Boulos et al, participants were 

administered light stimuli on the first two evenings after a flight from Zurich to New York. 
48

Although BL treatment resulted in a greater delay in endogenous melatonin secretion compared 

to DL, there were no differences between the two groups in sleep efficiency, sleep quality, 

daytime sleepiness, jet-lag severity or mood.197 In another study involving night-shift and 

examining the effect of various cycles of light exposure on endogenous melatonin and the sleep 

cycle, 3 or 5 cycles of BL administration were not different in their effects on the phase of the 

melatonin rhythm nor on sleep quality, performance, or subjective feelings of tiredness.211 (Table 

22) 

Two studies involving application of light stimuli to individuals with delayed sleep phase 

syndrome found no effect of BL on the phase of the endogenous melatonin rhythm nor on 

mood,188 189 total sleep period,189 total sleep time,188 189 morning sleepiness,197 or sleep quality,188

relative to DL. (Table 22) 

In the study by Boulos et al., no correlation was found between dim light melatonin onset and 

performance following the BL intervention.197 (Table 22) 

People with a Disorder that may or may not be Accompanied by a Sleep Disorder. 

Two studies examined the effect of light on individuals with seasonal affective disorder 

(SAD) and found no effect of BL on either levels203 or timing201 of endogenous melatonin 

secretion, compared to DL. These results were accompanied by a lack of effect of BL on 

mood,201 alertness,201 sleepiness,203 total sleep duration,201 time of awakening,201 and sleep 

onset,201 compared to DL. In a similar study, BL resulted in a greater phase advance of 

endogenous melatonin compared to DL and this effect was accompanied by an earlier tendency 

for sleep termination and no change in accumulation of wakefulness.212 In the study by Gordijn 

et al., no correlation was found between changes in phase of endogenous melatonin and wake-up 

time.212 (Table 23) 

Intervention: manipulation of the sleep schedule 

Manipulation of the sleep schedule is designed to affect the sleep cycle. The majority of 

studies in this category examined the effect of alterations in the sleep schedule in normal 

sleepers,177 180 181 184 186 198 200 202 213-217 although one study examined the effect of this type of 

intervention on both normal sleepers and depressed individuals (who may have an accompanying 

sleep disorder).185 While many studies assessed the effect of prolonged sleep deprivation on 

endogenous melatonin,181 185 198 202 213 214 216 others assessed the effect of partial sleep 

deprivation,200 sleep restriction177 180 or sleep period advance/delay184 186 215 217 on endogenous 

melatonin. (Evidence Table C-6) 

The results of the various studies in this category are inconsistent. For example, of the 

studies examining the effect of prolonged sleep deprivation on normal sleepers, endogenous 

melatonin was found to increase in some studies,198 214 decrease in another study202 or remain 

unchanged in other studies181 185 213 216 during or after periods of sleep deprivation. In a study by 

Redwine et al., sleep deprivation of normal sleepers during the early night did not affect 

endogenous melatonin levels during either the early or late parts of the night.200 

Of the studies examining the effect of sleep restriction regimens on endogenous melatonin, 

one study examined the effect of timing of napping in darkness on endogenous melatonin and 

found that morning napping resulted in a phase delay of endogenous melatonin, while afternoon 

napping did not affect the phase of endogenous melatonin.177 In a similar study, the sleep 

restriction regimen involved either a short nap during the night or a short nap during the night 

accompanied by a short nap during the late afternoon. The sleep restriction conditions resulted 

in a phase delay of endogenous melatonin with continued elevation of melatonin levels at the end 
49

of the nocturnal secretory phase.180 It is important to note that changes in napping patterns 

would change patterns of light exposure, which itself, could have affected endogenous melatonin 

in these studies, depending on the timing of naps in relation to the endogenous melatonin 

rhythm. 

Four studies examined the effect of sleep period advance/delay on endogenous melatonin.184 

186 215 217 In a study by Weibel et al., day-active study participants were subjected to an acute 

shift of their sleep period to daytime; endogenous melatonin was not affected by this shift.215 

Jelinkova-Vondrasova et al. reported a phase advance of one hour within six days of the 

endogenous melatonin rhythm following a three hour advance of the sleep period and a phase 

delay of one hour in six days following a subsequent three hour delay of the sleep period.184 In a 

similar study, when the sleep/wake cycle was shortened by one hour per day, the melatonin 

rhythm did not achieve complete adjustment within the period of investigation, and when the 

time shift was reversed by a seven hour delay within two days, resynchronization was achieved 

satisfactorily only within seven days.186 In a study by Danilenko et al, a two-hour phase advance 

of the sleep period resulted in a small advance in the endogenous melatonin rhythm.217

Intervention: administration of a tryptophan-free mixture 

In these types of studies, administration of a tryptophan-free mixture was designed to reduce 

endogenous melatonin levels. In a study by Arnulf et al., administration of a tryptophan-free 

mixture mid-morning, which resulted in reduced serum tryptophan, did not alter endogenous 

melatonin levels, mood, sleep latency, total sleep time, total sleep duration, duration of 

wakefulness after sleep onset, stages one-two and three to four of NREM sleep and REM sleep, 

but did result in increased REM latency.175 

Summary: Endogenous melatonin and the sleep/wake cycle 

To summarize, our literature review indicated a link between endogenous melatonin and the 

sleep cycle. A key result was that a decrease in endogenous melatonin levels was often 

accompanied by increased latency to sleep and decreased duration of sleep, as well as increased 

vigilance and performance during waking hours. In addition, changes in the rhythm of 

endogenous melatonin were often accompanied by changes in the sleep rhythm. 

What are the basic mechanisms by which melatonin produces sleepiness? 

None of the studies identified through our search met our initial inclusion criteria for this 

question of the review, namely, that the study characterize and/or evaluate a mechanism by 

which melatonin produces sleepiness in humans. Thus, the inclusion criteria for this question of 

the review were revised; a study was considered relevant to this question of the review if it 

fulfilled the inclusion criteria of the question relating to the effect of melatonin in normal 

sleepers and the question relating to the effect of melatonin in people with sleep disorders, and 

the report provided a proposed mechanism by which melatonin produces sleepiness, based on 

findings of the study. Eleven studies met the revised inclusion criteria for this question of the 

review. See Evidence Table C-7 for a description of study design characteristics and overall 

quality scores of these studies. 

The mechanisms by which melatonin induces sleepiness in humans have not been fully 

elucidated. However, a number of hypotheses exists: the mechanism may involve a phase-shift 

of the endogenous circadian pacemaker, a reduction in core body temperature and/or a direct 
50

action on somnogenic areas of the brain. Studies of the effects of melatonin in humans have led 

to postulates of the mechanism of action of melatonin that either favour or refute one or a 

number of the current hypotheses of the mechanism by which melatonin promotes sleepiness. 

A number of investigators that have been involved in studies of the effect of melatonin on 

people with sleep disorders have supported the notion that melatonin induces sleepiness through 

a re-entrainment of the endogenous circadian pacemaker and not through a direct action on 

somnogenic structures of the brain.65 74 152 In one case, this conclusion was based on findings 

that melatonin advanced sleep onset time without increasing sleep duration,74 while in another 

case it was based on findings that melatonin did not affect polysomnographic and subjective 

measures of sleep quality152 and in yet another case was based on findings that melatonin did not 

affect sleep duration.65 By contrast, others have proposed that the sleep-inducing effects of 

melatonin may not be mediated by a shift of the endogenous circadian oscillator and may be due 

to direct actions of the hormone, based on findings that melatonin improved the quality of sleep 

and increased its duration without affecting either sleep onset time or sleep latency.70 Andrade et 

al. have concluded that melatonin is not a sedative/hypnotic, based on findings that evening 

melatonin administration advanced sleep onset without producing drowsiness or hangover effects 

the next day.54 Edwards et al. drew the same conclusion based on the finding that melatonin had 

no significant effect on the ease of getting to sleep or the number of waking episodes in jet-lag 

sufferers.218

A number of investigators that have been involved in studies of the effect of melatonin on 

normal sleepers have supported the hypothesis that melatonin promotes sleepiness via a direct 

action on somnogenic structures of the brain.92 123 219 220 Zhdanova et al. proposed that their 

findings of decreased sleep onset latency and latency to stage two sleep with evening 

administration of melatonin is mediated by a direct action of melatonin rather than via a 

biological timing mechanism.220 In a study by Terlot et al.,219 afternoon administration of 

melatonin resulted in increased feelings of sleepiness, fatigue and confusion and decreased 

feelings of vigor and concentration, leading the investigators to argue that since the effects of 

afternoon administration of melatonin were similar to those observed with comparable doses 

administered at noon or in the evening, the effects of melatonin are not-time dependent and, 

therefore, may not be mediated by a phase-shifting effect on the endogenous circadian clock.219 

In a study by Matsumoto et al., morning administration of melatonin was found to increase sleep 

duration in diurnal sleep, without affecting rectal temperature during this sleep. Based on these 

results, the investigators suggested that melatonin has a direct hypnotic effect on diurnal sleep.92 

Satomura et al. supported the latter notion based on findings that daytime administration of 

melatonin resulted in increased sleep duration and efficiency and, in the case of the higher dose 

of melatonin, a lack of a hypothermic effect.123

In a study by Mishima et al., morning administration of 9 mg of melatonin to normal sleepers 

had a hypnotic effect, while 3 mg of melatonin did not have this effect. However, both doses 

induced the same degree of body temperature suppression and the hypnotic effect of exogenous 

melatonin was sustained during a period when serum melatonin levels and body temperature had 

returned to physiological values. These findings led the investigators to support the hypothesis 

that the sleep-inducing action of melatonin is likely not mediated by suppression of body 

temperature.221 In a study by Holmes et al., afternoon administration of melatonin to normal 

sleepers resulted in a reduction in sleep onset latency and an accompanying decrease in core 

body temperature, leading the investigators to suggest that the sleep-promoting property of 

melatonin may involve modulation of core body temperature.222 
51

How is endogenous melatonin involved in circadian rhythms? 

The scope of this question was limited to an analysis of how endogenous melatonin is 

involved in the temperature rhythm. The analysis of evidence relevant to this question was 

approached in a similar manner as for the question relating to the link between endogenous 

melatonin and the sleep cycle, in that we addressed the link between endogenous melatonin and 

the temperature rhythm. A study was considered relevant to this question of the review if it 

involved an intervention that altered endogenous melatonin levels or the temperature rhythm, 

such as a manipulation of light/dark exposure or body temperature, and it examined either 

melatonin levels in blood, urine, saliva or CSF or an aspect of the temperature rhythm, 

depending on which of these variables was manipulated. Thus, if the study intervention was 

designed to manipulate endogenous melatonin, then it was necessary that the study examine the 

effect of this manipulation on an aspect of the temperature rhythm, and vice-versa. These 

criteria allow for an understanding of the relationship between endogenous melatonin and the 

temperature rhythm via assessment of the effect of manipulation of one variable on the other. 

Twenty-four studies were relevant to this question of the review. The overall quality score, 

based on the Downs and Black Checklist, ranged from 11 to 19 on a 29-point scale; most studies 

had a score between 16 and 19 and eight studies had a score between 11 and 15.176 178 179 182 183 

223-225 The quality of reporting ranged from five to nine on an 11-point scale; one study had a 

score of 5,176 11 studies had a score of six or seven178 182 183 189 191 193 194 223-226 and 12 studies had 

a score between eight and nine.128 179 199 204-206 208-210 212 227 228 The external validity of studies 

ranged from zero to three on a three-point scale; most studies had a score of zero, four studies 

had a score of one128 191 194 199 and one study had a score of three.189 The internal validity of 

studies ranged from five to nine on a 13-point scale; most studies had a score of eight or nine, 

two studies had a score of five or six179 224 and two studies had a score of seven.176 225 None of 

the studies relevant to this question of the review reported a power calculation or addressed 

whether the study had sufficient power to detect a clinically significant effect where the 

probability value for a difference being due to chance was less than 5 percent. See Evidence 

Table C-8 for a description of design characteristics and overall quality scores of studies relevant 

to this question of the review. 

One of two types of interventions was employed in the studies relevant to this question of the 

review: manipulation of light/dark exposure or manipulation of body temperature. Here, we 

provide the results of a qualitative analysis of evidence surrounding the relationship between 

endogenous melatonin and the temperature rhythm according to the interventions that have been 

used to manipulate one of the variables of this relationship. 

 

Intervention: manipulation of light/dark exposure 

The studies that employed this intervention can be categorized as those involving normal 

sleepers, people with a sleep disorder and people with a disorder that may or may not be 

accompanied by a sleep disorder. For most studies, a comparison was made between the effects 

of light of different intensities on endogenous melatonin and the temperature rhythm, with the 

light of lower intensity serving as a control. The levels of light intensity varied widely across 

studies, such that a comparison of “bright” and “dim” light involved very different light levels 

across studies. Here, we use “brighter” to denote the light of higher intensity and “dimmer” to 

denote the light of lower intensity, for studies in which a comparison was made between the 
52

effects of light of different intensities, in order to highlight the fact that these light levels were 

relative and do not necessarily indicate “bright” or “dim” light in absolute terms. 

Normal Sleepers. The nature, magnitude, duration and timing of the light stimulus 

intervention varied across studies. Most studies involved direct application of brighter (BL) or 

dimmer (DL) stimuli,128 176 183 191 194 199 204-206 208 209 223-225 228 while others involved application of 

these signals within the context of dawn simulation179 or a video display terminal.182 Most 

studies compared the effect of BL to DL,128 176 179 182 183 191 194 199 204-206 208 223-225 228 while one 

study compared the effect of evening versus morning BL administration.199 The magnitude of 

the light stimuli ranged from 0.1 lux to 200 lux for DL administration and 45 lux to 13 000 lux 

for BL administration and the duration of light stimuli application ranged from 2 to 36 hours, 

over hours to weeks. The timing of light administration varied from early morning to late night. 

Most studies involved ocular light administration,176 179 182 183 191 194 199 204-206 208 209 223 225 228 while 

two studies involved extra-ocular light administration applied to the bend of the knee.128 224 

Some studies involved application of light stimuli under conditions of prolonged sleep 

deprivation.183 194 204 206 209 224 225 228 (Evidence Table C-8) 

Most studies involved application of light stimuli during the evening or night,128 176 182 183 191 

194 204-206 223-225 while some studies involved light exposure during the morning or night,199

morning,179 daytime208 or during a prolonged period of sleep deprivation.209 228 Of the studies 

involving application of ocular light stimuli during the evening or night, some studies found that 

BL delayed the onset of endogenous melatonin secretion, relative to DL204 223 and all studies 

found that BL suppressed endogenous melatonin levels, relative to DL. The delay in the phase 

of the melatonin rhythm was accompanied by a delay in the core body temperature rhythm in one 

study,204 while the change in phase of the melatonin rhythm was not accompanied by a change in 

the value or timing of the core body temperature minima in another study.223 Of the studies that 

found a suppression of endogenous melatonin levels with BL, many studies found an 

accompanying increase in core body temperature,176 182 194 205 206 while one study found no 

change in core body temperature.191 In a study by Strassman et al., the suppression of 

endogenous melatonin levels was accompanied by an increase in minimum rectal temperature 

and no change in the maximum rectal temperature,225 while in a study by Daurat et al., the 

suppression of endogenous melatonin levels was accompanied by a reduction and delay in the 

temperature minimum.206 In studies by Horne et al. and Bunnell et al., the suppression of 

endogenous melatonin was not accompanied by any change in oral temperature183 or tympanic 

temperature.176 In a study by Wright et al., whereby light exposure occurred during a 45-hour 

period of sleep deprivation, BL resulted in suppression of endogenous melatonin levels 

accompanied by increased body temperature, relative to DL.228 In a similar study by Daurat et 

al., whereby either BL or a light/dark cycle were imposed on subjects for 36 hours during sleep 

deprivation, there were no differences in endogenous melatonin levels between conditions. 

However, during one of the follow-up nights, the BL group showed increased rectal temperature 

compared to the light/dark group, although the phase of the temperature rhythm was not 

different.209 In a study by Lushington et al., BL administered behind the knee during the 

daytime did not have an effect on endogenous melatonin or the phase of nocturnal core body 

temperature, relative to DL administration.128 In a similar study, extra-ocular light exposure in 

the evening did not affect either the phase of the melatonin rhythm or core body temperature.224 

In a study by Gordijn et al., the application of light stimuli in the evening resulted in the 

suppression of endogenous melatonin levels during the early evening, without a change in the 

phase of the melatonin rhythm, compared to morning light exposure. This effect was 
53

accompanied by increased body temperature without a change in the phase of the temperature 

rhythm.199 In a study by Wakamura et al., ocular light stimuli were administered during the 

daytime and resulted in a suppression of endogenous melatonin levels, which was accompanied 

by a reduction in minimum core body temperature, no change in maximum core body 

temperature and an advance of the core body temperature rhythm.208 (Table 24) 

In a study by Danilenko et al., morning BL exposure suppressed endogenous melatonin 

levels, and the phase shift in the melatonin rhythm (DLMOn and DLMOff) was correlated with 

the phase shift in the temperature rhythm.{Danilenko, Wirz-Justice, et al. 2000 #22510} By 

contrast, in a study by Kubota et al., a correlation was not found between the change in phase of 

the melatonin rhythm and that of the temperature rhythm, following BL administration.204 (Table 

25) 

People with a Sleep Disorder. A number of studies in this category involved shift workers,178 

193 210 while another study involved people with delayed sleep phase syndrome.189 In the case of 

all studies involving night-shift workers, light stimuli were administered during the night-shift,178 

189 193 210 and in the case of the study involving people with delayed sleep phase syndrome light 

stimuli were administered in the early morning.189 The magnitude of the light stimuli ranged 

from 0.1 lux to 300 lux for dim/control light administration and 400 lux to 4300 lux for BL 

administration. The duration of light stimuli application ranged from 4 periods of 40-minute 

exposures to an entire night-shift, over hours to days. All studies involved ocular light 

administration. (Evidence Table C-8) 

Of the studies involving night-shift work,178 193 210 BL delayed the melatonin rhythm in two 

studies193 210 and had no effect on endogenous melatonin levels in another study,178 relative to 

DL. Moreover, while the delay in the melatonin rhythm was accompanied by a phase delay in 

core body temperature in one study,193 it was not accompanied by a change in the temperature 

rhythm in another study.210 The lack of effect of BL on endogenous melatonin levels, relative to 

DL, in the study by Costa et al., was paralleled by a lack of effect on the temperature rhythm.178

(Table 26) 

In a study by Ando et al., patients with delayed sleep phase syndrome received either 500 lux 

for three hours over 12 days prior to awakening or 0.1 lux of the same timing. BL had no 

significant effect on the phase of either the melatonin or temperature rhythm, compared to DL.189

People with a Disorder that may or may not be Accompanied by a Sleep Disorder. One study 

involved application of either morning or evening light to people with non-seasonal depression. 

Morning administration of light resulted in a phase advance of both the melatonin and 

temperature rhythms compared to evening light administration.212 Moreover, no correlation was 

found between the shifts in the phase of the melatonin and temperature rhythms.212

Intervention: manipulation of body temperature 

In a study by Fletcher et al., participants were exposed to heat of 32V, 138W from 0230h 

until termination of the sleep period. Heating induced an increase in core body temperature, 

without an effect on endogenous melatonin levels.227 In a similar study, participants were 

exposed to light of different color temperature and the light of higher color temperature was 

found to increase core body temperature and decrease endogenous melatonin levels.226

Summary: Endogenous melatonin and the temperature rhythm 

To summarize, our literature review indicated evidence of a link between endogenous 

melatonin and the temperature rhythm. Specifically, a reduction in endogenous melatonin levels 
54

was often accompanied by an increase in core body temperature, and a shift in the rhythm of 

endogenous melatonin was often accompanied by a similar shift in the rhythm of core body 

temperature. 

How do the benefits and harms of melatonin compare to those of other approved 

pharmacological treatments for sleep disorders? 

Only four studies compared the effects of melatonin to other pharmacological treatments for 

sleep disorders in terms of sleep variables; three of these involved normal sleepers123 222 229 and 

one of these involved people suffering from jet-lag.61 The overall quality score, according to the 

Down’s and Black Checklist, ranged from 11 to 20 on a 29-point scale and the quality of 

reporting ranged from four to eight on an 11-point scale. The external validity of studies ranged 

from zero to one on a three-point scale; two studies had a score of zero123 229 and two studies had 

a score of one.222 230 The internal validity of studies ranged from seven to 11 on a 13-point scale; 

two studies had a score of seven,123 229 one study had a score of eight222 and one study had a 

score of 11.61 For none of the studies was a power calculation reported. See Evidence Table C9 for a description of design characteristics and overall quality scores of studies relevant to this 

question of the review. 

Of the studies involving normal sleepers, two studies compared the effects of melatonin and 

triazolam,123 229 while another study compared the effect of melatonin and zopiclone,222 on sleep 

variables. In a study by Satomura et al., participants received either 1, 3 or 6 mg melatonin or 

0.125 mg triazolam at 13:30h; there were no differences in the effect of the two agents on total 

sleep time, sleep efficiency, and REM latency. Melatonin decreased sleep onset latency to a 

greater extent than triazolam, however, the effect of these compounds on sleep onset latency was 

not significantly different from placebo. The authors did not report on adverse events or adverse 

effects of the two agents, precluding a comparison of the harms of these agents.123 In a similar 

study by Ferini-Strambi et al., participants received either 100 mg melatonin or 0.125 mg 

triazolam at 22:30h; there were no differences in the effect of the two agents on total sleep time, 

sleep onset latency, wakefulness after sleep onset, sleep efficiency, number of awakenings, 

percent time spent in the various sleep stages, REM latency and REM periods. As in the study 

by Satomura et al., the authors did not report on adverse effects of the two agents, precluding a 

comparison of the harms of these agents.229 In a study by Holmes et al., normal sleepers 

received either 5mg melatonin or 7.5mg zopiclone at 14:00h and sleep onset latency was 

assessed hourly from 11:00h to 20:00h using a modified multiple sleep latency test. Zopiclone 

reduced sleep onset latency to a greater extent than melatonin at 15:00h and from 17:00h to 

19:00h. The authors did not report on adverse events or adverse effects of the two agents.222

In a study comparing melatonin and zolpidem, air travellers, crossing six to nine time-zones, 

received either 5mg melatonin or 10mg zolpidem on an eastbound return flight to Switzerland 

and once daily at bedtime on four consecutive days after the flight.61 The agents did not differ in 

their effects on total sleep time, sleep latency, number of awakenings, wakefulness after sleep 

onset and overall sleep quality during the flight. Moreover, the agents did not differ in overall 

sleep quality, sleep onset latency, number of awakenings and wakefulness after sleep onset 

across the four nights following the flight. When subjects were asked to rate the effectiveness of 

their study medication in alleviating jet-lag, the responses did not differ between agents. In 

general, out of the 35 people taking melatonin, only one person reported adverse events, while 

six people out of 34 people taking zolpidem reported adverse events. The individual taking 
55

melatonin who reported adverse events suffered from insomnia and palpitations. Of the 

individuals taking zolpidem who reported adverse events, four people reported nausea, two 

people reported vomiting, two people reported confusion, one person reported dizziness, two 

people reported headache, one person reported lack of concentration, one person reported 

amnesia, one person reported trembling, one person reported agitation, one person reported 

palpitation, one person reported difficulties in articulation and one person reported dry mouth.61

Overall Grade of Evidence Pertaining to Effectiveness and Safety of Melatonin 

The source of funding was either not reported or unclear for the majority of studies relevant 

to the questions relating to the effectiveness of melatonin in people with sleep disorders and the 

safety of melatonin. Of the studies for which the source of funding was described, most studies 

received public sources of funding. For studies in which there was a discrepancy in the number 

of participants enrolled in the study and the number of participants for whom data was analyzed, 

the planning or conduct of an intention-to-treat analysis was reported in only two studies relevant 

to the question relating to the effectiveness of melatonin in people with sleep disorders 78 144 and 

two studies relevant to the question relating to the safety of melatonin.78 135 The overall evidence 

surrounding the effectiveness of melatonin for treatment of sleep disorders and the safety of 

melatonin was graded using the framework of the Oxford Centre for Evidence-based Medicine 

(Table 27). The evidence surrounding the effectiveness of melatonin for the treatment of sleep 

disorders receives a grade of “A” and a level of evidence designation of “1b”. The evidence 

surrounding the safety of melatonin receives a grade of “B” and a level of evidence designation 

of “2b”. 
56

Flow Diagram 2: Study Retrieval and Selection for Melatonin and Sleep Disorders Review 

References yielded from database 

searches 

n=1884

Hand-searching Screening of Titles and Abstracts

 Application of Inclusion Criteria 

Studies included in the review 

n=139

Studies to assess for potential 

inclusion in the review: 

n= 935
57

Figure 1: Meta-Graph: Sleep Onset Latency in Normal Sleepers 

 
58

Figure 2: Funnel Plot: Sleep Onset Latency in Normal Sleepers _seES

_ES

-50 -25 0 25

.73

26.4

Abbreviations: _ES: effect size, _seES: standard error of effect size; note that the smaller studies are associated 

with a larger standard error. 
59

Figure 3: Meta-Graph: Sleep Efficiency in Normal Sleepers 
60

Figure 4: Funnel Plot: Sleep Efficiency in Normal Sleepers _seES

_ES

-5 0 5 10 15

.7

7.5

Abbreviations: _ES: effect size, _seES: standard error of effect size; note that the smaller studies are associated 

with a larger standard error. 
61

Figure 5: Meta-Graph: REM Latency in Normal Sleepers 
62

Figure 6: Funnel Plot: REM Latency in Normal Sleepers _seE

S

_ES

-15 0 15 30 45

2.5

16.5

Abbreviations: _ES: effect size, _seES: standard error of effect size; note that the smaller studies are associated 

with a larger standard error. 
63

Figure 7: Meta-Graph: Sleep Onset Latency in People with a Primary Sleep Disorder 
64

Figure 8: Funnel Plot: Sleep Onset Latency in People with a Primary Sleep Disorder _seES

_ES

-50 -25 0 25

.51

70

Abbreviations: _ES: effect size, _seES: standard error of effect size; note that the smaller studies are associated 

with a larger standard error. 
65

Figure 9: Meta-Graph: Sleep Efficiency in People with a Primary Sleep Disorder 
66

Figure 10: Funnel Plot: Sleep Efficiency in People with a Primary Sleep Disorder _seES

_ES

-2 0 2 4 6 8 10

.74

7.8

Abbreviations: _ES: effect size, _seES: standard error of effect size; note that the smaller studies are associated 

with a larger standard error. 
67

Figure 11: Meta-Graph: Sleep Onset Latency in People with a Secondary Sleep Disorder 
68

Figure 12: Meta-Graph: Sleep Efficiency in People with a Secondary Sleep Disorder 
69

Figure 13: Meta-Graph: Sleep Onset Latency in People Suffering from Sleep Restriction 
70

Figure 14: Funnel Plot: Sleep Onset Latency in People Suffering from Sleep Restriction _seES

_ES

-15 -10 -5 0 5

.64

6.7

Abbreviations: _ES: effect size, _seES: standard error of effect size; note that the smaller studies are associated 

with a larger standard error. 
71

Figure 15: Meta-Graph: Sleep Efficiency in People Suffering from Sleep Restriction 
72

Figure 16: Meta-Graph: Headaches 
73

Figure 17: Meta-Graph: Dizziness 
74

Figure 18: Meta-Graph: Nausea 
75

Figure 19: Meta-Graph: Drowsiness 
76
77

Table 5: Number of Studies relevant to Individual Questions of the Review and Type of Analysis Applied to 

Data Relevant to these Questions

Question Number of Studies Relevant 

to Question 

Type of Analysis Applied to Data 

Relevant to Question 

Formulations of melatonin 8: 

(RCTs) 

Qualitative and Quantitative 

Pharmacology of melatonin 26: 

(RCTs, CCTs and Case 

Series) 

Qualitative 

Endogenous melatonin and the 

sleep cycle 

44: 

(RCTs and CCTs) 

Qualitative 

Mechanism of action of melatonin 11: 

(RCTs and CCTs) 

Qualitative 

Effect of melatonin on normal 

sleepers 

21: 

(RCTs and CCTs) 

Quantitative 

Endogenous melatonin and 

circadian rhythms 

24: 

(RCTs and CCTs) 

Qualitative 

Effectiveness of melatonin among 

types of sleep disorders 

30: 

(RCTs) 

Quantitative 

Effectiveness of melatonin among 

types of populations 

29: 

(RCTs) 

Quantitative 

Effect of melatonin on people with 

sleep disorders 

30: 

(RCTs) 

Quantitative 

Appropriate dosage of melatonin 

for treatment of sleep disorders 

29: 

(RCTs) 

Quantitative 

Appropriate timing of melatonin 

administration for treatment of 

sleep disorders 

0 Quantitative 

Adverse effects of melatonin 34: 

(RCTs and CCTs) 

Quantitative 

Adverse effects of melatonin as a 

function of dose, timing, and 

patient factors 

33: 

(RCTs and CCTs) 

Quantitative 

Melatonin and other 

pharmacological treatments for 

sleep disorders 

4: 

(RCTs and CCTs) 

Qualitative 

Abbreviations: RCT: randomized controlled clinical trial; CCT: controlled clinical trial 
78

Table 6: Subgroup and Sensitivity Analysis: Sleep Onset Latency in Normal Sleepers 

Subgroup Categorization Number 

of 

studies 

Point 

Estimate 

(min) 

95 percent 

Confidence 

Interval 

(min) 

Heterogeneity Deeks’ 

ChiSquare 

p-value 

Male 14 -4.4 -6.3, -2.5 Moderate 

(I2

:46.5 percent) 

Gender 

Mixed 6 -3.2 -5.4, -1.0 Substantial 

(I2

: 51.1 percent) 

0.24 

Use of Yes 1 -0.5 -2.5, 1.5 NA 

Concurrent 

Medication 

No 10 -4.0 -5.3, -2.6 Minimal 

(I2

: 11.0 percent) 

NA 

< 1 mg 5 -7.6 -11.7, -3.5 Moderate 

(I2

: 37.9 percent) 

1-3 mg 10 -6.1 -9.1, -3.2 Substantial 

(I2

: 54.0 percent) 

4-5 mg 6 -2.6 -4.2, -1.1 Substantial 

(I2

: 57.5 percent) 

6-10 mg 7 -6.1 -8.9, -3.3 Moderate 

(I2

: 30.6 percent) 

Dosage of 

Melatonin 

Administration 

> 10 mg 2 -3.4 -7.6, 0.8 Negligible 

(I2

: 0 percent) 

NA 

< 1800h 11 -4.6 -6.0, -3.2 Moderate 

(I2

: 29.4 percent) 

Timing of 

Melatonin 

Administration > 1800h 10 -3.2 -5.5, -1.0 Moderate 

(I2

: 41.9 percent) 

0.002 

< 1 week 14 -4.2 -5.6, -2.8 Moderate 

(I2

: 43.7 percent) 

1-2 weeks 1 -6.3 -14.3, 1.7 NA 

Duration of 

Melatonin 

Administration 

3-4 weeks 5 -2.5 -6.9, 2.0 Moderate 

(I2

: 27.9 percent) 

0.03 

Polysomnography 14 -3.7 -5.0, -2.4 Moderate 

(I2

: 25.0 percent) 

Actigraphy 4 -2.1 -4.6, 0.4 Moderate 

(I2

: 34.5 percent) 

Method of 

Measurement 

of Sleep 

Outcomes 

Questionnaire 2 -8.8 -12.5, -5.2 Negligible 

(I2

: 0 percent) 

0.001 

Yes 8 -3.9 -6.5, -1.3 Substantial 

(I2

: 55.1 percent) 

Explicit 

Statement in 

Report that 

Subjects did 

not Suffer from 

a Sleep 

Disorder 

No 12 -4.1 -5.8, -2.4 Moderate 

(I2

: 43.5 percent) 

0.35 

Daytime 9 -4.6 -6.0, -3.2 Moderate 

(I2

: 30.9 percent) 

Time of Sleep 

Night time 13 -3.0 -4.9, -1.0 Moderate 

(I2

: 32.5 percent) 

NA 

Yes 3 -4.2 -5.7, -2.6 Negligible 

(I2

: 0 percent) 

Use of Multiple 

Sleep Onset 

Latency Test No 17 -4.0 -5.7, -2.2 Substantial 

(I2

: 51.1 percent) 

0.16 

Parallel 2 -4.5 -10.6, 1.6 Negligible 

(I2

: 0 percent) 

Study Design 

Crossover 18 -3.9 -5.4, -2.5 Substantial 

(I2

: 51.8 percent) 

0.67 
79

Table 6: Subgroup and Sensitivity Analysis: Sleep Onset Latency in Normal Sleepers (continued) 

Subgroup Categorization Number 

of 

studies 

Point 

Estimate 

(min) 

95 percent 

Confidence 

Interval 

(min) 

Heterogeneity Deeks’ 

ChiSquare 

p-value 

10-15 (low) 4 -3.8 -4.9, -2.7 Negligible 

(I2

: 0 percent) 

16-20 

(moderate) 

15 -5.0 -7.4, -2.7 Moderate 

(I2

: 44.3 percent) 

Quality Score 

21-25 (high) 1 -0.5 -2.5, 1.5 NA 

0.01 

Abbreviations: NA: not applicable, min: minutes 
80

Table 7: Subgroup and Sensitivity Analyses: Sleep Efficiency in Normal Sleepers 

Subgroup Categorization Number 

of 

studies 

Point 

Estimate 

(percent) 

95 percent 

Confidence 

Interval 

(percent) 

Heterogeneity Deeks’ 

ChiSquare 

p-value 

Male 11 2.8 0.6, 4.9 Substantial 

(I2

: 58.1 percent) 

Gender 

Mixed 2 1.8 -0.9, 4.5 Substantial 

(I2

: 52.2 percent) 

0.73 

Yes 6 2.2 0.1, 4.3 Moderate 

(I2

: 24.4 percent) 

Use of 

Concurrent 

Medication No 1 0.9 -0.5, 2.2 NA 

NA 

< 1 mg 4 3.4 0.6, 6.1 Negligible 

(I2

: 0 percent) 

1-3 mg 6 5.1 2.9, 7.3 Minimal 

(I2

: 12.7 percent) 

4-5 mg 2 0.7 -0.4, 1.9 Negligible 

(I2

: 0 percent) 

6-10 mg 5 4.8 -1.1, 10.7 Substantial 

(I2

: 76.6 percent) 

Dosage of 

Melatonin 

Administration 

> 10 mg 1 1.8 -1.5, 5.1 NA 

NA 

< 1800h 6 1.0 -0.6, 2.5 Moderate 

(I2

: 43.2 percent) 

Timing of 

Melatonin 

Administration > 1800h 7 4.4 1.5, 7.4 Moderate 

(I2: 43.4 percent) 

0.01 

< 1 week 9 3.3 0.9, 5.7 Substantial 

(I2

: 65.5 percent) 

1-2 weeks 0 NA NA NA 

Duration of 

Melatonin 

Administration 

3-4 weeks 4 1.1 -0.2, 2.3 Negligible 

(I2

: 0 percent) 

0.46 

Polysomnography 10 3.0 0.6, 5.3 Substantial 

(I2

: 62.9 percent) 

Actigraphy 3 1.3 0.0, 2.5 Negligible 

(I2

: 0 percent) 

Method of 

Measurement 

of Sleep 

Outcomes 

Questionnaire 0 NA NA NA 

0.78 

Yes 6 1.5 -0.2, 3.1 Moderate 

(I2

: 33.8 percent) 

Explicit 

Statement in 

Report that 

Subjects do 

not Suffer from 

a Sleep 

Disorder 

No 7 3.7 0.5, 6.9 Substantial 

(I2: 66.4 percent) 

0.41 

Daytime 5 8.0 1.0, 15.0 Substantial 

(I2

: 70.6 percent) 

Time of Sleep 

Night time 10 1.2 -0.0, 2.4 Moderate 

(I2

: 20.2 percent) 

NA 

Study Design Parallel 1 0.0 -4.1, 4.1 NA 

Crossover 12 2.6 0.9, 4.3 Substantial 

(I2

: 57.0 percent) 

0.50 

10-15 (low) 2 7.5 -5.4, 20.3 Substantial 

(I2

: 82.2 percent) 

16-20 (mod.) 10 2.4 0.4, 4.5 Substantial 

(I2

: 52.1 percent) 

Quality Score 

21-25 (high) 1 0.9 -0.5, 2.2 NA 

0.44 

Abbreviations: NA: not applicable
81

Table 8: Subgroup and Sensitivity Analyses: REM Latency in Normal Sleepers 

Subgroup Categorization Number 

of 

studies 

Point 

Estimate 

(min) 

95 percent 

Confidence 

Interval 

(min) 

Heterogeneity Deeks’ 

ChiSquare 

p-value 

Male 9 -1.2 -6.2, 3.9 Minimal 

(I2

: 17.8 percent) 

Gender 

Mixed 2 17.7 -8.0, 43.5 Substantial 

(I2: 80.6 percent) 

0.006 

Use of Yes 0 NA NA NA 

Concurrent 

Medication 

No 6 -4.0 -8.1, 0.1 Negligible 

(I2

: 0 percent) 

NA 

< 1 mg 4 -7.1 -18.9, 4.7 Moderate 

(I2

: 34.2 percent) 

1-3 mg 6 12.7 6.8, 18.6 Negligible 

(I2

: 0 percent) 

4-5 mg 3 15.2 -7.2, 37.5 Substantial 

(I2

: 92.0 percent) 

6-10 mg 3 3.8 -7.9, 15.5 Negligible 

(I2

: 0 percent) 

Dosage of 

Melatonin 

Administration 

> 10 mg 1 -13.6 -45.9, 18.7 NA 

NA 

< 1800h 4 4.3 -7.0, 15.5 Minimal 

(I2

: 13.9 percent) 

Timing of 

Melatonin 

Administration > 1800h 7 2.6 -5.6, 10.7 Substantial 

(I2

: 65.3 percent) 

0.21 

< 1 week 8 0.4 -5.3, 6.2 Moderate 

(I2

: 39.2 percent) 

1-2 weeks 0 NA NA NA 

Duration of 

Melatonin 

administration 

3-4 weeks 3 11.2 -13.5, 35.9 Substantial 

(I2: 69.2 percent) 

0.04 

Yes 6 2.5 -7.5, 12.5 Substantial 

(I2

: 68.7 percent) 

Explicit 

Statement in 

Report that 

Subjects do 

not Suffer from 

a Sleep 

Disorder 

No 5 4.8 -2.2, 11.9 Negligible 

(I2

: 0 percent) 

0.09 

Daytime 2 12.4 -0.0, 24.9 Negligible 

(I2

: 0 percent) 

Time of Sleep 

Night time 10 0.9 -5.9, 7.6 Substantial 

(I2

: 50.0 percent) 

NA 

Use of Multiple Yes 1 12.6 -0.3, 25.5 NA 

Sleep Onset 

Latency Test 

No 10 1.2 -5.6, 7.9 Substantial 

(I2

: 50.3 percent) 

0.04 

10-15 (low) 2 3.9 -20.3, 28.1 Substantial 

(I2

: 54.0 percent) 

16-20 (mod.) 9 1.8 -5.2, 8.8 Substantial 

(I2

: 54.5 percent) 

Quality Score 

21-25 (high) 0 NA NA NA 

0.11 

Abbreviations: REM: rapid eye movement, NA: not applicable, min: minutes 
82

Table 9: Subgroup and Sensitivity Analyses: Sleep Onset Latency in People with a Primary Sleep Disorder 

Subgroup Categorization Number 

of 

studies 

Point 

Estimate 

(min) 

95 percent 

Confidence 

Interval 

(min) 

Heterogeneity Deeks’ 

ChiSquare 

 p-value 

Children 1 -17.0 -33.5, -0.5 NA 

Adult 7 -11.2 -27.7, 5.4 Substantial 

(I2

: 84.0 percent) 

Age 

Elderly 4 -7.8 -17.4, 1.7 Substantial 

(I2

: 69.6 percent) 

0.002 

Ethnicity Caucasian 2 -17.5 -33.9, -1.2 Negligible 

(I2

: 0 percent) 

NA 

Use of Yes 1 -14.0 -28.7, 0.7 NA 

Concurrent 

Medication 

No 1 1.7 -30.6, 34.0 NA 

NA 

< 1 mg 2 -0.9 -5.4, 3.6 Negligible 

(I2

: 0 percent) 

1-3 mg 5 -6.0 -12.9, 0.8 Moderate 

(I2

: 28.0 percent) 

Dosage of 

Melatonin 

Administration 

4-5 mg 6 -13.3 -30.3, 3.7 Substantial 

(I2

: 90.0 percent) 

NA 

< 1 week 1 -9.7 -20.5, 1.1 NA 

1-2 weeks 5 -7.9 -17.5, 1.6 Negligible 

(I2

: 0 percent) 

Duration of 

Melatonin 

Administration 

3-4 weeks 6 -12.4 -21.9, -2.8 Substantial 

(I2: 90.3 percent) 

0.07 

Polysomnography 5 -14.2 -27.9, -0.5 Substantial 

(I2

: 89.5 percent) 

Actigraphy 3 -8.1 -21.3, 5.0 Substantial (I2: 

70.0 percent) 

Method of 

Measurement 

of Sleep 

Outcomes 

Questionnaire 4 -2.3 -23.5, 18.9 Negligible 

(I2

: 0 percent) 

0.001 

Insomnia 10 -4.3 -8.4, -0.1 Moderate 

(I2

: 44.9 percent) 

Primary 

Diagnosis 

Delayed SleepPhase 

Syndrome 

2 -38.8 -50.3, -27.3 Negligible 

(I2: 0 percent) 

< 0.00001 

Parallel 2 -17.1 -32.4, -1.8 Negligible 

(I2

: 0 percent) 

Study Design 

Crossover 10 -9.9 -17.2, -2.5 Substantial 

(I2

: 83.8 percent) 

0.03 

Moderate (2-3) 4 -5.4 -11.8, 0.9 Moderate 

(I2

: 37.2 percent) 

Quality Score 

High (4-5) 8 -13.1 -28.9, 2.8 Substantial 

(I2

: 86.7 percent) 

0.13 

Unclear 10 -9.6 -17.2, -2.0 Substantial 

(I2

: 82.7 percent) 

Allocation 

Concealment 

Adequate 2 -15.3 -26.3, -4.4 Negligible 

(I2

: 0 percent) 

0.007 

Abbreviations: NA: not applicable, min: minutes 
83

Table 10: Subgroup and Sensitivity Analyses: Sleep Efficiency in People with a Primary Sleep Disorder 

Subgroup Categorization Number 

of 

studies 

Point 

Estimate 

(percent) 

95 percent 

Confidence 

Interval 

(percent) 

Heterogeneity Deeks’ 

ChiSquare 

p-value 

Adult 6 -0.0 -1.6, 1.5 Minimal 

(I2

: 16.1 percent) 

Age 

Elderly 3 3.6 -0.8, 8.0 Substantial 

(I2: 73.0 percent) 

0.004 

Use of Yes 1 8.0 4.1, 11.9 NA 

Concurrent 

Medication 

No 1 -1.4 -4.3, 1.5 NA 

NA 

< 1 mg 2 3.4 -4.6, 11.3 Substantial 

(I2

: 78.8 percent) 

1-3 mg 5 2.4 -1.7, 6.5 Substantial 

(I2

: 77.9 percent) 

Dosage of 

Melatonin 

Administration 

4-5 mg 4 -0.0 -1.4, 1.3 Negligible 

(I2

: 0 percent) 

