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Suggested Reference

Beros, A., Farquhar, C., Nagels, H. E., Showell, M. G., Fernando, A., & Jordan, V.

(2021). Pharmacological interventions for jet lag. The Cochrane database of systematic reviews, 2021(10). doi:10.1002/14651858.cd014611

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Library

Cochrane Database of Systematic Reviews

Pharmacological interventions for jet lag (Protocol)

Beros A, Farquhar C, Nagels HE, Showell MG, Fernando A, Jordan V

Beros A, Farquhar C, Nagels HE, Showell MG, Fernando A, Jordan V.

Pharmacological interventions for jet lag (Protocol).

Cochrane Database of Systematic Reviews 2021, Issue 10. Art. No.: CD014611.

DOI: 10.1002/14651858.CD014611.

www.cochranelibrary.com

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T A B L E O F C O N T E N T S

HEADER... 1

ABSTRACT... 1

BACKGROUND... 2

OBJECTIVES... 3

METHODS... 3

ACKNOWLEDGEMENTS... 6

REFERENCES... 7

APPENDICES... 9

CONTRIBUTIONS OF AUTHORS... 15

DECLARATIONS OF INTEREST... 15

SOURCES OF SUPPORT... 16

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[Intervention Protocol]

Pharmacological interventions for jet lag

Angela Beros¹, Cindy Farquhar¹, Helen E Nagels¹, Marian G Showell¹, Antonio Fernando², Vanessa Jordan¹

1Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. ²Practice 92, Auckland, New Zealand

Contact address: Angela Beros, [email protected].

Editorial group: Cochrane Common Mental Disorders Group, Cochrane Gynaecology and Fertility Group.

Publication status and date: New, published in Issue 10, 2021.

Citation: Beros A, Farquhar C, Nagels HE, Showell MG, Fernando A, Jordan V. Pharmacological interventions for jet lag (Protocol).

Cochrane Database of Systematic Reviews 2021, Issue 10. Art. No.: CD014611. DOI: 10.1002/14651858.CD014611.

A B S T R A C T

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

This review aims to evaluate both the beneficial and adverse effects of pharmacological interventions for jet lag in people who undertake air travel across at least two time zones.

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B A C K G R O U N D

Description of the condition

Jet lag can occur when a person flies across at least two time zones. It results from a person's internal circadian clock (an approximately 24-hour cycle) not being able to adapt quickly enough to the sleep-wake pattern required in the new time zone (AASM 2014). The internal circadian clock runs essential circadian rhythms, particularly the sleep-wake cycle. The criteria for diagnosing jet lag are set out in the third edition of the International Classification of Sleep Disorders (ICSD-3) (AASM 2014), as follows:

1. "There is a complaint of insomnia or excessive daytime sleepiness, accompanied by a reduction of total sleep time, associated with transmeridian [crossing of time zones] jet travel across at least two time zones;

2. There is an associated impairment of daytime function, general malaise, or somatic symptoms (e.g., gastrointestinal disturbance) within one to two days after travel; and

3. The sleep disturbance is not better explained by another current sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder."

The severity and duration of jet lag symptoms can vary widely among people but they tend to increase as the number of time zones travelled increases (AASM 2014; Sack 2009). In particular, symptoms appear to become more noticeable once three or more time zones have been crossed (Waterhouse 2007) and are worse in eastward travel than in westward travel (Herxheimer 2002; Monk 2000). Jet lag appears to affect all age, sex and ethnic groups (AASM 2014), and it is possible that travellers aged 60 years and over have more difficulty coping with jet lag than those who are younger (Monk 2005).

It is estimated that it takes about one day per time zone travelled for circadian rhythms to adjust to a new time zone; it may take several weeks, in the case of more than six time zones being travelled, due to circadian rhythms potentially shifting in the wrong direction (AASM 2014). Jet lag differs from 'travel fatigue', a broader term that relates to stressors related to travel, such as cramped conditions, disruption of sleep schedules and general dehydration, as opposed to changes in time zones, (Waterhouse 2007).

Description of the intervention

A pharmacologic substance (drug) is "any substance, other than food, that is used to prevent, diagnose, treat or relieve symptoms of a disease or abnormal condition" (NCI 2021). It is also referred to as "a substance that alters mood or body function, or that can be habit-forming or addictive, especially a narcotic" (NCI 2021). Pharmacological substances that are used to help alleviate jet lag can broadly be classified as chronobiotics (drugs that can cause an internal shift in circadian rhythms), hypnotics (drugs that are sleep-promoting agents), or stimulants (drugs that are wakefulness-promoting agents), with some substances fitting into more than one category (Arendt 2018; Coste 2009). These substances (and their approximate usual dosage) include the following.

• Chronobiotics: Melatonin (dose 0.05 mg to 5 mg) has been shown to shift circadian rhythms and can be administered orally,

sublingually, or way of transdermal patches. The timing of melatonin use in order to shift circadian rhythms is complicated and depends on knowledge of a person's circadian rhythm and their response to an attempt to phase shift those rhythms.

