Melatonin for the prevention and treatment of jet lag Herxheimer A, Petrie kj



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Spitzer 87  

Spitzer RL, Terman M, Terman JS, Williams JBW. Columbia jet lag scale. Biometrics 

Res. 

Waterhouse 97  

Waterhouse J, Reilly T, Atkinson. Jet-lag. Lancet 1997;350:1611-16. 



Winget 84  

Winget CM, DeRoshia CW, Markley CL, Holley DC. A review of the human 

physiological changes associated with desynchronosis of biological rhythms. Aviat 

Space Environ Med 1984;55:1085-96. 



Zhdanova 00  

Zhdanova IV. The role of melatonin in sleep and sleep disorders. In: Culebras A, editor

(s). Sleep Disorders and Neurological Disease. New York - Basel: Marcel Dekker, 

2000:137-157. 



Cover sheet     

Melatonin for the prevention and treatment of jet lag

Reviewer(s)

Herxheimer A, Petrie KJ



Contribution 

of Reviewer(s)

AH wrote the protocol, searched for relevant 

papers, assessed and reviewed them, wrote the text 

of the review 

KJP contributed to the protocol, searched for 

relevant papers, assessed and reviewed them, and 

contributed to the text of the review 

Issue protocol 

first published

Information not available



Issue review 

first published

Information not available



Date of most 

recent 

amendment

11 May 2001



Date of most recent 

substantive 

amendment

22 August 2000



Most recent changes

Information not supplied by reviewer



Date new studies 

sought but none found

Information not supplied by reviewer



Date new studies 

found but not yet 

included/excluded

Information not supplied by reviewer



Date new studies 

Information not supplied by reviewer




Sources of support 

Extramural sources of support to the review 

!

No sources of support supplied 



Intramural sources of support to the review 

!

University of Auckland NEW ZEALAND 



!

UK Cochrane Centre UK 



Synopsis 

Jet-lag is caused by the body's de-synchronisation of the body clock and the day-night cycle at the 

traveller's destination, which is out of balance. 

In order to prevent jet-lag, researchers have examined melatonin (an important hormone), which 

plays a key role in regulating the body's natural rhythm. Randomised trials were carried out in airline 

passengers, airline staff and military personnel, in order to assess whether the oral use of melatonin 

would decrease the symptoms of jet-lag. In nine out of ten trials, melatonin decreased the symptoms 

of jet-lag. High dosages are not needed, but timing of the dose is critical. It was concluded that 

melatonin is effective in preventing or reducing jet-lag and it aids overall adaptation to the different 

time zones  



Tables & Graphs     

!

MetaView graphs



 

The figures and graphs in Cochrane Reviews display the Peto Odds Ratio and the Weighted 

Mean Difference by default. These are not always the methods used by reviewers when 

found and 

included/excluded

Date reviewers' 

conclusions section 

amended

Information not supplied by reviewer



Contact 

address

Dr Andrew Herxheimer  

Emeritus Fellow 

UK Cochrane Centre 

9 Park Crescent 

London N3 2NL 

UK 

Telephone: +44 20 8346 5470 



Facsimile: +44 20 8346 0407 

E-mail: andrew_herxheimer@compuserve.com



Cochrane 

Library 

number

CD001520


Editorial 

group

Cochrane Depression Anxiety & Neurosis Group



Editorial 

group code

HM-DEPRESSN 




combining data in their review. You should check the text of the review for a description of the 

statistical methods used.  

!

List of comparisons



  

!

Additional tables



  

!

Table of included studies



  

!

Table of excluded studies



  

!

Table of ongoing studies 



List of comparisons       

Fig 01 GLOBAL JET-LAG RATINGS 

01.01.00 Global jet-lag ratings 

 

Tables of other data       

Tables of other data are not available for this review 

Additional 

tables    

Table 01 Global jet-lag rating (Visual Analogue Scale, VAS): 0= no jet-lag; 100= maximum 

Table 02 Single case reports of possible adverse effects reported in cases outside RCTs  

Trial  

Number of 

flights  

Melatonin 

 

Placebo  

Diff M -

P (S. E.) 