NA 

< 1 week 1 0.3 -4.4, 5.0 NA 

1-2 weeks 5 0.8 -2.1, 3.8 Moderate 

(I2

: 45.6 percent) 

Duration of 

Melatonin 

Administration 

3-4 weeks 3 2.6 -2.1, 7.2 Substantial 

(I2: 85.7 percent) 

0.91 

Polysomnography 5 0.2 -2.1, 2.6 Moderate 

(I2

: 31.1 percent) 

Actigraphy 3 3.1 -1.2, 7.5 Substantial 

(I2

: 85.9 percent) 

Method of 

Measurement 

of Sleep 

Outcomes 

Questionnaire 1 -3.0 -18.3, 12.3 NA 

0.48 

Insomnia 8 1.7 -0.8, 4.1 Substantial 

(I2

: 67.3 percent) 

Primary 

Diagnosis 

Sleep-Phase 

Syndrome 

1 0.2 -3.7, 4.1 NA 

0.75 

Moderate (2-3) 4 1.7 -1.2, 4.6 Moderate 

(I2

: 34.0 percent) 

Quality Score 

High (4-5) 5 1.3 -1.9, 4.5 Substantial 

(I2: 75.3 percent) 

0.39 

Unclear 8 0.3 -0.9, 1.5 Minimal 

(I2

: 6.3 percent) 

Allocation 

Concealment 

Adequate 1 8.0 4.1, 11.9 NA 

0.0002 

Abbreviations: NA: not applicable 
84

Table 11: Subgroup and Sensitivity Analyses: Sleep Onset Latency in People with a Secondary Sleep 

Disorder 

Subgroup Categorization Number 

of 

studies 

Point 

Estimate 

(min) 

95 percent 

Confidence 

Interval (min) 

Heterogeneity Deeks’ 

ChiSquare 

 p-value 

Children 3 -18.1 -29.4, -6.8 Negligible 

(I2

: 0 percent) 

Age 

Adult 3 -6.6 -24.6, 11.4 Substantial 

(I2

: 79.2 percent) 

0.0001 

Gender Female 1 -12.9 -27.6, 1.8 NA NA 

1-3 mg 2 -4.6 -29.8, 20.6 Substantial 

(I2

: 78.1 percent) 

4-5 mg 1 -23.4 -45.2, -1.6 NA 

Dosage of 

Melatonin 

Administration 

6-10 mg 1 -13.5 -32.5, 5.5 NA 

NA 

1-2 weeks 2 -25.7 -43.3, -8.0 Negligible 

(I2

: 0 percent) 

3-4 weeks 2 -4.6 -29.8, 20.6 Substantial 

(I2

: 78.1 percent) 

Duration of 

Melatonin 

Administration 

 > 4 weeks 2 -13.1 -24.8, -1.5 Negligible 

(I2

: 0 percent) 

< 0.00001 

Polysomnography 1 5.8 2.5, 9.1 NA 

Actigraphy 3 -14.5 -25.0, -4.1 Negligible 

(I2

: 0 percent) 

Method of 

Measurement of 

Sleep Outcomes 

Questionnaire 2 -25.7 -43.3, -8.0 Negligible 

(I2

: 0 percent) 

< 0.00001 

Co-Morbidity Schizophrenia 2 -4.6 -29.8, 20.6 Substantial 

(I2

: 78.1 percent) 

NA 

Study Design Parallel 1 -13.5 -32.5, 5.5 NA 

Crossover 5 -13.5 -29.7, 2.8 Substantial 

(I2

: 81.0 percent) 

0.08 

Unclear 5 -17.4 -26.4, -8.4 Negligible 

(I2

: 0 percent) 

Allocation 

Concealment 

Adequate 1 5.8 2.5, 9.1 NA 

< 0.00001

Abbreviations: NA: not applicable, min: minutes 
85

Table 12: Sensitivity and Subgroup Analyses: Sleep Efficiency in People with a Secondary Sleep Disorder

Subgroup Categorization Number 

of studies 

Point 

Estimate 

(percent) 

95 percent 

Confidence 

Interval 

(percent) 

Heterogeneity Deeks’ 

ChiSquare 

p-value 

Children 1 3.4 -3.9, 10.7 NA 

Adult 3 2.6 -1.3, 6.4 Substantial 

(I2

: 52.9 percent) 

Age 

Elderly 2 2.0 0.2, 3.8 Negligible 

(I2

: 0 percent) 

0.89 

Use Concurrent 

Medication 

Yes 3 2.3 -1.4, 6.0 Moderate 

(I2

: 48.9 percent) 

NA 

1-3 mg 3 1.9 -0.5, 4.3 Moderate 

(I2

: 47.4 percent) 

Dosage of 

Melatonin 

Administration 6-10 mg 3 2.2 0.1, 4.3 Negligible 

(I2

: 0 percent) 

NA 

1-2 weeks 1 2.0 -4.1, 8.1 NA 

3-4 weeks 4 2.5 -0.5, 5.4 Moderate 

(I2

: 32.6 percent) 

Duration of 

Melatonin 

Administration 

> 4 weeks 1 2.0 0.1, 3.9 NA 

0.99 

Polysomography Method of 1 0.0 -2.7, 2.7 NA 

Measurement of 

Sleep Outcomes Actigraphy 5 2.6 1.0, 4.2 Negligible 

(I2

: 0 percent) 

0.28 

Co-Morbidity Schizophrenia 2 2.3 -2.9, 7.4 Substantial 

(I2

: 72.5 percent) 

NA 

Parallel 2 2.2 0.3, 4.0 Negligible 

(I2

: 0 percent) 

Study Design 

Crossover 4 2.0 -0.7, 4.7 Moderate 

(I2: 23.8 percent) 

0.93 

Unclear 4 2.6 1.0, 4.3 Negligible 

(I2

: 0 percent) 

Allocation 

Concealment 

Adequate 2 0.3 -2.2, 2.8 Negligible 

(I2

: 0 percent) 

0.33 

Abbreviations: NA: not applicable 
86

Table 13: Subgroup and Sensitivity Analyses: Sleep Onset Latency in People Suffering from Sleep 

Restriction

 

Subgroup Categorization Number 

of studies 

Point 

Estimate 

(min) 

95 percent 

Confidence 

Interval 

(min) 

Heterogeneity Deeks’ 

ChiSquare 

p-value 

Use of 

Concurrent 

Medication 

No 2 -3.4 -10.4, 3.7 Substantial 

(I2

: 56.7 percent) 

NA 

< 1 mg 1 -11.8 -23.6, -0.0 NA 

1-3 mg 2 -4.5 -17.3, 8.3 Substantial 

(I2

: 75.3 percent) 

4-5 mg 5 -1.0 -4.0, 2.1 Minimal 

(I2

: 18.2 percent) 

Dosage of 

Melatonin 

Administration 

10-20 mg 1 -2.0 -7.5, 3.5 NA 

NA 

Polysomnography 2 -6.6 -14.7, 1,5 Negligible 

(I2

: 0 percent) 

Actigraphy 1 0.8 -2.7, 4.3 NA 

Method of 

Measurement 

of Sleep 

Outcomes Questionnaire 6 -1.1 -2.2, 0.1 Negligible 

(I2

: 0 percent) 

0.24 

Jet Lag 3 -4.7 -12.6, 3.1 Minimal 

(I2

: 16.9 percent) 

Shift Work 5 -0.8 -1.9, 0.3 Negligible 

(I2

: 0 percent) 

Type of Sleep 

Restriction 

Deprivation 1 -9.0 -19.2, 1.2 NA 

0.17 

Parallel 4 -6.1 -11.9, -0.2 Negligible 

(I2

: 0 percent) 

Study Design 

Crossover 5 -0.8 -1.9, 0.3 Negligible 

(I2: 0 percent) 

0.08 

High (4-5) 5 -1.2 -4.6, 2.3 Minimal 

(I2

: 18.6 percent) 

Quality Score 

Moderate (2-3) 4 -0.9 -2.7, 0.8 Minimal 

(I2: 12.2 percent) 

1.00 

Unclear 6 -1.4 -3.8, 1.1 Moderate 

(I2

: 26.2 percent) 

Allocation 

Concealment 

Adequate 3 -0.5 -3.7, 2.7 Negligible 

(I2

: 0 percent) 

0.73 

Abbreviations: NA: not applicable, min: minutes 

 
87

Table 14: Subgroup and Sensitivity Analyses: Sleep Efficiency in People Suffering from Sleep Restriction

Subgroup Categorization Number 

of 

studies 

Point 

Estimate 

(percent) 

95 percent 

Confidence 

Interval 

(percent) 

Heterogeneity Deeks’ 

ChiSquare 

p-value 

Polysomnography 2 1.8 0.1, 3.5 Negligible 

(I2

: 0 percent) 

Actigraphy 1 0.2 -3.9, 4.3 NA 

Method of 

Measurement 

of Sleep 

Outcomes Questionnaire 2 -0.2 -1.1, 0.6 Negligible 

(I2

: 0 percent) 

0.11 

Jet Lag 1 2.9 -1.4, 7.2 NA 

Shift Work 3 -0.2 -1.1, 0.6 Negligible 

(I2

: 0 percent) 

Type of Sleep 

Restriction 

Deprivation 1 1.6 -0.2, 3.4 NA 

0.10 

Parallel 2 1.8 0.1, 3.5 Negligible 

(I2

: 0 percent) 

Study Design 

Crossover 3 -0.2 -1.1, 0.6 Negligible 

(I2

: 0 percent) 

0.11 

High (4-5) 2 -0.2 -1.1, 0.6 Negligible 

(I2

: 0 percent) 

Quality Score 

Moderate (2-3) 3 1.6 0.0, 3.1 Negligible 

(I2: 0 percent) 

0.14 

Unclear 2 -0.2 -1.1, 0.6 Negligible 

(I2

: 0 percent) 

Allocation 

Concealment 

Adequate 3 1.6 0.0, 3.1 Negligible 

(I2

: 0 percent) 

0.14 

Abbreviations: NA: not applicable 

 
88

Table 15: Subgroup Analysis: Headaches 

Subgroup Categorization Number 

of 

studies 

Risk 

Difference 

95 percent 

Confidence 

Interval 

Heterogeneity Deeks’ 

ChiSquare 

p-value 

Male 3 0.04 -0.13, 0.19 Negligible 

(I2

: 0 percent) 

Gender 

Female 2 0.00 -0.07, 0.07 Negligible 

(I2: 0 percent) 

NA 

Children 6 -0.02 -0.08, 0.03 Negligible 

(I2

: 0 percent) 

Adult 22 0.00 -0.02, 0.03 Negligible 

(I2

: 0 percent) 

Age 

Elderly 5 0.00 -0.06, 0.06 Negligible 

(I2

: 0 percent) 

0.74 

1-3 mg 8 0.00 -0.05, 0.04 Negligible 

(I2

: 0 percent) 

4-5 mg 14 0.00 -0.03, 0.04 Minimal 

(I2

: 18.9 percent) 

6-10 mg 9 0.00 -0.04, 0.04 Negligible 

(I2

: 0 percent) 

Dosage 

> 10 mg 2 0.00 -0.20, 0.20 Negligible 

(I2: 0 percent) 

NA 

Fast Release 3 -0.06 -0.14, 0.02 Negligible 

(I2

: 0 percent) 

Formulation 

Slow Release 4 0.00 -0.05, 0.05 Negligible 

(I2

: 0 percent) 

NA 

Abbreviations: NA: not applicable 
89

Table 16: Subgroup Analysis: Dizziness 

Subgroup Categorization Number 

of 

studies 

Risk Difference 95 percent 

Confidence 

Interval 

Heterogeneity Deeks’ 

ChiSquare 

p-value 

Male 2 0.00 -0.19, 0.19 Negligible 

(I2

: 0 percent) 

Gender 

Female 2 0.00 -0.07, 0.07 Negligible 

(I2: 0 percent) 

NA 

Children 6 0.02 -0.04, 0.08 Negligible 

(I2

: 0 percent) 

Adult 21 0.00 -0.02, 0.02 Negligible 

(I2

: 0 percent) 

Age 

Elderly 5 0.00 -0.06, 0.06 Negligible 

(I2

: 0 percent) 

1.00 

1-3 mg 8 0.00 -0.04, 0.05 Negligible 

(I2

: 0 percent) 

4-5 mg 14 0.00 -0.02, 0.03 Negligible 

(I2

: 0 percent) 

6-10 mg 7 0.00 -0.04, 0.04 Negligible 

(I2

: 0 percent) 

Dosage 

> 10 mg 2 0.00 -0.20, 0.20 Negligible 

(I2: 0 percent) 

NA 

Fast Release 3 0.05 -0.04, 0.15 Minimal (I2: 

14.6 percent) 

Formulation 

Slow Release 4 0.00 -0.05, 0.05 Negligible 

(I2

: 0 percent) 

NA 

Abbreviations: NA: not applicable 
90

Table 17: Subgroup Analysis: Nausea 

 

Subgroup Categorization Number 

of 

studies 

Risk 

Difference 

95 percent 

Confidence 

Interval 

Heterogeneity Deeks’ 

ChiSquare 

p-value 

Male 2 0.00 -0.19, 0.19 Negligible 

(I2

: 0 percent) 

Gender 

Female 2 0.00 -0.07, 0.07 Negligible 

(I2: 0 percent) 

NA 

Children 6 -0.02 -0.08, 0.03 Negligible 

(I2

: 0 percent) 

Adult 21 0.00 -0.02, 0.02 Negligible 

(I2

: 0 percent) 

Age 

Elderly 5 0.00 -0.06, 0.06 Negligible 

(I2

: 0 percent) 

0.81 

1-3 mg 8 0.00 -0.03, 0.03 Negligible 

(I2

: 0 percent) 

4-5 mg 14 -0.01 -0.04, 0.02 Negligible 

(I2

: 0 percent) 

6-10 mg 9 0.00 -0.04, 0.03 Negligible 

(I2

: 0 percent) 

Dosage 

> 10 mg 2 0.00 -0.20, 0.20 Negligible 

(I2: 0 percent) 

NA 

Fast Release 3 -0.02 -0.08, 0.03 Negligible 

(I2

: 0 percent) 

Formulation 

Slow Release 4 0.00 -0.04, 0.05 Negligible 

(I2

: 0 percent) 

NA 

Abbreviations: NA: not applicable 
91

Table 18: Subgroup Analysis: Drowsiness 

 

Subgroup Categorization Number 

of 

studies 

Risk 

Difference 

95 percent 

Confidence 

Interval 

Heterogeneity Deeks’ 

ChiSquare 

p-value 

Male 3 0.19 -0.21, 0.60 Substantial 

(I2

: 76.6 percent) 

Gender 

Female 2 0.00 -0.07, 0.07 Negligible 

(I2: 0 percent) 

NA 

Children 5 0.00 -0.06, 0.06 Negligible 

(I2

: 0 percent) 

Adult 24 0.00 -0.02, 0.02 Negligible 

(I2

: 0 percent) 

Age 

Elderly 6 0.01 -0.04, 0.05 Negligible 

(I2

: 0 percent) 

1.00 

1-3 mg 8 -0.01 -0.06, 0.04 Negligible 

(I2

: 0 percent) 

4-5 mg 13 0.00 -0.03, 0.03 Negligible 

(I2

: 0 percent) 

6-10 mg 9 0.01 -0.04, 0.05 Negligible 

(I2

: 0 percent) 

Dosage 

> 10 mg 2 0.32 -0.37, 1.01 Substantial 

(I2: 86.4 percent) 

NA 

Fast Release 2 -0.07 -0.19, 0.06 Negligible 

(I2

: 0 percent) 

Formulation 

Slow Release 4 -0.01 -0.06, 0.04 Negligible 

(I2

: 0 percent) 

NA 

Abbreviations: NA: not applicable 
92

Table 19: Effect of Manipulation of Light/Dark Exposure on Endogenous Melatonin and the Sleep Cycle in 

Normal Sleepers: Manipulation during Evening or Night 

Study Endogenous Melatonin Sleep Cycle Assessment of 

Correlation 

Bunnell, 1992 ↓ endogenous MLT levels ↑ REM latency and NREM 

period length, ≠ REM cycle 

and period length 

Not conducted 

Burgress, 2001 ↓ endogenous MLT levels ↑ SOL Not conducted 

Cajochen, 2000 ↓ endogenous MLT levels ↑ alertness and performance Positive correlation 

was found between 

changes 

Daurat, 1996 ↓ endogenous MLT levels ↑ alertness and performance Not conducted 

Dollins, 1993 ↓ endogenous MLT levels ≠ alertness and performance Not conducted 

Higuchi, 2003 ↓ endogenous MLT levels ≠ alertness and performance Not conducted 

Horne, 1991 ↓ endogenous MLT levels ↑ alertness and performance Not conducted 

Kubota, 2002 Delayed MLT rhythm Delayed sleep onset No correlation was 

found between 

changes 

Lavoie, 2003 ↓ endogenous MLT levels ≠ SOL, ≠ alertness and 

performance 

None of the vigilance 

variables were found to 

correlate to 

endogenous MLT 

levels. 

Abbreviations: MLT: melatonin, SOL: sleep onset latency, REM: rapid eye movement, NREM: non-REM, ↑: 

increased ↓: decreased, ≠: no change in 
93

Table 20: Effect of Manipulation of Light/Dark Exposure on Endogenous Melatonin and the Sleep Cycle in 

Normal Sleepers: Manipulation During Morning or Daytime 

Study Endogenous Melatonin Sleep Cycle Assessment of 

Correlation 

Danilenko, 2000 Advance of MLT rhythm, ↓

endogenous MLT levels 

↑ alertness, Phase of MLT rhythm 

was correlated to 

sleepiness and midpoint of sleep 

Dijk, 1989 Advance of MLT rhythm ↓ sleep duration and REM 

sleep, ≠ REM latency, 

percent time spent in 

various sleep stages and 

sleep quality 

No correlation between 

phase of MLT rhythm, 

and sleep duration 

Wakamura, 2000 ↓ endogenous MLT levels ↑ alertness Not conducted 

Abbreviations: MLT: melatonin, REM: rapid eye movement, ↑: increased, ↓: decreased, ≠: no change in 
94

Table 21: Effect of Manipulation of Light/Dark Exposure on Endogenous Melatonin and the Sleep Cycle in 

Normal Sleepers: Manipulation Involves Unique Conditions 

Study Endogenous Melatonin Sleep Cycle Assessment of 

Correlation 

Daurat, 1997 ≠ endogenous MLT levels ≠ TST, REM latency, WASO 

and REM sleep 

Not conducted 

Gordijn, 1999 ↓ endogenous MLT, ≠

phase of MLT rhythm 

↑ movement time, ↓

duration of first REM 

episode, delayed sleep 

termination, ≠ sleep latency 

and REM latency 

Not conducted 

Lushington, 2002 ≠ endogenous MLT levels or 

phase of MLT rhythm 

↑ wakefulness Not conducted 

Wehr, 1991 ↓ duration of nocturnal 

endogenous MLT 

↓ sleep period Not conducted 

Abbreviations: MLT: melatonin, TST: total sleep time, REM: rapid eye movement, WASO: wakefulness after sleep 

onset, ↑: increased ↓: decreased, ≠: no change in 
95

Table 22: Effect of Manipulation of Light/Dark Exposure on Endogenous Melatonin and the Sleep Cycle in 

People with Sleep Disorders 

Study Endogenous Melatonin Sleep Cycle Assessment of 

Correlation 

Ando, 1999 ≠ phase of MLT rhythm ≠ total sleep period, total 

sleep time and sleep quality 

Not conducted 

Bougrine, 1995 ≠ phase of MLT rhythm ≠ sleep quality, performance 

and subjective feelings of 

tiredness 

Not conducted 

Boulos, 2002 Delay in MLT rhythm ≠ sleep efficiency, sleep 

quality, daytime sleepiness, 

jet-lag severity or mood 

No correlation was 

found between phase 

of MLT rhythm and 

performance 

Budnick, 1995 ↓ endogenous MLT ≠ total sleep time, ↑

alertness and performance 

Not conducted 

Cole, 2002 ≠ phase of MLT rhythm ≠ mood, total sleep time, 

sleep quality, morning 

sleepiness 

Not conducted 

Costa, 1997 ≠ endogenous MLT levels ≠ alertness and performance Not conducted 

Horowitz, 2001 Delay in MLT rhythm ≠ sleep start time and wake 

time, ↑ alertness and 

performance 

Not conducted 

Kelly, 1997 Delay in MLT rhythm ↑ sleep time and continuity, 

≠ sleep latency, ↑ alertness 

and performance 

Not conducted 

Ross, 1995 Not explicitly stated ↓ sleep latency, ≠ sleep 

duration, sleep quality, night 

awakenings and mood 

Not conducted 

Yoon, 2000 Delay in MLT rhythm ↑ alertness and performance Not conducted 

Abbreviations: MLT: melatonin, ↑: increased ↓: decreased, ≠: no change in 
96

Table 23: Effect of Manipulation of Light/Dark Exposure on Endogenous Melatonin and the Sleep Cycle in 

People with a Disorder that may or may not be Accompanied by a Sleep Disorder 

Study Endogenous Melatonin Sleep/Wake Cycle Assessment of 

Correlation 

Gordijn, 1998 Advance of MLT rhythm Earlier tendency for sleep 

termination 

No correlation was 

found between phase 

of MLT rhythm and 

wake-up time 

Koorengevel, 2001 ≠ phase of MLT rhythm ≠ mood, alertness, total 

sleep duration, time of 

awakening and sleep onset 

Not conducted 

Partonen, 1996 ≠ endogenous MLT levels ≠ sleepiness Not conducted 

Abbreviations: MLT: melatonin, ↑: increased, ↓: decreased, ≠: no change in 
97

Table 24: Effect of Manipulation of Light/Dark Exposure on Endogenous Melatonin and the Sleep Cycle in 

Normal Sleepers: Manipulation During Evening or Night 

Study Endogenous Melatonin Temperature Rhythm Assessment of 

Correlation 

Bunnell, 1992 ↓ endogenous MLT levels ↑ core body temperature, 

≠ tympanic temperature 

Not conducted 

Burgress, 2001 ↓ endogenous MLT levels ↑ core body temperature Not conducted 

Cagnacci, 1993 Delayed MLT rhythm, ↓

endogenous MLT levels 

≠ value or timing of core 

body temperature minima 

Not conducted 

Cajochen, 2000 ↓ endogenous MLT levels ≠ core body temperature Not conducted 

Daurat, 1996 ↓ endogenous MLT levels ↑ core body temperature, 

reduced and delayed 

temperature minima 

Not conducted 

Eastman, 2000 ≠ MLT rhythm ≠ core body temperature Not conducted 

Higuchi, 2003 ↓ endogenous MLT levels ↑ core body temperature Not conducted 

Horne, 1991 ↓ endogenous MLT levels ≠ oral temperature Not conducted 

Kubota, 2002 Delayed MLT rhythm, ↓

endogenous MLT levels 

Delay in core body 

temperature minima 

No correlation was 

found between the 

change in phase of 

MLT rhythm and 

temperature rhythm 

Lavoie, 2003 ↓ endogenous MLT levels ↑ core body temperature Not conducted 

Lushington, 2002 ≠ endogenous MLT levels 

or rhythm 

≠ nocturnal core body 

temperature rhythm 

Not conducted 

Strassman, 1991 ↓ endogenous MLT levels ↑ minimal rectal 

temperature, ≠ maximal 

rectal temperature 

Not conducted 

Abbreviations: MLT: melatonin, ↑: increased ↓: decreased, ≠: no change in 
98

Table 25: Effect of Manipulation of Light/Dark Exposure on Endogenous Melatonin and the Sleep Cycle in 

Normal Sleepers: Manipulation Involved Unique Conditions 

Study Endogenous Melatonin Temperature rhythm Assessment of 

Correlation 

Danilenko, 2000 ↓ endogenous MLT 

levels, shift in MLT 

rhythm 

Shift in temperature 

rhythm 

Shifts in MLT rhythm 

and temperature 

rhythm were 

correlated 

Daurat, 1997 ≠ endogenous MLT ↑ rectal temperature, ≠

phase of temperature 

rhythm 

Not conducted 

Eastman, 2000 ≠ phase of MLT rhythm ≠ core body temperature Not conducted 

Gordijn, 1999 ↓ endogenous MLT 

levels, ≠ phase of MLT 

rhythm 

↑ body temperature, ≠

phase of temperature 

rhythm 

Not conducted 

Lushington, 2002 ≠ endogenous MLT levels ≠ phase of core body 

temperature rhythm 

Not conducted 

Wakamura, 2000 ↓ endogenous MLT levels ↓ minimum core body 

temperature, ≠ maximum 

core body temperature, 

advance of the core body 

temperature rhythm 

Not conducted 

Wright, 1997 ↓ endogenous MLT levels ↑ body temperature Not conducted 

Abbreviations: MLT: melatonin, ↑: increased, ↓: decreased, ≠: no change in 
99

Table 26: Effect of Manipulation of Light/Dark Exposure on Endogenous Melatonin and the Sleep Cycle in 

People with a Sleep Disorder 

Study Endogenous Melatonin Temperature rhythm Assessment of 

Correlation 

Ando, 1999 ≠ MLT rhythm ≠ temperature rhythm Not conducted 

Costa, 1997 ≠ endogenous MLT levels ≠ temperature rhythm Not conducted 

Horowitz, 2001 Delay MLT rhythm Delay of core body 

temperature rhythm 

Not conducted 

Kelly, 1997 Delay MLT rhythm ≠ temperature rhythm Not conducted 

Abbreviations: MLT: melatonin, ↑: increased, ↓: decreased, ≠: no change in 
100

Table 27: Oxford Centre for Evidence-based Medicine Levels of Evidence 

Grade of Recommendation Level of Evidence Therapeutic Use 

1a SR (with homogeneity) of RCTs 

1b Individual RCT (with Narrow 

Confidence Interval) A 

1c All or none 

2a SR (with homogeneity) of cohort 

studies 

2b 

Individual cohort study (including 

low quality RCT; e.g., ,80 percent 

follow-up) 

2c “Outcomes Research” 

3a SR (with homogeneity) of casecontrol studies 

B 

3b Individual case control study 

C 4 Case series (and poor quality cohort 

and case-control studies) 

D 5 

Expert opinion without explicit 

critical appraisal, or based on 

physiology, bench research or “first 

principles” 

Abbreviations: SR: systematic review, RCT: randomized controlled trial

Adapted from http://minerva.minervation.com/cebm/documents/levels_cebm_23nov99.rtf 
101

Chapter 4. Discussion 

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 confidence interval (CI): -5.3 min., -2.6 min.). 

The magnitude of this effect appears to be clinically insignificant. The moderate 

heterogeneity across studies may be partially explained by differences in the timing and 

duration of melatonin administration, the method of measurement of sleep outcomes and 

the overall quality of studies. 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. 

The substantial heterogeneity across studies analyzed for this outcome may be partially 

explained by differences in the timing of melatonin administration. 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 1mg 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. The substantial heterogeneity in results across studies may be 

partially explained by differences in the gender of the population and the duration of 

melatonin administration. 

• 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 17 years) (WMD: -17.0 min., 95 percent CI: -33.5 min, 

-0.5 min.) than in adults (18-65 years) (WMD: -11.2; 95 percent CI: -27.7 min, 5.4 min.) or 
102

elderly patients (greater than 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. The 

substantial heterogeneity across studies may be partially explained by differences in the age 

of the population, their primary diagnosis, study design, the method of measurement of 

sleep outcomes and whether allocation of participants to interventions was concealed. 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. The substantial heterogeneity in the results across studies may be 

partially explained by the age of the population and whether allocation of participants to 

interventions was concealed. 

• 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. The substantial heterogeneity 

across studies may be partially explained by the age of the population, the duration of 

melatonin administration, the method of measurement of sleep outcomes and whether 

allocation of participants to interventions was concealed. 

• 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. 

See Table 28 for a summary of the evidence surrounding the effect of melatonin on sleep in 

various populations. 
103

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 Mechanisms 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 are different 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 14.75pg/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 blood-brain-barrier 

• The basic mechanism by which melatonin produces sleepiness in humans is unclear, 

although three main hypothesis have been proposed; the mechanism may involve a phaseshift 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 
104

two variables was often not conducted, and in cases where it was conducted, the results 

were mixed. 

Discussion of Key Observations of this Review 

Effectiveness of Melatonin in Normal Sleepers 

One cannot draw strong conclusions regarding the effect of melatonin on the sleep cycle of 

normal sleepers due to the heterogeneity in results of studies relevant to this topic, evidence of 

possible publication bias in this selection of studies, and the relatively low quality of these 

studies. The results of this review suggest that the heterogeneity across studies may partially be 

due to details of the intervention, such as the timing and duration of melatonin administration, as 

well as the method of measurement of sleep outcomes, the gender of the population and the 

overall quality of studies. Indeed, the timing of melatonin administration has been shown to 

predict its effect on circadian rhythms, such that melatonin delays circadian rhythms following 

morning administration and advances circadian rhythms following afternoon or early evening 

administration.231 In addition to timing of melatonin administration, the results of studies may be 

affected by the particular method used to assess sleep outcomes. The studies employed either 

polysomnography, actigraphy or questionnaires/sleep diaries. Indeed, many studies have found a 

discrepancy in the results obtained by actigraphy and/or sleep diaries compared to 

polysomnography. There is evidence that actigraphy overestimates sleep parameters such as 

sleep onset latency and sleep efficiency,232 233 however, there is other evidence that actigraphy 

and sleep diaries underestimate sleep efficiency and total sleep time.234 Kushida et al. (2001)235

have not found a difference in sleep efficiency and total sleep time by the three methods. A 

“first night effect” has been described with the use of polysomnography to measure sleep 

outcomes in children236 and adults,237 whereby laboratory conditions tend to result in more 

awakenings and less REM sleep during the first night of recording compared to subsequent 

nights. Such an effect would tend to underestimate the effect of melatonin on sleep, but could be 

bypassed by longer study duration. 

Our literature review indicated that melatonin decreased sleep onset latency and increased 

sleep efficiency in normal sleepers and that the effect on sleep efficiency, but not on sleep onset 

latency, was more pronounced in normal sleepers that were given melatonin and tested during 

the day versus those that were given melatonin and tested during the night. These results may 

reflect differences in the conditions of studies involving daytime sleep versus night time sleep. 

For example, many of the studies involving daytime sleep used the Multiple Sleep Onset Latency 

Test (MSLT) to assess sleep onset latency, and sleep opportunities were relatively short 

compared to those for night-time sleepers. Thus, the increased sleep efficiency in normal 

sleepers tested during the daytime compared to the night-time could simply reflect shorter sleep 

opportunities. However, the possibility exists that melatonin is more effective in maintaining 

daytime sleep compared to night-time sleep in normal sleepers. The finding that melatonin 

significantly increased REM latency only when administered at doses between 1 and 3mg, and 

not at lower or higher doses, may indicate that melatonin modulates sleep architecture in normal 

sleepers in a dose-dependent manner. However, given that melatonin did not have any overall 

effect on sleep efficiency in this population, further research into the pharmacodynamics of 

melatonin in terms of its effect on REM latency in normal sleepers is required to confirm the 

possible dose-dependency of this effect. 
105

Effectiveness of Melatonin in the 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 re-setting of the 

endogenous clock. That is, the reduction in sleep onset latency would decrease exposure to 

evening light, which normally delays the pacemaker,12 such that individuals would only receive 

phase-advancing morning light,12 advancing the rhythm of endogenous melatonin and alleviating 

the sleep disorder. The finding that the effect of melatonin on sleep onset latency in people with 

primary sleep disorders was greater for children than adults or the elderly was based on only one 

study involving children,59 and the effect of melatonin on sleep efficiency in people with 

secondary sleep disorders did not vary with age. Thus, one cannot draw a firm conclusion on the 

effect of age on the effectiveness of melatonin in people with primary sleep disorders, and 

further research in this area is required. Our literature survey indicates that there is no evidence 

to suggest that the effect of melatonin on sleep onset latency in people with primary sleep 

disorders and on sleep efficiency in people with secondary sleep disorders is dependent on dose 

or duration of melatonin administration. Similarly, we found no evidence to suggest that the 

effect of melatonin on sleep onset latency and sleep efficiency in normal sleepers is dose 

dependent. These findings appear to contrast with the finding that the effect of melatonin on 

REM latency in normal sleepers is dose-dependent. It appears that research into the 

pharmacodynamics of melatonin with respect to the dose-dependence of the effect of melatonin 

on various sleep parameters is required. 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. 

It is noteworthy that the observations of this review regarding the effects of melatonin on 

people with primary sleep disorders are based on studies with relatively short trial durations of 

four weeks or less. Therefore, the effects of melatonin on sleep onset latency and sleep 

efficiency reported here may reflect only the short-term effects of melatonin on this population. 

It is necessary that trials of longer duration be conducted in order to determine the long-term 

effects of melatonin on this population. 

Interestingly, the authors did not come across studies involving the use of melatonin in 

people with sleep apnoea, a type of sleep disorder. The search strategies employed in this review 

would have captured such studies, which suggests that research in this area is lacking. 

Nonetheless, it is important to consider that the effects of melatonin reported herein may not be 

applicable to people with sleep apnoea, and research into the area of melatonin and sleep apnoea 

is necessary in order to understand the effects of exogenous melatonin on this population. 

The authors noted the working definitions of sleep onset latency in the studies included in the 

review. For studies employing sleep diary, questionnaire or actigraphy in the measurement of 
106

SOL, and for which a definition of SOL was provided in the report, this outcome was defined in 

a similar manner across studies. By contrast, for studies employing polysomnography in the 

measurement of SOL, and for which a definition of SOL was provided in the report, this 

outcome was defined slightly differently across studies. In the current review, a subgroup 

analysis was conducted based on the method of measurement of sleep outcomes. This analysis 

allowed us to examine whether the differences in the working definitions of SOL among studies 

employing sleep diary/questionnaire, compared to studies employing polysomnography, for 

measurement of sleep outcomes, could potentially yield differences in the observed effect of 

melatonin on SOL. However, the subtle differences in the working definitions of SOL in studies 

employing polysomnography precluded us from performing a subgroup analysis based on 

working definition within this group of studies, since individual subgroups of this analysis would 

be based on only one study in most cases and would not provide meaningful results. Future 

research in the area of melatonin and sleep disorders requires that working definitions of primary 

outcomes be clearly defined such that appropriate comparisons across studies can be made. 

Effectiveness of Melatonin in People with Secondary Sleep Disorders 

The summary estimate of the effect of melatonin on sleep onset latency in people with 

secondary sleep disorders is markedly changed by the results of a study by Shamir et al.132 

When the results of this study are incorporated into the analysis, the results suggest that 

melatonin does not have an effect on sleep onset latency in people with secondary sleep 

disorders, whereas if the results of this study are omitted, they suggest that melatonin does have 

an effect. Moreover, although the summary estimate indicated that melatonin increased sleep 

efficiency in people with secondary sleep disorders, the study by Shamir et al. did not find such 

an increase. 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. It is also noteworthy that this study was of 

sufficient duration to bypass the “first night effect”, which would tend to underestimate the effect 

of melatonin on sleep efficiency. Thus, although the results of this study are markedly different 

from other studies of this category, its results appear to be valid. It is possible that this 

discrepancy is due to publication or reporting bias, but with only six studies in this category, this 

bias is impossible to verify. 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. 

Similar to the observations related to the effects of melatonin on people with primary sleep 

disorders, the observations of this review regarding the effects of melatonin on people with 

secondary sleep disorders are based on studies with relatively short trial durations of four weeks 

or less. Therefore, the effects of melatonin on sleep onset latency and sleep efficiency reported 

here may reflect only the short-term effects of melatonin on this population. It is necessary that 

trials of longer duration be conducted in order to determine the long-term effects of melatonin on 

this population. 

It is noteworthy that the increase in sleep efficiency with melatonin in people with secondary 

sleep disorders was accompanied by an increase in total sleep time, but no evidence of a change 

in wakefulness after sleep onset (WASO). This apparent inconsistency may be explained by the 

difference in the number of studies that reported on the various outcomes; while six studies 

reported on sleep efficiency and nine studies reported on total sleep time, only three studies 
107

reported on WASO. Thus, the outcomes for which there were more data indicated evidence of 

an effect of melatonin, while the outcome for which there was little data showed a lack of 

evidence of an effect of melatonin. The latter finding may simply indicate that the there was 

insufficient power to detect evidence of an effect of melatonin on WASO. 

Effectiveness of Melatonin in People Suffering from Sleep Restriction 

Disorders 

 

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.100 102 These reviews 

assessed the effectiveness of melatonin in alleviating jet lag by examining the effect of this 

hormone on global assessments of jet lag, which encompass assessments of both the daytime 

fatigue and sleep disturbance aspects of jet lag. 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. The current review differs from the previous reviews 

in that the objective was to determine the effectiveness of melatonin in alleviating the sleep 

disturbance aspect of jet lag, and not the daytime sleepiness aspect of this 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. The lack of substantial 

heterogeneity or evidence of possible publication bias across studies of this category and the 

moderate to high quality of the studies lend support to the results of the current review. 

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. 

Formulations and Pharmacology of Melatonin 

In general, the quality of reporting of the content and quality of the various formulations of 

melatonin that have been used in assessing its effectiveness and safety was poor, and it remains 

unclear which formulation of melatonin is optimal for the potential treatment of sleep disorders. 

The details of the formulations used in studies of the pharmacology of melatonin were often not 

reported, which precluded a quantitative analysis of the half-life of melatonin. Nonetheless, it 

appears that melatonin has a short half-life, which would tend to suggest that a sustained-release 

formulation of melatonin would be more effective than a fast-release formulation of melatonin in 

treating sleep disorders. However, it was unclear from our review of the literature whether the 

effectiveness of melatonin varies by formulation, and future research in this area is required. 

The finding that exogenous melatonin penetrates the blood-brain-barrier in one study suggests 

that exogenous melatonin exerts its effects via a similar mechanism as endogenous melatonin. 
108

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 the effectiveness of melatonin in the treatment of 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. 

Link Between Endogenous Melatonin and the Sleep Cycle 

Our literature review indicated evidence of a link between endogenous melatonin and the 

sleep cycle. A key result was that a decrease in endogenous melatonin levels was often 

accompanied by increased latency to sleep and decreased duration of sleep, as well as increased 

vigilance and performance during waking hours. In addition, changes in the rhythm of 

endogenous melatonin were often accompanied by changes in the sleep rhythm. This 

relationship between endogenous melatonin and the sleep cycle is consistent with a role for 

exogenous melatonin in the alteration of the sleep cycle in humans. However, the nature of this 

relationship remains to be defined; it is unclear under what conditions a change in endogenous 

melatonin will be accompanied by a change in the sleep cycle and how these conditions would 

affect the magnitude and direction of these changes. A better understanding of this relationship 

would add to our knowledge of the conditions under which the effects of exogenous melatonin 

can be optimized. We also found evidence that manipulation of the sleep schedule can produce 

alterations in endogenous melatonin; however, the direction of these changes varied across 

studies. It is likely that the variation across studies is due to the particular conditions of sleepschedule alterations as well the timing of assessment of the melatonin rhythm. It is important to 

note the possibility that the primary function of the inhibition of the superior cervical ganglion 
109

by light may be inhibition of pupil dilation rather than inhibition of endogenous melatonin 

secretion by the pineal gland, such that the effect of light on endogenous melatonin may be a 

secondary effect of light in humans. 

Link Between Endogenous Melatonin and the Temperature Rhythm 

Similar to the analysis of the link between endogenous melatonin and the sleep cycle, our 

literature review indicated evidence of a link between endogenous melatonin and the temperature 

rhythm. Specifically, a reduction in endogenous melatonin levels was often accompanied by an 

increase in core body temperature, and a shift in the rhythm of endogenous melatonin was often 

accompanied by a similar shift in the rhythm of core body temperature. The observation of a 

phase-link in the melatonin and temperature rhythms is consistent with current knowledge that 

the same biological clock, the SCN, controls both of these rhythms.238 It has been suggested that 

exogenous melatonin induces sleepiness via a reduction in core body temperature, and the 

relationship between changes in endogenous melatonin and the temperature rhythm is consistent 

with this proposed mechanism. Only two studies examined the effect of manipulation of body 

temperature on endogenous melatonin, and the results were opposite. Additional research in this 

area is required to elucidate the effect of temperature on endogenous melatonin. 

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 effect of melatonin on people with 

primary and secondary sleep disorders, beyond four weeks, remains to be determined. The 

short-term and long-term effects of melatonin on people with sleep apnea also need to be 

determined. The safety of melatonin in 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. There are very few studies that compare the benefits and 

harms of melatonin and other pharmacological treatments for sleep disorders, and more research 

in this area is necessary. 
110

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 shift-work 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 

• There is evidence of a link between endogenous melatonin and the temperature rhythm. 
111

Table 28: Summary of the Evidence Surrounding the Effect of Melatonin on Sleep in Various Populations 

Normal 

Sleepers 

Primary Sleep 

Disorder 

Secondary Sleep 

Disorder 

Sleep Restriction 

Sleep Onset Latency Decreased 

WMD: -3.9 min; 

95 percent CI: -

5.3 min., -2.6 

min. 

N=20 

Decreased 

WMD: -10.7 min.; 

95 percent CI: -

17.6 min., -3.7 

min. 

N=12 

 

No Effect 

N=6 

No Effect 

N=9 

Sleep Efficiency Increased 

WMD: 2.3 

percent; 95 

percent CI: 0.7 

percent, 3.9 

percent 

N=13 

No Effect 

N=9 

Increased 

WMD: 1.9 

percent; 95 

percent CI: 0.5 

percent, 3.3 

percent 

N=6 

No Effect 

N=5 

Abbreviations: WMD: weighted mean difference, CI: confidence interval
112
113

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131

List of Excluded Studies 

Seven hundred and ninety-six studies were excluded from the review. Of these, 328 

were reviews, book chapters or commentaries, and have not been included in this chapter. 

Other reasons for exclusion included inappropriate topic (n=36), study design (n=272), 

intervention (n=21), population (n=7) and outcomes (n=101). Three studies were not 

included because of inadequate reporting of outcomes. The reports of 25 studies were 

unobtainable at the time of this writing and two were realized upon completion of the 

final report. 

Excluded-Topic 

We sought to synthesize evidence related to four topic areas, including the physiology 

and pharmacology of melatonin; the populations that would benefit most from melatonin 

treatment; the effectiveness of melatonin treatment; and the safety of melatonin 

treatment. The following studies were excluded because the topic of the study was not 

appropriate to any of the questions of the review. 

Brainard GC, Hanifin JP, Greeson JM et al. Action 

spectrum for melatonin regulation in humans: 

evidence for a novel circadian photoreceptor. English. 

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Brainard GC, Hanifin JP, Rollag MD et al. Human 

melatonin regulation is not mediated by the three cone 

photopic visual system. English. 86. 2001:433-6. 

2001045653). 

Brismar K, Hylander B, Eliasson K, Rossner S, 

Wetterberg L. Melatonin secretion related to sideeffects of beta-blockers from the central nervous 

system. English. 223. 1988:525-30. 

Cajochen C, Wyatt JK, Czeisler CA, Dijk DJ. 

Separation of circadian and wake duration-dependent 

modulation of EEG activation during wakefulness. 

English. 114. 2002:1047-60. 2002360738). 

Cornwell AC, Feigenbaum P, Kim A. SIDS, abnormal 

nighttime REM sleep and CNS immaturity. English. 

29. 1998:72-9. 

Costantini A, Paoli F. Melatonin: Quantitative 

Analysis in Pharmaceutical Oral Dosage Forms Using 

Thin-Layer Chromatography (Tlc) Densitometry. 

English. 53. 1998:443-7. 

Daya S, Walker RB, Glass BD, Anoopkumar-Dukie S. 