Generally, melatonin should be given in the early morning, prior to travelling westward, or in the early evening, prior to travelling eastward (Arendt 2009). Hydrocortisone (dose 20 mg), taken on awakening, may also work as a chronobiotic (Stewart 2019); as may caffeine, which has been shown to cause a large phase delay (Burke 2015; Piérard 2001).

• Hypnotics: Both benzodiazepines (such as temazepam (dose 15 mg to 30 mg), triazolam (dose 0.125 mg to 0.25 mg), diazepam (dose 5 mg to 25 mg), lorazepam (dose 0.5 mg to 1 mg) and chlordiazepoxide (dose 5 mg to 25 mg)) and non- benzodiazepine Z-drugs (such as zaleplon (dose 5 mg to 10 mg), zolpidem (dose 5 mg to 10 mg), zopiclone (dose 3.75 to 7.5 mg) and eszopiclone (dose 1 mg to 3 mg)) are recommended for jet lag (Hertenstein 2017; Kim 2021). Hypnotics should be taken prior to bed, and ideally, for safety reasons, after a flight, and not during it. As they have side effects and are addictive (particularly benzodiazepines), hypnotics should only be used for the short term (less than one week) (Arendt 2018; Coste 2009; Sack 2009). Melatonin (dose 3 mg to 5 mg) can also act as a hypnotic when taken two to three hours before bedtime (Herxheimer 2002; Mishima 1997; Waterhouse 2007; Zhandova 1997). The effectiveness of administering melatonin at bedtime may be affected by the extent to which that bedtime coincides with the optimal time for taking melatonin for circadian phase-shifting purposes (Arendt 2009).

More recently, melatonin agonists, which are also generally taken right before bed (such as agomelatine (dose 25 mg), ramelteon (dose 8 mg), tasimelteon (dose 20 mg), and long- release melatonin (dose 2 mg)) have also been developed as a treatment for jet lag (Williams 2016).

• Stimulants: Caffeine is commonly taken to avert sleepiness caused by jet lag and may be administered as a beverage, tablet, or capsule (dose 200 mg to 250 mg) (Choy 2001). More recently, drugs developed for excessive sleepiness (modafinil (dose 200 mg) and armodafinil (dose 150 mg)) have been proposed for the treatment of jet lag and are generally taken in the morning (Arendt 2018; Coste 2009; Czeisler 2005; Rosenberg 2010). Although drugs for excessive sleepiness have not been approved by the US Food and Drug Administration (FDA) for jet lag, it appears that they are being prescribed 'off-label' for such use (Arendt 2018).

How the intervention might work

Circadian rhythms are internally generated and help to coordinate the timing of some of the body's mental and physical systems, most notably the sleep-wake cycle, but also other processes, such as core temperature and digestion. These rhythms are regulated by a 'master clock' located in the suprachiasmatic nucleus (SCN) of the hypothalamus (Chokroverty 2017a; Shanahan 1997). The circadian rhythm is adjusted by rhythmic external cues, the most potent being light, though other factors, such as meal timing and exercise may also have an influence (Johnston 2014; Krauchi 2002;

Shanahan 1997; Youngstedt 2016). The effect of these time cues depends on when they are presented, and can cause the circadian clock to have a phase advance, phase delay, or no effect at all (Waterhouse 2007). As night falls, the 'master clock' initiates the release of melatonin, a sleep-promoting hormone. The release of

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melatonin is halted with exposure to daylight (Sack 2009; Shanahan 1997).

Jet lag arises when there is a rapid change in time zones, as the body's circadian rhythms are unable to adapt quickly enough to immediately match the sleep-wake pattern required by the new destination (Arendt 2018; Waterhouse 2007).

Chronobiotics alleviate jet lag by helping the 'master clock' synchronise more quickly with the new environment, through the creation of the required phase shift (Arendt 2018; Waterhouse 2007). Melatonin, as well as melatonin-agonists and slow- release melatonin, act via melatonin MT1 and/or MT2 receptors (Dubocovich 2007; Liu 2016). MT1 is associated with acute suppression of SCN electrical activity and the induction of sleep, whilst MT2 is responsible for phase-shifting (Liu 2016). Cortisol also performs an important function in the sleep-wake cycle, rising rapidly before waking, and dropping to its lowest levels in the evening around bedtime (Chokroverty 2017b). Following a rapid change in time zones, cortisol levels take a period of time to reflect the sleep-wake pattern required by the new destination (Paragliola 2021). It is possible, therefore, that taking glucocorticoids (such as hydrocortisone) in the morning, at the destination, may counteract jet lag by acting as an awakening signal (Arendt 2018).

Unlike chronobiotics, hypnotics and stimulants are not generally intended to help circadian phase-shifting, but instead are used to help promote sleep and wakefulness at the appropriate times in the new time zone (Arendt 2018; Sack 2009). Benzodiazepines and non-benzodiazepine Z-drugs help induce sleep by increasing the activity of gamma-aminobutyric acid (GABA), which reduces the activity of neurons in the brain and central nervous system (Hertenstein 2017). Coffee, as a stimulant, promotes wakefulness, as it blocks sleepiness-inducing adenosine (Volkow 2015). The mode of action for drugs developed for excessive sleepiness is unclear, but is partially due to increased dopamine activity (Madras 2006; Volkow 2009).