 

Notes  

 

87 Arendt 

Placebo 9, 

Melatonin 8 

9.8 SD 0.8  55.4 SD 

4.5 


-45.6 

(2.2) 


 

 

88 Arendt 



[crossover study] 

Placebo 52, 

Melatonin 52 

18.1 SD 


15.5 

40.5 SD 


15.5 

-22.6 


(4.6) 

Within-subject 

comparisons 

 

89 Petrie [NZ-



London-NZ, 

crossover study] 

Placebo 20, 

Melatonin 20 

35.8 SD 

16.5 


56.7 SD 

24.5  


-20.9 

(0.66) 


Eastward & 

westward results not 

reported separately 

 

Claustrat 



Placebo 15, 

Melatonin 15 

28.0 SD 

7.4 


47.7 SD 

12.2 28.0 

SD 7.4 

-19.7 


(3.7) 

 

 



Nickelsen - 

eastward flights 

Placebo 9, 

Melatonin 9 

52.3 SD 

21.7 


66.3 SD 

19.7 


-14 (9.8)  Not statistically 

significant 

 

TOTAL 


participants & 

Weighted Means 

Placebo 105, 

Melatonin 

104  

25.3  


48.1 

-22.8 


 

 

 



 

 

 



 

 

 



[Nickelsen - 

westward flights] 

[Placebo 9, 

Melatonin 9] 

26 

35 


- 9  

 

 



Case no/ Ref  

Effects and comment  

Days 

use  

Sex / Age    


BRAIN 

 

 



 

 

1 Force 97 



transient psychotic episode [possible 

overdose] 

F 73 


 

2 Dalton 00 

mixed affective state in depressed woman - 

withdrawn from clinical trial of M for 

insomnia 

7 d 


 

3 11 NZ 



hallucination, paranoia - recovered on 

stopping 

2 d 

M ? 


 

4 10 US 


confusion, insomnia, tachycardia, abnormal 

thinking. Recurred on rechallenge 

1 d 

F 38 


 

5 07 US 


ataxia, dizziness, headache. "recovered with 

sequelae"  

4 d  

F 81 


 

6 29 US 


headache, hypertonia, tremor - improved on 

stopping. [was also taking unspecified 

vitamins] 

5 d 


F 28 

 

7 35 US 



paraesthesia, tachycardia - improved on 

stopping 

1 d 

F 41 


 

8 Ellis 96  

headache, odd taste in mouth - reported during 

clinical trial of M for insomnia [2 patients?] 

7 d  

?? 


 

9* Sheldon 98 

convulsant effects in 4 of 6 severely 

neurologically disabled children with seizures, 

treated with M for sleep disorders 

 

14 d 



7months; 7, 

8 & 9 yr 

 

10 40 US 



convulsion - recurrence when medication was 

continued 

M 40 


 

BLOOD CLOTTING 

 

 

 



 

11* 08 US 

eye haemorrhage, purpura, reduced 

prothrombin - suspected interaction with 

warfarin 

8 d 


M 84 

 

12* 09 US 



nosebleed, reduced prothrombin - suspected 

interaction with warfarin 

5 d 

F 51 


 

13* 21 US 

reduced prothrombin - suspected interaction 

with warfarin. Was taking M 10mg daily 

M 48 


 

14* 24 US 

reduced prothrombin - suspected interaction 

with warfarin. Also taking digoxin, frusemide, 

diclofenac 

F 72 



 

15* 26 US 

prothrombin affected [not clear how] - 

suspected interaction with warfarin. 

 



??  



 

16* 27 US 

prothrombin affected [not clear how] - 

suspected interaction with warfarin. 

M 61 


 

CARDIOVASCULAR   

 

 

 



 

17 16 US 

ventricular arrhythmia 

?F 



 

18 41 AUS 

chest pain, dyspnoea, fatigue, atrial fibrillation, 

paresis - recovered, no sequelae  

 

1 d 


F 58 

 



Table of included studies       

19 47 CAN 

tachycardia 

 

  



F ? 


 

20 05 US 

arrhythmia, tachycardia, dizziness, 

paraesthesia - also on nicotine, pyridoxine 

 

8 d 


F 46 

 

21 06 US 



angina, palpitation, hypotension - also on 

vitamins, oestrogen, testosterone 

 



F 46 



 

22 13 US 

chest pain, dyspnoea - also on thyroxine 

M 45 



 

23 37 US 

fatigue, syncope 

1 d 


F 63 

 

SKIN 



 

 

 



 

24/25* Bardazzi 98 IT  fixed drug eruption in 2 men: erythemato-

vesicular plaques on the penis, appearing 6-8 

hr after rechallenge, disappearing within 10 d 

few d  M 35 & 42   

 

 



 

 

 



 

 

 



 

 

Study__Methods__Participants_Interventions__Outcomes__Notes__A__co'>Study



Methods

Participants Interventions

Outcomes

Notes

A

co

87 

Arendt 

Double-blind. 