The effect of variations in pH and temperature on 

stability of melatonin in aqueous solution. English. 

31. 2001:155-8. 

Dijk DJ, Investigator: Dijk DJ. Circadian variation of 

EEG power spectra in NREM and REM sleep in 

humans: dissociation from body temperature. English. 

8. 1999:189-95. 

Dijk DJ, Shanahan TL, Duffy JF, Ronda JM, Czeisler 

CA. Variation of electroencephalographic activity 

during non-rapid eye movement and rapid eye 

movement sleep with phase of circadian melatonin 

rhythm in humans. English. 505. 1997:851-8. 

1998014724). 

Ebisawa T, Kajimura N, Uchiyama M et al. Alleic 

variants of human melatonin 1a receptor: function and 

prevalence in subjects with circadian rhythm sleep 

disorders. English. 262. 1999:832-7. 

Ebisawa T, Uchiyama M, Kajimura N et al. Genetic 

polymorphisms of human melatonin 1b receptor gene 

in circadian rhythm sleep disorders and controls. 

English. 280. 2000:29-32. 

Ebisawa T, Uchiyama M, Kajimura N et al. 

Association of structural polymorphisms in the human 

period3 gene with delayed sleep phase syndrome. 

English. 2. 2001:342-6. 2001164928). 

Fauteck JD, Lerchl A, Bergmann M et al. The adult 

human cerebellum is a target of the neuroendocrine 

system involved in the circadian timing. English. 179. 

1994:60-4. 

Gaddy JR, Rollag MD, Brainard GC. Pupil size 

regulation of threshold of light-induced melatonin 

suppression. English. 77. 1993:1398-401. 
132

Goh VH, Tong TY, Lim CL, Low EC, Lee LK. 

Circadian disturbances after night-shift work onboard 

a naval ship. English. 165. 2000:101-5. 

Hohjoh H, Takasu M, Shishikura K, Takahashi Y, 

Honda Y, Tokunaga K. Significant association of the 

arylalkylamine N-acetyltransferase ( AA-NAT) gene 

with delayed sleep phase syndrome. English. 4. 

2003:151-3. 

Huether G, Hajak G, Reimer A et al. The MetabolicFate of Infused L-Tryptophan in Men - Possible 

Clinical Implications of the Accumulation of 

Circulating Tryptophan and Tryptophan-Metabolites. 

English. 109. 1992:422-32. 

Iuvone PM. Circadian rhythms of melatonin 

biosynthesis in retinal photoreceptor cells: signal 

transduction, interactions with dopamine, and 

speculations on a role in cell survival. Kato S , 

Osborne NN , Tamai M_. Proceedings of an 

International Symposium: Retinal degeneration and 

regeneration. Amsterdam/New York: Kugler Pub., 

1996: 3-16. 

Karkela J, Vakkuri O, Kaukinen S, Huang WQ, 

Pasanen M. The influence of anaesthesia and surgery 

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2002:30-6. 

Mishima K MYSKTTEMSMaHY. Circadian 

rhythmicity of cell-mediated immunity in human and 

influences of sleep deprivation. 1998. CN-00282999. 

Monteleone P, Catapano F, Tortorella A, Di Martino 

S, Maj M. Plasma melatonin and cortisol circadian 

patterns in patients with obsessive-compulsive 

disorder before and after fluoxetine treatment. 

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Murck H, Steiger A. Mg2+ reduces ACTH secretion 

and enhances spindle power without changing delta 

power during sleep in men -- possible therapeutic 

implications. English. 137. 1998:247-52. 

Palazidou E, Franey C, Arendt J, Stahl S, Checkley S. 

Evidence for a functional role of alpha-1 

adrenoceptors in the regulation of melatonin secretion 

in man. English. 14. 1989:131-5. 

Palazidou E, Papadopoulos A, Ratcliff H, Dawling S, 

Checkley SA. Noradrenaline uptake inhibition 

increases melatonin secretion, a measure of 

noradrenergic neurotransmission, in depressed 

patients. eng. 22. 1992:309-15. 

Palazidou E, Papadopoulos A, Sitsen A, Stahl S, 

Checkley S. An alpha 2 adrenoceptor antagonist, Org 

3770, enhances nocturnal melatonin secretion in man. 

English. 97. 1989:115-7. 

Payne JK. The trajectory of fatigue in adult patients 

with breast and ovarian cancer receiving 

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anaesthesia for surgery can influence circulating 

melatonin during daylight hours. English. 42. 

1998:1050-6. 

Sassone-Corsi P, Whitmore D, Cermakian N, Foulkes 

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Circadian Melatonin synthesis. 5th International 

Arnold Rikli symposium: Biologic effects of light. 

1998: 3-10. 

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in patients with Alzheimer's disease. English. 308. 

2001:9-12. 

Stoschitzky K, Sakotnik A, Lercher P et al. Influence 

of beta-blockers on melatonin release. English. 55. 

1999:111-5. 

Suvanto S, Harma M, Laitinen JT. The prediction of 

the adaptation of circadian rhythms to rapid time zone 

changes. English. 36. 1993:111-6. 1993064055). 

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melatonin suppression: evidence for a novel non-rod, 

non-cone photoreceptor system in humans. English. 

535. 2001:261-7. 

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of a Novel Series of Tricyclic Indan Derivatives as 

Melatonin Receptor Agonists. English. 45. 

2002:4222-39. 

Weaver DR, Reppert SM. The Mel1a melatonin 

receptor gene is expressed in human suprachiasmatic 

nuclei. English. 8. 1996:109-12. 

Wehr TA, Schwartz PJ, Turner EH, Feldman-Naim S, 

Drake CL, Rosenthal NE. Bimodal patterns of human 

melatonin secretion consistent with a two-oscillator 

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Yuan H, Chan CW, Sturner WQ, Pang SF, Brown 

GM. Comparison of [125I]iodomelatonin binding sites 

in infant cerebellum of sudden infant death syndrome 

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1995:154-8. 
133

Excluded-Design

In general, only controlled clinical trials were included for each 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. The following studies did not have the design that was appropriate to 

the question(s) of the review to which they were potentially relevant. 

Aeschbach D, Sher L, Postolache TT, Matthews JR, 

Jackson MA, Wehr TA. A longer biological night in 

long sleepers than in short sleepers. English. 88. 

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17. 1982:547-54. 

Anonymous. Jet lag takes flight with melatonin. 

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melatonin suppression in response to light in patients 

with delayed sleep phase syndrome. English. 18. 

2001:263-71. 

Arendt J. Use of melatonin in circadian rhythm 

disturbances. English. 9. 1993:469-71. 1993297394). 

Attenburrow ME, Dowling BA, Sharpley AL, Cowen 

PJ. Case-control study of evening melatonin 

concentration in primary insomnia[comment]. 

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Barnes RG, Forbes MJ, Arendt J. Shift type and 

season affect adaptation of the 6-sulphatoxymelatonin 

rhythm in offshore oil rig workers. English. 252. 

1998:179-82. 

Baskett JJ, Cockrem JF, Todd MA. Melatonin levels 

in hospitalized elderly patients: a comparison with 

community based volunteers. English. 20. 1991:430-

4. 

Baskett JJ, Wood PC, Broad JB, Duncan JR, English 

J, Arendt J. Melatonin in older people with age-related 

sleep maintenance problems: a comparison with age 

matched normal sleepers. English. 24. 2001:418-24. 

Benhaberou-Brun D, Lambert C, Dumont M. 

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sleep complaints in night nurses. English. 22. 

1999:877-85. 

Berga SL, Yen SS. Circadian pattern of plasma 

melatonin concentrations during four phases of the 

human menstrual cycle. English. 51. 1990:606-12. 

Bersani G, Garavini A. Melatonin add-on in manic 

patients with treatment resistant insomnia. English. 

24. 2000:185-91. 

Bersani G, Garavini A. Evening melatonin 

administration in manic patients with treatment 

resistant insomnia. Italian. 35. 2000:126-30. 

2000201901). 

Birketvedt GS, Florholmen J, Sundsfjord J et al. 

Behavioral and neuroendocrine characteristics of the 

night-eating syndrome[comment]. J Am Med Assoc 

1999; 282(7):657-63. 

Bjorksten KS, Basun H, Wetterberg L. Disorganized 

sleep-wake schedule associated with neuroendocrine 

abnormalities in dementia A clinical study. English. 

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Blaicher W, Speck E, Imhof MH et al. Melatonin in 

postmenopausal females. English. 263. 2000:116-8. 

Blazejova K, Nevsimalova S, Illnerova H, Hajek I, 

Sonka K. Sleep disorders and the 24-hour profile of 

melatonin and cortisol [Czech]. Czech. 101. 

2000:347-51. 

Boivin DB, James FO. Circadian adaptation to nightshift work by judicious light and darkness exposure. 

English. 17. 2002:556-67. 

Boivin DB, James FO, Santo JB, Caliyurt O, Chalk C. 

Non-24-hour sleep-wake syndrome following a car 

accident. English. 60. 2003:1841-3. 

Bojkowski CJ, Arendt J. Annual changes in 6-

sulphatoxymelatonin excretion in man. English. 117. 

1988:470-6. 

Brismar K, Mogensen L, Wetterberg L. Depressed 

melatonin secretion in patients with nightmares due to 

beta-adrenoceptor blocking drugs. English. 221. 

1987:155-8. 

Bruce J, Tamarkin L, Riedel C, Markey S, Oldfield E. 

Sequential cerebrospinal fluid and plasma sampling in 

humans: 24-hour melatonin measurements in normal 
134

subjects and after peripheral sympathectomy. English. 

72. 1991:819-23. 

Brusco LI, Fainstein I, Marquez M, Cardinali DP. 

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treatment stabilizes chronobiologic and cognitive 

symptoms in Alzheimer's disease. English. 19. 

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DJ, Investigator: Dijk DJ. EEG and ocular correlates 

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Campbell SS, Murphy PJ. Extraocular circadian 

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Carden SM. Entrainment of Free-running Circadian 

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R W Brandes, A R Kendall, and A J Lewy New Engl J 

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Carskadon MA, Wolfson AR, Acebo C, Tzischinsky 

O, Seifer R. Adolescent sleep patterns, circadian 

timing, and sleepiness at a transition to early school 

days. English. 21. 1998:871-81. 

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Checkley SA, Murphy DG, Abbas M et al. Melatonin 

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1993:332-7. 

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effect of melatonin in patients with fibromyalgia: a 

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once-repeated study of nocturnal plasma melatonin 

patterns and sleep recordings in six normal young 

men. eng. 3. 1986:301-10. 

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melatonin rhythm is maintained in human African 

trypanosomiasis. English. 68. 1998:64-70. 

Coetzee JA, Theron JJ, van der Merwe CA. 

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for treatment of sundowning in elderly persons with 

dementia - A preliminary study. English. 31. 2000:65-

76. 2000335738). 

Comperatore CA, Lieberman HR, Kirby AW, Adams 

B, Crowley JS. Melatonin efficacy in aviation 

missions requiring rapid deployment and night 

operations. English. 67. 1996:520-4. 

Costa G, Bertoldi A, Kovacic M, Ghirlanda G, Minors 

DS, Waterhouse JM. Hormonal secretion of nurses 

engaged in fast-rotating shift systems... XIIth 

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1997:S35-9. 

Costa G, Koller M. Melatonin excretion during night 

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EO. Melatonin secretion after surgery. English. 356. 

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Cronin AJ, Keifer JC, Rung G, Shaheen J. 

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circadian rhythm a physiological feature associated 

with healthy longevity? A study of long-living 

subjects and their progeny. English. 18. 2001:99-107. 

Czeisler CA, Shanahan TL, Klerman EB et al. 

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135

patients by exposure to bright light[comment]. 

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Dagan Y, Yovel I, Hallis D, Eisenstein M, Raichik I. 

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treatment of delayed sleep phase syndrome (DSPS). 

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Dalton EJ, Rotondi D, Levitan RD, Kennedy SH, 

Brown GM. Use of slow-release melatonin in 

treatment-resistant depression. English. 25. 2000:48-

52. 

Danilenko KV, Putilov AA, Russkikh GS, Duffy LK, 

Ebbesson SO. Diurnal and seasonal variations of 

melatonin and serotonin in women with seasonal 

affective disorder. English. 53. 1994:137-45. 

Dawson D, Encel N, Lushington K. Improving 

adaptation to simulated night shift: timed exposure to 

bright light versus daytime melatonin administration. 

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De Leersnyder H, De Blois MC, Claustrat B et al. 

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Smith-Magenis syndrome. English. 139. 2001:111-6. 

de Leiva A, Tortosa F, Peinado MA, Serrano J, 

Rodriguez-Espinosa J, Puig-Domingo M. Episodic 

nyctohemeral secretion of melatonin in adult humans: 

lack of relation with LH pulsatile pattern. English. 

122. 1990:76-82. 

Deacon S, Arendt J. Adapting to phase shifts, II 

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Deacon S, Arendt J. Adapting to phase shifts, I An 

experimental model for jet lag and shift work. 

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Deacon SJ, Arendt J. Phase-shifts in melatonin, 6-

sulphatoxymelatonin and alertness rhythms after 

treatment with moderately bright light at night. 

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Demisch LRTaGK. Influence of chronic badrenoreceptor blocker treatment on sleep quality and 

melatonin secretion. 25. 1992:98. CN-00279899. 

den Boer JA, Westenberg HG. Behavioral, 

neuroendocrine, and biochemical effects of 5-

hydroxytryptophan administration in panic disorder. 

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Dijk DJ, Duffy JF, Riel E, Shanahan TL, Czeisler CA. 

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Duffy JF, Dijk DJ, Hall EF, Czeisler CA, Investigator: 

Czeisler CA. Relationship of endogenous circadian 

melatonin and temperature rhythms to self-reported 

preference for morning or evening activity in young 

and older people. English. 47. 1999:141-50. 

Duffy JF, Zeitzer JM, Rimmer DW, Klerman EB, Dijk 

DJ, Czeisler CA. Peak of circadian melatonin rhythm 

occurs later within the sleep of older subjects. 

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Englund CE LRKD. Bright light amelioration of shift 

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of melatonin to treat sleep-wake-rhythm disorders in 

children who are visually impaired. English. 90. 

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Etzioni A, Luboshitzky R, Tiosano D, Ben-Harush M, 

Goldsher D, Lavie P. Melatonin replacement corrects 

sleep disturbances in a child with pineal tumor. 

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Fainstein I, Bonetto AJ, Brusco LI, Cardinali DP. 

Effects of melatonin in elderly patients with sleep 

disturbance: A pilot study. English. 58. 1997:990-

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Coblentz A. Sleepiness during night-shift - Sleeping 

habits or melatonin rhythm? A laboratory study. 

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Fauteck J, Schmidt H, Lerchl A, Kurlemann G, 

Wittkowski W. Melatonin in epilepsy: first results of 

replacement therapy and first clinical results. English. 

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Fauteck J-D, Schmidt H, Kurlemann G, Wittkowski 

W. Melatonin rhythms and therapeutic application of 

melatonin in children with severe sleep disturbances 

of different etiology. Experimental and Clinical 

Endocrinology and Diabetes 1997; 105(Sup 1):112. 

Fertl E, Auff E, Doppelbauer A, Waldhauser F. 

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parkinsonian patients: evidence for phase-shifting 

properties of l-dopa. English. 5. 1993:227-34. 

Fiorina P, Lattuada G, Silvestrini C, Ponari O, 

Dall'Aglio P. Disruption of nocturnal melatonin 

rhythm and immunological involvement in ischaemic 

stroke patients. English. 50. 1999:228-31. 

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Force RWHLBM. Psychotic episode after melatonin. 

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Foret J, Daurat A, Touitou Y, Aguirre A, Benoit O. 

The effect on body temperature and melatonin of a 39-

H constant routine with two different light levels at 

nighttime. English. 13. 1996:35-45. 1996185479). 

Friedmann PD, Herman DS, Freedman S, Lemon SC, 

Ramsey S, Stein MD. Treatment of sleep disturbance 

in alcohol recovery: A national survey of addiction 

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Fujita Y, Asukata I, Ohkoshi H et al. Effect of jet lag 

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circadian type reflects the phase of the melatonin 

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Gilbert SS, van den Heuvel CJ, Dawson D. Daytime 

melatonin and temazepam in young adult humans: 

equivalent effects on sleep latency and body 

temperatures. English. 514 . 1999:905-14. 

Gould EL, Loesch DZ, Martin MJ, Hagerman RJ, 

Armstrong SM, Huggins RM. Melatonin profiles and 

sleep characteristics in boys with fragile X syndrome: 

a preliminary study. English. 95. 2000:307-15. 

Griefahn B. The validity of the temporal parameters of 

the daily rhythm of melatonin levels as an indicator of 

morningness. English. 19. 2002:561-77. 

Griefahn B, Blaszkewicz M, Gerngro H, Romer HC. 

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Griefahn B, Kunemund C, Golka K, Thier R, Degen 

G. Melatonin synthesis: a possible indicator of 

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Grof E, Grof P, Brown GM, Arato M, Lane J. 

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Hajak G, Rodenbeck A, Staedt J, Bandelow B, 

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Hansen T, Bratlid T, Lingjarde O, Brenn T. Midwinter 

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Harma M, Laitinen J, Partinen M, Suvanto S. The 

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Hatonen T, Kirveskari E, Heiskala H, Sainio K, 

Laakso ML, Santavuori P. Melatonin ineffective in 

neuronal ceroid lipofuscinosis patients with 

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Hayakawa T, Kamei Y, Urata J, Shibui K. Trials of 

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rhythm studies in neuronal ceroid-lipofuscinosis 

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Hoban TM, Lewy AJ, Sack RL, Singer CM. The 

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variation in the human circadian rhythm: dissociation 

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treatment of sleep disturbances in children with 

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Iguchi H, Kato KI, Ibayashi H. Melatonin serum 

levels and metabolic clearance rate in patients with 

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Ihara H, Madokoro S, Nakagawa H, Misaki K, Ito T, 

Isaki K. A case of delayed sleep phase syndrome: 

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rhythm in plasma melatonin concentration of the 

urbanized man: the effect of summer and winter time. 

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Jan JE, Hamilton D, Seward N, Fast DK, Freeman 

RD, Laudon M. Clinical trials of controlled-release 

melatonin in children with sleep-wake cycle disorders. 

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Jan MM. Melatonin for the treatment of handicapped 

children with severe sleep disorders. English. 23. 

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Johnson K, Page A, Williams H, Wassemer E, 

Whitehouse W. The use of melatonin as an alternative 

to sedation in uncooperative children undergoing an 

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Environmental Health 1998; 13((4)):221-6. 

Vasavan Nair NP, Schwartz G, Ng Ying Kin NMK, 

Thakur M. Melatonin and cortisol circadian rhythms 

in Alzheimer's Disease patients and normal elderly 

subjects. International Congress Series -AmsterdamExcerpta Medica Then Elsevier Science 1998; 

1152:357-62. 

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Circadian profiles of melatonin in melancholic 

depressed patients and healthy subjects in relation to 

cortisol secretion and sleep. English. 71. 1997:151-

61. 

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total sleep loss in cerebral Whipple's disease: a 

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U, Waldhauser M, Wurtman RJ. Fall in nocturnal 

serum melatonin during prepuberty and pubescence. 

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Wehr TA. In short photoperiods, human sleep is 

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Whitson PA, Putcha L, Chen YM, Baker E, 

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cortisol assessment of circadian shifts in astronauts 

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Wikner J, Hirsch U, Wetterberg L, Rojdmark S. 

Fibromyalgia--a syndrome associated with decreased 

nocturnal melatonin secretion[comment]. English. 49. 

1998:179-83. 

Wikner J, Svanborg E, Wetterberg L, Rojdmark S. 

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1997:1002-7. 

Williams G, Pirmohamed J, Minors D et al. 

Dissociation of body-temperature and melatonin 

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fatigue syndrome. English. 16. 1996:327-37. 

Willig RP, Braun W, Commentz JC, Stahnke N. 

Circadian fluctuation of plasma melatonin in PraderWilli's syndrome and obesity . English. 279. 

1986:411-5. 

Wirz-Justice A, Graw P, Krauchi K et al. Morning or 

night-time melatonin is ineffective in seasonal 

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Wright KPJ, Myers BL, Plenzler SC, Drake CL, Badia 

P. Acute effects of bright light and caffeine on 

nighttime melatonin and temperature levels in women 

taking and not taking oral contraceptives. English. 

873. 2000:310-7. 

Wyatt JK, Ritz-De Cecco A, Czeisler CA, Dijk DJ. 

Circadian temperature and melatonin rhythms, sleep, 

and neurobehavioral function in humans living on a 

20-h day. English. 277. 1999:R1152-R1163. 

1999390941). 

Yang CM, Spielman AJ, D'Ambrosio P, Serizawa S, 

Nunes J, Birnbaum J. A single dose of melatonin 

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2001:272-81. 

Yoon IY, Song BG. Role of morning melatonin 

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19. 2002:903-13. 

Youngstedt SD, Kripke DF, Elliott JA. Melatonin 

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Youngstedt SD, Kripke DF, Elliott JA, Klauber MR. 

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2001:264-72. 

Zhao ZY, Xie Y, Fu YR, Bogdan A, Touitou Y. Aging 

and the circadian rhythm of melatonin: a crosssectional study of Chinese subjects 30-110 yr of age. 

English. 19. 2002:1171-82. 
144

Zhdanova IV, Wurtman RJ, Wagstaff J. Effects of a 

low dose of melatonin on sleep in children with 

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1999180932). 

Zisapell N. Melatonin-dopamine interactions: From 

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2001:605-16. 2002184809).

Excluded-Population

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. Studies involving animals were excluded. The following studies did not 

have the population that was appropriate to the question(s) of the review to which they 

were potentially relevant. 

Ayala-Guerrero F, Pineda BBT, Hernandez MA, 

Mexicano G. Effect of Melatonin on Sleep. 

Proceedings- Western Pharmacology Society 1998; 

41:25-8. 

Kalsbeek A, Strubbe JH, Buijs RM. Circadian control 

of corticosterone, melatonin and insulin release: 

important roles for suprachiasmatic nucleus efferents 

and the autonomic nervous system. International 

Congress Series -Amsterdam- Excerpta Medica Then 

Elsevier Science 1998; 1152:411-4. 

Oxenkrug GF, Requintina PJ. Melatonin and jet lag 

syndrome: experimental model and clinical 

implications. eng. 8. 2003:139-48. 

Sharma VK, Chidambaram R, Yadunandam AK. 

Melatonin enhances the sensitivity of circadian 

pacemakers to light in the nocturnal field mouse Mus 

booduga. English. 297A. 2003:160-8. 

Slotten H, Pitrosky B, Pevet P. Entrainment of Rat 

Circadian Rhythms by Daily Administration of 

Melatonin: Influence of the Mode of Administration. 

Advances in Experimental Medicine and Biology 

1999; 460:279-82. 

Vachharajani NN, Yeleswaram K, Boulton DW. 

Preclinical pharmacokinetics and metabolism of BMS214778, a novel melatonin receptor agonist. English. 

92. 2003:760-72. 

Wirz-Justice A, Cajochen C, Kruchi K, Mri D, Graw 

P. Timed Melatonin Administration on Circadian 

Rhythms and Vigilance States CONFERENCE 

ABSTRACT. 1996. CN-00285692. 

Excluded-Intervention 

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. The following 

studies involved either an inappropriate intervention or a co-intervention. 

Bougrine S, Mollard R, Ignazi G, Coblentz A. Days 

off and bright light: Effects on adaptation to night 

work. English. 21. 1998:187-98. 1998058963). 

Cagnacci A, Soldani R, Yen SS. Contemporaneous 

melatonin administration modifies the circadian 

response to nocturnal bright light stimuli. English. 

272. 1997:R482-6. 

De Leersnyder H, Bresson JL, de Blois MC et al. Beta 

1-adrenergic antagonists and melatonin reset the clock 

and restore sleep in a circadian disorder, SmithMagenis syndrome. English. 40. 2003:74-8. 

De Leersnyder H, De Blois MC, Vekemans M et al. 

beta<inf>1</inf>-adrenergic antagonists improve 

sleep and behavioural disturbances in a circadian 
145

disorder, Smith-Magenis syndrome. English. 38. 

2001:586-90. 2001318554). 

Dolberg OT, Hirschmann S, Grunhaus L. Melatonin 

for the treatment of sleep disturbances in major 

depressive disorder. English. 155. 1998:1119-21. 

Haffmans PMJ, Sival RC, Lucius SAP, Cats Q, Van 

Gelder L. Bright light therapy and melatonin in motor 

restless behaviour in dementia: A placebo-controlled 

study. English. 16. 2001:106-10. 2001046585). 

Hajak G, Rodenbeck A, Adler L et al. Nocturnal 

melatonin secretion and sleep after doxepin 

administration in chronic primary insomnia. English. 

29. 1996:187-92. 

Hajak G, Rodenbeck A, Bandelow B, Friedrichs S, 

Huether G, Ruther E. Nocturnal plasma melatonin 

levels after flunitrazepam administration in healthy 

subjects. English. 6. 1996:149-53. 

Krauchi K, Cajochen C, Danilenko KV, Wirz-Justice 

A. The hypothermic effect of late evening melatonin 

does not block the phase delay induced by concurrent 

bright light in human subjects. English. 232. 

1997:57-61. 

Leibenluft E, Schmidt PJ, Turner EH et al. Effects of 

leuprolide-induced hypogonadism and testosterone 

replacement on sleep, melatonin, and prolactin 

secretion in men. English. 82. 1997:3203-7. 

Loo H, Hale A, D'haenen H. Determination of the 

dose of agomelatine, a melatoninergic agonist and 

selective 5-HT<inf>2C</inf> antagonist, in the 

treatment of major depressive disorder: A placebocontrolled dose range study. English. 17. 2002:239-

47. 2002340721). 

Nave R, Iani C, Herer P, Gopher D, Lavie P. Residual 

effects of daytime administration of melatonin on 

performance relevant to flight. English. 131. 2002:87-

95. 

Okawa M, Uchiyama M, Ozaki S, Shibui K, Ichikawa 

H. Circadian rhythm sleep disorders in adolescents: 

clinical trials of combined treatments based on 

chronobiology. English. 52. 1998:483-90. 

Rose DA, Kahan TL. Melatonin and sleep qualities in 

healthy adults: pharmacological and expectancy 

effects. English. 128. 2001:401-21. 

Schlager DS. Early-morning administration of shortacting beta blockers for treatment of winter 

depression. English. 151. 1994:1383-5. 

Shilo L, Sabbah H, Hadari R et al. The effects of 

coffee consumption on sleep and melatonin secretion. 

English. 3. 2002:271-3. 2002227153). 

Strassman RJ, Peake GT, Qualls CR, Lisansky EJ. 

Lack of an acute modulatory effect of melatonin on 

human nocturnal thyrotropin and cortisol secretion. 

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Takahashi T, Sasaki M, Itoh H et al. Re-entrainment 

of the circadian rhythms of plasma melatonin in an 11-

h eastward bound flight. English. 55. 2001:275-6. 

2001225754). 

Tanaka H, Kakutani S, Araki A, Fukuda I, Oka R, Cho 

K. Combined use of melatonin and low-dose 

flunitrazepam for treatment of sleep disturbance in a 

child with spastic quadriplegia: evaluation using 

polysomnography [Japanese]. Japanese. 34. 

2002:528-32. 

Tooley GA, Armstrong SM, Norman TR, Sali A. 

Acute increases in night-time plasma melatonin levels 

following a period of meditation. English. 53. 

2000:69-78. 

Youngstedt SD, Kripke DF, Elliott JA. Circadian 

phase-delaying effects of bright light alone and 

combined with exercise in humans. English. 282. 

2002:R259-66.

Excluded-Outcome 

A study was included for a particular question of the review if it analyzed at least 

one of the pre-determined outcomes relevant to that question. The following studies did 

not report on any of the outcomes that were appropriate to the question(s) of the review to 

which they were potentially relevant. 

Akbulut H, Icli F, Buyukcelik A, Akbulut KG, 

Demirci S. The role of granulocyte-macrophagecolony stimulating factor, cortisol, and melatonin in 

the regulation of the circadian rhythms of peripheral 

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breast cancer. English. 26. 1999:1-8. 

Anton-Tay FDJLaF-GA. On the effect of melatonin 

upon human brain. Its possible therapeutic 

implications. 10. 1971:841-50. CN-00334726. 
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by melatonin: preliminary results of controlled double 

blind trial. English. 292. 1986:1170. 

Arendt J, Bojkowski C, Folkard S et al. Some effects 

of melatonin and the control of its secretion in 

humans. English. 117. 1985:266-83. 

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Waterhouse J. Are there hangover-effects on physical 

performance when melatonin is ingested by athletes 

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Attenburrow ME, Dowling BA, Sargent PA, Sharpley 

AL, Cowen PJ. Melatonin phase advances circadian 

rhythm. English. 121. 1995:503-5. 

Bellipanni G, Bianchi P, Pierpaoli W, Bulian D, Ilyia 

E. Effects of melatonin in perimenopausal and 

menopausal women: a randomized and placebo 

controlled study. English. 36. 2001:297-310. 

Bojkowski CJ AMEJea. Suppression of nocturnal 

plasma melatonin and 6-sulphatoxymelatonin by 

bright and dim light in man. 19. 1987:437-40. CN00381007; EMBASE 1987206723). 

Braam W, Smits M. Melatonin Treatment for Chronic 

Sleep Problems in People With Intellectual Disability: 

a Randomized Placebo-Controlled Study. English. 44. 

2000:110. 

Bruhl T, Pflug B, Kohler W, Touitou Y, Lemmer B . 

Bright light in the morning but not in the evening 

affects circadian rhythms in plasma cAMP, melatonin 

and cortisol in healthy subjects. 7. 1990:29-32. CN00358323; EMBASE 1990369642). 

Byerley WF, Risch SC, Gillin JC et al. Biological 

effect of bright light. 13. 1989:683-6. CN-00261859. 

Cagnacci A, Soldani R, Yen SS. Hypothermic effect 

of melatonin and nocturnal core body temperature 

decline are reduced in aged women. English. 78. 

1995:314-7. 

Cajochen C, Krauchi K, von Arx MA, Mori D, Graw 

P, Wirz-Justice A. Daytime melatonin administration 

enhances sleepiness and theta/alpha activity in the 

waking EEG. English. 207. 1996:209-13. 

Carman JS, Post RM, Buswell R, Goodwin FK. 

Negative effects of melatonin on depression. English. 

133. 1976:1181-6. 

Deacon S, English J, Arendt J. Acute phase-shifting 

effects of melatonin associated with suppression of 

core body temperature in humans. English. 178. 

1994:32-4. 

Demitrack MA, Lewy AJ, Reus VI. Pineal-adrenal 

interactions: the effect of acute pharmacological 

blockade of nocturnal melatonin secretion. English. 

32. 1990:183-9. 

Dijk DJ, Roth C, Landolt HP et al. Melatonin effect 

on daytime sleep in men: suppression of EEG low 

frequency activity and enhancement of spindle 

frequency activity. English. 201. 1995:13-6. 

Emser W, Dechoux R, Weiland M, Wirz-Justice A. 

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the human electroretinogram. English. 49. 1993:686-

7. 

Fourtillan JB, Brisson AM, Fourtillan M, Ingrand I, 

Decourt JP, Girault J. Melatonin secretion occurs at a 

constant rate in both young and older men and women. 

English. 280. 2001:E11-22. 

Gasio PF, Krauchi K, Cajochen C et al. Dawn-Dusk 

Simulation Light Therapy of Disturbed Circadian 

Rest- Activity Cycles in Demented Elderly. English. 

38. 2003:207-16. 

Graw P, Werth E, Krauchi K, Gutzwiller F, Cajochen 

C, Wirz-Justice A. Early morning melatonin 

administration impairs psychomotor vigilance. 

English. 121. 2001:167-72. 

Hashimoto S, Kohsaka M, Nakamura K, Honma H, 

Honma S, Honma K. Midday exposure to bright light 

changes the circadian organization of plasma 

melatonin rhythm in humans. English. 221. 1997:89-

92. 

Hatonen T, Alila A, Laakso ML. Exogenous 

melatonin fails to counteract the light-induced phase 

delay of human melatonin rhythm. English. 710. 

1996:125-30. 

Heiman DL. Effects of melatonin on nocturnal sleep 

and athletic performance the next day. English. 12. 

2002:56. 2002077304). 

Hughes RJ, Badia P. Sleep-promoting and 

hypothermic effects of daytime melatonin 

administration in humans. English. 20. 1997:124-31. 

Jean-Louis G, von Gizycki H, Zizi F. Predictors of 

subjective sleepiness induced by melatonin 

administration. English. 47. 1999:355-8. 

Kahan TL, Hays J, Hirashima B, Johnston K. Effects 

of melatonin on dream bizarreness among male and 

female college students. English. 2. 2000:74-83. 

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Kirby AWa, Clayton M, Rivera P, Comperatore CA. 

Melatonin and the reduction or alleviation of stress. 

English. 27. 1999:78-85. 

Klerman EB, Shanahan TL, Brotman DJ et al. Photic 

resetting of the human circadian pacemaker in the 

absence of conscious vision. English. 17. 2002:548-

55. 

Krahn LE, Lin SC, Klee GG, Lu PY, Ory SJ, 

Zimmermann RC. The effect of presynaptic 

catecholamine depletion on 6-hydroxymelatonin 

sulfate: A double blind study of alpha-methyl-paratyrosine. English. 9. 1999:61-6. 1999057206). 

Krauchi K, Cajochen C, Mori D, Graw P, Wirz-Justice 

A. Early evening melatonin and S-20098 advance 

circadian phase and nocturnal regulation of core body 

temperature. English. 272. 1997:R1178-88. 

Kripke DF, Mullaney DJ, Klauber MR, Risch SC, 

Gillin JC. Controlled Trial of Bright Light for 

Nonseasonal Major Depressive-Disorders. Biological 

Psychiatry 1992; 31(2):119-34. 

Kunz D, Bes F. Exogenous melatonin in periodic limb 

movement disorder: an open clinical trial and a 

hypothesis. English. 24. 2001:183-7. 

Laakso ML, Hatonen T, Stenberg D, Alila A, Smith S. 

One-hour exposure to moderate illuminance (500 lux) 

shifts the human melatonin rhythm. English. 15. 

1993:21-6. 

Lagarde D, Chappuis B, Billaud PF, Ramont L, 

Chauffard F, French J. Evaluation of pharmacological 

aids on physical performance after a transmeridian 

flight. English. 33. 2001:628-34. 

Leibenluft E F-NSTEWTRN. Effects of exogenous 

melatonin administration and withdrawal in five 

patients with rapid-cycling bipolar disorder. [see 

comments.]. 58. 1997:383-8. CN-00144872. 

Lemmer B, Bruhl T, Witte K, Pflug B, Kohler W, 

Touitou Y. Effects of bright light on circadian patterns 

of cyclic adenosine monophosphate, melatonin and 

cortisol in healthy subjects. English. 130. 1994:472-7. 

Leppamaki S, Partonen T, Vakkuri O, LA nnqvist J, 

Partinen M, Laudon M. Effect of controlled-release 

melatonin on sleep quality, mood, and quality of life 

in subjects with seasonal or weather-associated 

changes in mood and behaviour. English. 13. 

2003:137-45. 

Lewy AJ, Ahmed S, Latham Jackson JM, Sack RL. 

Melatonin shifts human circadian rhythms according 

to a phase-response curve. English. 9. 1992:380-92. 

1992309837). 

Lewy AJ, Bauer VK, Cutler NL et al. Morning vs 

evening light treatment of patients with winter 

depression[comment]. English. 55. 1998:890-6. 

Lieberman HR, Garfield G, Waldhauser F, Lynch HJ, 

Wurtman RJ. Possible behavioral consequences of 

light-induced changes in melatonin availability. 

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Lindblom N, Heiskala H, Hatonen T et al. No 

evidence for extraocular light induced phase shifting 

of human melatonin, cortisol and thyrotropin rhythms. 

English. 11. 2000:713-7. 

Lingjaerde O, Bratlid T, Hansen T. Insomnia during 

the "dark period" in northern Norway An explorative, 

controlled trial with light treatment. English. 71. 

1985:506-12. 

Lissoni P, Rovelli F, Pittalis S et al. [Therapy with 

melatonin does not suppress its endogenous 

production in healthy volunteers] [Italian]. Italian. 90. 

1999:84-5. 

Lockley SW, Skene DJ, James K, Thapan K, Wright J, 

Arendt J. Melatonin administration can entrain the 

free-running circadian system of blind subjects. 

English. 164. 2000:R1-6. 

Mallo C, Zaidan R, Faure A, Brun J, Chazot G, 

Claustrat B. Effects of a four-day nocturnal melatonin 

treatment on the 24 h plasma melatonin, cortisol and 

prolactin profiles in humans. English. 119. 1988:474-

80. 

Manfredini R, Manfredini F, Conconi F. Standard 

melatonin intake and circadian rhythms of elite 

athletes after a transmeridian flight. English. 28. 

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Matsumoto M, Sack RLa, Blood ML, Lewy AJ. The 

amplitude of endogenous melatonin production is not 

affected by melatonin treatment in humans. English. 

22. 1997:42-4. 

Matsumoto Y, Mishima K, Satoh K et al. Total sleep 

deprivation induces an acute and transient increase in 

NK cell activity in healthy young volunteers. English. 

24. 2001:804-9. 

McIntyre IM, Norman TR, Burrows GD, Armstrong 

SM. Melatonin rhythm in human plasma and saliva. 

English. 4. 1987:177-83. 

McIntyre IM, Norman TR, Burrows GD, Armstrong 

SM. Human melatonin response to light at different 

times of the night. English. 14. 1989:187-93. 

McLellan TM, Gannon GA, Zamecnik J, Gil V, 

Brown GM. Low doses of melatonin and diurnal 
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effects on thermoregulation and tolerance to 

uncompensable heat stress. English. 87. 1999:308-16. 

Mclellan TM, Smith IF, Gannon GA, Zamecnik J. 

Melatonin Has No Effect on Tolerance to 

Uncompensable Heat Stress in Man. English. 83. 

2000:336-43. 

Middleton B, Arendt J, Stone BM. Complex effects of 

melatonin on human circadian rhythms in constant 

dim light. English. 12. 1997:467-77. 

Middleton BA, Stone BM, Arendt J. Melatonin and 

fragmented sleep patterns. English. 348. 1996:551-2. 

Miyauchi F, Nanjo K, Kato H, Sasaki T, Yonezawa 

M, Tsukada Y. The effects of light exposure on 

plasma concentrations of melatonin, LH, FSH and 

prolactin in women [Japanese]. Japanese. 66. 

1990:737-46. 

Miyauchi F, Nanjo K, Otsuka K. Effects of continuous 

lighting on secretion of melatonin and pituitary 

hormones in women [Japanese]. Japanese. 43. 

1991:529-34. 

Monteleone P, Esposito G, La Rocca A, Maj M. Does 

bright light suppress nocturnal melatonin secretion 

more in women than men? English. 102. 1995:75-80. 

Nagtegaal JE, Laurant MW, Kerkhof GA, Smits MG, 

van der Meer YG, Coenen AM. Effects of melatonin 

on the quality of life in patients with delayed sleep 

phase syndrome. English. 48. 2000:45-50. 

Nathan PJ, Burrows GD, Norman TR. Melatonin 

sensitivity to dim white light in affective disorders. 

English. 21. 1999:408-13. 

Nathan PJ, Burrows GD, Norman TR. The effect of 

dim light on suppression of nocturnal melatonin in 

healthy women and men. English. 104. 1997:643-8. 

Nathan PJ, Salmon K, Maguire KP, Burrows GD, 

Norman TR. The Pharmacodynamic Effects of Single 

Oral Doses of Melatonin in Humans. 1998. CN00283202. 

Nave R, Herer P, Haimov I, Shlitner A, Lavie P. 

Hypnotic and hypothermic effects of melatonin on 

daytime sleep in humans: lack of antagonism by 

flumazenil. English. 214. 1996:123-6. 

Nishiyama K, Yasue H, Moriyama Y et al. Acute 

effects of melatonin administration on cardiovascular 

autonomic regulation in healthy men. English. 141. 

2001:E9. 

O'Meara KH, Rogers NL, Powell IV JP, Carlin MM, 

Szuba MP, Dinges DF. Subjective adaptation during 

chronic sleep restriction at an adverse circadian phase. 

Sleep 2002; 25(Abstract Supplement):A310-1. 

Paccotti P, Terzolo M, Piovesan A, Torta M, Vignani 

A, Angeli A. Effects of exogenous melatonin on 

human pituitary and adrenal secretions Hormonal 

responses to specific stimuli after acute administration 

of different doses at two opposite circadian stages in 

men. English. 15. 1988:279-87. 

Park SJ, Tokura H. Bright light exposure during the 

daytime affects circadian rhythms of urinary 

melatonin and salivary immunoglobulin A. English. 

16. 1999:359-71. 

Parry BL, Cover H, Mostofi N et al. Early Versus Late 

Partial Sleep-Deprivation in Patients With 

Premenstrual Dysphoric Disorder and Normal 

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Paul MA, Brown G, Buguet A et al. Melatonin and 

zopiclone as pharmacologic aids to facilitate crew rest. 

English. 72. 2001:974-84. 

Pawlikowski M, Kolomecka M, Wojtczak A, Karasek 

M. Effects of six months melatonin treatment on sleep 

quality and serum concentrations of estradiol, cortisol, 

dehydroepiandrosterone sulfate, and somatomedin C 

in elderly women. English. 23. 2002:17-9. 

Peled N, Shorer Z, Peled E, Pillar G. Melatonin effect 

on seizures in children with severe neurologic deficit 

disorders. English. 42. 2001:1208-10. 

Pierard C, Beaumont M, Enslen M et al. 

Resynchronization of hormonal rhythms after an 

eastbound flight in humans: effects of slow-release 

caffeine and melatonin. English. 85. 2001:144-50. 

Ribeiro DC, Hampton SM, Morgan L, Deacon S, 

Arendt J. Altered postprandial hormone and metabolic 

responses in a simulated shift work environment. 

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Rice J, Mayor J, Tucker HA, Bielski RJ. Effect of 

light therapy on salivary melatonin in seasonal 

affective disorder. 56. 1995:221-8. CN-00186130; 

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Rogers NL, Phan O, Kennaway DJ, Dawson D. Effect 

of daytime oral melatonin administration on 

neurobehavioral performance in humans. English. 25. 

1998:47-53. 

Rogers NL, Van Dongen HP, Powell IV JW et al. 

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restriction at an adverse circadian phase. Sleep 2002; 

25(Abstract Supplement):A126-7. 
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Sack RL, Lewy AJ, Blood ML, Stevenson J, Keith 

LD. Melatonin administration to blind people: phase 

advances and entrainment. English. 6. 1991:249-61. 

Samel A, Wegmann HM, Vejvoda M, Maass H, 

Gundel A, Schutz M. Influence of melatonin treatment 

on human circadian rhythmicity before and after a 

simulated 9-hr time shift. English. 6. 1991:235-48. 

Satoh K, Mishima K. Hypothermic action of 

exogenously administered melatonin is dosedependent in humans. English. 24. 2001:334-40. 

Sharkey KM, Eastman CI. Melatonin phase shifts 

human circadian rhythms in a placebo-controlled 

simulated night-work study. English. 282. 

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Shilo L, Dagan Y, Smorjik Y et al. Effect of 

melatonin on sleep quality of COPD intensive care 

patients: a pilot study. English. 17. 2000:71-6. 