Why it is important to do this review

Since 2010, the number of airline passengers has increased by at least 3.6% each year (apart from the years 2020 and 2021, due to the impacts of COVID-19) (ICAO 2019). In 2019, airlines worldwide carried around 4.5 billion passengers (ICAO 2019). Apart from any further potential impacts of COVID-19, it has been estimated that the demand for air transport will increase by an average of 4.3% per annum over the next 20 years (ICAO 2021). It is likely, therefore, that there is a significant interest in interventions available to alleviate jet lag, and that this interest will only increase.

This review follows the Cochrane Review published in 2002 on melatonin for the prevention and treatment of jet lag (Herxheimer 2002), and will update that review with respect to melatonin, as well as expand on its findings by adding other pharmacological interventions. This review will also complement a recent non-Cochrane systematic review that evaluated the evidence for non-pharmacological interventions for jet lag (Bin 2019), and hence will help to provide people with a more complete picture of the effectiveness of all current jet lag interventions.

O B J E C T I V E S

This review aims to evaluate both the beneficial and adverse effects of pharmacological interventions for jet lag in people who undertake air travel across at least two time zones.

M E T H O D S

Criteria for considering studies for this review

Types of studies

We will include randomized controlled trials (RCTs). We will exclude quasi-RCTs (randomized parallel-arm RCTs in which allocation is decided by an approximation of randomization (e.g. allocation by participant ID number)).

Types of participants

People who undertake air travel across at least two time zones (whether actual or simulated).

Types of interventions

We will include trials comparing pharmacological treatments via oral, sublingual or transdermal routes, versus any other pharmacological treatments or placebo or no treatment; where administered or taken before, during and/or after travel, and including combinations of treatments.

We will exclude any trials where the intervention is a homeopathic or herbal remedy (including Chinese herbal medicine).

Types of outcome measures Primary outcomes

1. Subjective overall rating of jet lag evaluated with any scale designed to measure jet lag; for example, the Columbia Jet Lag Scale (Spitzer 1999) and the Liverpool Jet Lag Questionnaire (Waterhouse 2000)

2. Overall rate of any adverse events (including nausea and headaches), reported either as a composite measure or separately

Secondary outcomes

1. Subjective ratings of mood (e.g. Profile of Mood States questionnaire (McNair 1971))

2. Subjective ratings of sleep (e.g. Karolinska Sleepiness Scale (Åkerstedt 1990) and sleep diaries)

3. Objective measures of sleep (e.g. laboratory measurements such as polysomnography and actigraphy)

4. Circadian phase assessment (e.g. salivary dim light melatonin onset (DLMO) for melatonin and urine assays for metabolites of cortisol and melatonin)

5. Overall rate of withdrawal due to adverse events (including nausea and headaches)

Depending on available data, we plan to synthesise outcomes in different time frames following arrival at the destination time zone (day 1 being the day of arrival): short-term (days 1 to 8) and longer- term (day 9 and upwards). If a study reports an outcome more than once within a time frame, we will select the outcome reported at the latest point within the time frame.

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Search methods for identification of studies

We will search for all RCTs of pharmacological interventions for jet lag, regardless of publication status, without language restriction, and in consultation with the Information Specialists from the Cochrane Common Mental Disorders (CCMD) and the Cochrane Gynaecology and Fertility (CGF) Groups.

Electronic searches

1) We will search the following electronic databases for relevant trials:

• CENTRAL via the Cochrane Register of Studies Online (CRSO) Web platform (to search from inception to present) (Appendix 1);

• MEDLINE, Ovid platform (to search from 1946 to present) (Appendix 2);

• Embase, Ovid platform (to search from 1980 to present) (Appendix 3);

• PsycINFO, Ovid platform (to search from 1806 to present) (Appendix 4); and

• Allied and Complementary Medicine Database (AMED), Ovid platform (to search from 1985 to present) (Appendix 5).

The MEDLINE search will be combined with the Cochrane highly sensitive search strategy for identifying RCTs, which appears in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). The Embase and PsycINFO searches will be combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) www.sign.ac.uk/what- we-do/methodology/search-filters/.

2 ) Other electronic sources of trials will include:

• Latin American and Caribbean Health Sciences Literature (LILACS) and other Spanish- and Portuguese-language regional databases found in the online Virtual Health Library Regional Portal (VHL) (pesquisa.bvsalud.org/portal) (to search from inception to present) (Appendix 6);

• Google Scholar for recent trials not yet indexed in the major databases, Web platform (to search first page only) (Appendix 7);

and

• Epistemonikos database, Web platform (to search from inception to present) (Appendix 8).

Searching other resources

We will also search two international trial registries for ongoing trials: the ClinicalTrials.gov database, a service of the US National Institutes of Health (clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (ICTRP) (trialsearch.who.int) (Appendix 9).

We will handsearch reference lists of all relevant trials and systematic reviews retrieved by the search, and will contact experts in the field to determine if there are any additional studies.