Treatment 

allocated 

according to a 

computer 

programme, 

decoded only 

after data 

collection 

was complete.

17 


volunteers 

(10 women, 

7 men) aged 

29-68 years 

flying from 

San 


Francisco or 

Los Angeles 

eastwards to 

London (8 

time zones) 

after having 

stayed in 

California 

for 14 days.

Oral 


melatonin 

5mg + 300mg 

lactose in 

gelatine 

capsule (n=8) 

or lactose 

300mg (n=9)

taken at 18.00 

local time on 

day of 


departure and 

2 preceding 

days, and 

then at 


bedtime 

(22.00 - 

24.00) for the 

first 4 days 

after return to 

the UK. 


['pre+post']

Activity patterns measured 

by wrist meters (n=16), 

oral temperature, mood 

self-rating, psychological 

tests, sleep duration and 

quality, rating of subjective 

feelings of jet lag. Urine 

assays for major metabolite 

of melatonin and of 

cortisol.

 

A



88 

Arendt 

Double-blind 

cross-over 

study


52 of 61 

participants 

flying from 

the UK to 

Melatonin 

5mg or 


placebo. For 

eastward 

Self-rated jet lag (VAS), 

symptoms


This study is 

briefly 


reported by 

Skene 1989 

B



Australia & 

New 


Zealand and 

back 


completed 

the 


crossover.

flights this 

was taken for 

2 days before 

the flight at 

the local time, 

which 

corresponded 



to 2am at the 

destination 

time zone, 

and for 4 days 

after arrival at 

the local 

bedtime 

['pre+post']. 

For westward 

flights 


melatonin or 

placebo was 

taken at the 

local bedtime 

for 4 days 

after arrival

in congress 

proceedings



89 Petrie  Double-blind, 

placebo 


controlled, 

cross-over 

trial

20 


volunteers 

(8 women, 

12 men) 

aged 28 to 

68, flying 

eastward 

from New 

Zealand to 

London 

through 12 



time zones 

on a 26-hour 

flight. They 

returned on 

a similar 

westward 

flight 3 

weeks later.

Gelatin 

capsule of 

melatonin 

5mg + 


lactose, or 

lactose daily 

at between 

10.00 and 

12.00 local 

time for 3 

days before 

each flight 

and on the 

day of flight, 

then between 

22.00 and 

24.00 

(destination 



time) for 3 

days after 

their arrival. 

Participants 

were 

randomised to 



receive 

melatonin 

either on the 

outward or 

the return 

flight 


['pre+post']

Feelings of jet lag and 

tiredness assessed by 

analogue scales, profile of 

mood states questionnaire, 

hours of sleep. On 10th day 

after arrival, retrospective 

rating of jet lag, estimate of 

how many days it had 

taken for sleep pattern and 

energy to return to normal. 

The participants recorded 

possible side effects

 

B




91 

Nickelsen 

Double-blind  36 

volunteers 

(26M 10F) 

flying 

westward 



from 

Frankfurt to 

USA and 2 

weeks later 

in the 

reverse 


direction. In 

12 the time 

shift was 6-7 

hr, in 12 8-9 

hr, in 12 10-

11 hr.


After the 

westbound 

flight 

participants 



took 

melatonin 

5mg or 

placebo at 



bedtime for 7 

consecutive 

days. After 

the eastbound 

flight they 

took the same 

dose for 5 

days ['post']

Sleepiness self-rated on 

Stanford scale, log of rest/ 

activity schedule

 

B



92 

Claustrat 

Double-blind 30 healthy 

volunteers 

flying from 

North 

America to 



France, 

having 


stayed in N 

America for 

7 days or 

longer


Melatonin 

8mg capsule 

(n=15; 8 

men) or 


placebo 

(n=15; 10 

men) on the 

day of flight 

and at 

bedtime on 



the following 

3 days ['post']