Siegrist C, Benedetti C, Orlando A et al. Lack of 

changes in serum prolactin, FSH, TSH, and estradiol 

after melatonin treatment in doses that improve sleep 

and reduce benzodiazepine consumption in sleepdisturbed, middle-aged, and elderly patients. English. 

30. 2001:34-42. 

Slotten HA, Krekling S. Does melatonin have an 

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melatonin in the treatment of jet lag. English. 52. 

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Strassman RJ, Qualls CR, Jonathan Lisansky E, Peake 

GT. Sleep deprivation reduces LH secretion in men 

independently of melatonin. English. 124. 1991:646-

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Suhner A, Schlagenhauf P, Tschopp A, Hauri-Bionda 

R, Friedrich-Koch A, Steffen R. Impact of melatonin 

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in human subjects. English. 323. 2002:17-20. 

Tanaka H, Araki A, Ito J, Tasaki T, Miyamoto A, Cho 

K. Improvement of hypertonus after treatment for 

sleep disturbances in three patients with severe brain 

damage. English. 19. 1997:240-4. 

Touitou Y, Benoit O, Foret J et al. Effects of a twohour early awakening and of bright light exposure on 

plasma patterns of cortisol, melatonin, prolactin and 

testosterone in man. English. 126. 1992:201-5. 

Tozawa T, Mishima K, Satoh K et al. Melatonin 

replacement therapy for rest-activity rhythm disorders 

in patients with senile dementia of Alzheimer's type. 

1998. CN-00285146. 

Trinder J, Armstrong SM, O'Brien C, Luke D, Martin 

MJ. Inhibition of melatonin secretion onset by low 

levels of illumination. English. 5. 1996:77-82. 

Tzischinsky O, Lavie P. Melatonin possesses timedependent hypnotic effects. English. 17. 1994:638-45. 

Uchiyama M, Okawa M, Shibui K et al. Poor recovery 

sleep after sleep deprivation in delayed sleep phase 

syndrome. English. 53. 1999:195-7. 

van de Luit L, van der Meulen J, Cleophas TJ, 

Zwinderman AH. Amplified amplitudes of circadian 

rhythms and nighttime hypotension in patients with 

chronic fatigue syndrome: improvement by inopamil 

but not by melatonin. English. 49. 1998:903-8. 

Wassmer E, Carter PF, Quinn E et al. Melatonin is 

useful for recording sleep EEGs: a prospective audit of 

outcome. English. 43. 2001:735-8. 

Wassmer E, Quinn E, Whitehouse W, Seri S. 

Melatonin as a sleep inductor for 

electroencephalogram recordings in children. English. 

112. 2001:683-5. 

Williams G, Waterhouse J, Mugarza J, Minors D, 

Hayden K. Therapy of circadian rhythm disorders in 

chronic fatigue syndrome: no symptomatic 

improvement with melatonin or phototherapy. 

English. 32. 2002:831-7. 

Wirz-Justice A, Werth E, Renz C, Muller S, Krauchi 

K. No evidence for a phase delay in human circadian 

rhythms after a single morning melatonin 

administration. English. 32. 2002:1-5. 

Zaidan R, Geoffriau M, Brun J et al. Melatonin is able 

to influence its secretion in humans: description of a 

phase-response curve. English. 60. 1994:105-12. 

Zhdanova IV, Piotrovskaya VR. Melatonin treatment 

attenuates symptoms of acute nicotine withdrawal in 

humans. English. 67. 2000:131-5. 

Zimmermann RC, Krahn L, Klee G, Delgado P, Ory 

SJ, Lin SC. Inhibition of presynaptic catecholamine 

synthesis with alpha-methyl-para-tyrosine attenuates 

nocturnal melatonin secretion in humans. English. 79. 

1994:1110-4.
150

Excluded-Reporting 

The following studies did not provide an adequate amount of information 

regarding their outcomes for their inclusion in the quantitative analysis. 

Cardinali DP, Gvozdenovich E, Kaplan MR et al. A 

double blind-placebo controlled study on melatonin 

efficacy to reduce anxiolytic benzodiazepine use in the 

elderly. English . 23. 2002:55-60. 

Lushington K, Pollard K, Lack L, Kennaway DJ, 

Dawson D. Daytime melatonin administration in 

elderly good and poor sleepers: effects on core body 

temperature and sleep latency. English. 20. 

1997:1135-44. 

Spitzer RL, Terman M, Williams JB et al. Jet lag: 

clinical features, validation of a new syndromespecific scale, and lack of response to melatonin in a 

randomized, double-blind trial. English. 156. 

1999:1392-6. 

Excluded-Un-Obtainable 

The reports of the following studies could not be obtained. 

Arendt J. Investigations on the Use of Light and 

Melatonin for Alleviation of Problems Related to 

Jetlag and Shift Work. Biologic Effects of Light; 

1993; 219-27. 

Arendt J, Aldhous M. Further evaluation of the 

treatment of jet-lag by melatonin: a double-blind 

crossover study. Annual Review of 

Chronopharmacology 1988; 5:53-5. 

Arendt J, Aldhous M, Wright J. Synchronization of a 

disturbed sleep-wake cycle in a blind man by 

melatonin treatment. 1. 1988:772-3. 

Boivin DB, Czeisler CA, Investigator: Czeisler CA. 

Resetting of circadian melatonin and cortisol rhythms 

in humans by ordinary room light. English. 9. 

1998:779-82. 

Claustrat B, Brun J, Geoffriau M, Zaidan R, Mallo C, 

Chazot G. Nocturnal plasma melatonin profile and 

melatonin kinetics during infusion in status 

migrainosus. English. 17. 1997:511-7; discussion 487. 

Cole RJ CLKDAKEJaRK. Light mask treatment of 

circadian phase disorders. Conference abstract. 1997. 

CN-00279503. 

Dollins AB, Lynch HJ, Deng MH, Wurtman RJ, 

Lieberman HR. Effects of bright light on human 

nocturnal performance, mood and serum melatonin 

levels. 17. 1991:729. 

Effects of Exogenous Melatonin on Mood and Sleep 

Efficiency in EM Residents Working Night Shifts. 

Academic Emergency Medicine 1999; 6(Number 

5):502. 

Haworth J. A pilot, double-blind, placebo controlled, 

parellel group study of the effect of melatonin 

treatment in patients with Alzheimer's disease and 

sleep. 2001. CN-00342737. 

Ho SC. Sleep regulation in old people: the role of 

bright light and melatonin. English.2001:400 p. 

Ishizaki A, Sugama M, Takeuchi N. Usefulness of 

melatonin for developmental sleep and 

emotional/behavior disorders--studies of melatonin 

trial on 50 patients with developmental disorders 

[Japanese]. Japanese. 31. 1999:428-37. 

Kato M, Kajimura N, Sekimoto M, Watanabe T. 

Melatonin treatment for rhythm disorder. Psychiatry 

and Clinical Neurosciences 1998; 52(Number 2):262-

3. 

Kendel K, Cramer H, Wita C. Influence of melatonin 

on EEG and human sleep: automatic EEG analyses 

and polygraphic night sleep investigations [abstract]. 

34. 1973:698-9. CN-00300970. 

Krahn LE, Lu PY, Klee G, Lin S-C, Zimmermann RC. 

The Effect of Modified Acute Tryptophan Depletion 

on Melatonin and Sleep Architecture. 1996. CN00215506. 

 Lavie P, Luboshitzky R. Melatonin: Possible Role in 

Human Sleep and Reproduction. Symposium; 9th: 

Bioscience. ?, 190?: 209-22. 

Moreno J, Belmont A, Heinze G et al. 

Chronopharmacology of melatonin in a group of 

normal subjects in Mexico city. Spanish. 20. 1997:8-

12. 1998022130). 
151

Nathan PJ SKMKBGaNT. The Pharmacokinetics of 

Different Oral Formulations of Melatonin: An Acute 

Study in Humans. 1998. CN-00283203. 

Neuroendocrinology Letters 2001; 22(No 4). 

Reiter EKGSRUMWFaBG. Sleeping disorders in 

retarded children: Does Melatonin have a sustained 

sleep-inducing effect? 147. 1999:907. CN-00339080. 

Rodenbeck A, Hajak G, Cohrs S, Staedt J. 

Desynchronisation Between Light - Dark Cycle, Sleep 

- Wake Rhythm and Circadian Melatonin: Treatment 

of "Sleep - Wake Rhythm Disorders". Biometeorology 

-International Congress 1996; 14 abstracts(1):105. 

Sack LR and Lewy LA. Melatonin Advances 

Circadian Rhythms In Humans. 1988. CN-00284219. 

Serfaty M. Double-blind randomised controlled crossover trial to determine the effect of low dose 

melatonin on sleep disorders in the elderly. 2000. CN00303217. 

Singer C, Colling E, Tractenberg R et al. The Adcs 

Clinical Trial of Melatonin for the Sleep Disturbance 

of Alzheimer's Disease: Case Report of an Unusual 

Sleep/Wake Cycle and Response to Melatonin. 

English. 10. 2002:92. 

Smith MG. Impact of sleep/wake schedule disorders at 

daytime functioning: influence of melatonin. 6. 

1999:177. CN-00309319. 

Wehr TA, Moul DE, Barbato G et al. Conservation of 

photoperiod-responsive mechanisms in humans. 

English. 265. 1993:R846-57.

Addendum 

The authors acknowledge the existence of the following two studies, which they 

became aware of only upon completion of the final report. 

Garfinkel D, Laudon M, Zisapel N. Improvement of 

sleep quality by controlled-release melatonin in 

benzodiazepine-treated elderly insomniacs. English. 

24. 1997:223-31. 1997049410). 

Smits MG, Nagtegaal EE, van der Heijden J, Coenen 

AM, Kerkhof GA. Melatonin for chronic sleep onset 

insomnia in children: a randomized placebo-controlled 

trial. English. 16. 2001:86-92.

Definitions of Terminology 

The definitions of key words, as they are used in this report, are provided below. 

endogenous melatonin = melatonin levels in either blood/serum/plasma, urine, saliva or 

cerebrospinal fluid and/or phase of melatonin rhythm in either 

blood/serum/plasma, urine, saliva or cerebrospinal fluid 

effectiveness = the degree to which an intervention does what it is intended to do, under 

ordinary conditions 

exogenous melatonin =melatonin that is administered to individuals from a source 

outside of the body 

half-life of melatonin (t1/2) = time required for circulating levels of melatonin to be 

reduced to half of its peak value 

percentage time in REM sleep (% time spent in REM sleep)= amount of time spent in 

REM sleep expressed as a percentage of total sleep time 

REM latency = amount of time required to begin REM sleep after sleep onset 

sleep disorder = primary sleep disorder, secondary sleep disorder, sleep restriction 

• primary sleep disorder = sleep disorder is not accompanied by another clinical 

problem that could potentially be its cause 

• secondary sleep disorder = sleep disorder is accompanied by another clinical 

problem that may be its cause 

• sleep restriction = sleep disorder is due to altered sleep schedules or transmeridian 

air travel, such as in shift-work disorder and jet-lag, respectively. 

sleep efficiency = amount of time spent asleep expressed as a percentage of the time 

spent in bed

sleep onset latency (SOL) = amount of time required before the onset of stage one sleep 

after retiring to bed 

sleep quality = overall quality of sleep 

total sleep time (TST)= total time spent asleep while in bed 

wakefulness after sleep onset (WASO) = amount of time spent awake in bed following

first attainment of stage one sleep 

153
1

Appendix A: Exact Search Strings 

Search Strategies 

Evidence Table A-1: MEDLINE: melatonin and sleep disorders 

Evidence Table A-2: EMBASE: melatonin and sleep disorders 

Evidence Table A-3: CINAHL: melatonin and sleep disorders 

Evidence Table A-4: CENTRAL: melatonin and sleep disorders 

Evidence Table A-5: Science Citation Index: melatonin and sleep disorders 

Evidence Table A-6: Global Health [CAB Health]: melatonin and sleep disorders 

Evidence Table A-7: PubMed: melatonin and sleep disorders
2

Evidence Table A-1: MEDLINE: melatonin and sleep disorders

MEDLINE 1966 to June, Week 3, 2003 

Set # and Keyword Search 

1. exp MELATONIN/ 

2. melatonin.mp. 

3. melatonine.mp. 

4. 73-31-4.rn. 

5. 5-Methoxy-N-acetyltryptamine.mp. 

6. N-Acetyl-5-methoxytryptamine.mp. 

7. luzindole.mp. 

8. or/1-7 

9. exp Sleep Disorders/ 

10. sleep disorder$.mp. 

11. dyssomnia$.mp. 

12. insomnia$.mp. 

13. narcoleps$.mp. 

14. hypersomnia$.mp. 

15. central alveolar hypoventilat$.mp. 

16. periodic limb movement$.mp. 

17. restless leg.mp. 

18. nocturnal eating.mp. 

19. nocturnal drinking.mp. 

20. time-zone change$.mp. 

21. jet lag.mp. 

22. parasomnia$.mp. 

23. confusional arousal$.mp. 

24. rhythmic movement disorder$.mp. 

25. nocturnal leg cramp$.mp. 

26. nightmare$.mp. 

27. nocturnal paroxysmal dystonia$.mp. 

28. sudden unexplained nocturnal death syndrome.mp. 

29. SUNDS.mp. 

30. snoring.mp. 

31. snore$.mp. 

32. congenital central hypoventilation.mp. 

33. sudden infant death syndrome$.mp. 

34. exp Sudden Infant Death/ 

35. SIDS.mp. 

36. subwakefulness.mp. 

37. fragmentary myoclonus.mp. 

38. hypnagogic hallucination$.mp. 

39. (sleep$ or circadian$).mp. 

40. exp Sleep/ 

41. exp arousal/ 

42. or/9-41 

43. 8 and 42 

44. RANDOMIZED CONTROLLED TRIAL.pt. 

45. CONTROLLED CLINICAL TRIAL.pt. 

46. RANDOMIZED CONTROLLED TRIALS/ 

47. RANDOM ALLOCATION/ 

48. DOUBLE BLIND METHOD/ 

49. SINGLE-BLIND METHOD/ 

50. or/44-49 

51. ANIMAL/ not HUMAN/ 

52. 50 not 51 

53. CLINICAL TRIAL.pt. 

54. exp CLINICAL TRIALS/ 

55. (clin$ adj25 trial$).ti,ab. 

56. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab. 
3

Evidence Table A-1: MEDLINE: melatonin and sleep disorders (continued) 

Medline 1966 to June, Week 3, 2003 

Set # and Keyword Search 

57. PLACEBOS/ 

58. placebo$.ti,ab. 

59. random$.ti,ab. 

60. RESEARCH DESIGN/ 

61. or/53-60 

62. 61 not 51 

63. 62 not 52 

64. COMPARATIVE STUDY/ 

65. exp EVALUATION STUDIES/ 

66. FOLLOW UP STUDIES/ 

67. PROSPECTIVE STUDIES/ 

68. (control$ or prospectiv$ or volunteer$ or cohort$ or case series).ti,ab,sh. 

69. or/64-68 

70. 69 not 51 

71. 70 not (52 or 63) 

72. 52 or 63 or 70 

73. meta-analysis.pt. 

74. (meta-anal$ or metaanal$).mp. 

75. (((quantitativ$ adj3 review$1) or quantitativ$) adj3 overview$).mp. 

76. (((systematic adj3 review$1) or systematic) adj3 overview$1).mp. 

77. (((methodologic adj3 review$1) or methodologic) adj3 overview$).mp. 

78. (integrat$ adj5 research).mp. 

79. (quantitativ$ adj3 synthes$).mp. 

80. or/73-79 

81. review.pt. or (review$ or overview$).mp. 

82. (medline or medlars or pubmed or index medicus or embase or cochrane).mp. 

83. (scisearch or web of science or psycinfo or psychinfo or cinahl or cinhal).mp. 

84. (excerpta medica or psychlit or psyclit or current contents or science citation index or sciences citation 

index).mp. 

85. (hand search$ or manual search$).mp. 

86. ((((electronic adj3 database$) or bibliographic) adj3 database$) or periodical index$).mp. 

87. (pooling or pooled or mantel haenszel).mp. 

88. (peto or der simonian or dersimonian or fixed effect$).mp. 

89. ((combine$ or combining) adj5 (data or trial or trials or studies or study or result or results)).mp. 

90. or/82-89 

91. 81 and 90 

92. 80 or 91 

93. (hta$ or health technology assessment$ or biomedical technology assessment$).mp. 

94. technology assessment, biomedical/ or biomedical technology asssessment/ 

95. 93 or 94 

96. 92 or 95 

97. limit 43 to review 

98. 43 and 96 

99. 97 or 98 

100. 43 and 72 

101. 99 not 100 

102. limit 100 to human 

103. limit 101 to human
4

Evidence Table A-2: EMBASE: melatonin and sleep disorders 

EMBASE 1988 to Week 26, 2003 

Set # and Keyword Search

1. exp MELATONIN/ 

2. melatonin.mp. 

3. melatonine.mp. 

4. 73-31-4.rn. 

5. 5-Methoxy-N-acetyltryptamine.mp. 

6. N-Acetyl-5-methoxytryptamine.mp. 

7. luzindole.mp. 

8. or/1-7 

9. exp Sleep Disorders/ 

10. sleep disorder$.mp. 

11. dyssomnia$.mp. 

12. insomnia$.mp. 

13. narcoleps$.mp. 

14. hypersomnia$.mp. 

15. central alveolar hypoventilat$.mp. 

16. periodic limb movement$.mp. 

17. restless leg.mp. 

18. nocturnal eating.mp. 

19. nocturnal drinking.mp. 

20. time-zone change$.mp. 

21. jet lag.mp. 

22. parasomnia$.mp. 

23. confusional arousal$.mp. 

24. rhythmic movement disorder$.mp. 

25. nocturnal leg cramp$.mp. 

26. nightmare$.mp. 

27. nocturnal paroxysmal dystonia$.mp. 

28. sudden unexplained nocturnal death syndrome.mp. 

29. SUNDS.mp. 

30. snoring.mp. 

31. snore$.mp. 

32. congenital central hypoventilation.mp. 

33. sudden infant death syndrome$.mp. 

34. exp Sudden Infant Death/ 

35. SIDS.mp. 

36. subwakefulness.mp. 

37. fragmentary myoclonus.mp. 

38. hypnagogic hallucination$.mp. 

39. (sleep$ or circadian$).mp. 

40. exp Sleep/ 

41. exp arousal/ 

42. exp wakefulness/ 

43. or/9-42 

44. exp Melatonin Receptor/ 

45. exp MELATONIN DERIVATIVE/ 

46. or/8,44-45 

47. 46 and 43 

48. Randomized Controlled Trial/ 

49. exp Randomization/ 

50. Double Blind Procedure/ 

51. Single Blind Procedure/ 

52. or/48-51 

53. Clinical Trial/ 

54. (clin$ adj25 trial$).mp. 

55. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).mp. 

56. exp Placebo/ 

57. (placebo$ or random$).mp.
5

Evidence Table A-2: EMBASE: melatonin and sleep disorders (continued) 

EMBASE 1988 to Week 26, 2003 

Set # and Keyword Search

58. exp Methodology/ 

59. exp Comparative Study/ 

60. exp Evaluation/ 

61. exp Follow Up/ 

62. exp Prospective Study/ 

63. (control$ or prospectiv$ or volunteer$).mp. 

64. or/53-63 

65. 52 or 64 

66. (cohort$ or case series).mp. 

67. exp cohort analysis/ 

68. exp Case Study/ 

69. or/66-68 

70. or/65,69 

71. meta-analysis.pt. 

72. (meta-anal$ or metaanal$).mp. 

73. (((quantitativ$ adj3 review$1) or quantitativ$) adj3 overview$).mp. 

74. (((systematic adj3 review$1) or systematic) adj3 overview$1).mp. 

75. (((methodologic adj3 review$1) or methodologic) adj3 overview$).mp. 

76. (integrat$ adj5 research).mp. 

77. (quantitativ$ adj3 synthes$).mp. 

78. or/71-77 

79. review.pt. or (review$ or overview$).mp. 

80. (medline or medlars or pubmed or index medicus or embase or cochrane).mp. 

81. (scisearch or web of science or psycinfo or psychinfo or cinahl or cinhal).mp. 

82. (excerpta medica or psychlit or psyclit or current contents or science citation index or sciences citation 

index).mp. 

83. (hand search$ or manual search$).mp. 

84. ((((electronic adj3 database$) or bibliographic) adj3 database$) or periodical index$).mp. 

85. (pooling or pooled or mantel haenszel).mp. 

86. (peto or der simonian or dersimonian or fixed effect$).mp. 

87. ((combine$ or combining) adj5 (data or trial or trials or studies or study or result or results)).mp. 

88. or/80-87 

89. 79 and 88 

90. 78 or 89 

91. (hta$ or health technology assessment$ or biomedical technology assessment$).mp. 

92. technology assessment, biomedical/ or biomedical technology asssessment/ 

93. 91 or 92 

94. 90 or 93 

95. Review/ 

96. 94 or 95 

97. 47 and 70 

98. 47 and 96 

99. limit 97 to human 

100. limit 98 to human 

101. Nonhuman/ 

102. 99 not 101 

103. 100 not 101
6

Evidence Table A-3: CINAHL: melatonin and sleep disorders 

CINAHL 1982 to June Week 4, 2003 

Set # and Keyword Search

1. exp MELATONIN/ 

2. melatonin.mp. 

3. melatonine.mp. 

4. 73-31-4.rn. 

5. 5-Methoxy-N-acetyltryptamine.mp. 

6. N-Acetyl-5-methoxytryptamine.mp. 

7. luzindole.mp. 

8. or/1-7 

9. exp Sleep Disorders/ 

10. sleep disorder$.mp. 

11. dyssomnia$.mp. 

12. insomnia$.mp. 

13. narcoleps$.mp. 

14. hypersomnia$.mp. 

15. central alveolar hypoventilat$.mp. 

16. periodic limb movement$.mp. 

17. restless leg.mp. 

18. nocturnal eating.mp. 

19. nocturnal drinking.mp. 

20. time-zone change$.mp. 

21. jet lag.mp. 

22. parasomnia$.mp. 

23. confusional arousal$.mp. 

24. rhythmic movement disorder$.mp. 

25. nocturnal leg cramp$.mp. 

26. nightmare$.mp. 

27. nocturnal paroxysmal dystonia$.mp. 

28. sudden unexplained nocturnal death syndrome.mp. 

29. SUNDS.mp. 

30. snoring.mp. 

31. snore$.mp. 

32. congenital central hypoventilation.mp. 

33. sudden infant death syndrome$.mp. 

34. exp Sudden Infant Death/ 

35. SIDS.mp. 

36. subwakefulness.mp. 

37. fragmentary myoclonus.mp. 

38. hypnagogic hallucination$.mp. 

39. (sleep$ or circadian$).mp. 

40. exp Sleep/ 

41. exp arousal/ 

42. exp wakefulness/ 

43. or/9-42 

44. 8 and 43 

45. random assignment/ 

46. random sample/ 

47. crossover design/ 

48. exp clinical trials/ 

49. exp comparative studies/ 

50. "control (research)".mp. 

51. control group/ 

52. factorial design/ 

53. quasi-experimental studies/ 

54. nonrandomized trials/ 

55. placebos/ 

56. meta analysis/ 

57. clinical nursing research.mp. or clinical research/
7

Evidence Table A-3: CINAHL: melatonin and sleep disorders (continued) 

CINAHL 1982 to June Week 4, 2003 

Set # and Keyword Search 

58. community trials/ or experimental studies/ or one-shot case study/ 

59. community trials/ or experimental studies/ or one-shot case study/ or pretest-posttest design/ or solomon 

four-group design/ or static group comparison/ or study design/ 

60. (clinical trial or systematic review).pt. 

61. random$.mp. 

62. ((singl$ or doubl$ or tripl$ or trebl$) adj10 (blind$ or mask$)).mp. 

63. (cross?over or placebo$ or control$ or factorial or sham$).mp. 

64. ((clin$ or intervention$ or compar$ or experiment$ or preventive or therapeutic) adj10 trial$).mp. 

65. (meta?analy$ or systematic review$).mp. 

66. or/45-65 

67. convenience sample/ 

68. exp research, allied health/ or research, medical/ or research, nursing/ 

69. research question/ 

70. nursing practice, research-based/ 

71. research methodology/ 

72. exp evaluation research/ 

73. [evaluation/mt] 

74. concurrent prospective studies/ or prospective studies/ 

75. (nursing interventions or research).pt. 

76. or/67-75 

77. 66 or 76 

78. 44 and 77 

79. meta-analysis.pt. 

80. (meta-anal$ or metaanal$).mp. 

81. (((quantitativ$ adj3 review$1) or quantitativ$) adj3 overview$).mp. 

82. (((systematic adj3 review$1) or systematic) adj3 overview$1).mp. 

83. (((methodologic adj3 review$1) or methodologic) adj3 overview$).mp. 

84. (integrat$ adj5 research).mp. 

85. (quantitativ$ adj3 synthes$).mp. 

86. or/79-85 

87. review.pt. or (review$ or overview$).mp. 

88. (medline or medlars or pubmed or index medicus or embase or cochrane).mp. 

89. (scisearch or web of science or psycinfo or psychinfo or cinahl or cinhal).mp. 

90. (excerpta medica or psychlit or psyclit or current contents or science citation index or sciences citation 

index).mp. 

91. (hand search$ or manual search$).mp. 

92. ((((electronic adj3 database$) or bibliographic) adj3 database$) or periodical index$).mp. 

93. (pooling or pooled or mantel haenszel).mp. 

94. (peto or der simonian or dersimonian or fixed effect$).mp. 

95. ((combine$ or combining) adj5 (data or trial or trials or studies or study or result or results)).mp. 

96. or/88-95 

97. 87 and 96 

98. 86 or 97 

99. (hta$ or health technology assessment$ or biomedical technology assessment$).mp. 

100. technology assessment, biomedical/ or biomedical technology asssessment/ 

101. 99 or 100 

102. 98 or 101 

103. limit 44 to (review or systematic review) 

104. or/102-103 

105. 44 and 104 

106. cohort.mp. 
8

Evidence Table A-3: CINAHL: melatonin and sleep disorders (continued) 

CINAHL 1982 to June Week 4, 2003 

Set # and Keyword Search 

107. case series.mp. 

108. exp case studies/ 

109. case study.pt. 

110. or/106-108 

111. 44 and 110 

112. 105 not 78 

113. 78 or 111 
9

Evidence Table A-4: CENTRAL: melatonin and sleep disorders 

CENTRAL - Issue 2 2003 3rd Quarter, 2003 

Set # and Keyword Search 

1. MELATONIN single term (MeSH) 316 

2. melatonin 454 

3. melatonine 2 

4. 73-31-4 0 

5. 5-methoxy-n-acetyltryptamine 0 

6. n-acetyl-5-methoxytryptamine 6 

7. luzindole 0 

8. (1 or 2 or 3 or 4 or 5 or 6 or 7) 456 

9. SLEEP DISORDERS explode all trees (MeSH) 1643 

10. dyssomnia* 3 

11. insomnia* 1625 

12. narcoleps* 73 

13. hypersomnia* 66 

14. (central next alveolar next hypoventilat*) 0 

15. (periodic next limb next movement*) 30 

16. (restless next leg) 9 

17. (nocturnal next eating) 1 

18. (nocturnal next drinking) 0 

19. (time-zone next change*) 0 

20. (jet next lag) 33 

21. parasomnia* 12 

22. (confusional next arousal*) 0 

23. (rhythmic next movement next disorder*) 0 

24. (nocturnal next leg next cramp*) 20 

25. nightmare* 90 

26. (nocturnal next paroxysmal next dystonia*) 1 

27. (sudden next unexplained next nocturnal next death next syndrome) 0 

28. sunds 0 

29. snoring 156 

30. snore* 76 

31. (congential next central next hypoventilation) 0 

32. (sudden next infant next death next syndrome*) 41 

33. sids 27 

34. subwakefulness 0 

35. (fragmentary next myoclonus) 0 

36. (hypnagogic next hallucination*) 2 

37. sleep* or circadian* 8680 

38. SLEEP explode all trees (MeSH) 2300 

39. AROUSAL explode all trees (MeSH) 3330 

40. (9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 

27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39) 12449 

41. (8 and 40) 290 

 
10

Evidence Table A-5: Science Citation Index: melatonin and sleep disorders 

Science Citation Index Search performed July 4, 2003

Set # Results Search History 

28 265 21 OR 22 OR 23 OR 24 OR 25 OR 26 OR 27 DocType=All document types; 

Language=All languages; Database(s)=SCI-EXPANDED, SSCI, A&HCI; 

Timespan=1975-2003 

27 44 8 AND 17 DocType=All document types; Language=All languages; 

Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

26 177 8 AND 16 DocType=All document types; Language=All languages; 

Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

25 27 #8 AND #15 DocType=All document types; Language=All languages; 

Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

24 151 8 AND 14 DocType=All document types; Language=All languages; 

Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

23 9 8 AND 13 DocType=All document types; Language=All languages; 

Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

22 18 8 AND 12 DocType=All document types; Language=All languages; 

Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

21 12 8 AND 11 DocType=All document types; Language=All languages; 

Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

20 48 #18 OR #19 DocType=All document types; Language=All languages; 

Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

19 13 #8 AND #10 DocType=All document types; Language=All languages; 

Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

18 36 #8 AND #9 DocType=All document types; Language=All languages; 

Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

17 >100,000 TS=random* DocType=All document types; Language=All languages; 

Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

16 67,296 TS=placebo* DocType=All document types; Language=All languages; 

Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

15 69,106 TS=clinical trial* DocType=All document types; Language=All languages; 

Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

14 69,590 TS=(single-blind*) OR TS=(double-blind*) DocType=All document types; 

Language=All languages; Database(s)=SCI-EXPANDED, SSCI, A&HCI; 

Timespan=1975-2003 

13 68,166 TS=cohort* OR TS=case series DocType=All document types; Language=All 

languages; Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

12 >100,000 TS=follow up OR TS=prospective DocType=All document types; Language=All 

languages; Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

11 32,268 TS=randomized controlled trial* OR TS=controlled clinical trial* OR TS=random 

allocation OR TS=randomly allocated OR TS=research design OR TS=comparative 

stud* OR TS=evaluation stud* DocType=All document types; Language=All 

languages; Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

10 74,601 TS=quantitative synthes* OR TS=hta* OR TS=(health technology assessment*) OR 

TS=(biomedical technology assessment*) OR TS=meta analys* OR TS=metaanalys* OR TS=metaanalys* OR TS=(quantitativ* review*) OR TS=(quantitativ* 

overview*) OR TS=overview* DocType=All document types; Language=All 

languages; Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

9 >100,000 TS=review* DocType=All document types; Language=All languages; 

Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

8 1,468 #6 AND #7 DocType=All document types; Language=All languages; 

Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 
11

Evidence Table A-5: Science Citation Index: melatonin and sleep disorders (continued) 

Science Citation Index Search performed July 4, 2003 

Set # Results Search History 

7 67,627 TS=sleep disorder* OR TS=dyssomnia* OR TS=insomnia* OR TS=narcoleps* OR 

TS=hypersomnia* OR TS=central alveolar hypoventilat* OR TS=periodic limb 

movement* OR TS=restless leg OR TS=nocturnal eating OR TS=nocturnal drinking 

OR TS=time zone* OR TS=jet lag* OR TS=parasomnia* OR TS=confusional arousal* 

OR TS=rhythmic movement disorder* OR TS=nocturnal leg cramp* OR 

TS=nightmare* OR TS=nocturnal paroxysmal dystonia* OR TS=sudden unexplained 

nocturnal death syndrome* OR TS=SUNDS OR TS=snore* OR TS=snoring OR 

TS=congenital central hypoventilation OR TS=(sudden infant death syndrome) OR 

TS=SIDS OR TS=subwakefulness OR TS=fragmentary myoclonus OR 

TS=hypnagogic hallucination* OR TS=sleep* OR TS=circadian OR TS=arousal OR 

TS=arouse DocType=All document types; Language=All languages; 

Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

6 11,454 #1 OR #2 OR #3 OR #4 OR #5 DocType=All document types; Language=All 

languages; Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

5 92 TS=luzindole DocType=All document types; Language=All languages; 

Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

4 80 TS=N-Acetyl-5-methoxytryptamine DocType=All document types; Language=All 

languages; Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

3 15 TS=5-Methoxy-N-acetyltryptamine DocType=All document types; Language=All 

languages; Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

2 1 TS=73-31-4 DocType=All document types; Language=All languages; 

Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 

1 11,450 TS=melatonin OR TS=melatonine DocType=All document types; Language=All 

languages; Database(s)=SCI-EXPANDED, SSCI, A&HCI; Timespan=1975-2003 
12

Evidence Table A-6: Global Health [CAB Health]: melatonin and sleep disorders 

Global Health [CAB Health] Search performed July 8, 2003

Set # and Keyword Search

Set Items Description

S1 203 MELATONIN OR MELATONINE OR 5?METHOXY?N?ACETYLTRYPTAMINE OR 

N?ACETYL?5?METHOXYTRYPTAMINE OR LUZINDOLE 

S2 2735 SLEEP? OR DYSSOMNIA? OR INSOMNIA? OR NARCOLEPS? OR HYPERSOMNIA? 

S3 287 PARASOMNIA? OR NIGHTMARE? OR SUNDS OR SNORING OR SNORE? OR SIDS 

S4 1502 SUBWAKEFUL? OR AROUS? OR CIRCADIAN 

S5 0 CENTRAL(W)ALVEOLAR(W)HYPOVENTILAT? 

S6 0 PERIODIC(W)LIMB(W)MOVEMENT? 

S7 6 RESTLESS(W)LEG? 

S8 13 NOCTURNAL(W)EAT? 

S9 5 NOCTURNAL(W)DRINK? 

S10 9 TIME?ZONE? OR TIME(W)ZONE? 

S11 17 JET?LAG? OR JET(W)LAG? 

S12 0 CONFUSIONAL(W)AROUS? 

S13 0 RHYTHMIC(W)MOVEMENT(W)DISORDER? 

S14 4 NOCTURNAL(W)LEG(W)CRAMP? 

S15 0 NOCTURNAL(W)PAROXYSMAL(W)DYSTONIA? 

S16 1 SUDDEN(W)UNEXPLAINED(W)NOCTURNAL(W)DEATH(W)SYNDROME? 

S17 0 CONGENITAL(W)CENTRAL(W)HYPOVENTILAT? 

S18 435 SUDDEN(W)INFANT(W)DEATH? 

S19 0 FRAGMENTARY(W)MYOCLUNUS 

S20 0 HYPNAGOGIC(W)HALLUCINATION? 

S21 3 CATAPLEX? OR NIGHT(W)TERROR? 

S22 4530 S2 OR S3 OR S4 OR S7 OR S8 OR S9 OR S10 OR S11 OR S14 OR S16 OR S18 OR S 

21 

S23 36 S1 AND S22 
13

Evidence Table A-7: PubMed: melatonin and sleep disorders 

PubMed Search performed July 9, 2002

Set # and Keyword Search 

Search Most Recent Queries Time Result 

20 Search 17 NOT 16 Field: All Fields, Limits: 180 Days, Human 14:53:23 7 

18 Search 17 NOT 16 14:52:57 525 

19 Search 13 AND 14 Field: All Fields, Limits: 180 Days, Human 14:52:41 21 

16 Search 13 AND 14 14:52:23 1146 

17 Search 13 AND 15 14:51:59 729 

15 Search (meta analys*) OR (metaanalys*) OR (review*) OR (overview*) 

OR (quantitative synthes*) OR (HTA) OR (health technology 

assessment) OR (biomedical technology assessment) OR 

(systematic[sb]) 

14:51:29 1287351 

14 Search (randomized controlled trial [PTYP] OR drug therapy [SH] OR 

therapeutic use [SH:NOEXP] OR random* [WORD]) OR (random 

allocation) OR (randomly allocated) OR (single blind*) OR (double blind*) 

OR (clinical trial*) OR (placebo*) OR (research design*) OR 

(comparative stud*) OR (evaluation stud*) OR (follow up stud*) OR 

(prospective stud*) OR (cohort*) OR (case series) 

14:51:11 2845077 

13 Search #11 AND #12 14:50:53 4218 

12 Search ((sleep [MESH]) OR (Sleep Disorders [MESH]) OR (Arousal 

[MESH]) OR (sleep*) OR (sleep disorder*) OR (dyssomnia*) OR 

(insomnia*) OR (narcoleps*) OR (hypersomnia*) OR (central alveolar 

hypoventilat*) OR (periodic limb movement*) OR (nocturnal eating) OR 

(nocturnal drinking) OR (time-zone*) OR (time zone*) OR (jet lag*) OR 

(parasomnia*) OR (confusional arousal*) OR (rhythmic movement 

disorder*) OR (nocturnal leg cramp*) OR (nightmare*) OR (nocturnal 

paroxysmal dystonia*) OR (sudden unexplained nocturnal death 

syndrome*) OR (SUNDS) OR (snoring) OR (snore*) OR (congential 

central hypoventilat*) OR (sudden infant death syndrome*) OR (SIDS) 

OR (subwakefulness) OR (fragmentary mycoclonus) OR (hypnagogic 

hallucination*) OR (arous*) OR (circadian)) 

14:50:17 163039 

11 Search (Melatonin [MESH]) OR (Melatonin*) OR (73-31-4) OR (5-

Methoxy-N-acetyltryptamine) OR (N-Acetyl-5-methoxytryptamine) OR 

(luzindole) OR (N-acetyl-methoxytryptamine)) 

14:49:37 10374 
14

BIO ABS Search performed July 4, 2003

Keyword Search

((randomized controlled trial*) or (controlled clinical trial*) or (random allocation) or (randomly allocated) or 

(single blind*) or (double blind*) or (clinical trial*) or (placebo*) or (research design*) or (comparative stud*) 

or (evaluation stud*) or (follow up stud*) or (prospective stud*) or (cohort*) or (case series) or (meta analys*) 

or (metaanalys*) or (review*) or (overview*) or (quantitative synthes*) or (HTA) or (health technology 

assessment) or (biomedical technology assessment) or (random*)) and (((Melatonin*) or (73-31-4) or (5-

Methoxy-N-acetyltryptamine) or (N-Acetyl-5-methoxytryptamine) or (luzindole) or (N-acetylmethoxytryptamine) or (N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)acetamide) or (3-(2-acetamidoethyl)-5-

methoxyindole) or (N-(2-(5-Methyxyindol-3-yl)ethyl)acetamide)) and ((sleep*) or (sleep disorder*) or 

(dyssomnia*) or (insomnia*) or (narcoleps*) or (hypersomnia*) or (central alveolar hypoventilat*) or (periodic 

limb movement*) or (nocturnal eating) or (nocturnal drinking) or (time-zone*) or (time zone*) or (jet lag*) or 

(parasomnia*) or (confusional arousal*) or (rhythmic movement disorder*) or (nocturnal leg cramp*) or 

(nightmare*) or (nocturnal paroxysmal dystonia*) or (sudden unexplained nocturnal death syndrome*) or 

(SUNDS) or (snoring) or (snore*) or (congential central hypoventilat*) or (sudden infant death syndrome*) or 

(SIDS) or (subwakefulness) or (fragmentary mycoclonus) or (hypnagogic hallucination*) or (arous*) or 

(circadian))) 

International Pharmaceutical Abstracts 1970 to August, 2003 

This database was searched using the same strategy as for MEDLINE. 

PreMEDLINE Search performed June 30and July 4, 2003 

This database was searched using the same strategy as for MEDLINE. 

NLM Gateway Search performed August 13, 2003 

Searched for books and conference proceedings using ‘melatonin*’ and ‘sleep’ 

OCLC Papers First and Proceedings First Search performed July 11, 2003

Searched for conference proceedings using ‘melatonin*’ and ‘sleep’ 

TOXLINE Search performed July 4, 2003 

Keyword Search

(((((melatonin*) OR (73-31-4) OR (5-Methoxy-N-acetyltryptamine) OR (luzindole) OR (N-Acetyle-5-

methyxoytryptamine)) AND (circadian*) AND ((randomized controlled trial*) or (controlled clinical trial*) or 

(random allocation) or (randomly allocated) or (single blind*) or (double blind*) or (clinical trial*) or (placebo*) 

or (research design*) or (comparative stud*) or (random*) or (evaluation stud*) or (follow up stud*) or 

(prospective stud*) or (cohort*) or (case series) or (meta analys*) or (metaanalys*) or (review*) or 

(overview*) or (quantitative synthes*) or (HTA) or (health technology assessment) or (biomedical technology 

assessment)))) NOT ((((melatonin*) OR (73-31-4) OR (5-Methoxy-N-acetyltryptamine) OR (luzindole) OR 

(N-Acetyle-5-methyxoytryptamine)) AND ((sleep*) OR (sleep disorder*) OR (dyssomnia*) OR (insomnia*) 

OR (narcoleps*) OR (hypersomnia*) OR (central alveolar hypoventilat*) OR (periodic limb movement*) OR 

(nocturnal eating) OR (nocturnal drinking) OR (time-zone*) OR (time zone*) OR (jet lag*) OR (parasomnia*) 

OR (confusional arousal*) OR (rhythmic movement disorder*) OR (nocturnal leg cramp*) OR (nightmare*) 

OR (nocturnal paroxysmal dystonia*) OR (sudden unexplained nocturnal death syndrome*) OR (SUNDS) 

OR (snoring) OR (snore*) OR (congential central hypoventilat*) OR (sudden infant death syndrome*) OR 
15

(SIDS) OR (subwakefulness) OR (fragmentary mycoclonus) OR (hypnagogic hallucination*) OR (arous*)) 

AND ((randomized controlled trial*) or (controlled clinical trial*) or (random allocation) or (randomly 

allocated) or (single blind*) or (double blind*) or (clinical trial*) or (placebo*) or (research design*) or 

(comparative stud*) or (random*) or (evaluation stud*) or (follow up stud*) or (prospective stud*) or (cohort*) 

or (case series) or (meta analys*) or (metaanalys*) or (review*) or (overview*) or (quantitative synthes*) or 

(HTA) or (health technology assessment) or (biomedical technology assessment))))) 

Hand-searched Associated Professional Sleep Society abstracts 1999-2003 
16

Appendix B: Quality Assessment and Data 

Extraction Forms 

Form B-1: Quality Assessment Form: Jadad Scale and Allocation Concealment for 

Quality Assessment of RCTs 

Form B-2: Quality Assessment Form: Downs and Black Checklist for Quality 

Assessment of non-RCTs 

Form B-3: Data Extraction Form
17

Form B-1: Jadad Scale and Allocation Concealment for Quality 

Assessment of RCTs 

 

Study # _______________ Initials of Assessor: _____

 

Part 1 (from Jadad – Controlled Clin Trials 1996; 17:1-12) 

 

1. Was the study described as randomized (this includes the use of words 

such as randomly, random and randomization)? 

Yes = 1 No = 0 

2. Was the study described as double-blind? 

Yes = 1 No = 0 

3. Was there a description of withdrawals and drop-outs? 

Yes = 1 No = 0 

Additional points: Add 1 point if: 

Method to generate the sequence of randomization was described and 

was appropriate (e.g. table of random numbers, computer generated, 

coin tossing, etc.) 

Method of double-blinding described and appropriate (identical 

placebo, active placebo, dummy) 

Point deduction: Subtract 1 point if: 

Method of randomization described and it was inappropriate 

(allocated alternately, according to date of birth, hospital number, etc.) 