Data collection and analysis

Selection of studies

Two or more review authors (from AB, HN, VJ, MS, AF and CF) will conduct an initial screen of titles and abstracts retrieved by the search. One review author (AB) will then retrieve the full texts

of all potentially eligible studies. Two or more review authors (from AB, HN, VJ, MS, AF and CF) will independently examine these full-text articles for compliance with the inclusion criteria, and will select eligible studies. We will use the Covidence software for both stages of the screening process. We will correspond with study investigators as required to clarify study eligibility.

If a disagreement about study eligibility cannot be resolved by discussion amongst two or more review authors, one review author not involved in this decision process, who would serve as a neutral arbiter, will make the final decision. We will document the selection process with a PRISMA flow chart (Liberati 2009).

Data extraction and management

Two or more review authors (from AB, HN, VJ, MS and AF) will independently extract data from eligible studies, using a data extraction form designed and pilot-tested by the authors. If a disagreement cannot be resolved by discussion amongst two or more review authors, one review author not involved in this decision process, who would serve as a neutral arbiter, will make the final decision. Data extracted will include study characteristics and outcome data. Where studies have multiple publications, the review authors will collate multiple reports of the same under a single study ID with multiple references. We will correspond with study investigators for further data on methods and/or results, as required.

Assessment of risk of bias in included studies

Two or more review authors (from AB, HN, VJ, MS and AF) will independently assess the included studies for risk of bias using the Cochrane 'Risk of Bias 2' (RoB 2) assessment tool (Sterne 2019). We will carry out the risk of bias assessments for all outcomes. The effect of interest will be the effect of assignment to the intervention at baseline, regardless of whether the interventions are received as intended (the 'intention-to-treat' principle).

RoB 2 assesses domains of bias as follows:

• bias arising from the randomization process;

• bias due to deviations from intended interventions;

• bias due to missing outcome data;

• bias in measurement of the outcome;

• bias in selection of the reported result;

• bias arising from the timing and recruitment of participants (cluster-RCTs only); and

• bias arising from period and carryover effects (cross-over RCTs only).

These domain-level judgements provide the basis for an overall risk of bias judgement for the specific trial result being assessed.

We will classify judgements as 'low risk of bias', 'some concerns' and 'high risk of bias', as suggested by the tool in response to answers to signalling questions for each domain, and an algorithm in the tool. We will then reach our overall judgement following the algorithm in the tool, as recommended in Chapter 8 of the Cochrane Handbook (Higgins 2021). If a disagreement cannot be resolved by discussion amongst two or more review authors, one review author not involved in this decision process, who would serve as a neutral arbiter, will make the final decision. We will describe all judgements fully and present the consensus judgements in the main review document (as a table, as a figure, and within a forest plot of results).

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We will use the RoB 2 Excel tool to implement RoB 2 (available on the riskofbias.info website) and will store data for access in an online open-access repository (such as 'Figshare').

Measures of treatment effect

For dichotomous data (e.g. people with and without jet lag as determined by applying a cut-off point to any scale designed to measure jet lag), we will use the number of events in the control and intervention groups of each study to calculate Mantel-Haenszel risk ratios (RRs). For continuous data (e.g. rating of jet lag as determined by any scale designed to measure jet lag), we will calculate the mean difference (MD) between treatment groups, if all studies report the outcome in exactly the same way. If similar outcomes are reported on different scales (e.g. different scales that are used to measure a subjective overall rating of jet lag) we will calculate the standardized mean difference (SMD). If scales have different directions of effect, we will reverse the direction of effect of individual studies, if required, to ensure consistency across trials.

We will treat ordinal data (e.g. jet lag scores obtained from jet lag scales) as continuous data. We will present 95% confidence intervals (CIs) for all outcomes. Where data to calculate RRs or MDs are not available, we will utilise the numerical data available. For example, if dichotomous data supplies percentages with sample numbers, we can use this to calculate RRs. For continuous data, if alternate measurement of error (e.g. test statistics, P values) are supplied, we will use these to calculate CIs.

Unit of analysis issues

The primary analysis will be per person randomized. We will include cross-over studies if the wash-out period is at least one day for each time zone crossed up to and including the crossing of six time zones and if the wash-out period is several weeks for the crossing of more than six time zones. If the wash-out period is insufficient, we will only use the first arm of the trial, as the effect of jet lag would not be the same in the second half of the trial.

For cluster-randomised studies, we will report the methods used to analyze cluster-randomised trials, and whether the risk of unit of analysis error was dealt with appropriately. Where the analysis was carried out appropriately, we will consider the studies for meta- analysis and use the reported effect sizes and standard errors in generic inverse variance meta-analysis. Where the analysis was inappropriate, we may perform approximately correct analyses, if the necessary information can be extracted (Higgins 2021). The approach used will be to adjust standard errors accordingly where a reliable estimate of the intracluster correlation coefficient (ICC) can be obtained, or, in cases where a reliable estimate of the ICC cannot be obtained, we will use a summary measures approach and perform the analysis at the cluster level (for example, using the proportion of those in each cluster experiencing the event of interest).

For multi-arm studies, we will keep the treatment arms separate and divide the control group.

Dealing with missing data

We will analyze the data on an intention-to-treat basis as far as possible (i.e. including all randomized participants in analysis, in the groups to which they were randomized). Attempts will be made to obtain missing data from the original trialists. We will not impute values for missing data.