Sleepiness, mood, sleep, 

tiredness, efficiency at 

work, sleep latency, 

global effectiveness, 

symptoms

Three 


volunteers 

performed a 

double-blind 

cross-over 

trial within 

the study

B

93 Petrie  Double-blind  52 

international 

airline cabin 

crew ( 26 M, 

26 F) 

returning to 



New 

Zealand 


from 

London via 

Los Angeles 

to complete 

a 9-day tour 

of duty


3 treatment 

groups: 


melatonin 

(5mg daily at 

a time 

corresponding 



to 

evening/night 

at the 

destination) 



from 3 days 

before arrival 

until 5 days 

after arrival) 

n=14 

['pre+post']; 



melatonin 

(placebo for 3 

days then 

melatonin 

5mg daily for 

5 days) 


['post']. n=15; 

and placebo, 

Self-rated jet lag (VAS), 

tiredness, drowsiness; SSS 

(Stanford sleepiness scale), 

POMS (Profile of Mood 

States)

 

A




n=15.

97 

Spitzer 

Double-blind 257 

volunteers 

travelling 

eastwards 

across 6 

time zones

Melatonin 

5mg or 0.5mg 

at bedtime or 

early evening 

on day of 

flight and 

then for 5 

further days 

['post']


Jet lag measured by new 

Columbia Jet Lag scale

Insufficient 

adaptation 

in the new 

time zone 

before 

performing 



the study on 

the return 

flight

B

98 



Suhner a 

Double-blind 320 

volunteers 

(age range 

20 - 65 

years; 172 

men) from 

the 


University 

of Zurich 

travel clinic, 

flying 


eastwards 

through six 

to eight time 

zones. 


Exclusion 

criteria: use 

of a beta-

blocker or 

hypnotic, 

psychiatric 

disorder, 

severe sleep 

disorder, 

leukaemia, 

endocrine 

disorder, 

melanoma, 

severe 


allergy, 

pregnancy. 

142 

travelled 



from 

America to 

Europe, 92 

from Europe 

to Asia. 

These 


numbers 

exclude 86 

people who 

were either 

a) Melatonin 

0.5mg b) 

melatonin 

5mg c) 


melatonin 

2mg 


controlled- 

release d) 

placebo. All 

were taken 

daily at 

bedtime for 

the first 4 

days after the 

flight ['post'].

Sleep quality and daytime 

sleepiness (sleep logs and 

Karolinska sleepiness 

scale), mood (POMS) and 

symptoms 

(questionnaire).Compliance 

was assessed using the 

electronic Medication 

Event Monitoring System 

[MEMS] and a 

questionnaire. Symptoms 

were noted 

Participants 

were asked 

to maintain 

a regular 

sleep-wake 

cycle during 

the baseline 

and the four 

testing days 

and to limit 

their 


nicotine, 

caffeine and 

alcohol 

consumption 

to normal 

levels


A


Table of excluded studies     

Table of ongoing studies     

A table of ongoing studies is not available for this review 

The Cochrane Library

non-


compliant or 

withdrew for 

a medical 

reason.


98 

Suhner b 

Double-blind; 

computer 

randomisation

160 

volunteer 



travellers 

(80 men) 

flying 

eastwards 



from 

America to 

Switzerland 

across 6 to 9 

time zones 

after a stay 

of at least 7 

days in 


America. 

137 


completed 

the study.

Four groups: 

a) melatonin 

5mg, b) 

zolpidem 

10mg, c) 

both, or d) 

placebo, 

using the 

double 

dummy 


technique. 

The 


medication 

was taken 

between 5 

and 9 pm 

local time on 

the day of the 

flight and 

then for 4 

days at 

bedtime 


['post']

Sleep quality, profile of 

mood states, symptoms, 

wrist activity monitoring 

(n=80), subjective rating of 

jet lag, and of efficacy of 

the medication. 

Compliance was assessed 

electronically (MEMS) and 

by questionnaire. 23 

participants who missed 

one or more doses were 

excluded from the analysis. 

Symptoms were noted 

 

A

Study



Reason for exclusion

Arendt 95, 

97a, 97b  

These three broad reviews only briefly summarise the authors' controlled and 

uncontrolled studies and puts together the results for 474 subjects given melatonin 

and 112 given placebo; of these 86 took part in both arms of a crossover study. 

Randomisation is not mentioned. 

Comperatore 

96  

The study examined the effect of melatonin on sleep loss and cognitive 

impairment in soldiers engaging in night operations immediately on arrival in the 

Middle East after flying eastwards across eight time zones. Neither adaptation to 



local time, nor jet lag was assessed  


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