Method of double-blinding described but it was inappropriate 

(comparison of tablet vs injection with no double dummy) 

OVERALL SCORE (Maximum 5)

Score 

______ 

______ 

______ 

______ 

______ 

-_____ 

-_____ 

______ 
18

 

Part 2 (from Schulz – JAMA 1995; 273:408-12) 

 

Concealment of treatment allocation:  Adequate 

 Inadequate 

 Unclear 

 

Adequate: e.g. central randomization; numbered/coded containers; drugs 

prepared by pharmacy; serially numbered, opaque, sealed envelopes 

 Inadequate: e.g. alternation, use of case record numbers, dates of birth or day of 

week; open lists 

 Unclear: Allocation concealment approach not reported or fits neither above 

category 
19

Form B-2: Downs and Black Checklist for Quality Assessment of 

non- RCTs 

Quality Assessor: _______ Reference Number: ___________ 

Date: day___ mo___ yr___ First author: _________________ 

(from Downs and Black, J Epidemiol Community Health 1998;52:377-384) 

Reporting 

1. Is the hypothesis/aim/objective of the study clearly described? This question 

refers to a clear statement of the objective, i.e. to measure the effectiveness of x in 

population y with respect to z, even if x, y and z are not clearly described (see 

questions 2, 3 and 4) 

Yes 1 

No 0 

2. Are the main outcomes to be measured clearly described in the Introduction or 

Methods section? If the main outcomes are first mentioned in the Results section, 

the question should be answered no. In case-control studies the case definition should 

be considered the outcome. 

Yes 1 

No 0 

3. Are the characteristics of the patients included in the study clearly described in 

the Introduction or Methods section? In cohort studies and trials, inclusion and or 

exclusion criteria should be given. In case-control studies, a case definition and the 

source for controls should be given. 

Yes 1 

No 0 
20

4. Are the interventions of interest clearly described in the Introduction or 

Methods section? Treatments and placebo (where relevant) that are to be compared 

should be clearly described. 

Yes 1 

No 0 

5. Are the distributions of principal confounders in each group of subjects to be 

compared clearly described? A list of principal confounders is provided. 

Yes 2 

Partially 1 

No 0 

6. Are the main findings of the study clearly described? Simple outcome data 

(including denominators and numerators) should be reported for all major findings so 

that the reader can check the major analyses and conclusions. This question does not 

cover statistical tests, which are considered below. 

Yes 1 

No 0 

7. Does the study provide estimates of the random variability in the data for the 

main outcomes? In non-normally distributed data the inter-quartile range of results 

should be reported. In normally distributed data the standard error, standard deviation 

or confidence intervals should be reported. If the distribution of the data is not 

described, it must be assumed that the estimates used were appropriate and the 

question should be answered yes. 

Yes 1 

No 0 
21

8. Have all important adverse events that may be a consequence of the intervention 

been reported? This should be answered yes if the study demonstrates that there 

was a comprehensive attempt to measure adverse events. (A list of possible adverse 

events is provided). 

Yes 1 

No 0 

9. Have the characteristics of patients lost to follow-up been described? This should 

be answered yes where there were no losses to follow-up or where losses to follow-up 

were so small that findings would be unaffected by their inclusion. This should be 

answered no where a study does no report the number of patients lost to follow-up. 

Yes 1 

No 0 

10. Have 95 percent CIs and/or actual probability values been reported (e.g. 0.035 

rather than <0.05) for the main outcomes except where the probability value is 

less than 0.001? (both CI and p value, either CI or p value, neither) 

Yes 1 

No 0 

External validity 

11. Were the subjects asked to participate in the study representative of the entire 

population from which they were recruited? The study must identify the source 

population for patients and describe how the patients were selected. Patients would 

be representative if they comprised the entire source population, an unselected sample 

of consecutive patients, or a random sample. Random sampling is only feasible 

where a list of all members of the relevant population exists. Where a study does not 

report the proportion of the source population from which the patients are derived, the 

question should be answered as unable to determine. 

Yes 1 

No 0 

Unable to 

determine 

0 
22

12. Were those subjects who were prepared to participate representative of the 

entire population from which they were recruited? The proportion of those asked 

who agreed should be stated. Validation that the sample was representative would 

include demonstrating that the distribution of the main confounding factors was the 

same in the study sample and the source population. 

Yes 1 

No 0 

Unable to 

determine 

0 

13. Were the staff, places, and facilities where the patients were treated, 

representative of the treatment the majority of patients receive? For the study to 

be answered yes the study should demonstrate that the intervention was representative 

of that in use in the source population. The question should be answered no if, for 

example, the intervention was undertaken in a specialist centre unrepresentative of the 

hospitals most of the source population would attend. 

Yes 1 

No 0 

Unable to 

determine 

0 

Internal validity – bias 

14. Was an attempt made to blind study subjects to the intervention they have 

received? For studies where the patients would have no way of knowing which 

intervention they received, this should be answered yes. 

Yes 1 

No 0 

Unable to 

determine 

0 
23

15. Was an attempt made to blind those measuring the main outcomes of the 

intervention?

Yes 1 

No 0 

Unable to 

determine 

0 

16. If any of the results of the study were based on “data dredging”, was this made 

clear? Any analyses that had not been planned at the outset of the study should be 

clearly indicated. If no retrospective unplanned subgroup analyses were reported, 

then answer yes. 

Yes 1 

No 0 

Unable to 

determine 

0 

17. In trials and cohort studies, do the analyses adjust for different lengths of followup of patients, or in case-control studies, is the time period between the 

intervention and outcome the same for cases and controls? Where follow-up was 

the same for all study patients that answer should be yes. If different lengths of 

follow-up were adjusted for by, for example, survival analysis the answer should be 

yes. Studies where differences in follow-up are ignored should be answered no. 

Yes 1 

No 0 

Unable to 

determine 

0 
24

18. Were the statistical tests used to assess the main outcomes appropriate? The 

statistical techniques used must be appropriate to the data. For example nonparametric methods should be used for small sample sizes. Where little statistical 

analysis has been undertaken but where there is no evidence of bias, the question 

should be answered yes. If the distribution of the data (normal or not) is not 

described it must be assumed that the estimates used were appropriate and the 

question should be answered yes. 

Yes 1 

No 0 

Unable to 

determine 

0 

19. Was compliance with the interventions reliable? Where there was non compliance 

with the allocated treatment or where there was contamination of one group, the 

question should be answered no. For studies where the effect of any misclassification 

was likely to bias any association to the null, the question should be answered yes. 

Yes 1 

No 0 

Unable to 

determine 

0 

20. Were the main outcome measures used accurate (valid and reliable)? For studies 

where the outcome measured are clearly described, the question should be answered 

yes. For studies which refer to other work or that demonstrates the outcome measures 

are accurate, the question should be answered as yes. 

Yes 1 

No 0 

Unable to 

determine 

0 
25

Internal validity – confounding (selection bias) 

21. Were the patients in different intervention groups (trials and cohort studies) or 

were the cases and controls (case-control studies) recruited from the same 

population? For example, patients for all comparison groups should be selected 

from the same hospital. The question should be answered unable to determine for 

cohort and case-control studies where there is no information concerning the source 

of patients included in the study. 

Yes 1 

No 0 

Unable to 

determine 

0 

22. Were study subjects in different intervention groups (trials and cohort studies) 

or were the cases and controls (case-control studies) recruited over the same 

period of time? For a study which does not specify the time period over which 

patients were recruited, the question should be answered as unable to determine. 

Yes 1 

No 0 

Unable to 

determine 

0 

23. Were the subjects randomized to intervention groups? Studies which state that 

subjects were randomized should be answered yes except where method of 

randomization would not ensure random allocation. For example alternate allocation 

would score no because it is predictable. 

Yes 1 

No 0 

Unable to 

determine 

0 
26

24. Was the randomized intervention assignment concealed from both patients and 

health care staff until recruitment was complete and irrevocable? All nonrandomized studies should be answered no. If assignment was concealed from 

patients but not from staff, it should be answered no. 

Yes 1 

No 0 

Unable to 

determine 

0 

25. Was there adequate adjustment for confounding in the analyses from which the 

main findings were drawn? This question should be answered no for trials if: the 

main conclusions of the study were based on analyses of treatment rather than 

intention to treat; the distribution of known confounders in the different treatment 

groups was not described; or the distribution of known confounders different between 

the treatment groups but was not taken into account in the analyses. In nonrandomized studies if the effect of the main confounders was not investigated or 

confounding was demonstrated but no adjustment was made in the final analyses the 

question should be answered as no. 

Yes 1 

No 0 

Unable to 

determine 

0 

26. Were losses to patients to follow-up take into account? (yes, no, unable to 

determine) If the numbers of patients lost to follow-up are not reported, the question 

should be answered as unable to determine. If the proportion lost to follow-up was 

too small to affect the main findings, the question should be answered yes. 

Yes 1 

No 0 

Unable to 

determine 

0 
27

Power 

27. Was a power calculation reported for the primary outcome? 

Yes 1 

No 0 

Unable to 

determine 

0 

28. Did the study have sufficient power to detect a clinically important effect where 

the probability value for a difference being due to chance in less than 5 percent?

Yes 1 

No 0 

Unable to 

determine 

0 
28

Form B-3: Data Extraction Form 

GENERAL INFORMATION 

To be extracted from all studies. 

RECORD ID QUESTIONS OF 

REVIEW TO WHICH 

STUDY IS RELEVANT 

REVIEWER/ 

DATE 

VERIFIER/ 

DATE 

FIRST AUTHOR YEAR OF 

PUBLICATION 

COUNTRY WHERE FUNDING 

STUDY TOOK 

PLACE PRIVATE PUBLIC 

OBJECTIVE (S) DESIGN AS 

REPORTED BY 

AUTHOR 

PROTOCOL 
29

GENERAL INFORMATION (continued)To be extracted from all studies 

POPULATION INCLUSION 

CRITERIA 

EXCLUSION 

CRITERIA 

NUMBER OF 

PEOPLE 

ELIGIBLE FOR 

THE STUDY 

NUMBER OF 

PEOPLE 

ENROLLED IN 

THE STUDY 

NUMBER AND 

TYPE OF 

COMPARISON 

GROUPS 

NUMBER OF 

PARTICIPANTS 

WHO WITHDREW 

FROM THE STUDY 

AND GROUP 

FROM WHICH 

THEY WITHDREW 

INTERVENTION(S) PRIMARY 

OUTCOME(S) 

SECONDARY 

OUTCOME(S) 

DO PARTICIPANTS 

SUFFER FROM 

A METABOLIC 

DISORDER? IF 

SO, WHAT 

TYPE? 

ARE 

PARTICIPANTS 

ON ANY 

MEDICATION? IF 

SO, WHAT 

TYPE? 
30

GENERAL INFORMATION (continued)To be extracted from all studies BASELINE CHARACTERISTICS OF PARTICIPANTS AS A WHOLE AND ACCORDING TO TREATMENT GROUP GENDER AGE ETHNICITY OTHER 

TREATMENT 

PERIOD FOLLOW-UP PERIOD 

WAS AN 

INTENTION TO 

TREAT ANALYSIS 

PLANNED OR 

CONDUCTED? 

OTHER COMMENTS CONCLUSION 
31

GENERAL INFORMATION (continued) To be extracted from studies relevant to the following questions of the review: 2, 5, 9, 12 

FORMULATION OF 

MELATONIN 

ADMINISTERED 

TO PARTICIPANTS 

CONTENT AND 

QUALITY OF 

FORMULATION OF 

MELATONIN 

ADMINISTERED TO 

PARTIPANTS 

DOSAGE, REGIMEN 

AND ROUTE OF 

MELATONIN 

ADMINISTRATION 

To be extracted from studies relevant to the following questions of the review: 2, 5, 9 TYPE OF SLEEP DISORDER FROM WHICH PARTICIPANTS SUFFER 

PRIMARY SLEEP 

DISORDER

SECONDARY SLEEP 

DISORDER 

SLEEP 

RESTRICTION 
32

OUTCOME MEASURES 

To be extracted from studies relevant to the following questions of the review: 2, 3, 6 

[MLT] IN SERUM [MLT] IN URINE [MLT] IN SALIVA 

To be extracted from studies relevant to the following questions of the review: 3, 5, 9 

SLEEPINESS/ 

FATIGUE/ 

ALERTNESS/ 

MOOD 

IN THE EVENING 

SLEEPINESS/ 

FATIGUE/ 

ALERTNESS/ 

MOOD 

IN THE DAYTIME 

SLEEP ONSET 

LATENCY (SOL) 

TOTAL SLEEP 

TIME (TST) 

SLEEP 

QUALITY 

WAKEFULNESS 

AFTER SLEEP 

ONSET (WASO) 

SLEEP 

EFFICIENCY 

SLEEP 

ARCHITECTURE 

REM LATENCY 

NUMBER OF 

REM 

EPISODES 

REM DURATION 

DIM LIGHT 

MELATONIN 

ONSET (DLMO) 
33

Appendix C: Evidence Tables 

Evidence Table C-1: Formulations of Melatonin: Study Characteristics 

Evidence Table C-2: Pharmacokinetics of Melatonin: Study Characteristics 

Evidence Table C-3: Melatonin and the Sleep Cycle: Study Characteristics 

Evidence Table C-4: Mechanisms by which Melatonin Produces Sleepiness: Study 

Characteristics 

Evidence Table C-5: Effect of Melatonin on Normal Sleepers: Study Characteristics 

Evidence Table C-6: Melatonin and the Temperature Rhythm: Study Characteristics 

Evidence Table C-7: Effect of Melatonin on People with Sleep Disorders: Study 

Characteristics 

Evidence Table C-8: Safety of Melatonin: Study Characteristics 

Evidence Table C-9: Melatonin Compared to Other Pharmacological Treatments for 

Sleep Disorders: Study Characteristics
34

Evidence Table C-1: Formulations of Melatonin: Study Characteristics Abbreviations: RCT: randomized controlled trial, MLT: melatonin, FR: fast-release, SR: slow-release, SD: standard deviation, mg

NS: not specified Author Year Population Sample Size N Study 

Design 

Intervention 

Almeida- 2003 Age (Years) Treatment Group RCT Formulation

Montes, LG Mean (SD): 50 (NS) Enrolled : 10 Double-blind Sustained-releaQuality Score 16 Range: 30-72 Analyzed: 10 Cross-over Route of Admini

 Gender Control Group Oral 

 Female: 4 Enrolled : 10 Dosage and Tim

 Male: 6 Analyzed : 10 0.3 mg or 1 mg  Ethnicity: NS Frequency and 

 Sleep Disorder: 

Insomnia

 One dose/day fo

Author Year Population Sample Size N Study 

Design 

Intervention 

Garfinkel, D 1995 Age (Years) Treatment Group RCT Formulation

Quality Score 24 Mean (SD): 76 (NS) Enrolled : 12 Double-blind Controlled-relea Range: 68-93 Analyzed: 12 Cross-over Route of Admini

 Gender Control Group Oral 

 Female: 5 Enrolled : 12 Dosage and Tim

 Male: 7 Analyzed : 12 2 mg of MLT 2h  Ethnicity: NS Frequency and 

 Sleep Disorder: 

Long-term insomnia

 One dose/night 

Author Year Population Sample Size N Study 

Design 

Intervention 

Haimov, I 1995 Age (Years) Treatment Group RCT Formulation

Quality Score 18 Mean (SD): 73.1 (3.9) Enrolled : 8 Double-blind Sustained-relea Range: NS Analyzed: 8 Cross-over Route of Admini

 Gender Control Group Oral 

 Female: 4 Enrolled : 8 Dosage and Tim

 Male: 4 Analyzed : 8 2 mg FR, 2 mg S

before desired b

 Ethnicity: NS Frequency and 

 Sleep Disorder: 

Insomnia

 One dose/day o

for 1 week, and 

 dose/day of 1 m
35

Author Year Population Sample Size N Study 

Design 

Intervention 

McArthur, A 1998 Age (Years) Treatment Group RCT FormulationQuality Score 21 Mean (SD): 10.1 (1.5) Enrolled : 9 Double-blind Immediate-relea Range 4-17 Analyzed: 9 Cross-over Route of Admini

 Gender Control Group Oral or by gastro

 Female: 9 Enrolled : 9 Dosage and Tim

 Male: 0 Analyzed : 9 Dosage based o

range 2.5-7.5 m

 Ethnicity: NS of MLT given 1h 

 Sleep Disorder: 

Sleep dysfunction 

 Frequency and 

 accompanying Rett 

Syndrome 

 One dose/day fo

Author Year Population Sample Size N Study 

Design 

Intervention 

Serfaty, M 2002 Age (Years) Treatment Group RCT Formulation

Quality Score 22 Mean (SD): 84.2 (7.6) Enrolled : 44 Double-blind Slow release ML Range: NS Analyzed: 25 Cross-over Route of Admini

 Gender Control Group Oral 

 Female: 9 Enrolled : 44 Dosage and Tim

 Male: 16 Analyzed : 25 6 mg of MLT at  Ethnicity: NS Frequency and 

 Sleep Disorder: 

Sleep disturbances 

 One dose/day fo

 accompanying 

dementia 

Author Year Population Sample Size N Study 

Design 

Intervention 

Shamir, E 2001 Age (Years) Treatment Group RCT Formulation

Quality Score 24 Mean (SD): 64.2 (14.3) Enrolled : 10 Double-blind Controlled-relea Range: 28-82 Analyzed: 8 Cross-over Route of Admini

 Gender Control Group Not specified 

 Female: 11 Enrolled : 12 Dosage and Tim

 Male: 11 Analyzed : 12 2.5 mg MLT, tim Ethnicity: NS Frequency and 
36

Author Year Population Sample Size N Study 

Design 

Intervention 

Smits, MG 2003 Age (Years) 3 treatments RCT FormulationQuality Score 25 Mean (SD): FR =0.5mg, 5mg Double-blind Fast-release or 

Treatment group 9.2 (2.1) CR= 2mg Parallel Route of Admini

Control group 10.1 (1.7) Treatment Groups Oral 

 Range: NS Enrolled : NS Dosage and Tim

 Gender Analyzed: NS 5 mg of MLT at 

Treatment group Frequency and 

 Female: 20 One dose/day fo Male: 6 Control Group

Control group Enrolled : NS 

 Female: 6 Analyzed : NS  Male: 29  Ethnicity: NS

 Sleep Disorder: 

Idiopathic chronic 

 sleep-onset 

insomnia 

Author Year Population Sample Size N Study 

Design 

Intervention 

Suhner, A 1998 Age (Years) 3 treatment groups RCT Formulation

Quality Score 20 Mean (SD): 36 (NS) 0.5 mg FR MLT Double-blind Fast-release or  Range: 20-65 5.0 mg FR MLT Parallel Route of Admini

 Gender 2 mg CR MLT NS 

 Female: 148 Treatment Groups Dosage and Tim

 Male: 172 Enrolled : NS 0.5 mg FR, 5.0 m

bedtime after 

 Ethnicity: NS Analyzed: NS 

 Sleep Disorder: Jet 

lag 

 Control Group Frequency and 

 Enrolled : NS One dose/day fo

flight 

 Analyzed : NS 
37

Evidence Table C-1: References1. Almeida Montes LG, Ontiveros Uribe MP, Cortes Sotres J et al. Treatment 

of primary insomnia with melatonin: A double-blind, placebo-controlled, crossover study. J Psychiatry Neurosci 2003; 28(3):191-196. 

2. Garfinkel D Laudon M, Zisapel N. Improvement of sleep equality in 

elderly people by controlled-release melatonin. Lancet 1995;346(8974):541-544. 

3. Haimov I, Lavie P, Laudon M et al. Melatonin replacement therapy of 

elderly insomniacs. Sleep 1995;18(7): 598-603. 

4. McArthur AJ, Budden SS. Sleep dysfunction in Rett syndrome: a trial of 

exogenous melatonin treatment. Develop Med Child Neurol 1998;40(3):186-92. 

5. Serfaty M, Kennell-Webb S, Warner J et al. Doub

placebo controlled trial of low dose melatonin for dementia. Int J Geriatr Psychiatry 2002;17(12):112

6. Shamir E, Barak Y, Shalman I et al. Melatonin tre

dyskinesia: a double-blind, placebo-controlled, croPsychiatry 2001; 58(11):1049-52. 

7. Smits MG Van Stel HF Van Der Heijden K et al. M

Health Status and Sleep in Children With IdiopathInsomnia: A Randomized Placebo-Controlled TrAdolesc Psychiatry 2003;42(11):1286-1293. 

8. Suhner A, Schlagenhauf P, Johnson R et al. Comp

determine the optimal melatonin dosage form for tChronobiol Int 1998;15(6):655-66. 
38

Evidence Table C-2 Pharmacokinetics of Melatonin: Study Characteristics Abbreviations: RCT: randomized controlled trial, CCT: controlled clinical trial, MLT: melatonin, FR: fast-release, SR: slow-release,

SD: standard deviation, SE: standard error, mg: milligrams, h: hours, NS: not specifiedControl Group received placebo unless otherwise indicated.Author Year Population Study Design N Intervention Aldhous, M 1985 Age (Years) CCT Formulation

Quality Score 14 mean: NS Blindedness: NS Slow-release MLT  range: 21-39 Parallel Route of Administration

 Gender Treatment Group Oral 

 female: 6 2mg MLT: Dosage and Timing

 male: 6 Enrolled: 5 2mg MLT gelatine-coate Co-Medication: NS Analyzed: 5 release tablets or 2mg M

 Sleep Disorder: None 2mg MLT slow-release: Frequency and Duration

 Enrolled: 5 1 capsule or dose/day fo Analyzed: 5  Control Group

2mg MLT in corn oil: 

 Enrolled: 4 

 Analyzed : 4 

Outcomes:Half-Life +/-SEM

2mg MLT capsules, fasting : 0.54h +/- 0.03h; 2 mg MLT in corn oil, fed: 0.67 +/- 0.03h

Time to Reach Peak +/- SEM

2 mg MLT capsules, fed: 0.46h +/-07h; 2 mg MLT in corn oil, fasting: 0.95 +/- 0.42h

AUC +/- SEM

AUC (time period not specified): 2mg MLT capsules, fed: 8036 +/- 2455 pg/mL, 2mg MLT capsules, 

fasting: 3712 +/- 703 pg-h/ml; 2 mg MLT in corn oil, fed: 5826 +/- 2644 pg-h/mL; 2 mg MLT in corn oil, fasting: 3953 +/- 1533 pg-h/mLAuthor Year Population Study Design N Intervention Benes, L 1997 Age (Years) RCT Formulation

Quality Score 16 mean (SD): 23(2) Blindedness: NS Not specified  range: 21-27 Cross-over Route of Administration

 Gender Treatment Group Oral (O), Transdermal (T

 female: 0 Enrolled: 12 Dosage and Timing

 male: 12 Analyzed: 12 0.76mg (oral), 8 mg (TD Co-Medication: None Control Group Frequency and Duration

 Sleep Disorder: None Enrolled: 12 Single dose for 3 days o

 Analyzed : 12 
39

Outcomes:Time to Reach Peak 

O: 1.3h (range 0.5 - 7h), TD: 13.0h (range 10.5 - 14h), TM: 7.9h (range 5-10.5h)

Peak [MLT] (Cmax)

O: 82.4 pg/mL (range 30 - 417 pg/mL), TD: 172.6 pg/mL (range 44 - 856 pg/mL), TM: 193.8 pg/mL (range 153 - 294 pg/mL)

AUC

AUC (0 - 24h): O: 894.3 pg-h/mL (range 247 - 4007), TD: 2226 pg-h/mL (range 626 - 8700), TM: 1820 pg-h/mL (range 1248 - 28Author Year Population Study Design N Intervention Cagnacci, A 1995 Age (Years) RCT Formulation

Quality Score 16 mean: NS Double-blind Not specified  range: 25-35 Cross-over Route of Administration

 Gender Treatment Group Oral 

 female: 12 Enrolled: 6 Dosage and Timing

 male: 0 Analyzed: 6 1mg MLT at 0800h, 0.75 Co-Medication: NS Control Group at 1200h 

 Sleep Disorder: None Enrolled: 6 Frequency and Duration

 Analyzed : 6 Single dose Outcomes:Time to Reach Peak

1.5 - 2h Peak [MLT] (Cmax) +/-SE

1984.14 +/- 425.07 pg/mL Author Year Population Study Design N Intervention Cagnacci, A 1996 Age (Years) RCT Formulation

Quality Score 13 mean: NS Double-blind Not specified  range: 25-35 Cross-over Route of Administration

 Gender Treatment Group Not specified 

 female: 7 Enrolled: 7 Dosage and Timing

 male: 0 Analyzed: 7 1 mg MLT at 0800h, 0.75 Co-Medication: NS Control Group at 1200h, total dose = 2.

 Sleep Disorder: None Enrolled: 7 Frequency and Duration

 Analyzed : 7 2.5mg/day for 2 days Outcomes:FP= Follicular Phase LP= Luteal Phase AUC +/-SE

AUC (0-24h): FP: 637.82 +/- 258.11 pg-h/ml; LP: 668.69 +/- 309.22 pg-h/ml
40

Author Year Population Study Design N Intervention Cavallo, A 1996 Age (Years) Case series FormulationQuality Score 17 mean: NS Blindedness: NS Not specified  range: 6-31yrs Treatment Group Route of Administration

 Gender Enrolled: 30 Intravenous 

 female: 18 Analyzed: 30 Dosage and Timing

 male: 12 0.5mug/kg MLT over 10  Co-Medication: NS Frequency and Duration

 Sleep Disorder: None Single dose 

Outcomes:Half-Life +/- SD

Total Population: 0.76h +/-0.13h. By subject groups: Prepubertal (9; 5M, 4F): 0.67 +/- 0.12 h; Pubertal (8; 4M, 4F): 0.78 +/- 0Adult females (7): 0.81 +/- 0.12; Adult males (9): 0.82 +/- 0.15; Adults, all (16): 0.79 +/- 0.10AUC +/-SD

AUC (time frame not clear): Total population: 327.5 +/- 145.9 pg-h/mL. By subject groups: Prepubertal (9; 5M, 4F): 250.9 +/- 91.8 pg-h/ml; Pubertal (8; 4M, 4F): 300.1 +/- 131.0 pg-h/ml; 

Adult females (7): 384.4 +/- 159.9 pg-h/ml; Adult males (9): 390.2 +/- 173.1 pg-h/ml; Adults, all (16): 376.9 +/- 154.3 pg-h/ml

Author Year Population Study Design N Intervention Dawson, D 1996 Age (Years) RCT Formulation

Quality Score 17 mean: NS Double-blind Not specified  range: 18-38 Cross-over Route of Administration

 Gender 4 MLT dose groups Oral 

 female: 21 0.1, 0.5, 1, or 5 mg; Dosage and Timing

 male: 11 Enrolled in each group: 8 0.1, 0.5, 1.0, or 5 mg ML Co-Medication: None Analyzed: NS Frequency and Duration

 Sleep Disorder: None Control group Single dose 

 Enrolled in each group: 8  Analyzed: NS Outcomes:Half-Life +/-SDTime to Reach Peak +/-SD

0.1 mg: 1.25 +/-0.48h, 0.5 mg: 0.88 +/-0.33h, 1.0 mg: 0.78 +/-0.47h, 5.0 mg: 0.97 +/-0.75hPeak [MLT] (Cmax) +/-SD

0.1 mg: 124.5+/-97.8 pg/mL, 0.5 mg: 709.4 +/- 702.0pg/mL, 1.0 mg: 

1356.3 +/- 1397.6 pg/mL, 5.0 mg: 5570.5 +/-3842.8 pg/mL 
41

Author Year Population Study Design N Intervention Deacon, S 1995 Age (Years) RCT FormulationQuality Score 20 mean (SD): 27.2(3.7) Double-blind Not specified  range: 23-34 Cross-over Route of Administration

 Gender Treatment Group Oral 

 female: 3 Enrolled: 6 Dosage and Timing

 male: 3 Analyzed: 6 0.05mg, 0.5mg or 5.0 mg  Co-Medication: None Control Group Frequency and Duration

 Sleep Disorder: None Enrolled: 6 Single dose of either 0.0

 Analyzed : 6 1 day, 1 day per sessionOutcomes:Half-Life +/-SEM

0.05 mg: 64.8 +/- 16.2, 0.5 mg: 42.6 +/- 12.6, 5.0 mg: 2 +/- 19.2 (units not specified) 

Time to Reach Peak 

0.05 mg: 0.5h, 0.5 mg: 1 h, 5.0 mg: 0.5hPeak [MLT] (Cmax) +/-SEM

0.05 mg: 118 +/- 37 pg/mL (range 13 - 274 pg/mL), 0.5 mg: 1327 +/- 491 pg/mL (range 454 - 3700 pg/mL), 5.0 mg: 18495 +/- 

3326 pg/mL (range 7830 - 31450) Author Year Population Study Design N Intervention Debus, O 2002 Age (Years) Case series Formulation

Quality Score 14 mean: 3.4 Blindedness: NS Not specified  range: one to five Treatment Group Route of Administration

 Gender Enrolled: 5 Oral 

 female: 2 Analyzed: 5 Dosage and Timing

 male: 3 Only Patient 3 5mg MLT at 2000h 

 Co-Medication: 1 

female took 

took melatonin Frequency and Duration

 chloral hydrate sleep 

medication 

 Single dose 

 Sleep Disorder: None

Outcomes:Time to Reach Peak +/-NS

Patient 3: 1.2hPeak [MLT] (Cmax) +/-NS

Patient 3: 18,650 pg/ml (in vCSF)
42

Author Year Population Study Design N Intervention Di, Wei-Di 1997 Age (Years) Case series FormulationQuality Score 8 mean: NS Blindedness: NS Not specified  range: 21-32 Treatment Group Route of Administration

 Gender Enrolled: 4 Intravenous (IV) and Ora

 female: 0 Analyzed: 4 Dosage and Timing

 male: 4 20ug MLT (IV) and 500u Co-Medication: NS occasions, timing: NS 

 Sleep Disorder: None Frequency and Duration

 Single dose Outcomes:Half-Life +/-SD

0.78h +/- 0.05h Peak [MLT] (Cmax)(range)480 - 9200 pg/mL Author Year Population Study Design N Intervention Dollins, A 1993 Age (Years) RCT Formulation

Quality Score 18 mean (SD): 25(1.47) Double-blind Not specified  range: 19-39 Cross-over Route of Administration

 Gender Treatment Groups Oral 

 female: 0 Group 1 enrolled: 20 Dosage and Timing

 male: 20 Ingested 10 mg MLT 10, 20, 40, or 80 mg MLT  Co-Medication: NS Group 2 enrolled: 20 Frequency and Duration

 Sleep Disorder: None Ingested 20 mg MLT Single dose 

Group 3 enrolled: 20 

 Ingested 40 mg MLT 

Group 4 enrolled: 20 

 Ingested 80 mg MLT  Control Group

Group 5 enrolled: 20 

 Ingested placebo. 

Total analysed: NS 

Outcomes:AUC +/-SEMAUC (1000h to 1630h): 10 mg: 12,228 +/-5736.1 pg/mL, 20 mg: 27,186 +/-14,268.5 pg/mL, 40 mg: 52,557 +/- 26,401.6pg/mL, 

80 mg: 106,223 pg/mL +/- 63.038.3 
43

Author Year Population Study Design N Intervention Dollins, A 1994 Age (Years) RCT FormulationQuality Score 18 mean (SD): 23.05(4.22) Double-blind Not specified  range: 18-24 Cross-over Route of Administration

 Gender Treatment Groups Oral 

 female: 0 0.1, 0.3, 1.0, 10mg Dosage and Timing

 male: 20 Enrolled: 20 0.1, 0.3, 1.0 or 10mg ML Co-Medication: NS Analyzed: 12 Frequency and Duration

 Sleep Disorder: None Control Group Single dose/group over 5 

 Enrolled: 20  Analyzed : 12 

All 20 subjects participated in each treatment group 

Outcomes:AUC +/- SEMAUC (0000h to 1730h): 0.1 mg: 213.2+/-25.02 pg/ml, 0.3 mg: 459.9 +/-62.7pg/ml, 1.0 mg: 1599.0 +/-141.7pg/ml, 10 mg: 21000.

Author Year Population Study Design N Intervention Helrich, E 2002 Age (Years) RCT Formulation

Quality Score 13 mean: 25 Blindedness: NS Not specified  range: NS Cross-over Route of Administration

 Gender Treatment Groups Intranasal 

 female: 0 200ug MLT Dosage and Timing

 male: 8 Enrolled: 8 0.200mg or 0.4mg MLT,  Co-Medication: NS Analyzed: 7 Frequency and Duration

 Sleep Disorder: None 400 ug MLT Single dose 

 Enrolled: 8  Analyzed : 8  Control Group 

 Enrolled: 8  Analyzed : 8 Outcomes:Half-Life +/-SD

0.2mg MLT: 0.73h +/- 0.12h, 0.4mg MLT: 1h +/- 0.33hAUC +/- SD

AUC (0 - 8h): 200ug MLT: 2.99 +/- 1.16, 400 ug MLT: 598 +/- 2.23 (units not specified)
44

Author Year Population Study Design N Intervention Hoffman, H 1998 Age (Years) RCT FormulationQuality Score 14 mean: NS Blindedness: NS Fast- and controlled-rele range: 25-35 Cross-over Route of Administration

 Gender Treatment Groups Oral 

 female: 0 Fast-release (A) Dosage and Timing

 male: 15 Enrolled: 15 A (5mg) or B(10mg) or C  Co-Medication: NS Analyzed: 15 between 0800h and 083

 Sleep Disorder: None Controlled-release (B) Frequency and Duration

 Enrolled: 15 Single dose  Analyzed: 15 

Controlled-release (C) 

 Enrolled: 15  Analyzed: 15 Outcomes:Half-Life

A: 0.64h, B: 0.80h, C: 0.84hTime to Reach Peak

Run 1: A: 0.5h, B: 0.75h, C: 0.5h; Run 2: A: NA, B: 3.5h, C: 3.5h

Peak [MLT] (Cmax)

Run 1: A: 4817.49 pg/mL, B: 3816.36 pg/mL, C: 2260.08 pg/mL Run 2: A: NA, B: 3028.93 pg/mL, C: 4067.22 pg/mL AUC

AUC (over 10 hour period): A: 4271.63 pg-h/mL, B: 8382.99 pg-h/mL, C: 9844.03 pg-h/mL AUC: (0 - infinity): A: 4276.27 pg-h/mL, B: 8454.99 pg-h/mL, C: 9911.39 pg-h/mLAuthor Year Population Study Design N Intervention Kane, M 1994 Age (Years) Case series Formulation

Quality Score 17 mean: NS Blindedness: NS Not specified  range: 13-83 Treatment Group Route of Administration

 Gender Enrolled: 5 Oral 

 female: 2 Analyzed: 5 Dosage and Timing

 male: 3 50mg MLT, timing: NS  Co-Medication: NS Frequency and Duration

 Sleep Disorder: None Every 4 hours for the sub

Outcomes:Time to Reach Peak

1-2 h Peak [MLT] (Cmax) +/-SE

41600 +/-17700 pg/mL 
45

Author Year Population Study Design N Intervention Kovacs, J 2000 Age (Years) Case Series FormulationQuality Score 15 mean (SD): 29.7(7.9) Blindedness: NS Not specified  range: NS Treatment Group Route of Administration

 Gender Enrolled: 17 Not specified 

 female: 5 Analyzed: NS Dosage and Timing

 male: 12 3 mg MLT at 1000h  Co-Medication: None Frequency and Duration

 Sleep Disorder: None Single dose 

Outcomes:Time to Reach Peak

1h Peak [MLT] (Cmax) +/-SD

4701 +/- 6415 pg/mL (range 940 - 27240 pg/mL) AUC +/- SD

AUC (0-16h): 9514 +/- 9152 pg-h/mL (range 2451 - 40302 pg-h/mL)Author Year Population Study Design N Intervention Lee, B 1997 Age (Years) CCT Formulation

Quality Score 10 mean: NS Blindedness: NS Not specified  range: NS Parallel Route of Administration

 Gender Treatment Group Oral 

 female: NS MLT Batch 1 Dosage and Timing

 male: NS Enrolled: 4 0.2 mg MLT at 1000h to  Co-Medication: NS Analyzed: NS Frequency and Duration

 Sleep Disorder: None Control Group Single dose 

MLT Batch 2 

 Enrolled: 6  Analyzed : NS Outcomes:Time to Reach Peak

Batch 1: 0.5h, Batch 2: 1.0hPeak [MLT] (Cmax) +/-SD

Batch 1: 117 +/- 21 pg/mL, Batch 2: 108 +/- 33 pg/mlAUC +/-SD

AUC (time frame not specified): Batch 1: 515.5 +/- 206.2 pg-h/mL Batch 2: 555.6 +/- 334.9 pg-h/mL
46

Author Year Population Study Design N Intervention Lewy, A.J 1998 Age (Years) CCT FormulationQuality Score 14 mean: NS Blindedness: NS Not specified  range: 22-77 Cross-over Route of Administration

 Gender Treatment Group Oral 

 female: 5 Enrolled: 6 Dosage and Timing

 male: 1 Analyzed: 6 0.5mg MLT, the average  Co-Medication: NS Control Group the morning dose was 08

 Sleep Disorder: None Enrolled: 6 and for the evening dose  Analyzed : 6 (range 1700-1800h)  Frequency and Duration

 Single dose Outcomes:Half-Life +/- SEM

after morning dose: 0.84h +/-0.1h, after evening dose: 1.06h +/-0.15h

Author Year Population Study Design N Intervention MacFarlane, J.G 1991 Age (Years) CCT FormulationQuality Score 20 mean: NS Double-blind Not specified  range: 25-85 Cross-over Route of Administration

 Gender Treatment Group Oral 

 female: 8 Enrolled: 6 Dosage and Timing

 male: 5 Analyzed: 6 75 mg MLT at 2200h  Co-Medication: Free of 

all neuro-

 Control Group Frequency and Duration

 active medications for 

at least 4 

 Enrolled: 7 1 capsule/day for 14 day

 weeks prior to the start 

of the study 

 Analyzed : 7 

 Sleep Disorder: Chronic 

insomnia

Outcomes: Time to Reach Peak1.5 h Peak [MLT] (Cmax)

64, 730 pg/mL 
47

Author Year Population Study Design N Intervention Niederhofer, H 2003 Age (Years) RCT FormulationQuality Score 17 female 17 Double-blind Not specified 

 mean: 15-18 Cross-over Route of Administration

 range: Treatment Group Oral 

male Enrolled: 20 Dosage and Timing

 mean 16 Analyzed: 20 MLT (0.1mg, 0.3mg) cap range: 14-18 Control Group each individuals fixed be

 Gender Enrolled: 20 Frequency and Duration

 female: 10 Analyzed : 20 1capusle/day for 7 days  male: 10  Co Medication: NS

 Sleep Disorder: Chronic 

insomnia 

 accompanying mental 

retardation 

Outcomes: Time to Reach Peak

about 2h Peak [MLT] (Cmax)

0.1mg: 79 pg/mL (range 63 - 118) , 0.3 mg: 234 pg/mL (range 144 - 301)

Author Year Population Study Design N Intervention Rajaratnam, SM 2002 Age (Years) CCT Formulation

Quality Score 17 mean (SD): 24.4(4.4) Double-blind Surged sustained releas range: NS Cross-over Route of Administration

 Gender Treatment Group Oral 

 female: 0 Enrolled: 8 Dosage and Timing

 male: 8 Analyzed: 8 1.5 mg MLT at 1600 h  Co-Medication: None Control Group Frequency and Duration

 Sleep Disorder: None Enrolled: 8 Daily dose for 8 days 

 Analyzed : 8 Outcomes: Time to Reach Peak

3h Peak [MLT] (Cmax) +/-NS

626 +/- 212 pg/mL 
48

Author Year Population Study Design N Intervention Shah, J 1999 Age (Years) RCT FormulationQuality Score 17 mean: NS Blindedness: NS Not specified  range: 60-73 Cross-over Route of Administration

 Gender Treatment Group Oral 

 female: 6 low dose MLT Dosage and Timing, Fre male: 6 Enrolled: 12 Low dose MLT: 0.11mg  Co-Medication: NS Analyzed: 11 Day 15; High dose MLT: 

 Sleep Disorder: None Control Group on Day 1 or 15 

high dose MLT 

 Enrolled: 12  Analyzed : 11 Outcomes: Half-Life

~ 2 hours and did not change with dose Time to Reach Peak +/-SDLow dose MLT: 5.8 +/-1.6h, High dose MLT: 5.5 +/-1.0h Peak [MLT] (Cmax) +/-SD

Low dose MLT: 56.9 +/- 50.8 pg/mL, High dose MLT: 179 +/-97.2 pg/mL AUC +/- SD

AUC (0 - 12 hours): Low dose MLT: 288 +/-213 pg-h/mL, High dose MLT: 1069 +/-679 pg-h/mL AUC (0 - infinity) (extrapolated): Low dose MLT: 318 +/-227 pg-h/mL, High dose MLT: 1234 +/- 856 pg-h/mLAuthor Year Population Study Design N Intervention Shirawaka, S 2001 Age (Years) CCT Formulation

Quality Score 10 mean (SD): 23.4(1.5) Blindedness: NS Not specified  range: NS Design: not clear Route of Administration

 Gender Treatment Group Oral 

 female: 0 Enrolled: NS Dosage and Timing

 male: 7 Analyzed: NS 3mg MLT capsules 15 m Co-Medication: NS Control Group polysomnographic recor

 Sleep Disorder: None Enrolled: NS Frequency and Duration

 Analyzed : NS 1 capsule/day for 2 days Outcomes: Time to Reach Peak

2.25h Peak [MLT] (Cmax)

1055.7 pg/mL 
49

Author Year Population Study Design N Intervention Shirakawa, S 1998 Age (Years) Not specified FormulationQuality Score 11 mean (SD): 31.1(1.1) Treatment Group Not specified  range: NS Enrolled: 7 Route of Administration

 Gender Analyzed: 7 Oral 

 female: 0 Dosage and Timing

 male: 7 3 mg MLT at 0930 h  Co-Medication: NS Frequency and Duration

 Sleep Disorder: None Single dose 

Outcomes: Time to Reach Peak

0.33h Peak [MLT] (Cmax) +/-NS

3561 +/- 1201 pg/mL Author Year Population Study Design N Intervention Van Den Heuvel, C 1999 Age (Years) CCT Formulation

Quality Score 15 mean (SD): 23.9(0.7) Double-blind Not specified  range: 17-20 Cross-over Route of Administration

 Gender Treatment Group Intravenous 

 female: 4 Enrolled: 8 Dosage and Timing

 male: 4 Analyzed: 8 3, 10, or 30ug MLT at 10 Co-Medication: None Control Group Frequency and Duration

 Sleep Disorder: None Enrolled: 8 Single dose per experim

 Analyzed : 8 Outcomes: Time to Reach Peak

0.25h Peak [MLT] (Cmax) +/- SE3 ug: 14.75 +/- 4.67 pg/mL, 10 ug: 34.84 +/- 5.97 pg/mL, 30 ug: 132.19 +/- 25.74 pg/mL

Author Year Population Study Design N Intervention Wright, J 1986 Age (Years) CCT Formulation

Quality Score 17 mean: NS Double-blind Not specified  range: 22-46 Cross-over Route of Administration

 Gender Treatment Group Oral 

 female: 2 Enrolled: 12 Dosage and Timing

 male: 10 Analyzed: 12 2 mg MLT at 1700h  Co-Medication: NS Control Group Frequency and Duration

 Sleep Disorder: None Enrolled: 12 Daily for 4 weeks each (

 Analyzed : 12 or 3 weeks (autumn) wit
50

Outcomes: Time to Reach Peak

1 h Peak [MLT] (Cmax)

1500 pg/mL Author Year Population Study Design N Intervention Zhdanova, I 2001 Age (Years) RCT Formulation

Quality Score 21 mean: NS Double-blind Not specified  range: >50 Cross-over Route of Administration

 Gender Treatment Groups Oral 

 female: NS 0.1,.03, or 3.0mg Dosage and Timing

 male: NS Enrolled: NS 0.1 mg, 0.3 mg, or 3.0 m Co-Medication: NS Analyzed: 30 Frequency and Duration

 Sleep Disorder: 

Insomnia

 Control Group Single dose/day for each 

 Enrolled: NS treatment lasted 4 weeks  Analyzed: 30 Outcomes: Time to Reach Peak

Within 2 hours of ingestion Peak [MLT] (Cmax)

0.1 mg: 84 pg/mL (range 59 - 120) , 0.3 mg: 220 pg/mL(range 124 - 297) , 3.0 mg: 1370 pg/mL (range 957 - 2440) 
51

Evidence Table C-2: References1. Aldous M, Franey C, Wright J et al. Plasma Concentrations of 

Melatonin in Man Following Oral Absorption of Different Preparations. 