If studies report sufficient detail to calculate mean differences, but report no information on the error associated with this (such as the standard deviation (SD), standard error and/or confidence intervals), we will assume the outcome to have a SD equal to the highest SD from other studies within the same analysis.

Assessment of heterogeneity

We will consider whether the clinical and methodological characteristics of the included studies are sufficiently similar for meta-analysis to provide a clinically meaningful summary. We will assess statistical heterogeneity by the measure of the I² statistic. An I² > 50% will be taken to indicate substantial heterogeneity (Deeks 2021).

Assessment of reporting biases

In view of the difficulty of detecting and correcting for reporting and publication bias, we will aim to minimise their potential impact by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. For missing outcomes, we will report known missing outcome results in the narrative analysis and will consider whether the outcome is likely to be biased as a result of the missing data. To ascertain whether there may be missing studies, we will use a funnel plot if there are ten or more studies in a meta- analysis, to explore the possibility of small study effects (a tendency for estimates of the intervention effect to be more beneficial in smaller studies)(Page 2021).

Data synthesis

In the primary analysis, we will include trials judged to be at overall low risk of bias as well as those with some concerns with regard to bias.

If the studies are sufficiently similar (I² ≤ 50 %), we will combine the data using a fixed-effect model in the following comparisons.

1. Chronobiotics versus placebo or no treatment 2. Hypnotics versus placebo or no treatment 3. Stimulants versus placebo or no treatment

4. Chronobiotics versus any other pharmacological treatment, stratified by comparator class

5. Hypnotics versus any other pharmacological treatment, stratified by comparator class

6. Stimulants versus any other pharmacological treatment, stratified by comparator class

7. Combinations of treatments versus any other pharmacological treatment or placebo or no treatment, stratified by comparator class/placebo or no treatment

Subgroup analysis and investigation of heterogeneity

Where data are available, we will conduct subgroup analyses to determine the separate evidence within the following subgroups.

1. Number of time zones crossed (≤ 6 vs > 6) 2. Direction of travel (eastward vs westward) 3. Age (≤ 18 years, 19-59 years, ≥ 60 years)

4. Type of traveller (airline crew vs airline passengers vs military personnel)

5. Class of airline passenger travel (economy class vs business class or first class)

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6. Type of agent for each drug class 7. Dose for each type of agent (high vs low)

8. Timing of intervention (before, during or after travel)

If we detect substantial heterogeneity (I² > 50%), we will explore possible explanations in subgroup analyses (e.g. differing populations) and/or sensitivity analysis (e.g. differing risk of bias, see below). We will take any statistical heterogeneity into account when interpreting the results, especially if there is any variation in the direction of effect.

Sensitivity analysis

We will conduct sensitivity analyses on all outcomes to determine whether the conclusions are robust to arbitrary decisions made regarding the eligibility and analysis. These analyses will include consideration of whether the review conclusions would have differed if:

• inclusion of studies was not restricted to those with overall low risk or with some concern with regard to bias;

• a random-effects model had been adopted;

• eligibility had been restricted to studies that used a validated or independent jet lag scale, such as the Columbia Jet Lag Scale or the Liverpool Jet Lag Questionnaire;

• eligibility had been restricted to studies that prohibited the use of alcohol for the duration of the study; or

• the summary effect measure had been the odds ratio rather than the risk ratio.

Summary of findings and assessment of the certainty of the evidence

We will prepare 'Summary of findings' tables using the GRADEpro software and Cochrane methods (GRADEpro GDT 2015;

Schünemann 2021). These 'Summary of findings' tables will evaluate the overall certainty of the body of evidence for all review outcomes.

We will assess the certainty of the evidence using the GRADE criteria: risk of bias, consistency of effect, imprecision, indirectness, and publication bias. Judgements about evidence certainty (high certainty, moderate certainty, low certainty, or very low certainty) will be made by at least two review authors (from AB, HN, VJ and MS), working independently. If any disagreements cannot be resolved by discussion amongst two or more review authors, one review author not involved in this decision process, who would serve as a neutral arbiter, will make the final decision. Judgements will be justified, documented, and incorporated into the reporting of results for each outcome. The overall RoB 2 judgement will be used to feed into the GRADE assessment.

The comparisons in the 'Summary of findings' tables will be:

1. Chronobiotics versus placebo or no treatment 2. Hypnotics versus placebo or no treatment 3. Stimulants versus placebo or no treatment

4. Chronobiotics versus any other pharmacological treatment 5. Hypnotics versus any other pharmacological treatment 6. Stimulants versus any other pharmacological treatment 7. Combinations of treatments versus any other pharmacological

treatment or placebo or no treatment

Comparisons 4-7 will only be presented as 'Summary of findings' tables if comparisons 1-3 show that the interventions help to relieve symptoms more than placebo/no treatment.

We will include the following outcomes in the 'Summary of findings' tables: subjective overall rating of jet lag; overall rate of any adverse events; subjective ratings of mood; subjective ratings of sleep;

and overall rate of withdrawal due to adverse events. Short- term outcomes (measured at day 1 to day 8) will be prioritised for presentation in the 'Summary of findings' tables. Longer-term outcomes (measured at day 9 and upwards) will only be presented in the 'Summary of findings' tables if measurements for short-term outcomes are not available.

We plan to extract study data, format our comparisons in data tables, and prepare the 'Summary of findings' tables before writing the results and conclusions of our review.

A C K N O W L E D G E M E N T S

The authors thank the Information Specialist of the Cochrane Common Mental Disorders (CCMD) Group for assistance in developing the search strategies, and Associate Professor Guy Warman for advising on the background sections, and on the choice of review outcomes.

The authors also thank Professors Emerti Josephine Arendt and Anna Wirz-Justice for their advice on the scope of the review.

The review authors and the CCMD Editorial Team are grateful to the peer reviewers (Andrew Anglemyer, James Cheeseman, Kari Clifford, Simon Davies, M Dulce Estevao, Ann E Fonfa and Nuala Livingstone) for their time and comments. They would also like to thank the copy editor, Hacsi Horvath.

Cochrane Review Group funding acknowledgement: the UK National Institute for Health Research (NIHR) is the largest single funder of the CCMD Group.

Disclaimer: the views and opinions expressed herein are those of the review authors and do not necessarily reflect those of the NIHR, the National Health Service, or the Department of Health and Social Care.

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R E F E R E N C E S

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A P P E N D I C E S

Appendix 1. CENTRAL via The Cochrane Register of Studies Online (CRSO) search strategy

Web platform

Search to present

#1 MESH DESCRIPTOR Jet Lag Syndrome EXPLODE ALL TREES

#2 MESH DESCRIPTOR Sleep Disorders, Circadian Rhythm EXPLODE ALL TREES

#3 ((jetlag* or jet lag*)):TI,AB,KY

#4 (circadian rhythm sleep disorder?):TI,AB,KY

#5 (travel fatigue):TI,AB,KY

#6 #1 OR #2 OR #3 OR #4 OR #5

#7 MESH DESCRIPTOR Air Travel EXPLODE ALL TREES

#8 travel*:TI,AB,KY

#9 aviation:TI,AB,KY

#10 ((aerospace or aeroplane* or aircraft or aviation)):TI,AB,KY

#11 ((airline* or air line* or air passenger* or aircrew or air crew)):TI,AB,KY

#12 (cabin crew):TI,AB,KY

#13 ((long haul* or longhaul*)):TI,AB,KY

#14 ((space adj (flight* or medic*))):TI,AB,KY

#15 #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14

#16 MESH DESCRIPTOR Biological Clocks EXPLODE ALL TREES

#17 ((((internal or biological or circardian) adj clock?) or cicardian rhythm?)):TI,AB,KY

#18 ((time shift* or timeshift* or time zone? or timezone?)):TI,AB,KY

#19 MESH DESCRIPTOR Sleep EXPLODE ALL TREES

#20 MESH DESCRIPTOR Sleep Deprivation EXPLODE ALL TREES

#21 MESH DESCRIPTOR Sleep Wake Disorders

#22 MESH DESCRIPTOR Sleep-Wake Transition Disorders EXPLODE ALL TREES

#23 MESH DESCRIPTOR Wakefulness EXPLODE ALL TREES

#24 (sleep* or wakeful* or awake):TI,AB,KY

#25 MESH DESCRIPTOR Sleep Initiation and Maintenance Disorders

#26 insomnia*:TI,AB,KY

#27 #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26

#28 #15 AND #27

#29 #6 OR #28

Appendix 2. MEDLINE search strategy

Ovid platform

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Search from 1946 to present

1 jet lag syndrome/ or sleep disorders, circadian rhythm/

2 (jetlag* or jet lag*).mp.

3 circadian rhythm sleep disorder?.mp.

4 travel fatigue.mp.

5 1 or 2 or 3 or 4 6 travel/

7 travel*.tw,kf.

8 exp aviation/

9 aerospace medicine/

10 (aerospace or aeroplane* or aircraft or aviation).tw,kf.

11 (airline* or air line* or air passenger* or aircrew or air crew).tw,kf.

12 cabin crew.tw,kf.

13 (long haul* or longhaul*).tw,kf.

14 exp space flight/

15 spacecraft?.tw,kf.

16 (space adj (flight* or medic*)).tw,kf.

17 or/6-16

18 biological clocks/ or circadian clocks/ or circadian rhythm/

19 (((internal or biological or circardian) adj clock?) or cicardian rhythm?).tw,kf.

20 (time shift* or timeshift* or time zone? or timezone?).tw,kf.

21 sleep/ or sleep deprivation/

22 sleep wake disorders/ or sleep-wake transition disorders/

23 wakefulness/ or wakefulness-promoting agents/

24 (sleep* or wakeful* or awake).tw,kf.

25 "sleep initiation and maintenance disorders"/

26 insomnia*.mp.

27 or/18-26 28 17 and 27 29 5 or 28

30 exp Pharmaceutical Preparations/

31 Pharma*.tw.

32 Drug*.tw. or drug therapy.fs.

33 (medical adj2 (treatment* or therap*)).tw.

34 (medicine* or medication*).tw.