Br J Clin Pharmacol 1985;19: 517-521 

2. Benes L, Claustrat B, Horriere F, Geoffriau M, Konsil J, Parrott KA et al. 

Transmucosal, oral controlled-release, and transdermal drug administration in human subjects: a crossover study with melatonin. J Pharm Sci. 1997;86:1115-9. 

3. Cagnacci A, Elliott JA, Yen, SS. Melatonin: a major regulator of the 

circadian rhythm of core temperature in humans. J Clin Endocrinol Metab 1992;75(2):447-52. 

4. Cagnacci A, Soldani R, Laughlin GA et al. Modification of circadian 

body temperature rhythm during the luteal menstrual phase: role of 

melatonin. J Appl Physiol 1996;80(1):25-9. 

5. Cavallo A Ritschel WA. Pharmacokinetics of melatonin in human sexual 

maturation. J Clin Endocrinol Metabolism 1996;81(5):1882- 

6. Dawson D, Gibbon S, Singh P. The hypothermic effect of melatonin on 

core body temperature: is more better? J Pineal Res 1996;20(4):192-7. 

7. Deacon S, Arendt J. Melatonin-induced temperature suppression and its 

acute phase-shifting effects correlate in a dose-dependent manner in humans. Brain Res 1995;688(1-2):77-85. 

8. Debus OM, Lerchl A, Bothe HW et al. Spontaneous central melatonin 

secretion and resorption kinetics of exogenous melatonin: a ventricular 

CSF study. J Pineal Res 2002;33(4):213-7. 

9. Di W-D, Kavda A, Johnston A et al. Variable Bioavalability of Oral 

Melatonin. N Engl J Med 1997;336(14):1028-129. 

10. Dollins AB, Lynch HJ, Wurtman RJ et al. Effect of pharmacological 

daytime doses of melatonin on human mood and performance. Psychopharmacol 1993;112(4):490-6. 

11. Dollins AB, Zhdanova IV, Wurtman RJ et al. Effect of inducing 

nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proc Nat Acad Sci USA 1994;91(5):1824-8. 

12. Helrich E, Neef C, Merkus FW. Population pharm

intranasally administered low dose melatonin. Br 2002;53:543-544. 

13. Hoffmann H, Dittgen M, Hoffmann A et al. Evalu

pulsatile delivery system for melatonin in human1998;53(7):462-6. 

14. Kane MA, Johnson A, Nash AE et al. Serum mela

melanoma patients after repeated oral administra1994;4(1):59-65. 

15. Kovacs J, Brodner W, Kirchlechner V et al. Mea

melatonin: a useful tool for monitoring serum meadministration. J Clin Endocrinol Metab 2000;85

16. Lee B-J, Ryu S-G, Choi H-G et al. Batch variatio

of oral sustained release melatonin-loaded sugar subjects. Arch Pharmacal Res 1997;20(6):555-55

17. Lewy AJ, Bauer VK, Ahmed S et al. The human p

(PRC) to melatonin is about 12 hours out of phasChronobiol Int 1998;15(1):71-83. 

18. MacFarlane JG, Cleghorn JM, Brown GM et al. T

melatonin on the total sleep time and daytime ale

insomniacs: a preliminary study. Biol Psychiatry 

19. Niederhofer H, Staffen W, Mair A et al. Brief repo

sleep in individuals with mental retardation and iDisord. 2003;33:469-72. 

20. Rajaratnam SM, Dijk DJ, Middleton B et al. Mela

human circadian rhythms with no evidence of chendogenous melatonin secretion or the 24-hour preproductive hormones. J Clin Endocrinol Metab 

21. Shah J, Langmuir V, Gupta SK. Feasibility and fu

melatonin in healthy subjects. J Clin Pharmacol 1

22. Shirakawa S-I, Tsuchiya S, Tsutsumi Y et al. Time 

serum melatonin levels after ingestion of melatonNeurosci 1998;52(2): 266-267.
52

23. Shirakawa SI, Sakamoto T, Uchimura N et al. Effect of melatonin on sleep 

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24. Van Den Heuvel CJ, Kennaway DJ Dawson D. Thermoregulatory and 

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Endocrinol Metab 1999;276(2 39-2):E249-E254. 

25. Wright J, Aldhous M, Franey C et al. The effects o

on endocrine function in man. Clin Endocrinol 19

26. Zhdanova IV, Wurtman RJ, Regan MM et al. Mel

relat
53

Evidence Table C-3: Melatonin and the Sleep Cycle: Study Characteristics Abbreviations: RCT: Randomized Controlled Trial, CCT: Controlled Clinical Trial, MLT: Melatonin, SD: Standard Deviation, SE: S

Error of the Mean, IR: Inter-quartile range, NS: Not Specified, BL: Bright Light, DL: Dim Light, E-O: Extra-Ocular, Ocular: Eye-direct

SAD: Seasonal Affective Disorder, LEET: Low Energy Emission Therapy, SWS: Slow-wave sleep

Author Year Population Sample Size N Study Design IntervenAndo, K 1999 Age (Years) Treatment Group RCT 

Treatment group: Enrolled : 6 Blindedness: NS 

Quality Score 19 Mean (SD): 34.4 (13.8) Analyzed: 5 Parallel  Range: NS Control Group

Control Group: Enrolled : 6 

 Mean (SD): 32.6 (8.1) Analyzed : 5  Range: NS  Gender:

Treatment group: 

 Female: 1  Male: 4 

Control Group: 

Treatme

BL Control: 

Placebo Mode of 

Ocular Dosage 

BL: 500  3 hoursFrequen

One sesSleep de

No 

 Female: 2  Male: 3  Sleep disorder: Delayed 

Sleep Phase Syndrome

Author Year Population Sample Size N Study Design IntervenArnulf, I 2002 Age (Years) Treatment Group RCT 

Quality Score 14 Mean (SD): 26 (5.9) Enrolled : 18 Double-blind  Range: 18-38 Analyzed: 17 Cross-over  Gender Control Group

 Female: 11 Enrolled : 18  Male: 7 Analyzed : 17  Sleep disorder: None

Treatme

TryptophControl: 

Placebo Mode of 

Oral Dosage 

Tryptophat 1030 Frequen

Single dSleep de

No 
54

Author Year Population Sample Size N Study Design IntervenBougrine, S 1995 Age (Years) Treatment Group CCT Quality Score 17 Treatment group: Enrolled : 4 Blindedness: NS  Mean (SD): NS Analyzed: 4 Parallel  Range: 20-30 

Control group: Control Group

 Mean (SD): NS Enrolled : 6  Range: 20-30 Analyzed : 6  Gender

 Female: NS  Male: NS  Sleep disorder: Shiftwork disorder

Treatme

BL durinControl: 

BL after Mode of 

Ocular Dosage 

BL durin3 hours shift: 3 chours (113:00h iFrequen

BL durinfor 3 daydays (CoBL after Sleep de

No 

Author Year Population Sample Size N Study Design IntervenBoulos, Z 2002 Age (Years) Treatment Group RCT 

Quality Score 19 Treatment group: Enrolled : 10 Blindedness: NS  Mean (SD): 27 (3.68) Analyzed: 8 Parallel  Range: 21-34 

Control Group: Control Group

 Mean (SD): 24.9 (2.85) Enrolled : 10  Range: 21-34 Analyzed: 8  Gender

Treatment group: 

 Female: 6  Male: 4 

Control Group: 

Treatme

BL Control: 

DL Mode of 

Ocular Dosage 

BL: 3000 (1900-22departurFrequen

One sesSleep de

No 

 Female: 6  Male: 4  Sleep disorder: Jet-lag
55

Author Year Population Sample Size N Study Design IntervenBudnick, LD 1995 Age (Years) Treatment Group CCT Quality Score 16 Median (IR): 35 (NS) Enrolled : 13 Blindedness: NS  Range: 24-52 Analyzed: 9 Cross-over  Gender Control Group

 Female: 2 Enrolled : 13  Male: 11 Analyzed : 9  Sleep disorder: Shiftwork disorder

Treatme

BL Control: 

DL Mode of 

Ocular Dosage 

BL: 6000on half otime: NS Frequen

One sesSleep de

No 

Author Year Population Sample Size N Study Design IntervenBunnell, D 1992 Age (Years) Treatment Group CCT 

Quality Score 12 Mean (SD): NS Enrolled : 5 Blindedness: NS  Range: 20-28 Analyzed: 5 Cross-over  Gender Control Group

 Female: 0 Enrolled : 5  Male: 5 Analyzed: 5  Sleep disorder: None

Treatme

BL Control: 

DL Mode of 

Ocular Dosage 

BL: 2500 to sleepFrequen

One sesSleep de

No 
56

Author Year Population Sample Size N Study Design IntervenBurgess, H 2001 Age (Years) Treatment Group CCT Quality Score 17 Mean (SE): 21.3 (2.7) Enrolled : 16 Double-blind  Range: NS Analyzed: 14 Cross-over  Gender Control Group

 Female: 8 Enrolled : 16  Male: 8 Analyzed : 14  Sleep disorder: None

Treatme

BL Control: DL Mode of 

Ocular Dosage 

BL: >30Clock timFrequen

Single sSleep de

No 

Author Year Population Sample Size N Study Design IntervenBuxton, OM 2000 Age (Years) Treatment Groups CCT 

Quality Score 14 Mean (SD): 23 (3) Morning nap: Blindedness: NS  Range: 20-30 Enrolled 6 Parallel  Gender Analyzed : 6  Female: 0 Afternoon nap:  Male: 25 Enrolled 6  Sleep disorder: None Analyzed : 5 

Evening nap: 

 Enrolled 6  Analyzed : 6 

 Control Group

TreatmeMorning nap in dControl: 

No nap Timing:Morning Afternoo2000 h); Evening Frequen

Single sSleep de

No 

 Enrolled : 7  Analyzed : 6 
57

Author Year Population Sample Size N Study Design IntervenCajochen, C 2000 Age (Years) Treatment Groups RCT Quality Score 16 Mean (SD): 27.8 (8.91) Enrolled : 23 Blindedness: NS  Range: 18-44 Analyzed: 20 Parallel  Gender Low level light 

 Female: 1 Enrolled : NS  Male: 22 Analyzed: NS  Sleep disorder: None Middle level light 

 Enrolled : NS  Analyzed : NS 

High level light 

 Enrolled : NS  Analyzed : NS 

Treatme

Low levelevel lighMode of 

Ocular Dosage 

Low leve230 lux; High levClock timFrequen

Single sSleep de

No 

Author Year Population Sample Size N Study Design IntervenCole, R 2002 Age (Years) Treatment Group RCT 

Quality Score 23 Treatment group: Enrolled : 29 Double-blind  Mean (SD): 25 (6.0) Analyzed : 28 Parallel  Range: 18-40 Control Group

 Gender Enrolled : 30 

 Female: 27 Analyzed : 26  Male: 32  Sleep disorder: Delayed 

Sleep Phase 

 Syndrome 

Treatme

BL Control: 

DL Mode of 

Ocular Dosage 

BL: 2700 (before Clock timFrequen

One sesSleep de

No 
58

Author Year Population Sample Size N Study Design IntervenCosta, G 1997 Age (Years) Treatment Group CCT Quality Score 15 Mean (SD): NS Enrolled : 5 Blindedness: NS  Range: 21-32 Analyzed: 5 Cross-over  Gender Control Group

 Female: 4 Enrolled : 5  Male: 1 Analyzed : 5  Sleep disorder: Shiftwork disorder

Treatme

BL Control: 

DL Mode of 

Ocular Dosage 

BL: 400-DL: 40 l4 periodintervalsFrequen

4 sessioSleep de

No 

Author Year Population Sample Size N Study Design IntervenDanilenko, KV 2000 Age (Years) Treatment Group RCT 

Quality Score 14 Mean (SD): 24.0 (4.8) Enrolled : 9 Blindedness: NS  Range: NS Analyzed: 5 Cross-over  Gender Control Group

 Female: 0 Enrolled : 9  Male: 9 Analyzed : 5  Sleep disorder: None

Treatme

Light DaControl:Control Mode of 

Ocular Dosage 

Dawn si(0330-06Dawn wControl 0730 h). Sleep tr0730 h) Frequen

One sesSleep de

No 
59

Author Year Population Sample Size N Study Design IntervenDanilenko, KV 2003 Age (Years) Treatment Group CCT Quality Score 16 Mean (SD): 24.9 (1.4) Enrolled : 12 Blindedness: NS  Range: 20-34 Analyzed: 10 Cross-over  Gender Control Group

 Female: 6 Enrolled : 12  Male: 4 Analyzed : 10  Sleep disorder: None

Treatme

AdvanceControl: 

Fixed sleTiming:Advancesleep: 2Frequen

Sleep tim6 days. Sleep de

Yes 

Author Year Population Sample Size N Study Design IntervenDaurat A 1996 Age (Years) Treatment Group CCT 

Quality Score 16 Mean (SD): 23.6 (1.05) Enrolled : 8 Blindedness: NS  Range: NS Analyzed: 8 Cross-over  Gender Control Group

 Female: 0 Enrolled : 8  Male: 8 Analyzed : 8  Sleep disorder: None

Treatme

ModeratControl: 

DL Mode of 

Ocular Dosage 

BL: 100014 hours Frequen

Single sSleep de

Yes 
60

Author Year Population Sample Size N Study Design IntervenDaurat, A 1997 Age (Years) Treatment Group CCT Quality Score 16 Mean (SEM): 23.6 (1.05) Enrolled : 10 Blindedness: NS  Range: NS Analyzed: 10 Cross-over  Gender Control Group

 Female: 0 Enrolled : 10  Male: 8 Analyzed : 10  Sleep disorder: None

Treatme

ModeratControl: 

DL Mode of 

Ocular Dosage 

BL: 1000hours duof sleepFrequen

Single sSleep de

Yes 

Author Year Population Sample Size N Study Design IntervenDijk, DJ 1989 Age (Years) Treatment Group CCT 

Quality Score 16 Mean (SD): 23.1 (2.5) Enrolled : 8 Blindedness: NS  Range: NS Analyzed: 8 Cross-over  Gender Control Group

 Female: 0 Enrolled : 8  Male: 8 Analyzed : 8  Sleep disorder: None

Treatme

BL Control:DL Mode of 

Ocular Dosage 

BL: 2000 (0600-09Frequen

Single sSleep de

No 
61

Author Year Population Sample Size N Study Design IntervenDollins, AB 1993 Age (Years) Treatment Group RCT Quality Score 16 Mean (SEM): 23.0 (1.16) Enrolled : 24 Blindedness: NS  Range: 19-39 Analyzed: 21 Cross-over  Gender Control Group

 Female: 0 Enrolled : 24  Male: 24 Analyzed : 21  Sleep disorder: None

Treatme

Illuminatdifferent Mode of 

Ocular Dosage 

300 lux, hours (1Frequen

One sesSleep de

No 

Author Year Population Sample Size N Study Design IntervenEcker, AJ 2000 Age (Years) Treatment Group B CCT 

Quality Score 10 Mean (SD): 28.5 (4.9) Enrolled : 4 Blindedness: NS  Range: NS Analyzed: 4 Parallel  Gender Treatment Group C Female: 5 Enrolled : 4  Male: 8 Analyzed : 4  Sleep disorder: None Control Group

 Enrolled : 5  Analyzed : 5 

TreatmeSleep reControl: 

Normal Timing:Control: 0606 h); Conditio0406 h); Conditio0406 h a(1324-14Frequen

One sesSleep de

Yes 
62

Author Year Population Sample Size N Study Design IntervenGordijn, MC 1998 Age (Years) Treatment Group CCT Quality Score 19 Mean (SD): 39.3 (12.1) Enrolled : 12 Blindedness: NS  Range: 23.6-56.5 Analyzed: 12 Cross-over  Gender Control Group

 Female: 6 Enrolled : 12  Male: 6 Analyzed : 12  Sleep disorder: None

Treatme

BL Control: 

DL Mode of 

Ocular Dosage 

BL: 2500 09:00 h Frequen

One sesweeks Sleep de

No 

Author Year Population Sample Size N Study Design IntervenGordijn, MC 1999 Patients: Treatment Groups CCT 

Quality Score 17 Age (Years) Patients: Blindedness: NS 

 Mean (SD): 38.3 (12.2) Enrolled : 10 Cross-over  Range: NS Analyzed: 8  Gender non-Patients:  Female: 5 Enrolled : 8  Male: 5 Analyzed: 8 

non-Patients: Control Groups

 Age (Years) Patients: 

 Mean (SD): 38.7 (12.9) Enrolled : 10  Range: NS Analyzed: 8  Gender non-Patients:  Female: 3 Enrolled : 8 

Treatme

BL Control: 

DL Mode of 

Ocular Dosage 

BL: 2500 0600-09or EvenFrequen

One sesSleep de

No 

 Male: 5 Analyzed: 8  Sleep disorder: Patients 

had Nonseasonal 

 Depression, which may 

or may not have 

 been accompanied by a 

sleep disorder. 
63

Author Year Population Sample Size N Study Design IntervenGoh, VH 2001 Age (Years) Treatment Group RCT Quality Score 18 Mean (SD): NS Enrolled : 7 Blindedness: NS  Range: 20-30 Analyzed: 7 Parallel  Gender Control Group

 Female: 0 Enrolled : 7  Male: 14 Analyzed : 7  Sleep disorder: None

Treatme

Total sleControl: 

Normal Timing:Sleep deh the daNormal Frequen

Single sSleep de

Yes 

Author Year Population Sample Size N Study Design IntervenGoichot, B 1998 Age (Years) Treatment Group CCT 

Quality Score 13 Mean (SD): NS Enrolled : 8 Blindedness: NS  Range: 23-30 Analyzed: 8 Cross-over  Gender Control Group

 Female: 0 Enrolled : 8  Male: 8 Analyzed: 8  Sleep disorder: None

Treatme

Sleep affollowed Control: 

Normal Timing:Sleep afDaytime Normal 0700 h) Frequen

Single sSleep de

Yes 
64

Author Year Population Sample Size N Study Design IntervenHiguchi, S 2003 Age (Years) Treatment Group RCT Quality Score 15 Mean (SD): 24.7 (5.6) Enrolled : 7 Blindedness: NS  Range: NS Analyzed: 7 Cross-over  Gender Control Group

 Female: 0 Enrolled : 7  Male: 7 Analyzed: 7  Sleep disorder: None

Treatme

Video didisplay Control: 

Video diMode of 

Ocular Dosage 

Bright dlux for 3 Frequen

One sesSleep de

No 

Author Year Population Sample Size N Study Design IntervenHorne, JA 1991 Age (Years) Treatment Group RCT 

Quality Score 15 Mean (SD): NS Enrolled : 12 Single-blinded  Range: 19-26 Analyzed: 12 Cross-over  Gender Control Group

 Female: 8 Enrolled : 12  Male: 4 Analyzed: 12  Sleep disorder: None

Treatme

BL Control: 

DL Mode of 

Ocular Dosage 

BL: 2000 (1800-06Frequen

10-min sSleep de

Yes 
65

Author Year Population Sample Size N Study Design IntervenHorowitz, TS 2001 Age (Years) Treatment Group RCT Quality Score 16 Mean (SD): 26.99 (6.22) Enrolled : 26 Blindedness: NS  Range: 20-40 Analyzed: 25 Cross-over  Gender Control Group

Treatment group: Enrolled : 28 

 Female: 10 Analyzed: 27  Male: 16 

Control: 

 Female: 18  Male: 10  Sleep disorder: Shiftwork disorder

Treatme

BL Control: 

DL Mode of 

Ocular Dosage 

BL: 2500 DL: 150 Frequen

One sesSleep de

No 

Author Year Population Sample Size N Study Design IntervenJelinkovaVondrasova, D 1999 Age (Years) Treatment Group CCT 

Quality Score 14 Mean (SD): NS Enrolled : 8 Blindedness: NS  Range: 20-24 Analyzed: 8 Cross-over  Gender Control Group

 Female: 5 Enrolled : 8  Male: 3 Analyzed: 8  Sleep disorder: None

Treatme

Shift of tthe slee2) 3-h ad2200-06Timing: 

3-h dela0900 h; 3-h advato 0600 Frequen

One sesSleep de

No 
66

Author Year Population Sample Size N Study Design IntervenJimerson, DC 1977 Patients: Treatment Group CCT Quality Score 15 Age (Years) Patients: Blindedness: NS 

 Mean (SD): NS Enrolled : 6 Cross-over  Range: 19-50 Analyzed: 5  Gender non-Patients:  Female: 5 Enrolled : 8  Male: 1 Analyzed: 5 

non-Patients: Control Group

 Age (Years) Patients: 

 Mean (SD): NS Enrolled : 6  Range: 19-65 Analyzed: 5 

Treatme

Sleep deControl: 

Normal Timing:Sleep deh the daNormal Frequen

Single sSleep de

Yes 

 Gender non-Patients: 

 Female: 2 Enrolled : 8  Male: 4 Analyzed: 5  Sleep disorder: Patients 

suffered from 

 Depression, which may 

or may not have 

 been accompanied by a 

sleep disorder. 

Author Year Population Sample Size N Study Design IntervenKelly, TL 1997 Age (Years) Treatment Groups CCT Quality Score 17 Mean (SD): NS LEET group Double-blind  Range: NS Enrolled : 12 Parallel  Gender Analyzed: 12  Female: 0 BL  Male: 45 Enrolled : 12 

LEET group Analyzed: 8 

 Age (Years) BL + LEET 

 Mean (SD): 24.8 (7.9) Enrolled : 11  Range: NS Analyzed: 11 

BL Control Group

 Age (Years) DL 

 Mean (SD): 22.5 (3.5) Enrolled : 10 

Treatme

BL and combineControl: 

DL Mode of 

Ocular Dosage LEET: 2periods. DL: 2000200 h) FrequenOne sesSleep de

No 

 Range: NS Analyzed: 7 

BL + LEET 

 Age (Years)
67

 Mean (SD): 23.4 (4.1)  Range: NS 

DL 

 Age (Years) Mean (SD): 25.2 (7.7)  Range: NS  Sleep disorder: Shiftwork disorder

Author Year Population Sample Size N Study Design IntervenKoorengevel, KM 2001 Age (Years) Treatment Group CCT 

Quality Score 19 Treatment group: Enrolled : 15 Double-blind  Mean (SD): 39.6 (12.2) Analyzed: 13 Parallel  Range: NS Control Group

Control group: Enrolled : 14 

 Mean (SD): 43.4 (12.4) Analyzed : 11  Range: NS  Gender

Treatment group: 

 Female: 11  Male: 4 

Control group: 

Treatme

Light theControl: 

Placebo Mode of 

E-O (beDosage 

13000 luFrequen

One sesSleep de

No 

 Female: 10  Male: 4  Sleep disorder: 

Participants suffered from 

 SAD, which may or may 

not be 

 accompanied by a sleep 

disorder. 
68

Author Year Population Sample Size N Study Design IntervenKubota, T 2002 Age (Years) Treatment Group CCT Quality Score 18 Mean (SD): 24 (NS) Enrolled : 9 Blindedness: NS  Range: 20-27 Analyzed: 9 Cross-over  Gender Control Group

 Female: 0 Enrolled : 9  Male: 9 Analyzed : 9  Sleep disorder: None

Treatme

BL Control: 

DL Mode of 

Ocular Dosage 

BL: 5000 5 hours Frequen

Single sSleep de

Yes 

Author Year Population Sample Size N Study Design IntervenLavoie, S 2003 Age (Years) Treatment Group CCT 

Quality Score 17 Mean (SD): 26.1 (4.2) Enrolled : 7 Blindedness: NS  Range: 22-35 Analyzed: 7 Parallel  Gender Control Group

 Female: 8 Enrolled : 7  Male: 6 Analyzed : 7  Sleep disorder: None

Treatme

BL Control: 

DL Mode of 

Ocular Dosage 

BL: 3000 (0030-04Frequen

Single sSleep de

Yes 
69

Author Year Population Sample Size N Study Design IntervenLushington, K 2002 Age (Years) Treatment Group CCT Quality Score 18 Mean (SD): 22.1 (3.0) Enrolled : 13 Single-blind  Range: 13-34 Analyzed: 13 Cross-over  Gender Control Group

 Female: 3 Enrolled : 13  Male: 10 Analyzed : 13  Sleep disorder: None

Treatme

Light Control: 

Placebo Mode of 

E-O (beDosage 

Light: 100400 h) Frequen

One sesSleep de

No 

Author Year Population Sample Size N Study Design IntervenMorris, M 1990 Age (Years) Treatment Group CCT Treatme

Quality Score 17 Mean (SD): 27 (NS) Enrolled : 8 Blindedness: NS Continuo Range: NS Analyzed: 8 Cross-over Control: 

 Gender Control Group Nightime 

 Female: 3 Enrolled : 8 Timing:  Male: 5 Analyzed : 8 Continuo

Nightime 

 Sleep disorder: None Frequen

 Single s Sleep de

 Yes 
70

Author Year Population Sample Size N Study Design IntervenPartonen, T 1996 Patients Treatment Group RCT Quality Score 19 Age (Years) Patients: Blindedness: NS 

 Mean (SEM): 40.2 (2.2) Enrolled : 7 Parallel  Range: 23-55 Analyzed: 7  Gender non-Patients:  Female: 16 Enrolled : 5  Male: 0 Analyzed: 5 

non-Patients Control Group

 Age (Years) Patients: 

 Mean (SEM): 41.6 (3.6) Enrolled : 9  Range: 24-64 Analyzed: 9  Gender non-Patients: 

Treatme

BL 1 hoControl: 

BL 15 mMode of 

Ocular Dosage 

BL: 3300 (betweeFrequen

One seswinter Sleep de

No 

 Female: 13 Enrolled : 8  Male: 0 Analyzed: 8  Sleep disorder: Patients 

suffered from SAD, 

 which may or may not be 

accompanied by a 

 sleep disorder. Author Year Population Sample Size N Study Design IntervenRao, ML 1996 Age (Years) Treatment Group RCT 

Quality Score 19 Median (IR): 25.5 (NS) Enrolled : 12 Single-blind  Range: 20-33 Analyzed: 12 Cross-over  Gender Control Group

 Female: 0 Enrolled : 12  Male: 12 Analyzed : 12  Sleep disorder: None

Treatme

SWS deControl: 

Normal Timing:SWS dehours (2Frequen

One sesSleep de

Yes 
71

Author Year Population Sample Size N Study Design IntervenRedwine, L 2000 Age (Years) Treatment Group CCT Quality Score 17 Mean (SD): 35.8 (10.12) Enrolled : 31 Blindedness: NS  Range: 25-65 Analyzed: 31 Cross-over  Gender Control Group

 Female: 0 Enrolled : 31  Male: 31 Analyzed : 31  Sleep disorder: None

Treatme

Partial sControl: 

UninterrTiming:Partial s5 hours Control (2200-07Frequen

One sesSleep de

Yes 

Author Year Population Sample Size N Study Design IntervenRoss, JK 1995 Age (Years) Treatment Group RCT 

Quality Score 17 Mean (SD): NS Enrolled : 8 Blindedness: NS  Range: 21-35 Analyzed: 7 Cross-over  Gender Control Group

 Female: 0 Enrolled : 7  Male: 14 Analyzed : 6  Sleep disorder: Shiftwork disorder

Treatme

BL Control: 

DL Mode of 

Ocular Dosage 

BL: 2500hours (1Frequen

One sesSleep de

No 
72

Author Year Population Sample Size N Study Design IntervenSalin-Pascual RJ 1988 Age (Years) Treatment Group CCT Quality Score 17 Mean (SD): 20.83 (2.97) Enrolled : 12 Blindedness: NS  Range: 16-26 Analyzed: 12 Cross-over  Gender Control Group

 Female: 3 Enrolled : 12  Male: 9 Analyzed : 12  Sleep disorder: None

Treatme

Sleep deControl: 

Normal Timing:Sleep dedeprivatNormal Frequen

Single sSleep de

Yes 

Author Year Population Sample Size N Study Design IntervenSamel A 1993 Age (Years) Treatment Group CCT 

Quality Score 15 Mean (SD): 23.0 (3.3) Enrolled : 8 Blindedness: NS  Range: 20-29 Analyzed: 8 Cross-over  Gender Control Group

 Female: 0 Enrolled : 8  Male: 8 Analyzed : 8  Sleep disorder: None

Treatme

Sleep-wControl: 

Normal Timing:Sleep-wNormal Frequen

One sesSleep de

Yes 

Author Year Population Sample Size N Study Design Intervenvon Treuer K 1996 Age (Years) Treatment Group CCT 

Quality Score 14 Mean (SD): NS Enrolled : 9 Blindedness: NS  Range: 17-29 Analyzed: 9 Cross-over  Gender Control Group

 Female: 0 Enrolled : 9  Male: 9 Analyzed : 9  Sleep disorder: None

Treatme

Sleep deControl: 

Control Timing:Sleep deh the daFrequen

Single sSleep de

Yes 
73

Author Year Population Sample Size N Study Design IntervenWakamura, T 2000 Age (Years) Treatment Group RCT Quality Score 17 Mean (SD): 20 (2) Enrolled : 7 Blindedness: NS  Range: 18-23 Analyzed: 7 Cross-over  Gender Control Group

 Female: 7 Enrolled : 7  Male: 0 Analyzed : 7  Sleep disorder: None

Treatme

BL Control: 

DL Mode of 

Ocular Dosage 

BL: 6000 bedtime Frequen

Single sSleep de

No 

Author Year Population Sample Size N Study Design IntervenWehr, TA 1991 Age (Years) Treatment Group CCT 

Quality Score 14 Mean (SD): NS Enrolled : 8 Blindedness: NS  Range: 20-36 Analyzed: 7 Cross-over  Gender Control Group

 Female: 0 Enrolled : 8

 Male: 8 Analyzed : 7  Sleep disorder: None

Treatme

SummeControl: 

Winter pDosage 

Summehours of Winter ph of darkClock timFrequen

Summefor 1 weWinter pweeks Sleep de

No 
74

Author Year Population Sample Size N Study Design IntervenWeibel, L 1997 Age (Years) Treatment Group RCT Quality Score 19 Mean (SD): NS Enrolled : 19 Non-blinded  Range: NS Analyzed: 19 Cross-over  Gender Control Group

 Female: 0 Enrolled : 19  Male: 19 Analyzed : 19  Sleep disorder: None

Treatme

Sleep pesleeping Control: 

Normal sleeping Timing:Sleep peNormal Frequen

Single sSleep de

Yes 

Author Year Population Sample Size N Study Design IntervenYoon I 2000 Age (Years) Treatment Group CCT 

Quality Score 8 Mean (SD): NS Enrolled : 17 Non-blinded  Range: 20-41 Analyzed: 17 Cross-over  Gender Control Group

 Female: NS Enrolled : 17  Male: NS Analyzed : 17  Sleep disorder: Shiftwork disorder

Treatme

Light-1, Control: 

Baseline Dosage 

Light-1: shift) folsunlight or 10000 Same ligsunlight/exposurFrequen

One sesSleep de

No 
75

Evidence Table C-3: Referneces 1. Ando K, Kripke DF Cole RJ. Light mask 500 lux treatment for 

delayed sleep phase syndrome. Prog Neuro-Psychopharmacol Biol Psychiatry 1999;23(1):15-24. 

2. Arnulf I, quintin P, Alvarez JC et al. Mid-morning tryptophan 

depletion delays REM sleep onset in healthy subjects. Neuropsychopharmacol 2001;23(5):843-51. 

3. Bougrine S, Mollard R, Ignazi G et al. Appropriate use of bright 

light promotes a durable adaptation to night-shifts and accelerates readjustment during recovery after a period of night-shifts. Work Stress 1995;9(2-3):314-26. 

4. Boulos Z, Macchi MM, Sturchler MP et al. Light visor treatment for 

jet lag after westward travel across six time zones. Aviat Space Environ Med 2002;73(10):953-63. 

5. Budnick LD, Lerman SE, Nicolich MJ. An evaluation of scheduled 

bright light and darkness on rotating shiftworkers: trial and limitations. Am J Ind Med 1995;27(6):771-82. 

6. Bunnell DE, Treiber SP, Phillips NH et al. Effects of evening 

bright light exposure on melatonin, body temperature and sleep. J Sleep Res 1992;1(1):17-23. 

7. Burgess HJ, Sletten T, Savic N et al. Effects of bright light and 

melatonin on sleep propensity, temperature, and cardiac activity at night. J Appl Physiol 2001;91(3):1214-22. 

8. Buxton OM, L'Hermite-Baleriaux M, Turek FW et al. Daytime naps 

in darkness phase shift the human circadian rhythms of melatonin and thyrotropin secretion. Am J Physiol - Reg Integr Comparative Physiol 2000;278(2):R373-82. 

9. Cajochen C, Zeitzer JM, Czeisler CA et al. Dose-response 

relationship for light intensity and ocular and electroencephalographic correlates of human alertness. Behav Brain Res 2000;115(1):75-83. 

10. Cole RJ, Smith JS, Alcala YC et al. Bright-light mask treatment of 

delayed sleep phase syndrome. J Biol Rhythms 2002;17(1):89-101. 

11. Costa G, Kovacic M, Bertoldi A et al. The use 

night work by nurses. Biol Rhythm Res 1997

12. Danilenko KV, Cajochen C, Wirz-Justice A. Is 

zeitgeber in humans? J Biol Rhythms 2003;1

13. Danilenko KV, Wirz-Justice A, Krauchi K et a

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14. Daurat A, Aguirre A, Foret J et al. Disruption 

36 hours of exposure to moderately bright lig1997;20(5):352-8. 

15. Daurat A, Foret J, Touitou Y et al. Detrimenta

light exposure on alertness, performance, anmorning. Neurophysiol Clin 1996;26(1):8-14. 

16. Dijk DJ, Beersma DGM, Daan S et al. Bright 

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17. Dollins AB, Lynch HJ Wurtman RJ et al. Effec

human nocturnal serum melatonin levels and Physiol Behav 1993;53(1):153-160. 

18. Ecker AJ, Schaechter J, Price NJ et al. Chan

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19. Goh VH, Tong TY, Lim CL et al. Effects of on

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20. Goichot B, Weibel L, Chapotot F et al. Effect 

sleep-wake cycle on three robust endocrine circadian clock. Am J Physiol 1998;275(2 Pt 

21. Gordijn MC, Beersma DG, Korte HJ et al. Eff

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22. Gordijn MC, Beersma DG, Korte HJ et al. Testing the hypothesis of 

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23. Higuchi S, Motohashi Y, Liu Y et al. Effects of VDT tasks with a 

bright display at night on melatonin, core temperature, heart rate, and sleepiness. J Appl Physiol 2003;94(5):1773-6. 

24. Horne JA, Donlon J, Arendt J. Green light attenuates melatonin 

output and sleepiness during sleep deprivation. Sleep 1991;14(3):233-40. 

25. Horowitz TS, Cade BE, Wolfe JM et al. Efficacy of bright light and 

sleep/darkness scheduling in alleviating circadian maladaptation to night work. Am J Physiol. Endocrinol Metab 2001;281(2):E384-91. 

26. Jelinkova-Vondrasova D, Hajek I, Illnerova H. Adjustment of the 

human circadian system to changes of the sleep schedule under dim light at home. Neurosci Lett 1999;265(2):111-4. 

27. Jimerson DC, Lynch HJ, Post RM et al. Urinary melatonin rhythms 

during sleep deprivation in depressed patients and normals. Life Sci 1977;20(9):1501-8. 

28. Kelly TL, Kripke DF, Hayduk R et al. Bright light and LEET effects 

on circadian rhythms, sleep and cognitive performance. Stress Med 1997;13(4):251-8. 

29. Koorengevel KM, Gordijn MC, Beersma DG et al. Extraocular light 

therapy in winter depression: a double-blind placebo-controlled study(erratum appears in Biol Psychiatry 2002; Jan 15;512.:194). Biol Psychiatry;2001;50(9):691-8. 

30. Kubota T, Uchiyama M, Suzuki H et al. Effects of nocturnal bright 

light on saliva melatonin, core body temperature and sleep propensity rhythms in human subjects. Neurosci Res 2002;42(2):115-22. 

31. Lavoie S, Paquet J, Selmaoui B et al. Vigilance levels during and 

after bright light exposure in the first half of the night. Chronobiol Int 2003;206.:1019-38. 

32. Lushington K, Galka R, Sassi LN et al. Extrao

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33. Morris M, Lack L, Barrett J. The effect of slee

nocturnal melatonin excretion. J Pineal Res 

34. Partonen T, Vakkuri O, Lamberg-Allardt C et 

light on sleepiness, melatonin, and 25-hydrowinter seasonal affective disorder. Biol Psyc1996;39(10):865-72. 

35. Rao ML, Pelzer E, Papassotiropoulos A et al

sleep deprivation influences blood serotonin melatonin concentrations in healthy subjects1996;40(7):664-7. 

36. Redwine L, Hauger RL, Gillin JC et al. Effects 

deprivation on interleukin-6, growth hormonemelatonin levels in humans. J Clin Endocrin2000;85(10):3597-603. 

37. Ross JK, Arendt J, Horne J et al. Night-shift w

sleep characteristics and bright light treatme1995;57(6),:169-74. 

38. Salin-Pascual RJ, Ortega-Soto H, Huerto-De

effect of total sleep deprivation on plasma min healthy human volunteers. Sleep 1988;11

39. Samel A, Wegmann HM, Vejvoda M. Pre-ada

space. Acta Astronaut 1993;29(8):593-9. 

40. von Treuer K, Norman TR, Armstrong SM. O

plasma melatonin, cortisol, prolactin, TSH, unormal sleep, sleep deprivation, and sleep re1996;20(1):7-14. 

41. Wakamura T, Tokura H. The influence of brig

daytime upon circadian rhythm of core tempeimplications for nocturnal sleep. Nurs Health 
77

42. Wehr TA. The durations of human melatonin secretion and sleep 

respond to changes in day length photoperiod.. J Clin Endocrinol Metab 1991;73(6):1276-80. 

43. Weibel L, Spiegel K, Gronfier C et al. Twenty-four-hour melatonin 

and core body temperature rhythms: Their adaptation in night 

workers. Am J Physiol - Reg Integr Compar41-3):R948-R954. 1997. 

44. Yoon I, Jeong D, Kwon K et al. Homeostatic 

in improving adaptation of rapidly rotating nigSleep 2000;23(Supp 2):A186.
78

Evidence Table C-4: Mechanisms by which Melatonin Produces Sleepiness: Study Characteristics Abbreviations: RCT: randomized controlled trial, CCT: controlled clinical trial, MLT: melatonin, FR: fast-release, SR: slow-release, 

standard error, mg: milligrams, h: hours, NS: not specifiedControl Group received placebo unless otherwise indicated

Author Year Population Sample Size N Study Design IntervenAlmeida- 2003 Age (Years) Treatment Group RCT 

Montes, LG Mean (SD): 50 (NS) Enrolled : 10 Double-blind Quality Score 5 Range: 30-72 Analyzed: 10 Cross-over  Gender Control Group

 Female: 4 Enrolled : 10  Male: 6 Analyzed : 10  Sleep Disorder: 

Insomnia

Formula

SustaineRoute o

Oral Dosage 0.3 mg obefore bFrequenOne dos

Author Year Population Sample Size N Study Design IntervenAndrade, C 2001 Age (Years) Treatment Group RCT 

Quality Score 4 Treatment group Enrolled : 18 Double-blind 

 Mean (SD): 59.7 (11.1) Analyzed: 18 Parallel  Range: 43-85 

Control group Control Group

 Mean (SD): 51.4 (14.2) Enrolled : 15  Range: 23-70 Analyzed : 15  Gender

Treatment group 

 Female: 4  Male: 14 

Control group 

 Female: 5  Male: 10  Sleep Disorder: 

Insomnia

FormulaNS Route o

Oral Dosage 3 mg MLFrequen

1 capsu2 capsualternate capsuleDuration

21 patiereceived treatmen= 5, PLB n= days, anpatients treatme
79

Author Year Population Sample Size N Study Design IntervenDahlitz, M 1991 Age (Years) Treatment Group RCT Quality Score 4 Mean (SD): NS Enrolled : 8 Double-blind  Range: 20-60 Analyzed: 8 Cross-over  Gender Control Group

 Female: 0 Enrolled : 8  Male: 8 Analyzed : 8  Sleep Disorder: 

Delayed sleep phase syndrome

Formula

NS Route o

Oral Dosage 5 mg MLFrequenOne dos

Author Year Population Sample Size N Study Design IntervenEdwards, BJ 2000 Age (Years) Treatment Group CCT 

Quality Score 22 Treatment Group Enrolled : 14 Double-blind 

 mean (SD): 40(13) Analyzed: 13 Parallel  range: NS Control Group

Control Group Enrolled : 17 

 mean (SD): 41(12) Analyzed : 13  range: NS  Gender

 female: 3 

Formula

Not speRoute o

Oral Dosage 5mg ML18:00-123:00h, destinateveningFrequen2 capsucapsule

 male: 28  Sleep Disorder: Jetlag

Author Year Population Sample Size N Study Design IntervenFolklard, S 1993 Age (Years) Treatment Group RCT 

Quality Score 3 Mean (SD): 29 (7) Enrolled : 7 Double-blind  Range: 21-48 Analyzed: 7 Cross-over  Gender Control Group

 Female: 2 Enrolled : 8  Male: 15 Analyzed : 8  Sleep Disorder: 

Night-shift disorder

Formula

NS Route o

Oral Dosage 5 mg MLFrequenOne dossleeps tbetween 
80

Author Year Population Sample Size N Study Design IntervenHolmes, A.L. 2002 Age (Years) Treatment Group CCT Quality Score 15 Mean (SD): 20.3 (0.6) Enrolled : 12 Double-blind  Range: 19-25 Analyzed: 12 Cross-over  Gender Control Group

 Female: 5 Enrolled : 12  Male: 7 Analyzed : 12  Sleep Disorder: 

Normal sleepers

Formula

NS Route o

Oral Dosage 5 mg MLFrequenSingle d

Author Year Population Sample Size N Study Design IntervenMishima, K 1997 Age (Years) Treatment Group RCT 

Quality Score 16 Mean (SD): 22.5 (1.9) Enrolled : 6 Single-blind  Range: Analyzed: 6 Cross-over  Gender Control Group

 Female: 0 Enrolled : 6  Male: 6 Analyzed : 6  Sleep Disorder: 

Normal sleepers

Formula

NS Route o

Oral Dosage 3 mg or FrequenOne dos

Author Year Population Sample Size N Study Design IntervenPetrie 1989 Age (Years) Treatment Group RCT 

Quality Score 20 Mean (SD): NS Enrolled : 20 Double-blind  Range: 28-68 Analyzed: 20 Cross-over  Gender Control Group

 Female: 8 Enrolled : 20  Male: 12 Analyzed : 20  Sleep Disorder: Jet 

Lag

Formula

NS Route o

NS Dosage 5 mg MLh local tFrequenOne dosduring flday for 3 
81

Author Year Population Sample Size N Study Design IntervenSatomura, T 2001 Age (Years) Treatment Group RCT Quality Score 11 Mean (SD): 23.7(1.7) Enrolled : 7 Single-blind  Range: NS Analyzed: 7 Cross-over  Gender Control Group

 Female: 0 Enrolled : 7  Male: 7 Analyzed : 7  Sleep Disorder: 

Normal sleepers

Formula

NS Route o

Oral Dosage 1 mg, 3 FrequenSingle d

Author Year Population Sample Size N Study Design IntervenTerlo, L 1997 Age (Years) Treatment Group CCT 

Quality Score 19 Mean (SD): 28(2) Enrolled : 10 Double-blind  Range: NS Analyzed: 10 Cross-over  Gender Control Group

 Female: 0 Enrolled : 10  Male: 10 Analyzed : 10  Sleep Disorder: 

Normal sleepers

Formula

NS Route o

Oral Dosage  0.1 mgh FrequenOne dosdays 

Author Year Population Sample Size N Study Design IntervenZhdanova, I 1995 Age (Years) Treatment Group RCT 

Quality Score 18 Mean (SD): 26.5(1.3) Enrolled : 6 Double-blind  Range: 25-64 Analyzed: 6 Cross-over  Gender Control Group

 Female: 0 Enrolled : 6  Male: 6 Analyzed : 6  Sleep Disorder: 

Normal sleepers

Formula

NS Route o

Oral Dosage 0.3 mg, between 21:00 h FrequenOne dos
82

Evidence Table C-4: References 1. Almeida Montes LG, Ontiveros Uribe MP, Cortes Sotres J et al. Treatment of primary insomnia with melatonin: A double-blind, placebocontrolled, crossover study. J Psychiatry Neurosci 2003; 28(3):191-196. 2. Andrade C, Srihari BS, Reddy KP et al. Melatonin in medically ill patients with insomnia: a double-blind, placebo-controlled study. J Clin Psychiatry 2001;62(1):41-5. 3. Dahlitz M, Alvarez B, Vignau J et al. Delayed sleep phase syndrome response to melatonin. Lancet 1991;337(8750):1121-4. 4. Edwards BJ, Atkinson G, Waterhouse J et al. Use of melatonin in recovery from jet-lag following an eastward flight across 10 time-zones. Ergon 2000;43(10):1501-13. 5. Folkard S, Arendt J, Clark M. Can melatonin improve shift workers' tolerance of the night shift? Some preliminary findings. Chronobiol Int 1993;10(5):315-20. 