35 or/30-34

36 Chronobiotic*.tw.

37 exp Melatonin/

38 Melatonin.tw.

39 LY 156735.tw.

40 (Circadin* or Tasimelteon* or Ramelteon* or HETLIOZ or Rozerem*).tw.

41 (donormil* or cirkadin*).tw.

42 (Agomelatin* or Valdoxan).tw.

43 (Tasimelteon* or hypocretin* or Orexin*).tw.

44 (suvorexant* or lemborexant*).tw.

45 exp receptor, melatonin, mt1/ or exp receptor, melatonin, mt2/

46 (agonist* adj2 (MT1 or MT2)).tw.

47 exp Sleep Aids, Pharmaceutical/

48 sleep aid*.tw.

49 or/36-48

50 exp "Hypnotics and Sedatives"/

51 exp Benzodiazepines/ or BZD*.tw. or nonbenzo*.tw.

52 (Hypnotic* or Sedative*).tw.

53 (diphenhydramine* or alimemazine* or chlorpheniramine* or clemastine* or cyproheptadine* or hydroxyzine* or ketotifen* or promethazine*).tw.

54 orexin receptor antagonist*.tw.

55 Benzodiazepin*.tw.

56 (temazepam* or triazolam*).tw.

57 (diazepam* or lorazepam*).tw.

58 chlordiazepoxide*.tw.

59 (bromazepam* or clorazepate* or flurazepam*).tw.

60 Z-drug*.tw.

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61 (Ambien* or zolpidem* or Zimovane*).tw.

62 (zopiclone* or Imovane* or zaleplon*).tw.

63 (Eszopiclone* or Lunesta*).tw.

64 (Nitrazepam* or Lormetazepam* or Medazepam).tw.

65 (Alprazolam* or Clobazam*).tw.

66 (Clonazepam* or Nitrazepam* or Oxazepam*).tw.

67 (antidepressant* or mirtazapine* or trazodone* or tricyclic*).tw.

68 or/50-67

69 exp Central Nervous System Stimulants/

70 (Armodafinil* or Nuvigi*).tw.

71 caffeine.tw. or Caffeine/

72 (Modafinil* or Provigil*).tw.

73 (amphetamin* or psychostimulant*).tw.

74 exp Glucocorticoids/

75 exp Hydrocortisone/

76 (Glucocorticoid* or hydrocortisone*).tw.

77 (Betamethasone* or Dexamethasone* or Methylprednisolone* or Prednisone).tw.

78 (prednisolone* or deflazacort* or fludrocortisone*).tw.

79 stimulant*.tw.

80 exp Methylphenidate/

81 (methylphenidate or dexamphetamine or amphetamine* or dexamfetamine).tw.

82 (lisdexamfetamine* or L-lysine-dextroamphetamine* or Vyvanse* or Tyvanse* or Elvanse* or methamphetamine* or Desoxyn*).tw.

83 or/69-82

84 35 or 49 or 68 or 83 85 29 and 84

86 randomized controlled trial.pt.

87 controlled clinical trial.pt.

88 randomized.ab.

89 randomised.ab.

90 placebo.tw.

91 clinical trials as topic.sh.

92 randomly.ab.

93 trial.ti.

94 (crossover or cross-over or cross over).tw.

95 or/86-94

96 exp animals/ not humans.sh.

97 95 not 96 98 85 and 97

Appendix 3. Embase search strategy

Ovid platform

Search from 1980 to present 1 exp jet lag/

2 circadian rhythm sleep disorder/

6 or/1-5 7 travel/

8 travel*.tw.

9 exp aviation/

10 aerospace medicine/

11 (aerospace or aeroplane* or aircraft or aviation).tw.

12 (airline* or air line* or air passenger* or aircrew or air crew).tw.

13 cabin crew.tw.

14 (long haul* or longhaul*).tw.

15 exp space flight/

16 spacecraft?.tw.

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17 (space adj (flight* or medic*)).tw.

18 or/7-17

19 biological rhythm/

20 circadian rhythm/

21 (((internal or biological or circardian) adj clock?) or cicardian rhythm?).tw.

22 (time shift* or timeshift* or time zone? or timezone?).tw.

23 sleep/

24 sleep deprivation/

25 sleep disorder/

26 parasomnia/

27 wakefulness promoting agent/ or wakefulness/

28 (sleep* or wakeful* or awake).tw.

29 insomnia/

30 insomnia*.tw.

31 or/19-30 32 18 and 31 33 6 or 32 34 exp drug/

35 drug*.tw.

36 pharma*.tw.

39 or/34-38

41 melatonin derivative/ or exp melatonin/ or melatonin 2 receptor/ or melatonin 1 receptor/ or melatonin receptor agonist/

42 Melatonin.tw.

43 LY 156735.tw.

45 (donormil* or cirkadin*).tw.

46 (Agomelatin* or Valdoxan).tw.

50 exp hypnotic agent/

51 sleep aid*.tw.

52 or/40-51

53 exp hypnotic sedative agent/

54 exp benzodiazepine derivative/

56 (diphenhydramine* or alimemazine* or chlorpheniramine* or clemastine* or cyproheptadine* or hydroxyzine* or ketotifen* or promethazine*).tw.

57 orexin receptor antagonist*.tw.

58 (Benzodiazepin* or BZD* or nonbenzo*).tw.

62 (bromazepam* or clorazepate* or flurazepam*).tw.

63 Z-drug*.tw.

67 (Nitrazepam* or Lormetazepam* or Medazepam).tw.

71 or/53-70

72 exp central stimulant agent/

74 caffeine.tw. or exp caffeine/

77 exp glucocorticoid/

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78 exp hydrocortisone/

82 stimulant*.tw.

83 exp methylphenidate/

84 (methylphenidate* or dexamphetamine* or amphetamine* or dexamfetamin*).tw.

86 or/72-85

87 39 or 52 or 71 or 86 88 33 and 87

89 Clinical Trial/

90 Randomized Controlled Trial/

91 controlled clinical trial/

92 multicenter study/

93 Phase 3 clinical trial/

94 Phase 4 clinical trial/

95 exp randomization/

96 Single Blind Procedure/

97 Double Blind Procedure/

98 Crossover Procedure/

99 Placebo/

100 Randomi?ed controlled trial$.tw.

101 Rct.tw.

102 (random$ adj2 allocat$).tw.

103 Single blind$.tw.

104 Double blind$.tw.

105 ((treble or triple) adj blind$).tw.

106 placebo$.tw.

107 prospective study/

108 or/89-107 109 case study/

110 case report.tw.

111 abstract report/ or letter/

112 Editorial.pt.

113 Letter.pt.

114 Note.pt.

115 or/109-114 116 108 not 115 117 88 and 116

Appendix 4. PsycINFO search strategy

Ovid platform

Search from 1806 to present 1 (jetlag* or jet lag*).mp.

4 or/1-3

5 exp Drug Therapy/

6 Pharmaceutical*.tw.

7 (Drug* or pharmacolog*).tw.

10 or/5-9

12 exp melatonin/

13 Melatonin.tw.

14 LY 156735.tw.

16 (Agomelatine* or Valdoxan).tw.

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20 sleep aid*.tw.

21 or/11-20

22 exp Hypnotic Drugs/ or exp Sedatives/ or exp Benzodiazepines/

24 Benzodiazepin*.tw.

28 Z-drug*.tw.

32 (Nitrazepam* or Lormetazepam*).tw.

36 or/22-35

37 exp Caffeine/ or exp Methylphenidate/ or exp CNS Stimulating Drugs/ or exp Amphetamine/

39 caffeine.tw.

42 exp Glucocorticoids/

43 exp Hydrocortisone/

46 stimulant*.tw.

48 (methylphenidate or dexamphetamine or amphetamine* or dexamfetamine).tw.

50 or/37-49

51 10 or 21 or 36 or 50 52 4 and 51

53 random.tw.

54 control.tw.

55 double-blind.tw.

56 clinical trials/

57 placebo/

58 exp Treatment/

59 or/53-58 60 52 and 59

Appendix 5. AMED search strategy

Ovid platform

Search from 1985 to present 1 exp Circadian rhythm/

4 (travel* adj5 (fatigue or tired*)).tw.

5 1 or 2 or 3 or 4

6 exp Travel/ or exp Aviation/

7 travel*.tw.

8 (aerospace or aeroplane* or aircraft or aviation).tw.

9 (airline* or air line* or air passenger* or aircrew or air crew).tw.

10 (long haul* or longhaul*).tw.

11 spacecraft?.tw.

12 (space adj (flight* or medic*)).tw.

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13 or/6-12

14 (((internal or biological or circardian) adj clock?) or cicardian rhythm?).tw.

15 (time shift* or timeshift* or time zone? or timezone?).tw.

16 Sleep/

17 Sleep disorders/

18 (sleep* or wakeful* or awake).tw.

19 insomnia*.mp.

20 or/14-19 21 13 and 20 22 5 or 21

23 randomized controlled trials/

24 randomized controlled trial.pt.

25 controlled clinical trial.pt.

26 placebo.ab.

27 random*.ti,ab.

28 trial.ti,ab.

29 groups.ab.

30 or/23-29 31 22 and 30

Appendix 6. LILACS search strategy

Web platform

Search to present

jetlag OR "jet lag" AND ( db:("IBECS" OR "LILACS" OR "BINACIS" OR "DECS"))

Appendix 7. Google Scholar search strategy

Web platform Search to present jetlag or "jet lag" random

Appendix 8. Epistemonikos search strategy

Web platform

Search to present

title:(jetlag) OR title:(jet lag)

Appendix 9. International Trial Registries; clinicaltrials.gov and The ICTRP search strategies

Web platform

Search to present Search one; "Jetlag"

Search two; "Jet lag"

C O N T R I B U T I O N S O F A U T H O R S

AB drafted the protocol

MS contributed to the drafting of the search strategies and commented on the draft VJ, HN, AF and CF commented on the draft

D E C L A R A T I O N S O F I N T E R E S T

AB, CF, VJ, MS, AF, and HN have no interests to declare.

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S O U R C E S O F S U P P O R T Internal sources

• Department of Obstetrics and Gynaecology, University of Auckland, New Zealand Salary support for Angela Beros

External sources

• No sources of support provided