6. Holmes AL, Gilbert SS, Dawson D. Melatonin anrelationship between sleep propensity and body temper2002;25(3):301-6. 7. Mishima K, Satoh K, Shimizu T et al. Hypnotic aof daytime-administered melatonin. Psychopharmacol 8. Petrie K, Conaglen JV, Thompson L et al. Effect after long haul flights. Br Med J 1989;298(6675):705-79. Satomura T, Sakamoto T, Shirakawa S et al. Hypmelatonin during daytime administration and its compaPsychiatry Clin Neurosci 2001;55(3):303-4. 10. Terlo L, Laudon M, Tarasch R et al. Effects of lolate afternoon napping and mood. Biol Rhythm Res 19911. Zhdanova IV, Wurtman RJ, Lynch HJ et al. Sleepdoses of melatonin ingested in the evening. Clin Pharm1995;57(5):552-8.
83

Evidence Table C-5: Effect of Melatonin on Normal Sleepers: Study Characteristics Abbreviations: RCT: randomized controlled trial, CCT: controlled clinical trial, MLT: melatonin, FR: fast-release, SR: slow-release, 

standard error, mg: milligrams, h: hours, NS: not specified 

Control group received placebo unless otherwise indicated Author Year Population Sample Size N Study Design Intervention Attenburrow M 1996 Age (Years) Treatment Group RCT 

Quality Score 17 mean: 53.9 Enrolled : 15 Double-blind  range: 41-67 Analyzed: 12 Cross-over  Gender Control Group

 female: 11 Enrolled : 15  male: 4 Analyzed : 12 

Formulation

Not specified Route of Adm

Not specified Dosage and T

0.3 or 1.0mg bedtime (2200Frequency an0.3 or 1.0mg/

Author Year Population Sample Size N Study Design Intervention Baskett, J 2003 Age (Years) Treatment Group RCT 

Quality Score 25 mean: NS Enrolled : 20 Double-blind  range: 60-84 Analyzed: 14 Cross-over  Gender

 female: 16  male: 4 Control Group

 Enrolled : 20  Analyzed : 14 

Formulation

Not specified Route of Adm

Oral Dosage and T

5mg MLT at bFrequency anI capsule/day 

Author Year Population Sample Size N Study Design Intervention Cajochen, C 1998 Age (Years) Treatment Group RCT 

Quality Score 18 mean (SD): 27(5) Enrolled : 10 Single-blind  range: NS Analyzed: 10 Cross-over  Gender Control Group

 female: 0 Enrolled : 10  male: 10 Analyzed : 10 

Formulation

Not specified Route of Adm

Oral Dosage and T

5 mg of MLT, Frequency an1 capsule/wee
84

Author Year Population Sample Size N Study Design Intervention Cajochen, C 1997 Age (Years) Treatment Group RCT Quality Score 16 mean: NS Enrolled : 8 Double-blind  range: 23-32 Analyzed: 8 Cross-over  Gender Control Group

 female: 0 Enrolled : 8  male: 8 Analyzed : 8 

Formulation

Not specified Route of Adm

Oral Dosage and T

5 mg MLT at Frequency anSingle dose 

Author Year Population Sample Size N Study Design Intervention Dollins, A.B. 1994 Age (Years) Treatment Group RCT 

Quality Score 18 mean (SD): 23.05(4.2

2) 

Enrolled : 20 Double-blind 

 range: 18-24 Analyzed: 20 Cross-over  Gender Control Group

 female: 0 Enrolled : 20  male: 20 Analyzed : 20 

Formulation

Not specified Route of Adm

Oral Dosage and T

0.1, 0.3, 1.0 oFrequency anI capsule/day 

Author Year Population Sample Size N Study Design Intervention Ferini-Strambi 1993 Age (Years) Treatment Group CCT 

Quality Score 14 mean (SD): 25.3(3.6) Enrolled : 6 Single-blind  range: NS Analyzed: 6 Cross-over  Gender Control Group

 female: 0 Enrolled : 6  male: 6 Analyzed : 6 

Formulation

Not specified Route of Adm

Oral Dosage and T

100mg MLT aFrequency an1 tablet on nig

Author Year Population Sample Size N Study Design Intervention Holmes, A.L. 2002 Age (Years) Treatment Group CCT 

Quality Score 15 mean (SD): 20.3(0.6) Enrolled : 12 Double-blind  range: 19-25 Analyzed: 12 Cross-over  Gender Control Group

 female: 5 Enrolled : 12  male: 7 Analyzed : 12 

Formulation

Not specified Route of Adm

Oral Dosage and T

5 mg MLT at Frequency anSingle dose 
85

Author Year Population Sample Size N Study Design Intervention James, S.P 1987 Age (Years) Treatment Group RCT Quality Score 17 mean: 29.9 Enrolled : 11 Double-blind  range: 21-40 Analyzed: 10 Cross-over  Gender Control Group

 female: 3 Enrolled : 11  male: 7 Analyzed : 10 

Formulation

Not specified Route of Adm

Not specified Dosage and T

1mg or 5mg Frequency an1mg or 5mg/d

Author Year Population Sample Size N Study Design Intervention Luboshitzky R 2000 Age (Years) Treatment Group CCT 

Quality Score 19 mean (SD): 23.9(2.4) Enrolled : 6 Double-blind  range: NS Analyzed: 6 Cross-over  Gender Control Group

 female: 0 Enrolled : 6  male: 6 Analyzed : 6 

Formulation

Not specified Route of Adm

Oral Dosage and T

6 mg MLT at Frequency an6mg/day for 1 

Author Year Population Sample Size N Study Design Intervention Matsumomo M 1999 Age (Years) Treatment Group CCT 

Quality Score 19 mean (SD): 23.7(1.3) Enrolled : 6 Single-blind  range: NS Analyzed: 6 Cross-over  Gender Control Group

 female: 0 Enrolled : 6  male: 6 Analyzed : 6 

Formulation

Not specified Route of Adm

Not specified Dosage and T

10 mg of MLT Frequency anSingle dose 

Author Year Population Sample Size N Study Design Intervention Mishima, K 1997 Age (Years) Treatment Group RCT 

Quality Score 16 mean (SD): 22.5(1.9) Enrolled : 6 Single-blind  range: NS Analyzed: 6 Cross-over  Gender Control Group

 female: 0 Enrolled : 6  male: 6 Analyzed : 6 

Formulation

Not specified Route of Adm

Oral Dosage and T

3mg or 9mg MFrequency an1 caspsule/da
86

Author Year Population Sample Size N Study Design Intervention Nave, R 1995 Age (Years) Treatment Group RCT Quality Score 19 mean (SD): 24.6(2.7) Enrolled : 12 Double-blind  range: NS Analyzed: 12 Cross-over  Gender Control Group

 female: 12 Enrolled : 12  male: 0 Analyzed : 12 

Formulation

Not specified Route of Adm

Oral Dosage and T

3mg or 6mg MFrequency anSingle dose/w

Author Year Population Sample Size N Study Design Intervention Nickelson, T 1989 Age (Years) Treatment Group CCT 

Quality Score 16 female mean (SD): 30.0(7.9) Enrolled : 12 Double-blind  male mean (SD): 30.4(6.2) Analyzed: 12 Parallel  female range: 23-46 Control Group

 male range: 20-39 Enrolled : 13  Gender Analyzed : 13 

 female: 11  male: 14 

Formulation

Not specified Route of Adm

Oral Dosage and T

50mg of MLT Frequency an1 capsule/day 

Author Year Population Sample Size N Study Design Intervention Pires, M.L 2001 Age (Years) Treatment Group RCT 

Quality Score 10 mean: NS Enrolled : 6 Double-blind  range: 22-24 Analyzed: 6 Cross-over  Gender Control Group

 female: 0 Enrolled : 6  male: 6 Analyzed : 6 

Formulation

Not specified Route of Adm

Oral Dosage and T

0.3 and 1.0 m2000, and 210Frequency an3 doses/day o

Author Year Population Sample Size N Study Design Intervention Reid, K 1996 Age (Years) Treatment Group CCT 

Quality Score 15 mean (SD): 20.3(2.4) Enrolled : 16 Double-blind  range: NS Analyzed: 16 Cross-over  Gender Control Group

 female: 0 Enrolled : 16  male: 16 Analyzed : 16 

Formulation

Not specified Route of Adm

Oral Dosage and T

5 mg MLT caFrequency anSingle dose 
87

Author Year Population Sample Size N Study Design Intervention Satomura, T 2001 Age (Years) Treatment Group RCT Quality Score 11 mean (SD): 23.7(1.7) Enrolled : 7 Single-blind  range: NS Analyzed: 7 Cross-over  Gender Control Group

 female: 0 Enrolled : 7  male: 7 Analyzed : 7 

Formulation

Not specified Route of Adm

Oral Dosage and T

1mg, 3mg, 6mFrequency anSingle dose 

Author Year Population Sample Size N Study Design Intervention Seabra, M.L. 2000 Age (Years) Treatment Group RCT 

Quality Score 20 mean (SD): 29(1) Enrolled : 30 Double-blind  range: 25-55 Analyzed: 30 Parallel  Gender Control Group

 female: 0 Enrolled : 10  male: 40 Analyzed : 10 

Formulation

Not specified Route of Adm

Oral Dosage and T

10 mg MLT o(approx. 2200Frequency an1 capusule/da

Author Year Population Sample Size N Study Design Intervention Terlo, L 1997 Age (Years) Treatment Group CCT 

Quality Score 19 mean (SD): 28(2) Enrolled : 10 Double-blind  range: NS Analyzed: 10 Cross-over  Gender Control Group

 female: 0 Enrolled : 10  male: 10 Analyzed : 10 

Formulation

Not specified Route of Adm

Oral Dosage and T

 0.1, 0.5 or 1mFrequency an1 tablet/day fo

Author Year Population Sample Size N Study Design Intervention Zhdanova, I 1995 Age (Years) Treatment Group RCT 

Quality Score 18 mean (SD): 26.5(1.3) Enrolled : 6 Double-blind  range: 25-64 Analyzed: 6 Cross-over  Gender Control Group

 female: 0 Enrolled : 6  male: 6 Analyzed : 6 

Formulation

Not specified Route of Adm

Oral Dosage and T

0.3mg and 1.02000h and 2100h Frequency anSingle dose fo
88

Author Year Population Sample Size N Study Design Intervention Zhdanova, I 1996 Age (Years) Treatment Group RCT Quality Score 16 mean (SD): 28.5(1.8) Enrolled : 12 Double-blind  range: NS Analyzed: 12 Cross-over  Gender Control Group

 female: 0 Enrolled : 12  male: 12 Analyzed : 12 

Formulation

Not specified Route of Adm

Oral Dosage and T

0.3 or 1.0mg before habitual bedtiFrequency an1 tablet/day fo

Author Year Population Sample Size N Study Design Intervention Zisapel, N 1997 Age (Years) Treatment Group CCT 

Quality Score 17 mean (SD): 28(2) Enrolled : 10 Double-blind  range: NS Analyzed: 10 Cross-over  Gender Control Group

 female: 0 Enrolled : 10  male: 10 Analyzed : 10 

Formulation

Not specified Route of Adm

Oral Dosage and T

2mg MLT at 1Frequency an1 tablet/day fo
89

Evidence Table C-5: References 1. Attenburrow ME, Cowen PJ, Sharpley AL. Low dose melatonin 

improves sleep in healthy middle-aged subjects. Psychopharmacol 

1996;126(2):179-81. 

2. Baskett JJ, Broad JB, Wood PC et al. Does Melatonin Improve Sleep in 

Older People? A Randomised Crossover Trial. Age Ageing 2003;32(2):164-170. 

3. Cajochen C, Krauchi K, Danilenko KV et al. Evening administration of 

melatonin and bright light: interactions on the EEG during sleep and 

wakefulness. J Sleep Res 1998;7(3):145-57. 

4. Cajochen C, Krauchi K, Mori D et al. Melatonin and S-20098 increase 

REM sleep and wake-up propensity without modifying NREM sleep 

homeostasis. Am J Physiol 1997;272(4 Pt 2):R1189-96. 

5. Dollins AB, Zhdanova IV, Wurtman RJ et al. Effect of inducing 

nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proceed Nat Acad Sci USA 1994; 91(5):1824-8. 

6. Ferini-Strambi L, Zucconi M, Biella G et al. Effect of melatonin on 

sleep microstructure: preliminary results in healthy subjects. Sleep 1993;16(8):744-7. 

7. Holmes AL, Gilbert SS, Dawson D. Melatonin and zopiclone: the 

relationship between sleep propensity and body temperature. Sleep 2002;25(3):301-6. 

8. James SP, Mendelson WB, Sack DA et al. The effect of melatonin on 

normal sleep. Neuropsychopharmacol 1987; 1(1):41-4. 

9. Luboshitzky R, Levi M, Shen-Orr Z et al. Long-term melatonin 

administration does not alter pituitary-gonadal hormone secretion in normal men. Hum Reprod 2000;15(1):60-5. 

10. Matsumoto M. The hypnotic effects of melatonin treatment on diurnal 

sleep in humans. Psychiatry Clin Neurosci 1999;53(2):243-5. 

11. Mishima K, Satoh K, Shimizu T et al. Hypnotic a

of daytime-administered melatonin. Psychopharm71. 

12. Nave R, Peled R, Lavie P. Melatonin improves e

Pharmacol 1995;275(2):213-6. 

13. Nickelsen T, Demisch L, Demisch K et al. Influe

of melatonin at various times of the day on fatigua placebo-controlled, double-blind trial. J Pineal 

14. Pires ML, Benedito-Silva AA, Pinto L et al. Acu

of melatonin on the sleep of young healthy subje2001;31(4):326-32. 

15. Reid K, Van den Heuvel C, Dawson D. Day-time 

administration: effects on core temperature and sSleep Res 1996;5(3):150-4. 

16. Satomura T, Sakamoto T, Shirakawa S et al. Hyp

melatonin during daytime administration and its triazolam. Psychiatry Clin Neurosci 2001;55(3):

17. Seabra ML, Bignotto M, Pinto LR Jr et al. Rando

clinical trial, controlled with placebo, of the toxicmelatonin treatment. J Pineal Res 2000;29(4):19

18. Terlo L, Laudon M, Tarasch R et al. Effects of lo

late afternoon napping and mood. Biol Rhythm R

19. Zhdanova IV, Wurtman RJ, Lynch HJ et al. Sleep

low doses of melatonin ingested in the evening. C1995;57(5):552-8. 

20. Zhdanova IV, Wurtman RJ, Morabito C et al. Eff

melatonin, given 2-4 hours before habitual bedtimyoung humans. Sleep 1996;19(5):423-31. 

21. Zisapel N, Tarash R, Laudon M. Effects of fast- a

melatonin formulations on daytime sleep and mo1996; Sitges, Spain; Pineal update: from molec

clinical implications.
90

Evidence Table C-6: Melatonin and the Temperature Rhythm: Study Characteristics RCT: Randomized Control Trial, CCT: Controlled Clinical Trial, MLT: Melatonin, SD: Standard Deviation, SE: Standard ErroSEM: Standard Error of the Mean, NS: Not Specified, BL: Bright Light, DL: Dim Light, E-O: Extra-Ocular, Ocular: Eye-direct

SAD: Seasonal Affective Disorder, LEET: Low Energy Emission TherapyAuthor Year Population Sample Size N Study Design IntervAndo, K 1999 Age (Years) Treatment Group RCT 

Quality Score 19 Treatment group: Enrolled : 6 Blindedness: NS  Mean (SD): 34.4 (13.8) Analyzed: 5 Parallel  Range: NS Control Group

Control Group: Enrolled : 6 

 Mean (SD): 32.6 (8.1) Analyzed : 5  Range: NS  Gender:

Treatment group: 

 Female: 1  Male: 4 

Control Group: 

Treat

BL ContrPlaceMode 

OculaDosaBL: 5for 3 FrequOne Sleep 

No 

 Female: 2  Male: 3  Sleep disorder: Delayed 

Sleep Phase Syndrome

Author Year Population Sample Size N Study Design IntervBunnell, D 1992 Age (Years) Treatment Group CCT 

Quality Score 12 Mean (SD): NS Enrolled : 5 Blindedness: NS  Range: 20-28 Analyzed: 5 Cross-over  Gender Control Group

 Female: 0 Enrolled : 5  Male: 5 Analyzed: 5  Sleep disorder: None

Treat

BL ContrDL Mode 

OculaDosaBL: 2prior FrequOne Sleep 

No 
91

Author Year Population Sample Size N Study Design IntervBurgess, H 2001 Age (Years) Treatment Group CCT Quality Score 17 Mean (SE): 21.3 (2.7) Enrolled : 16 Double-blind  Range: NS Analyzed: 14 Cross-over  Gender Control Group

 Female: 8 Enrolled : 16  Male: 8 Analyzed : 14  Sleep disorder: None

Treat

BL ContrDL Mode 

OculaDosaBL: >hoursFrequSinglSleep 

No 

Author Year Population Sample Size N Study Design IntervCagnacci, A 1993 Age (Years) Treatment Group CCT Quality Score 15 Mean (SD): NS Enrolled : 7 Blindedness: NS  Range: 23-34 Analyzed: 7 Cross-over  Gender Control Group

 Female: 7 Enrolled : 7  Male: 0 Analyzed: 7  Sleep disorder: None

Treat

BL ContrDL Mode 

OculaDosaBL: 30100DL: 1h) FrequSinglSleep 

No 
92

Author Year Population Sample Size N Study Design IntervCajochen, C 2000 Age (Years) Treatment Groups RCT Quality Score 16 Mean (SD): 27.8 (8.91) Enrolled : 23 Blindedness: NS  Range: 18-44 Analyzed: 20 Parallel  Gender Low level light 

 Female: 1 Enrolled : NS  Male: 22 Analyzed: NS  Sleep disorder: None Middle level light  Enrolled : NS  Analyzed : NS 

High level light 

 Enrolled : NS  Analyzed : NS 

Treat

Low lHigh Mode 

OculaDosaLow llight: High hoursFrequSinglSleep 

No 

Author Year Population Sample Size N Study Design IntervCosta, G 1997 Age (Years) Treatment Group CCT Quality Score 15 Mean (SD): NS Enrolled : 5 Blindedness: NS  Range: 21-32 Analyzed: 5 Cross-over  Gender Control Group

 Female: 4 Enrolled : 5  Male: 1 Analyzed : 5  Sleep disorder: Shiftwork disorder

Treat

BL ContrDL Mode 

OculaDosaBL: 4lux D4 perintervFrequ4 sesSleep 

No 
93

Author Year Population Sample Size N Study Design IntervDanilenko, KV 2000 Age (Years) Treatment Group RCT Quality Score 14 Mean (SD): 24.0 (4.8) Enrolled : 9 Blindedness: NS  Range: NS Analyzed: 5 Cross-over  Gender Control Group

 Female: 0 Enrolled : 9  Male: 9 Analyzed : 5  Sleep disorder: None

Treat

Dawn ContrContrMode 

OculaDosaDawn (0600Contr1.5 h FrequOne Sleep 

No 

Author Year Population Sample Size N Study Design IntervDaurat, A 1996 Age (Years) Treatment Group CCT Quality Score 16 Mean (SD): 23.6 (1.05) Enrolled : 8 Blindedness: NS  Range: NS Analyzed: 8 Cross-over  Gender Control Group

 Female: 0 Enrolled : 8  Male: 8 Analyzed : 8  Sleep disorder: None

Treat

ModeContrDL Mode 

OculaDosaBL: 114 hoFrequSinglSleep 

Yes 
94

Author Year Population Sample Size N Study Design IntervDaurat, A 1997 Age (Years) Treatment Group CCT Quality Score 16 Mean (SEM): 23.6 (1.05) Enrolled : 10 Blindedness: NS  Range: NS Analyzed: 10 Cross-over  Gender Control Group

 Female: 0 Enrolled :  Male: 8 Analyzed : 10  Sleep disorder: None 10 

Treat

ModeContrDL Mode 

OculaDosaBL: 114 hoof sleFrequSinglSleep 

Yes 
95

Author Year Population Sample Size N Study Design IntervEastman, CI 2000 Age (Years) Experiment 1: CCT Quality Score 11 Experiment 1: Treatment Group Blindedness: NS 

 Mean (SD): 25 (5.0) Enrolled : 16 Cross-over  Range: NS Analyzed: 14 

Experiment 2: Control Group

 Mean (SD): 25 (5.0) Enrolled : 16  Range: NS Analyzed : 14  Gender Experiment 2: 

Experiment 1: Treatment Group

 Female: 4 Enrolled : 4  Male: 12 Analyzed: 3 

Experiment 2: Control Group

 Female: 0 Enrolled : 4  Male: 4 Analyzed : 3  Sleep disorder: None

ExpeTreat

BL Contr

1) DLMode 

BL: EOculaMediDosaE-O leitheor 100600 FrequOne Sleep 

 Yes ExpeTreat

BL Contr

1) DLMode DL anOcula

Dosa

E-O leitheor 100900 FrequOne Sleep 

Yes
96

Author Year Population Sample Size N Study Design IntervFletcher, A 1999 Age (Years) Treatment Group CCT Quality Score 18 Mean (SD): 20.5 (1.2) Enrolled : 16 Blindedness: NS  Range: 18-23 Analyzed: 16 Cross-over  Gender Control Group

 Female: 7 Enrolled : 16  Male: 9 Analyzed: 16  Sleep disorder: None

Treat

Heat blankContrNo heblankDosa

Heat h to tClock FrequSinglSleep 

No 

Author Year Population Sample Size N Study Design IntervGordijn, MC 1998 Age (Years) Treatment Group CCT Quality Score 19 Mean (SD): 39.3 (12.1) Enrolled : 12 Blindedness: NS  Range: 23.6-56.5 Analyzed: 12 Cross-over  Gender Control Group

 Female: 6 Enrolled : 12  Male: 6 Analyzed : 12  Sleep disorder: None

Treat

BL ContrDL Mode 

OculaDosaBL: 20900 FrequOne Sleep 

No 
97

Author Year Population Sample Size N Study Design IntervGordijn, MC 1999 Patients: Treatment Group CCT Quality Score 17 Age (Years) Patients: Blindedness: NS 

 Mean (SD): 38.3 (12.2) Enrolled : 10 Cross-over  Range: NS Analyzed: 8  Gender non-Patients: 

 Female: 5 Enrolled : 8  Male: 5 Analyzed: 8 

non-Patients: Control Group

 Age (Years) Patients: 

 Mean (SD): 38.7 (12.9) Enrolled : 10  Range: NS Analyzed: 8  Gender non-Patients: 

 Female: 3 Enrolled : 8  Male: 5 Analyzed: 8 

Treat

BL ContrDL Mode 

OculaDosaBL: 2Mornor EvFrequOne Sleep 

No 

Sleep disorder: Patients 

suffered from 

Nonseasonal Depression, which may or may not be accompanied by a sleep disorder 

Author Year Population Sample Size N Study Design IntervHiguchi, S 2003 Age (Years) Treatment Group RCT 

Quality Score 15 Mean (SD): 24.7 (5.6) Enrolled : 7 Blindedness: NS  Range: NS Analyzed: 7 Cross-over  Gender Control Group

 Female: 0 Enrolled : 7  Male: 7 Analyzed: 7  Sleep disorder: None

Treat

Video displaContrVideo displaMode 

OculaDosaBrigh15 lux FrequOne Sleep 

No 
98

Author Year Population Sample Size N Study Design IntervHorne, JA 1991 Age (Years) Treatment Group RCT Quality Score 15 Mean (SD): NS Enrolled : 12 Single-blinded  Range: 19-26 Analyzed: 12 Cross-over  Gender Control Group

 Female: 8 Enrolled : 12  Male: 4 Analyzed: 12  Sleep disorder: None

Treat

BL ContrDL Mode 

OculaDosaBL: 2hours Frequ10-mSleep 

Yes 

Author Year Population Sample Size N Study Design IntervHorowitz, TS 2001 Age (Years) Treatment Group RCT Quality Score 16 Mean (SD): 26.99 (6.22) Enrolled : 26 Blindedness: NS  Range: 20-40 Analyzed: 25 Cross-over  Gender Control Group

Treatment group: Enrolled : 28 

 Female: 10 Analyzed: 27  Male: 16 

Control: 

 Female: 18  Male: 10  Sleep disorder: Shiftwork disorder

Treat

BL ContrDL Mode 

OculaDosaBL: 20500 DL: 1h) FrequOne Sleep 

No 
99

Author Year Population Sample Size N Study Design IntervKelly, TL 1997 Age (Years) Treatment Groups CCT Quality Score 17 Mean (SD): NS LEET group 12 Double-blind 

 Range: NS Enrolled : 12 Parallel  Gender Analyzed: 

 Female: 0 BL 

 Male: 45 Enrolled : 12 

LEET group Analyzed: 8 

 Age (Years) BL + LEET 

 Mean (SD): 24.8 (7.9) Enrolled : 11  Range: NS Analyzed: 11 

BL Control Group

 Age (Years) DL 

 Mean (SD): 22.5 (3.5) Enrolled : 10  Range: NS Analyzed: 7 

BL + LEET 

Treat

BL anand cContrDL Mode 

OculaDosaLEETperioDL: 20200 FrequOne Sleep 

No 

 Age (Years)

 Mean (SD): 23.4 (4.1)  Range: NS 

DL 

 Age (Years) Mean (SD): 25.2 (7.7)  Range: NS  Sleep disorder: Shiftwork disorder

Author Year Population Sample Size N Study Design IntervKubota, T 2002 Age (Years) Treatment Group CCT 

Quality Score 18 Mean (SD): 24 (NS) Enrolled : 9 Blindedness: NS  Range: 20-27 Analyzed: 9 Cross-over  Gender Control Group

 Female: 0 Enrolled : 9  Male: 9 Analyzed : 9  Sleep disorder: None

Treat

BL ContrDL Mode 

OculaDosaBL: 5for 5 FrequSinglSleep 

Yes 
100

Author Year Population Sample Size N Study Design IntervLavoie, S 2003 Age (Years) Treatment Group CCT Quality Score 17 Mean (SD): 26.1 (4.2) Enrolled : 7 Blindedness: NS  Range: 22-35 Analyzed: 7 Parallel  Gender Control Group

 Female: 8 Enrolled : 7  Male: 6 Analyzed : 7  Sleep disorder: None

Treat

BL ContrDL Mode 

OculaDosaBL: 3(0030FrequSinglSleep 

Yes 

Author Year Population Sample Size N Study Design IntervLushington, K 2002 Age (Years) Treatment Group CCT Quality Score 18 Mean (SD): 22.1 (3.0) Enrolled : 13 Single-blind  Range: 13-34 Analyzed: 13 Cross-over  Gender Control Group

 Female: 3 Enrolled : 13  Male: 10 Analyzed : 13  Sleep disorder: None

Treat

Light ContrPlaceMode 

E-O (DosaLight0400 FrequOne Sleep 

No 
101

Author Year Population Sample Size N Study Design IntervMorita, T 1996 Age (Years) Treatment Group RCT Quality Score 16 Mean (SD): 20.0 (0.63) Enrolled : 5 Blindedness: NS  Range: 19-21 Analyzed: 5 Cross-over  Gender Control Group

 Female: 0 Enrolled : 5  Male: 5 Analyzed : 5  Sleep disorder: None

Treat

DayliContr

DL Mode 

OculaDosaDaylitempWarmtemp(21000200 FrequSinglSleep 

No 

Author Year Population Sample Size N Study Design IntervStrassman, RJ 1991 Age (Years) Treatment Group CCT Quality Score 14 Mean (SE): 26.4 (1.90) Enrolled : 17 Blindedness: NS  Range: 20-36 Analyzed: 9 Cross-over  Gender Control Group

 Female: 0 Enrolled : 17  Male: 17 Analyzed : 9  Sleep Disorder: None

Treat

BL ContrDL Mode 

OculaDosaBL: > hours FrequSinglSleep 

Yes 
102

Author Year Population Sample Size N Study Design IntervWakamura, T 2000 Age (Years) Treatment Group RCT Quality Score 17 Mean (SD): 20 (2) Enrolled : 7 Blindedness: NS  Range: 18-23 Analyzed: 7 Cross-over  Gender Control Group

 Female: 7 Enrolled : 7  Male: 0 Analyzed : 7  Sleep disorder: None

Treat

BL ContrDL Mode 

OculaDosaBL: 6bedtiFrequSinglSleep 

No 

Author Year Population Sample Size N Study Design IntervWright, KP Jr 1997 Age (Years) Treatment Group RCT Quality Score 17 Mean (SD): 19.2 (NS) Enrolled : 46 Blindedness: NS  Range: 18-25 Analyzed: 40 Cross-over  Gender Control Group

 Female: 0 Enrolled : 46  Male: 46 Analyzed : 40  Sleep disorder: Sleep 

restriction

Treat

BL Contr

DL Mode 

OculaDosaBL: 2(2000FrequSinglSleep 

Yes 
103

Evidence Table C-6: References 1. Ando K, Kripke DF Cole RJ et al. Light mask 500 lux treatment for 

delayed sleep phase syndrome. Prog Neuro-Psychopharmacol Biol Psychiatry 1999;23(1):15-24. 

2. Bunnell DE, Treiber SP, Phillips NH et al. Effects of evening bright 

light exposure on melatonin, body temperature and sleep. J Sleep Res 

1992;1(1):17-23. 

3. Burgess HJ, Sletten T, Savic N et al. Effects of bright light and 

melatonin on sleep propensity, temperature, and cardiac activity at night. J Appl Physiol 2001;91(3):1214-22. 

4. Cagnacci A, Soldani R, Yen SS. The effect of light on core body 

temperature is mediated by melatonin in women. J Clin Endocrinol Metab 1993;76(4):1036-8. 

5. Cajochen C, Zeitzer JM, Czeisler CA et al. Dose-response relationship 

for light intensity and ocular and electroencephalographic correlates of human alertness. Behav Brain Res 2000;115(1):75-83. 

6. Costa G, Kovacic M, Bertoldi A et al. The use of a light visor during 

night work by nurses. Biol Rhythm Res 1997;28(1):16-25. 

7. Danilenko KV, Wirz-Justice A, Krauchi K et al. The human circadian 

pacemaker can see by the dawn's early light. J Biol Rhythms 2000;15(5):437-46. 

8. Daurat A, Aguirre A, Foret J et al. Disruption of sleep recovery after 36 

hours of exposure to moderately bright light. Sleep 1997;20(5):352-8. 

9. Daurat A, Foret J, Touitou Y et al. Detrimental influence of bright light 

exposure on alertness, performance, and mood in the early morning. 

Neurophysiol Clinique 1996;26(1):8-14. 

10. Eastman CI, Martin SK, Hebert M. Failure of extraocular light to 

facilitate circadian rhythm reentrainment in humans. Chronobiol Int 2000;17(6):807-26. 

11. Fletcher A, Van den Heuvel C, Dawson D. Sleep

blanket: Effects on core temperature, sleep, and madults. Sleep 1999;22(3):313-318. 

12. Gordijn MC, Beersma DG, Korte HJ et al. Effect

sleep displacement on dim light melatonin onset. 74. 

13. Gordijn MC, Beersma DG, Korte HJ et al. Testing 

circadian phase disturbance underlying depressive depression. J Biol Rhythms 1998;13(2):132-47. 

14. Higuchi S, Motohashi Y, Liu Y et al. Effects of V

display at night on melatonin, core temperature, heJ Appl Physiol 2003;94(5):1773-6. 

15. Horne JA, Donlon J, Arendt J. Green light attenua

and sleepiness during sleep deprivation. Sleep 199

16. Horowitz TS, Cade BE, Wolfe JM et al. Efficacy 

sleep/darkness scheduling in alleviating circadian work. Am J Physiol - Endocrinol Metab 2991;281

17. Kelly TL, Kripke DF, Hayduk R et al. Bright ligh

circadian rhythms, sleep and cognitive performanc1997;13(4):251-8. 

18. Kubota T, Uchiyama M, Suzuki H et al. Effects o

on saliva melatonin, core body temperature and slein human subjects. Neurosci Res 2002;42(2):115-2

19. Lavoie S, Paquet J, Selmaoui B et al. Vigilance lev

bright light exposure in the first half of the night. C2003;20:1019-38. 

20. Lushington K, Galka R, Sassi LN et al. Extraocul

not phase shift saliva melatonin rhythms in sleepinRhythms 2002:17(4):377-86. 
104

21. Morita T, Tokura H. Effects of lights of different color temperature on the 

nocturnal changes in core temperature and melatonin in humans. Appl Hum Sci 1996;15(5):243-6. 

22. Strassman RJ, Qualls CR, Lisansky EJ et al. Elevated rectal temperature 

produced by all-night bright light is reversed by melatonin infusion in 

men. J Appl Physiol 1991;71(6):2178-82. 

23. Wakamura T, Tokura H. The influence of bright l

upon circadian rhythm of core temperature and its nocturnal sleep. Nurs Health Sci 2000;2(1):41-9. 

24. Wright KP Jr, Badia P, Myers BL et al. Caffeine a

nighttime melatonin and temperature levels in sleeBrain Res 1997;747:78-84.
105

Evidence Table C-7: Effect of Melatonin on People with Sleep Disorders: Study Characteristics Abbreviations: RCT: randomized controlled trial, CCT: controlled clinical trial, MLT: melatonin, FR: fast-release, SR: slow-release, 

SD: standard deviation, SE: standard error, mg: milligrams, h: hours, NS: not specified

Control group received placebo unless otherwise indicated Author Year Population Sample Size N Study Design IntervenAlmeida-Montes, LG 2003 Age (Years) Treatment Group RCT 

 mean: 50 Enrolled : 10 Double-blind Quality Score 5 range: 30-72 Analyzed: 10 Cross-over  Gender Control Group

 female: 4 Enrolled : 10  male: 6 Analyzed : 10  Ethnicity: NS

 Sleep Disorder: 

Insomnia

Formula

SustaineRoute o

Oral Dosage 0.3 mg obedtime FrequenI capsule

Author Year Population Sample Size N Study Design IntervenAndrade, C 2001 Age (Years) Treatment Group RCT Quality Score 4 Treatment group Enrolled : 18 Double-blind 

 mean (SD): 59.7(11.1) Analyzed: 18 Parallel  range: 43-85 Control Group

Control group Enrolled : 15 

 mean (SD): 51.4(14.2) Analyzed : 15  range: 23-70  Gender

Treatment group 

 female: 4  male: 14 

Control group 

 female: 5  male: 10  Ethnicity: NS

 Sleep Disorder: 

Insomnia

Formula

Not specRoute o

Oral Dosage 3mg MLFrequen

I capsulcapsules alternate capsulesDuration

21 patien= 10) rtreatmen(melatonplacebo days; anpatients received  for 16 d
106

Author Year Population Sample Size N Study Design IntervenBaskett, J 2003 Age (Years) Treatment Group RCT Quality Score 5 mean: NS Enrolled : 20 Double-blind  range: 60-84 Analyzed: 14 Cross-over  Gender Control Group

 female: 10 Enrolled : 20  male: 10 Analyzed : 14  Ethnicity: NS

 Sleep Disorder: Sleep 

maintenance problems

Formula

Not specRoute o

Oral Dosage 5mg MLFrequenI capsule

Author Year Population Sample Size N Study Design IntervenBeaumont, M 2004 Age (Years) Treatment Group RCT Quality Score 3 mean (SD): 35.3(8.1) Double-blind 

 range: 19-47 Enrolled : 9 Parallel  Gender Analyzed: NS 

 female: 9 Control Group

 male: 18 Enrolled : 9  Ethnicity: 15 

Caucasians, 9 Hispanics 

and 3 African Americans 

 Analyzed : NS 

 Sleep Disorder: Jet 

lag

FormulaNot specRoute o

Not specDosage 5mg MLdays 2 a2300h Frequen5mg/day 

Author Year Population Sample Size N Study Design IntervenCamfield, P 1995 Age (Years) Treatment Group N of 1RCT FormulaQuality Score 4 mean: 8.8 Enrolled : 6 Double-blind Not spec range 3 to 13 Analyzed: 6 Cross-over Route o

 Gender Control Group Oral 

 female: 2 Enrolled : 6 Dosage 

 male: 4 Analyzed : 6 0.5 or 1. Ethnicity: NS Frequen

Sleep Disorder: 

Fragmented sleep patterns accompanying developmental disabilities 

For each trial, chireceived alternatiagent gi
107

Author Year Population Sample Size N Study Design IntervenDahlitz, M 1991 Age (Years) Treatment Group RCT Quality Score 4 mean: NS Enrolled : 8 Double-blind  range: 20-60 Analyzed: 8 Cross-over  Gender Control Group

 female: 0 Enrolled : 8  male: 8 Analyzed : 8  Ethnicity: Caucasian Sleep Disorder: 

Delayed sleep phase 

 syndrome 

Formula

Not specRoute o

Oral Dosage 5mg MLFrequen1 capsu

Author Year Population Sample Size N Study Design IntervenDawson, D 1998 Age (Years) Treatment Group RCT Quality Score 3 mean (SD): 65.67(1.68

) 

Enrolled : 12 Double-blind 

 range: >55 Analyzed: 12 Cross-over 

 Gender Control Group

 female: NS Enrolled : 12  male: NS Analyzed : 12  Ethnicity: NS

 Sleep Disorder: Sleep 

maintenance 

 insomnia 

Formula

Not specRoute o

Oral (MLDosage 0.5mg MFrequen0.5mg/d

Author Year Population Sample Size N Study Design IntervenDodge, N 2000 Age (Years) Treatment Group RCT 

Quality Score 4 mean: NS Enrolled : 20 Double-blind  range: 1-12 yrs Analyzed: 17 Cross-over  Gender Control Group

 female: NS Enrolled : 20  male: NS Analyzed : 17  Ethnicity: NS

Sleep Disorder: Sleep 

disturbance accompanying severe developmental disability 

Formula

Not specRoute o

Oral Dosage 5mg MLFrequen5mg/day week stu
108

Author Year Population Sample Size N Study Design IntervenEllis, C 1994 Age (Years) Treatment Group RCT Quality Score 4 mean (SD): 46(11) Enrolled : 15 Double-blind  range: 32-67 Analyzed: 15 Cross-over  Gender Control Group

 female: 6 Enrolled : 15  male: 9 Analyzed : 15  Ethnicity: NS

 Sleep Disorder: 

Psychophysiological 

 insomnia

Formula

Not specRoute o

Oral Dosage 5mg MLFrequen5mg/day 

Author Year Population Sample Size N Study Design IntervenFolklard, S 1993 Age (Years) Treatment Group RCT Quality Score 3 mean (SD): 29(7) Enrolled : 7 Double-blind  range: 21-48 Analyzed: 7 Cross-over  Gender Control Group

 female: 2 Enrolled : 8  male: 15 Analyzed : 8  Ethnicity: NS

 Sleep Disorder: Nightshift disorder

Formula

Not specRoute o

Oral Dosage 5mg MLFrequen1 capsusleeps tabetween 

Author Year Population Sample Size N Study Design IntervenGarfinkel, D 1995 Age (Years) Treatment Group RCT Quality Score 4 mean: 76 Enrolled : 12 Double-blind  range: 68-93 Analyzed: 12 Cross-over  Gender Control Group

 female: 5 Enrolled : 12  male: 7 Analyzed : 12  Ethnicity: NS

 Sleep Disorder: Longterm insomnia

Formula

ControlleRoute o

Oral Dosage 2 mg MLbedtime Frequen1 tablet/
109

Author Year Population Sample Size N Study Design IntervenHaimov, I 1995 Age (Years) Treatment Group RCT Quality Score 3 mean (SD): 73.1(3.9) Enrolled : 8 Double-blind  range: NS Analyzed: 8 Cross-over  Gender Control Group

 female: 4 Enrolled : 8  male: 4 Analyzed : 8  Ethnicity: NS

 Sleep Disorder: 

Insomnia

Formula

SustaineRoute o

Oral Dosage 2 mg FR MLT or release bedtime FrequenI tablet/dsustaine for 1 wesustaineMLT for 

Author Year Population Sample Size N Study Design IntervenJames, M 1997 Age (Years) Treatment Group RCT Quality Score 5 mean (SD): 29(8) Enrolled : 24 Double-blind  range: 20-41 Analyzed: 22 Cross-over  Gender Control Group

 female: 5 Enrolled : 24  male: 17 Analyzed : 22  Ethnicity: NS

 Sleep Disorder: Nightshift disorder

Formula

Not specRoute o

Oral Dosage  6 mg MconsecuFrequen6mg/day 4-6 consnight sh

Author Year Population Sample Size N Study Design IntervenJames, SP 1990 Age (Years) Treatment Group RCT Quality Score 3 mean: 33.4 Enrolled : 10 Double-blind  range: 20-57 Analyzed: 10 Cross-over  Gender Control Group

 female: 6 Enrolled : 10  male: 4 Analyzed : 10  Ethnicity: NS

 Sleep Disorder: 

Insomnia

Formula

Not specRoute o

Oral Dosage 1 mg or before bFrequen1mg or 5
110

Author Year Population Sample Size N Study Design IntervenJockovich, M 2000 Age (Years) Treatment Group RCT Quality Score 3 mean: 28.2 Enrolled : 19 Double-blind  range: NS Analyzed: 19 Cross-over  Gender Control Group

 female: 15 Enrolled : 19  male: 4 Analyzed : 19  Ethnicity: NS

 Sleep Disorder: Nightshift disorder

Formula

Not specRoute o

Oral Dosage 1 mg MLFrequen1 caplet/

Author Year Population Sample Size N Study Design IntervenJorgensen 1998 Age (Years) Treatment Group RCT Quality Score 4 mean: 32 Enrolled : 20 Double-blind  range: 25-40 Analyzed: 18 Cross-over  Gender Control Group

 female: 2 Enrolled : 20  male: 16 Analyzed : 18  Ethnicity: NS

 Sleep Disorder: Nightshift disorder

Formula

Not specRoute o

Oral Dosage 10 mg Mshift Frequen1 tablet/

Author Year Population Sample Size N Study Design IntervenKayumov, L 2001 Age (Years) Treatment Group RCT Quality Score 3 female; mean (SD): 30.8(12.4) Enrolled : 22 Double-blind  male; mean (SD): 35.6(14.0) Analyzed: 19 Cross-over  Gender Control Group

 female: 7 Enrolled : 22  male: 15 Analyzed : 19  Ethnicity: NS

 Sleep Disorder: 

Delayed sleep phase 

 syndrome

FormulaNot specRoute o

Oral Dosage 5 mg MLFrequen5mg/day 
111

Author Year Population Sample Size N Study Design IntervenMcArthur, A 1998 Age (Years) Treatment Group RCT FormulaQuality Score 3 mean (SD): 10.1(1.5) Enrolled : 9 Double-blind Immedia range: 4-17 yrs Analyzed: 9 Cross-over Route o

 Gender Control Group Oral or b

 female: 9 Enrolled : 9 Dosage 

 male: 0 Analyzed : 9 Dosage 

weight, 

 Ethnicity: NS range 2.

bedtime 

 Sleep Disorder: Sleep 

dysfunction 

 Frequen

 accompanying Rett 

syndrome 

 I capsule

Author Year Population Sample Size N Study Design IntervenO'cahllaghan 1999 Age (Years) Treatment Group RCT 

Quality Score 4 median: 11 Enrolled : 7 Double-blind  range: Feb-28 Analyzed: 7 Cross-over  Gender Control Group

 female: 4 Enrolled : 7  male: 3 Analyzed : 7  Ethnicity: NS

Sleep Disorder: 

Delayed sleep onset 

accompanying tuberous sclerosis 

Formula

Not specRoute o

Oral Dosage 5 mg MLbedtime Frequen1 capsu

Author Year Population Sample Size N Study Design IntervenSerfaty, M 2002 Age (Years) Treatment Group RCT Quality Score 5 mean (SD): 84.2(7.6) Enrolled : 44 Double-blind  range: NS Analyzed: 25 Cross-over  Gender Control Group

 female: 9 Enrolled : 44  male: 16 Analyzed : 25  Ethnicity: Not 

specified

Sleep Disorder: Sleep 

disorder 

associated with 

dementia

Formula

Slow relRoute o

Oral Dosage 6 mg MLFrequen1 tablet/
112

Author Year Population Sample Size N Study Design IntervenSerfaty, M 2003 Age (Years) Treatment Group RCT Quality Score 2 mean (SD): 39.9(11.8) Enrolled : NS Double-blind  range: NS Analyzed: NS Parallel  Gender Control Group

 female: 17 Enrolled : NS  male: 14 Analyzed : NS  Ethnicity: NS

Sleep Disorder: Sleep 

disorder 

accompanying 

depression

Formula

Slow-relRoute o

Oral Dosage 6 mg MLFrequen1 tablet/

Author Year Population Sample Size N Study Design IntervenShamir, E 2000 Age (Years) Treatment Group RCT Quality Score 4 mean (SD): 42.3(13.1) Enrolled : 14 Double-blind  range: 25-64 Analyzed: 14 Cross-over  Gender Control Group

 female: 3 Enrolled : 14  male: 11 Analyzed : 14  Ethnicity: NS

 Sleep Disorder: Poor 

sleep quality 

Formula

ControlleRoute o

Not specDosage 2mg MLdesired Frequen2 mg ML

Author Year Population Sample Size N Study Design IntervenShamir, E 2000 Age (Years) Treatment Group RCT Quality Score 4 mean (SD): 42(5) Enrolled : 27 Double-blind  range: 24-67 Analyzed: 19 Cross-over  Gender Control Group

 female: 7 Enrolled : 27  male: 12 Analyzed : 19  Ethnicity: NS

 Sleep Disorder: DSMIV insomnia 

 accompanying 

schizophrenia 

Formula

ControlleRoute o

Not specDosage 2mg MLdesired Frequen2 mg ML
113

Author Year Population Sample Size N Study Design IntervenSinger, C 2003 Age (Years) Treatment Group RCT Quality Score 4 mean (SD): 77.4 (8.9) Enrolled : 104 Double-blind  range: NS Analyzed: 104 Cross-over  Gender Control Group

 female: 88 Enrolled : 52  male: 69 Analyzed : 47  Ethnicity: NS

Sleep Disorder: Sleep 

disturbance

accompanying Alzheimer's disease 

Formula

ImmediaRoute o

Oral Dosage 10 mg Mhabitual Frequen1 capsu

Author Year Population Sample Size N Study Design IntervenSmits, M.G 2003 Age (Years) Treatment Group RCT Quality Score 5 mean (SD): Enrolled : 27 Double-blind 

Treatment Group 9.2 (2.1) Analyzed: 27 Cross-over 

Control Group 10.1 (1.7) Control Group

 range: NS Enrolled : 35  Gender Analyzed : 35 

Treatment Group 

 female: 7  male: 20 

Control Group 

 female: 6  male: 29  Ethnicity: White

Sleep Disorder: 

Idiopathic chronic 

sleep-onset insomnia 

Formula

Fast-releRoute o

Oral Dosage 5mg MLFrequen1 dose/ 
114

Author Year Population Sample Size N Study Design IntervenSuhner, A 1998 Age (Years) Treatment Group RCT Quality Score 4 mean: NS Enrolled : 240 Double-blind  range: NS Analyzed: 174 Parallel  Gender Control Group

 female: 148 Enrolled : 80  male: 172 Analyzed : 60  Ethnicity: NS

 Sleep Disorder: Jetlag 

Formula

Not specRoute o

Not specDosage 0.5mg FPLB at bon the fi1.52h) afollowing Frequen1 dose/deastwar

Author Year Population Sample Size N Study Design IntervenSuhner, A 2001 Age (Years) of 

Compliant (137)

 Treatment Group RCT 

Quality Score 4 mean: 41.3 Enrolled : 40 Double-blind  range: 18-68 Analyzed: 35 Parallel  Gender of Compliant 

(137)

 Control Group

 female: 67 Enrolled : 40  male: 70 Analyzed : 39  Ethnicity: NS

 Sleep Disorder: Jetlag 

Formula

Not specRoute o

Not specDosage 5mg ML(eastboubetween the placof deparschedule Frequen 1 dose/post-flig

Author Year Population Sample Size N Study Design IntervenWaldhauser 1990 Age (Years) Treatment Group RCT Quality Score 2 mean (SD): 26.4(4.8) Enrolled : 10 Double-blind  range: NS Analyzed: 10 Parallel  Gender Control Group

 female: 10 Enrolled : 10  male: 10 Analyzed : 10  Ethnicity: NS

 Sleep Disorder: 

Induced insomnia 

Formula

Not specRoute o

Oral Dosage 80mg MFrequenSingle d
115

Author Year Population Sample Size N Study Design IntervenWright, SW 1998 Age (Years) Treatment Group RCT Quality Score 4 mean: 38.6 Enrolled : 20 Double-blind  range: 32-45 Analyzed: 15 Cross-over  Gender Control Group

 female: 3 Enrolled : 20  male: 12 Analyzed : 15  Ethnicity: NS

 Sleep Disorder: Nightshift disorder

Formula

Not specRoute o

Oral Dosage 5 mg MLin the evFrequen5mg/nigwork 

Author Year Population Sample Size N Study Design IntervenZhdanova, I 2001 Age (Years) Treatment Group RCT Quality Score 2 mean: NS Enrolled : NS Double-blind  range: NS Analyzed: 30 Cross-over  Gender Control Group

 female: NS Enrolled : NS  male: NS Analyzed : 30  Ethnicity: NS

 Sleep Disorder: 

Insomnia

Formula

Not specRoute o

Oral Dosage 0.1 mg, NS Frequen1 capsuthen for inpatienCenter. 
116

Evidence Report C-7: References 1. Almeida Montes LG, Ontiveros Uribe MP, Cortes Sotres J et al. 

Treatment of primary insomnia with melatonin: A double-blind, placebocontrolled, crossover study. J Psychiatry Neurosci 2003; 28(3):191-196. 

2. Andrade C, Srihari BS, Reddy KP et al. Melatonin in medically ill 

patients with insomnia: a double-blind, placebo-controlled study. J Clin Psychiatry 2001;62(1):41-5. 

3. Baskett JJ, Broad JB, Wood PC et al. Does Melatonin Improve Sleep in 

Older People? A Randomised Crossover Trial. Age Ageing 2003;32(2):164-170. 

4. Beaumont M, Batejat D, Pierard C et al. Caffeine or melatonin effects on 

sleep and sleepiness after rapid eastward transmeridian travel. J Appl Physiol 2004; 96(1):50-8. 

5. Camfield P, Gordon K, Dooley J et al. Melatonin appears ineffective in 

children with intellectual deficits and fragmented sleep: six "N of 1" trials. J Child Neurol 1996;11(4):341-3. 

6. Dahlitz M, Alvarez B, Vignau J et al. Delayed sleep phase syndrome 

response to melatonin. Lancet 1991;337(8750):1121-4. 

7. Dawson D, Rogers NL, van den Heuvel CJ et al. Effect of sustained 

nocturnal transbuccal melatonin administration on sleep and temperature in elderly insomniacs. J Biol Rhythms 1998;13(6):532-8. 

8. Dodge NN, Wilson GA. Melatonin for treatment of sleep disorders in 

children with developmental disabilities. J Child Neurol 2001;16(8):581-4. 

9. Ellis CM, Lemmens G, Parkes JD. Melatonin and insomnia. J Sleep Res 

1996;5(1):61-5. 

10. Folkard S, Arendt J, Clark M. Can melatonin improve shift workers' 

tolerance of the night shift? Some preliminary findings. Chronobiol Int 1993;10(5):315-20. 

11. Garfinkel D, Laudon M, Zisapel N. Improvement of sleep equality in 

elderly people by controlled-release melatonin. Lancet. 1995;346(8974):541-544. 

12. Haimov I, Lavie P, Laudon M et al. Melatonin rep

elderly insomniacs. Sleep 1995;18(7):598-603. 

13. James M, Tremea MO, Jones JS et al. Can melaton

to night shift? Am J Emerg Med 1998;16(4):367-7

14. James SP, Sack DA, Rosenthal NE et al. Melatoni

insomnia. Neuropsychopharmacol 1990;3(1):19-2

15. Jockovich M, Cosentino D, Cosentino L et al. Effe

melatonin on mood and sleep efficiency in emergeworking night shifts. Acad Emerg Med 2000;7(8):

16. Jorgensen KM, Witting MD. Does exogenous mel

sleep or night alertness in emergency physicians wAnn Emerg Med 1998;31(6):699-704. 

17. Kayumov L, Brown G, Jindal R et al. A randomiz

placebo-controlled crossover study of the effect of on delayed sleep phase syndrome. Psychosomat M

18. McArthur AJ, Budden SS. Sleep dysfunction in R

exogenous melatonin treatment. Dev Med Child N92. 

19. O'Callaghan FJK, Clarke AA, Hancock E et al. Us

Sleep Disorders in Tuberous Sclerosis. Dev Med C

1999;41(2):123-126. 

20. Serfaty M, Kennell-Webb S, Warner J et al. Doub

placebo controlled trial of low dose melatonin for dementia. Int J Geriatr Psychiatry 2002;17(12):1

21. Serfaty MA, Osborne, D. Buszewicz,M.J et al. Th

Melatonin in Major Depression. Chronobiol Int 2

22. Shamir E, Laudon M, Barak Y et al. Melatonin im

patients with chronic schizophrenia. J Clin Psychi
117

23. Shamir E, Rotenberg VS, Laudon M et al. First-night effect of melatonin 

treatment in patients with chronic sc2000;20(6):691-4. hizophrenia. J Clin Psychopharmacol 

24. Singer C, Tractenberg RE, Kaye J et al. A multicenter, placebo-controlled 

trial of melatonin for sleep disturbance in Alzheimer's disease. Sleep 2003; 26(7):893-901. 

25. Smits MG, Van Stel HF, Van Der Heijden K et al. Melatonin Improves 

Health Status and Sleep in Children With Idiopathic Chronic Sleep-Onset 

Insomnia: A Randomized Placebo-Controlled Trial. J Am Acad Child Adolesc Psychiatry 2003;42(11):1286-1293. 

26. Suhner A, Schlagenhauf P, Hofer I et al. Effectiveness and tolerability of 

melatonin and zolpidem for the alleviation of jet lag. Aviat Space Environ Med 2001;72(7):638-46. 

27. Suhner A, Schlagenhauf P, Johnson R et al. Comp

determine the optimal melatonin dosage form for tChronobiol Int 1998;15(6):655-66. 

28. Waldhauser F, Saletu B, Trinchard-Lugan I. Sleep 

investigations on hypnotic properties of melatonin1990; 100(2):222-6. 

29. Wright SW, Lawrence LM, Wrenn KD et al. Rand

melatonin after night-shift work: efficacy and neur

effects(comment). Ann Emerg Med 1998;32(3 Pt 

 30. Zhdanova IV, Wurtman RJ, Regan MM et al. Mel

related insomnia. J Clin Endocrinol Metab 2001;8
118

Evidence Table C-8: Safety of Malatonin: Study Characteristics Abbreviations: RCT: randomized controlled trial, CCT: controlled clinical trial, MLT: melatonin, FS: fast-release, SR: slow-release, 

standard error, mg: milligrams, h: hours, NS: not specified 

Control group received placebo unless otherwise indicated 

Author Year Population Sample Size N Study Design IntervAndrade, C 2001 Age (Years) Treatment Group RCT 

Quality Score 25 Treatment Group Enrolled : 18 Double-blind  mean (SD): 59.7(11.1) Analyzed : 18 Parallel  range: 43-85 Control Group

Control Group Enrolled : 15 

 mean (SD): 51.4(14.2) Analyzed : 15  range: 23-70  Gender

Treatment Group 

 female: 4  male: 14 

Control Group 

 female: 5  male: 10  Sleep Disorder: insomnia

Formu

Not spRoute 

Oral Dosag3mg MFreque

I capsevery 4 capsthereaDurati

21 patplacebtreatm(melatplaceb10 daypatienn=2) r for 16 

Author Year Population Sample Size N Study Design IntervArendt, J 1984 Age (Years) Treatment Group CCT 

Quality Score 19 mean: NS Enrolled : 12 Double-blind  range: 22-46 Analyzed : 12 Cross-over  Gender Control Group

 female: 2 Enrolled : 12  male: 10 Analyzed : 12  Sleep Disorder: None

Formu

Not spRoute 

Oral Dosag2mg MFreque

2mg/d
119

Author Year Population Sample Size N Study Design IntervBaskett, J 2003 Age (Years) Treatment Group RCT Quality Score 25 mean: NS Enrolled : 20 Double-blind 

 range: 60-84 Analyzed: 14 Cross-over  Gender Control Group female: 16 Enrolled : 20  male: 4 Analyzed : 14 

Formu

Not spRoute 

Oral Dosag5mg MFreque

I caps

Author Year Population Sample Size N Study Design IntervClaustrat, B 1992 Age (Years) Treatment Group RCT 

Quality Score 19 mean (SD): Enrolled : 15 Double-blind 

Treatment group 36.3(8.9) Analyzed : 15 Cross-over 

Control group 35.7(6.4) Control Group

 range: NS Enrolled : 15  Gender Analyzed : 15 

 female:  7  5  8  10 

Treatment group Control group male: Treatment group Control group Sleep Disorder: Jet-lag

Formu

Not spRoute 

Oral Dosag8 mg MFreque

1 caps

Author Year Population Sample Size N Study Design IntervDahlitz, M 1991 Age (Years) Treatment Group RCT 

Quality Score 24 mean: NS Enrolled : 8 Double-blind  range: 20-60 Analyzed : 8 Cross-over  Gender Control Group

 female: 0 Enrolled : 8  male: 8 Analyzed : 8  Sleep Disorder: Delayed 

sleep 

 phase insomnia 

Formu

Not spRoute 

Oral Dosag5mg MFreque

1 caps
120

Author Year Population Sample Size N Study Design IntervDodge, N 2000 Age (Years) Treatment Group RCT Quality Score 22 mean: NS Enrolled : 20 Double-blind  range: 1-Dec Analyzed : 17 Cross-over  Gender Control Group

 female: NS Enrolled : 20  male: NS Analyzed : 17 

Sleep Disorder: Sleep 

disturbance 

accompanying severe developmental disability 

Formu

Not spRoute 

Oral Dosag5mg MFreque

5mg/d6 wee

Author Year Population Sample Size N Study Design IntervEdwards, BJ 2000 Age (Years) Treatment Group CCT 

Quality Score 22 Treatment Group Enrolled : 14 Double-blind  mean (SD): 40(13) Analyzed: 13 Parallel  range: NS Control Group

Control Group Enrolled : 17 

 mean (SD): 41(12) Analyzed : 13  range: NS  Gender

 female: 3  male: 28 

Formu

Not spRoute 

Oral Dosag5mg Mbetwe22:00 accordand fothree eFreque

2 caps1 caps

Author Year Population Sample Size N Study Design IntervEllis, C 1194 Age (Years) Treatment Group RCT 

Quality Score 20 mean (SD): 46(11) Enrolled : 15 Double-blind  range: 32-67 Analyzed : 15 Cross-over  Gender Control Group

 female: 6 Enrolled : 15  male: 9 Analyzed : 15 

Formu

Not spRoute 

Oral Dosag5mg M
121

Sleep Disorder: 

Psychophysiological 

insomnia 

Freque

1 capsdays 

Author Year Population Sample Size N Study Design IntervFraschini, F 1999 Age (Years) Treatment Group RCT 

Quality Score 18 mean: 32.5 Enrolled : 5 Double-blind  range: NS Analyzed : 5 Cross-over  Gender Control Group

 female: 1 Enrolled : 5  male: 4 Analyzed : 5  Sleep Disorder: None

Formu

Not spRoute 

Not spDosag5mg, 1NS Freque

1 dose

Author Year Population Sample Size N Study Design IntervGarfinkel, D 1995 Age (Years) Treatment Group RCT 

Quality Score 24 mean: 76 Enrolled : 12 Double-blind  range: 68-93 Analyzed : 12 Cross-over  Gender Control Group

 female: 5 Enrolled : 12  male: 7 Analyzed : 12  Sleep Disorder: Longterm insomnia

Formu

ControRoute 

Oral Dosag2 mg MbedtimFreque

1 table

Author Year Population Sample Size N Study Design IntervHood, E 1999 Age (Years) Treatment Group RCT 

Quality Score 12 mean: NS Enrolled : 15 Double-blind  range: NS Analyzed : 9 Cross-over  Gender Control Group

 female: NS Enrolled : 15  male: NS Analyzed : 9  Sleep Disorder: None

Formu

Not spRoute 

Not spDosag1mg MFreque

1mg/d

Author Year Population Sample Size N Study Design IntervJames, M 1998 Age (Years) Treatment Group RCT 

Quality Score 23 mean (SD): 29(8) Enrolled : 24 Double-blind 

Formu

Not sp
122

 range: 20-41 Analyzed : 22 Cross-over  Gender Control Group

 female: 5 Enrolled : 24  male: 17 Analyzed : 22  Sleep Disorder: Nightshift disorder

Route 

Oral Dosag6 mg MconseFreque

6mg/dshifts 

Author Year Population Sample Size N Study Design IntervJan, E 1994 Age (Years) Treatment Group RCT 

Quality Score 21 mean: NS Enrolled : 15 Double-blind  range: 6mon-13yr Analyzed : 15 Cross-over  Gender Control Group

 female: 2 Enrolled : 15  male: 13 Analyzed : 15  Sleep Disorder: Severe 

sleep problems

Formu

Not spRoute 

Not spDosag2-5mg Freque

2-5mg

Author Year Population Sample Size N Study Design IntervJean-Louis, G 1998 Age (Years) Treatment Group CCT 

Quality Score 21 mean (SD): 68.8(15.8) Enrolled : 10 Double-blind  range: NS Analyzed : NS Cross-over  Gender Control Group

 female: 6 Enrolled : 10  male: 4 Analyzed : NS 

Sleep Disorder: Sleep 

disturbance 

accompanying mild cognitive impairment 

Formu

Not spRoute 

Not spDosag6mg MFreque

6mg/d

Author Year Population Sample Size N Study Design IntervJockovich, M 2000 Age (Years) Treatment Group RCT 

Quality Score 22 mean: 28.2 Enrolled : 19 Double-blind  range: NS Analyzed : 19 Cross-over  Gender Control Group

 female: 15 Enrolled : 19  male: 4 Analyzed : 19  Sleep Disorder: Nightshift disorder

Formu

Not spRoute 

Oral Dosag1 mg Mbefore Freque

1 table
123

Author Year Population Sample Size N Study Design IntervJorgensen 1998 Age (Years) Treatment Group RCT Quality Score 22 mean: 32 Enrolled : 20 Double-blind  range: 25-40 Analyzed : 18 Cross-over  Gender Control Group

 female: 2 Enrolled : 20  male: 16 Analyzed : 18  Sleep Disorder: Nightshift disorder

Formu

Not spRoute 

Oral Dosag10 mg night sFreque

1 tabletime 

Author Year Population Sample Size N Study Design IntervKayumov, L 2001 Age (Years) Treatment Group RCT 

Quality Score 22 mean (SD): Enrolled : 22 Double-blind  female: 30.8(12.4) Analyzed : 19 Cross-over  male: 35.6(14.0) Control Group

 Gender Enrolled : 22 

 female: 7 Analyzed : 19  male: 15 

Sleep Disorder: Delayed 

sleep phase 

syndrome 

Formu

Not spRoute 

Oral Dosag5 mg MFreque

5mg/d

Author Year Population Sample Size N Study Design IntervMatsumomo M 1999 Age (Years) Treatment Group CCT 

Quality Score 19 mean (SD): 23.7(1.3) Enrolled : 6 Single-blind  range: NS Analyzed : 6 Cross-over  Gender Control Group

 female: 0 Enrolled : 6  male: 6 Analyzed : 6 

Formu

Not spRoute 

Not spDosag10 mg Freque
124

 Not spAuthor Year Population Sample Size N Study Design IntervMcArthur, A 1998 Age (Years) Treatment Group RCT Quality Score 21 mean (SD): 10.1(1.5) Enrolled : 9 Double-blind  range: 4-17 yrs Analyzed : 9 Cross-over  Gender Control Group

 female: 9 Enrolled : 9  male: 0 Analyzed : 9  Sleep Disorder: Sleep 

dysfunction 

 accompanying Rett 

syndrome 

FormuImmedRoute 

Oral oDosagDosagweighttaken Freque

I caps

Author Year Population Sample Size N Study Design IntervMonti, J 1999 Age (Years) Treatment Group CCT 

Quality Score 21 mean: NS Enrolled : 10 Single-blind  range: 66-86 Analyzed : 10 Cross-over  Gender Control Group

 female: 2 Enrolled : 10  male: 8 Analyzed : 10  Sleep Disorder: Insomnia 

Formu

Not spRoute 

Oral Dosag3 mg MFreque

3mg/d

Author Year Population Sample Size N Study Design IntervNaguib, M 1999 Age (Years) Treatment Group RCT 

Quality Score 25 mean: 29.7 5mg and 15mg MLT Double-blind  range: 19-44 Enrolled : 25 Cross-over  Gender Analyzed : 25 

 female: 75 Control Group

 male: 0 Enrolled : 25  Sleep Disorder: None Analyzed : 25 

Formu

Not spRoute 

Oral Dosag5mg aapproxbefore 
125

 anaes

Freque

Single 

Author Year Population Sample Size N Study Design IntervO'Callaghan, F 1999 Age (Years) Treatment Group RCT 

Quality Score 20 median: 11 Enrolled : 7 Double-blind  range: Feb-28 Analyzed : 7 Cross-over  Gender Control Group

 female: 4 Enrolled : 7  male: 3 Analyzed : 7  Sleep Disorder: Sleep 

disorder 

 accompanying Tuberous 

Sclerosis 

Formu

Not spRoute 

Oral Dosag5 mg Musual Freque

1 caps

Author Year Population Sample Size N Study Design IntervPaccoti, P 1987 Age (Years) Treatment Group CCT 

Quality Score 18 mean: NS Enrolled : 6 Double-blind  range: 22-32 Analyzed : 6 Cross-over  Gender Control Group

 female: 0 Enrolled : 6  male: 6 Analyzed : 6  Sleep Disorder: None

Formu

Not staRoute 

Oral Dosag100mg Freque

Single 

Author Year Population Sample Size N Study Design IntervPetrie 1989 Age (Years) Treatment Group RCT 

Quality Score 20 mean: NS Enrolled : 20 Double-blind  range: 28-68 Analyzed : 20 Cross-over  Gender Control Group

 female: 8 Enrolled : 20  male: 12 Analyzed : 20  Sleep Disorder: Jet-lag

Formu

Not spRoute 

Not spDosag5 mg M1200h Freque
126

 One d

during day fo

Author Year Population Sample Size N Study Design IntervPetrie 1993 Age (Years) Treatment Group RCT Quality Score 20 mean (SD): 34.9(7.7) Early MLT Double-blind 

 range: 25-52 Enrolled : NS Parallel  Gender Analyzed : NS 

 female: 26 Late MLT 

 male: 26 Enrolled : NS  Sleep Disorder: Jet lag Analyzed : NS 

 Control Group Enrolled : NS  Analyzed : NS 

Formu

Not spRoute 

Oral Dosag5 mg M0800h Freque

5 mg eMLT fo

Author Year Population Sample Size N Study Design IntervSeabra, M.L. 2000 Age (Years) Treatment Group RCT 

Quality Score 20 mean (SD): 29(1) Enrolled : 30 Double-blind  range: 25-55 Analyzed : 30 Parallel  Gender Control Group

 female: 0 Enrolled : 10  male: 40 Analyzed : 10  Sleep Disorder: None

Formu

Not spRoute 

Oral Dosag10 mg sleep Freque

1 caps

Author Year Population Sample Size N Study Design IntervSerfaty, M 2002 Age (Years) Treatment Group RCT 

Quality Score 22 mean (SD): 84.2(7.6) Enrolled : 44 Double-blind  range: NS Analyzed : 25 Cross-over  Gender Control Group

 female: 9 Enrolled : 44  male: 16 Analyzed : 25 

Formu

Slow-rRoute 

Oral Dosag6 mg M
127

 Sleep Disorder: Sleep 

disturbance 

 accompanying dementia 

Freque

1 table

Author Year Population Sample Size N Study Design IntervShamir, E 2000 Age (Years) Treatment Group RCT 

Quality Score 22 mean (SD): 74.0 (9.5) Enrolled : 10 Double-blind  range: 55-91 Analyzed : 10 Cross-over  Gender Control Group

 female: 11 Enrolled : 9  male: 8 Analyzed : 9  Sleep Disorder: None

Formu

Not spRoute 

Oral Dosag2 mg MFreque

2 mg/d

Author Year Population Sample Size N Study Design IntervShamir, E 2001 Age (Years) Treatment Group RCT 

Quality Score 24 mean (SD): 64.2(14.3) Enrolled : 10 Double-blind  range: 28-82 Analyzed : 8 Cross-over  Gender Control Group

 female: 11 Enrolled : 12  male: 11 Analyzed : 12  Sleep Disorder: Jet-lag 

Formu

ControRoute 

Not spDosag2.5 mg Freque

2.5 mg

Author Year Population Sample Size N Study Design IntervSmits, MG 2003 Age (Years) 3 treatments RCT 

Quality Score 25 mean (SD): FR =0.5mg, 5mg Double-blind 

Treatment group 9.2 (2.1) CR= 2mg Parallel Control group 10.1 (1.7) Treatment Groups

 range: NS Enrolled : NS  Gender Analyzed : NS 

Treatment group Control Group

 female: 20 Enrolled : NS 

Formu

Fast-reRoute 

Oral Dosag5 mg MFreque

5mg/d

 male: 6 Analyzed : NS 
128

Control group 

 female: 6  male: 29 

Sleep Disorder: 

Idiopathic chronic 

sleep-onset insomnia 

Author Year Population Sample Size N Study Design IntervSuhner, A 1998 Age (Years) 3 treatment groups RCT 

Quality Score 20 mean: 36 0.5 mg FR MLT Double-blind  range: 20-65 5.0 mg FR MLT Parallel  Gender 2 mg CR MLT 

 female: 148 Treatment Groups

 male: 172 Enrolled : NS  Sleep Disorder: Jet-lag Analyzed : NS 

 Control Group Enrolled : NS  Analyzed : NS 

Formu

ControRoute 

Not spDosag0.5 mg bedtimon the 1.52h) days aFreque

One deastwa

Author Year Population Sample Size N Study Design IntervSuhner, A 2001 Age (Years) of Compliant 

(137)

 Treatment Group RCT 

Quality Score 19 mean: 41.3 Enrolled : 40 Double-blind  range: 18-68 Analyzed : 35 Parallel  Gender of Compliant 

(137)

 Control Group

 female: 67 Enrolled : 40  male: 70 Analyzed : 39  Sleep Disorder: Jet-lag 

Formu

Not spRoute 

Not spDosag5mg Mon the return 1700h time adepenschedFreque

4 consbedtim
129

Author Year Population Sample Size N Study Design IntervVan Wieringen 2001 Age (Years) Treatment Group RCT Quality Score 21 mean (SD): 33.4(10.7) Enrolled : 40 Double-blind  range: NS Analyzed : 29 Parallel  Gender Control Group

 female: 59 Enrolled : 41  male: 22 Analyzed : 21 

Formu

Not spRoute 

Oral Dosag5mg MindividFreque

1 table

Sleep Disorder: Delayed 

melatonin 

onset as well as fatigue and sleep disturbance 

Author Year Population Sample Size N Study Design IntervWright, SW 1998 Age (Years) Treatment Group RCT 

Quality Score 17 mean: 38.6 Enrolled : 20 Double-blind  range: 32-45 Analyzed : 15 Cross-over  Gender Control Group

 female: 3 Enrolled : 20  male: 12 Analyzed : 15  Sleep Disorder: Nightshift disorder

Formu

Not spRoute 

Oral Dosag5 mg MbedtimFreque

5mg/nwork 

Author Year Population Sample Size N Study Design IntervWright, J 1986 Age (Years) Treatment Group CCT 

Quality Score 17 mean: NS Enrolled : 6 Double-blind  range: 22-46 Analyzed : 6 Cross-over  Gender Control Group

 female: 2 Enrolled : 6  male: 10 Analyzed : 6 

Formu

Not spRoute 

Not spDosag2mg MFreque

2mg/d
130

Evidence Table C-8: References 1. Andrade C, Srihari BS, Reddy KP et al. Melatonin in medically ill patients 

with insomnia: a double-blind, placebo-controlled study. J Clin Psychiatry 2001;62(1):41-5. 

2. Arendt J, Borbely AA, Franey C et al. The effects of chronic, small doses 

of melatonin given in the late afternoon on fatigue in man: a preliminary study. Neurosci Lett 1984;45(3):317-21. 

3. Baskett JJ, Broad JB, Wood PC et al. Does Melatonin Improve Sleep in 

Older People? A Randomised Crossover Trial. Age Ageing 2003;32(2): 

164-170. 

4. Claustrat B, Brun J, David M et al. Melatonin and jet lag: confirmatory 

result using a simplified protocol. Biol Psychiatry 1992;32(8):705-11. 

5. Dahlitz M, Alvarez B, Vignau J et al. Delayed sleep phase syndrome 

response to melatonin. Lancet 1991;337(8750):1121-4. 

6. Dodge NN, Wilson GA. Melatonin for treatment of sleep disorders in 

children with developmental disabilities. J Child Neurol 2001;16(8):581-4. 

7. Edwards BJ, Atkinson G, Waterhouse J et al. Use of melatonin in 

recovery from jet-lag following an eastward flight across 10 time-zones. 

Ergon 2000;43(10):1501-13. 

8. Ellis CM, Lemmens G, Parkes JD. Melatonin and insomnia. J Sleep Res 

1996;5(1):61-5. 

9. Fraschini F, Cesarani A, Alpini D et al. Melatonin Influences Human 

Balance. Biol Signals Recept 1999;8(1-2):111-119. 

10. Garfinkel D LMNDZN. Improvement of sleep equality in elderly people 

by controlled-release melatonin. Lancet 1995;346(8974):541-544. 

11. Hood EH, Buttross S, Parks B. A placebo-controlled, double-blind, 

crossover trial of melatonin in the management of sleep disturbances in 

children with behavioral disorders. J Invest Med 1999;47(2.):14A. 

12. James M, Tremea MO, Jones JS et al. Can melatonin improve adaptation 

to night shift? Am J Emerg Med 1998;16(4):367-70. 

13. Jan JE, Espezel H, Appleton RE. The treatment of sleep disorders with 

melatonin. Dev Med Child Neurol 1994;36(2):97-107. 

14. Jean-Louis G, von Gizycki H, Zizi F. Melatonin e

and cognition in elderly with mild cognitive impai1998;25(3):177-83. 

15. Jockovich M, Cosentino D, Cosentino L et al. Effe

melatonin on mood and sleep efficiency in emergeworking night shifts. Acad Emerg Med 2000;7(8):

16. Jorgensen KM, Witting MD. Does exogenous mel

sleep or night alertness in emergency physicians w

 Ann Emerg Med 1998;31(6):699-704. 17. Kayumov L, Brown G, Jindal R et al. A randomiz

placebo-controlled crossover study of the effect of on delayed sleep phase syndrome. Psychosom Me

18. Matsumoto M. The hypnotic effects of melatonin 

sleep in humans. Psychiatry Clin Neurosci 1999;5

19. McArthur AJ, Budden SS. Sleep dysfunction in R

exogenous melatonin treatment. Dev Med Child N92. 

20. Monti JM, Alvarino F, Cardinali D et al. Polysomn

effect of melatonin on sleep in elderly patients witinsomnia. Arch Gerontol Geriatr 1999;28(2)85-98

21. Naguib M, Samarkandi AH. Premedication With M

Blind, Placebo- Controlled Comparison With Mid1999; 82(6), 875-880. 

22. O'Callaghan FJK, Clarke AA, Hancock E et al. Us

Sleep Disorders in Tuberous Sclerosis. Dev Med C123-126. 

23. Paccotti P, Terzolo M, Torta M et al. Acute admin

two opposite circadian stages does not change respreleasing hormone, thyrotropin releasing hormone adult males. J Endocrinol Invest 1987;10(5):471-7

24. Petrie K, Conaglen JV, Thompson L et al. Effect o

after long haul flights. Br Med J 1989;298(6675):7
131

25. Petrie K, Dawson AG, Thompson L et al. A double-blind trial of 

melatonin as a treatment for jet lag in international cabin crew. Biol 

Psychiatry 1993;33(7):526-30. 

26. Seabra ML, Bignotto M, Pinto LR Jr et al. Randomized, double-blind 

clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res 2000;29(4):193-200. 

27. Serfaty M, Kennell-Webb S, Warner J et al. Double blind randomised 

placebo controlled trial of low dose melatonin for sleep disorders in dementia. Int J Geriatr Psychiatry 2002;17(12):1120-7. 

28. Shamir E, Barak Y, Plopsky I et al. Is melatonin treatment effective for 

tardive dyskinesia? J Clin Psychiatry 2000; 61(8):556-8. 

29. Shamir E, Barak Y, Shalman I et al. Melatonin treatment for tardive 

dyskinesia: a double-blind, placebo-controlled, crossover study. Arch Gen Psychiatry 2001;58(11):1049-52. 

30. Smits M, Van Stel H, Van Der Heijden K, et al. Melatonin Improves 

Health Status and Sleep in Children With Idiopathic Chronic Sleep-Onset 

Insomnia: A Randomized Placebo-Controlled TriaAdolesc Psychiatry 2003;42(11):1286-1293. 

31. Suhner A, Schlagenhauf P, Hofer I et al. Effective

melatonin and zolpidem for the alleviation of jet laMed 2001;72(7):638-46. 

32. Suhner A, Schlagenhauf P, Johnson R et al. Comp

determine the optimal melatonin dosage form for tChronobiol Int 1998; 15(6):655-66. 

33. Van Wieringen S, Jansen T, Smits MG et al. Mela

whiplash syndrome with delayed melatonin onset: controlled trial. Clin Drug Invest 2001;21(12):813

34. Wright J, Aldhous M, Franey C et al. The effects o

on endocrine function in man. Clin Endocrinol 19

35. Wright SW, Lawrence LM, Wrenn KD et al. Rand

melatonin after night-shift work: efficacy and neur

effects(comment). Ann Emerg Med 1998;32(3 Pt 
132

Evidence Table C-9: Melatonin Compared to Other Pharmacological Treatments for Sleep Disorders: Study CharacteristicAbbreviations: RCT: randomized controlled trial, CCT: controlled clinical trial, MLT: melatonin, FR: fast-release, SR: slow-release, standard error of the mean, mg: milligrams, h: hours, NS: not specified 

Author Year Population Sample Size N Study Design Intervention Author Year Population Sample Size N Study Design 

Ferini-Strambi, L 1993 Age (Years) MLT Group CCT 

Quality Score 14 Mean (SD): 25.3 (3.6) Enrolled : 6  Range: NS Analyzed: 6 Double-blind  Gender: Triazolam Group 

 Female: 0 Enrolled : 6 Cross-over  Male: 6 Analyzed : 6  Sleep disorder: None Placebo Group

 Enrolled : 6 

 Analyzed : 6 

Intervention Comparison: 

MLT vs.TriazoRoute of admi

Oral Dosage and T

MLT: 100 mg; (NS) at 2230 h Frequency and Single dose

Author Year Population Sample Size N Study Design Intervention Author Year Population Sample Size N Study Design 

Holmes, A 2002 Age (Years) MLT Group CCT 

Quality Score 15 Mean (SEM): 20.3 (0.6) Enrolled : 12 Double-blind  Range: 19-25 Analyzed: 12 Cross-over  Gender Zopiclone Group

 Female: 5 Enrolled : 12  Male: 7 Analyzed : 12  Sleep disorder: None PLB Group

 Enrolled : 12 

Intervention Comparison: 

MLT vs. ZopicRoute of admi

Oral Dosage and T

MLT: 5 mg; Zoat 1400 h Frequency and Single dose

Author Year Population Sample Size N Study Design Intervention Author Year Population Sample Size N Study Design 

Satomura, T 2001 Age (Years) MLT Group RCT 

Quality Score 11 Mean (SD): 23.7 (1.7) Enrolled : 7 Double-blind 

Range: NS Analyzed: 7 Cross-over Gender: Triazolam Group

Female: 0 Enrolled : 7 Male: 7 Analyzed : 7 Sleep disorder: None PLB Group

 Enrolled : 7 

 Analyzed : 7 

Intervention Comparison: 

MLT vs.TriazoRoute of admi

Oral Dosage and T

MLT: 1 mg, 3 PLB: NS at 13Frequency and Single dose
133

Author Year Population Sample Size N Study Design Intervention Suhner, A 2001 Age (Years) MLT Group RCT 

Quality Score 20 Mean (SD): 41.3 (NS) Enrolled : 35 Double-blind 

Range: 18-68 Analyzed: 34 Parallel Gender: Zopiclone Group

Female: 67 Enrolled : 34 Male: 70 Analyzed : 34 Sleep disorder: Jet-lag PLB Group

Enrolled : 39 

 Analyzed : 37 

Comparison: 

MLT vs. ZolpidRoute of admi

Oral Dosage and T

MLT: 5 mg; Zobetween 1700departure time (Clock time: NFrequency and Single dose duat bedtime for consecutive da
134

Evidence Table C-9 References 1. Ferini-Strambi L, Zucconi M, Biella G et al. Effect of melatonin on sleep 

microstructure: preliminary results in healthy subjects. Sleep 1993;16(8):744-7. 

2. Holmes AL, Gilbert SS, Dawson D. Melatonin and zopiclone: the 

relationship between sleep propensity and body temperature. Sleep 2002;25(3):301-6. 

3. Satomura T, Sakamoto T, Shirakawa S et al. Hyp

melatonin during daytime administration and its triazolam. Psychiatry Clin Neurosci 2001;55(3)

4. Suhner A, Schlagenhauf P, Hofer I et al. Effective

melatonin and zolpidem for the alleviation of jet laMed 2001;72(7):638-46.
Appendix D: Technical Expert Panel 

135
The following is a list of the members of the TEP with a brief description of some of their 

professional affiliations and areas of expertise:

(1) Dr. Irvin Mayers, Divisional Director of Pulmonary Medicine, University of Alberta 

(expertise in pulmonary medicine and sleep disorders) 

(2) Ms. Shirley Heschuk, Lecturer, University of Alberta (expertise in Pharmacy Law and 

Ethics, Non-Prescription Drugs, Nutrition, and CAM) 

(3) Dr. Constance Chik, Professor and Program Director of the Division of Endocrinology and 

Metabolism, University of Alberta (expertise in neuroendocrinology and pineal cell biology) 

(4) Dr. Christina Benishin, Associate Professor of Physiology, University of Alberta (expertise 

in pharmacology, physiology, and CAM) 

(5) Dr. Gary Hnatko, Associate Professor of Psychiatry, University of Alberta (expertise in 

psychiatry and sleep disorders) 

(6) Dr. Carina Majaesic, Pediatric Pulmonologist, University of Alberta Hospital (expertise in 

pulmonary medicine and immunology) 

(7) Dr. Nalaka Gooneratne, Assistant Professor, University of Pennsylvania (expertise in sleep 

and pulmonary critical care) 

(8) Dr. Irina Zhdanova, Associate Professor, Boston University (expertise in melatonin and 

sleep disorders) 

(9) Dr. Manisha Witmans, Pediatric Pulmonologist, University of Alberta Hospital (expertise in 

sleep disorders) 

(10) Dr. Larry Pawluk, Associate Clinical Professor of Psychiatry, University of Alberta 

(expertise in pharmacology and sleep disorders) 

(11) Dr. Catherine E. Ulbricht, Executive Director of Natural Standard Research 

Collaboration, Senior Attending Pharmacist Massachusetts General Hospital (expertise in 

CAM and pharmacology) 

(12) Dr. Ethan Basch, Chief Editor, Natural Standard Research Collaboration (expertise in 

CAM) 

(13) Dr. Adrianne E. Rogers, Professor of Pathology and Public Health, Boston University 

School of Medicine; Editorial Board Member of Natural Standard Research Collaboration 

(expertise in toxicology and pathology) 

136
(14) Dr. Paul Hammerness, Investigator, Pediatric Psychopharmacolgy Unit, Child and 

Adolescent Psychiatry, Massachusetts General Hospital; Editor and Author, Natural 

Standard Research Collaboration (expertise in CAM) 

(15) Dr. Serguei Aksentsev, Author, Natural Standard Research Collaboration (expertise in 

CAM) 

(16) Dr. Alan Carroll, Associate Clinical Professor, Department of Psychiatry, University of 

Alberta (expertise in psychiatry and neurodevelopment) 

137