This study will examine the effects of cortisol (hydrocortisone), melatonin, a combination of
cortisol and melatonin, and placebo (an inactive substance) on jet lag symptoms. Jet lag is a
term used to describe symptoms people commonly experience after rapid travel across several
time zones. The cause of jet lag is not known, but various hormones, including cortisol and
melatonin, have a day-to-night pattern of secretion and play a role in maintaining the body's
internal rhythms. This study will test whether taking cortisol, melatonin, or both can help
re-establish the body's day-night cycle and result in less jet lag.
People between 18 and 65 years of age who are planning a non-stop eastward flight with the
following characteristics may be eligible for this study:
- Crossing six to eight time zones (6 to 8 hours difference between Eastern Standard Time
and the destination)
- Destination between 30 and 50 latitudes (approximately Cairo to London)
- Evening flight (5 PM to midnight) with morning arrival
- Remaining abroad at least 4-10 days
Candidates must have a body mass index (BMI) between 20 and 30 kg/M (not too thin and not
overweight) and must not be taking medicines that affect sleep or cortisol or melatonin
levels. Prospective participants are screened with a medical history, blood tests, and check
of blood pressure, height, and weight.
Participants keep a sleep journal 3 days before the flight. For 1 day within 3 days of the
flight they fill out jet lag and sleepiness questionnaires and collect morning and bedtime
saliva samples for measurement of cortisol and melatonin. The saliva is collected by chewing
on two small cotton pads and spitting them into a tube. Premenopausal women provide a urine
sample the week before the flight to test for pregnancy. On the day of the flight, the
participants do not collect saliva or fill out sleep logs or questionnaires. They are given
two bottles with study medication. One bottle, labeled "AM," contains either hydrocortisone
or placebo; the other, labeled "PM," contains either melatonin or placebo.
Upon arriving at their destination in the morning, participants obtain a saliva sample and
take one of the capsules in the "AM" bottle. At bedtime, they collect saliva and then take
one of the "PM" capsules. They repeat the medication doses for a total of 4 days and repeat
the saliva collections on days 2 through 4, 7 and 10 after arrival. In addition, participants
complete jet lag and sleep questionnaires in the morning, afternoon, and just before bedtime
on the day of arrival and on days 2 through 4, 7 and 10.
After they return from their trip, participants are seen at the NIH Clinic to bring in their
saliva specimens and review their questionnaires with study investigators.
Jet lag resulting from rapid flight across several time zones is a common complaint of
travelers. The symptoms of jet lag are primarily described as daytime sleepiness, fatigue,
and impaired mental efficiency and can also include weakness and irritability. It is
considered to be due to the desynchronization between the internal circadian rhythm and the
new local day-night cycle at the traveler's destination. A means of rapidly resynchronizing
the circadian rhythm to the local time would benefit people who suffer severely from this
What actually underlies jet lag is a question that has not been fully answered. Various
endogenous hormones, including cortisol and melatonin, have a natural circadian rhythmicity
and play a role in maintaining the body's internal clock. Cortisol is produced by the
hypothalamic- pituitary-adrenal axis in a circadian manner and in response to stress. Normal
cortisol has a diurnal rhythm with a maximum level in the morning and a nadir during the
night. While a time shift does not change the total daily amount of cortisol that is
secreted, the temporal organization of the cortisol secretions is disrupted and the circadian
rhythm does not re-entrain for several days. Thus, the first few mornings in a new time zone
can be considered relatively cortisol-deficient because the traveler does not experience the
peak of cortisol at the time of awakening. Taking exogenous glucocorticoids at the proper
time may help re-entrain the circadian rhythm faster and result in less jet lag.
Melatonin is a hormone that is secreted nocturnally by the pineal gland. Exposure to bright
light diminishes its release while darkness triggers it. A recent meta-analysis has shown
that taking melatonin can alleviate symptoms of jet lag.
The aim of the present study is an attempt for the first time to attenuate jet lag symptoms
with hydrocortisone, melatonin, a combination of both hydrocortisone and melatonin or
Forty-eight normal volunteers will be randomized in blocks of eight to one of four treatment
arms: hydrocortisone (25 mg) alone, melatonin (5 mg) alone, hydrocortisone (25 mg) and
melatonin (5 mg) in combination, and placebo. Volunteers will travel in an eastwardly
direction across 6-8 time zones. Upon morning arrival at the new destination, volunteers will
obtain a saliva sample and then take 25 mg hydrocortisone (or placebo). At the target bedtime
of (10 pm to midnight local time) they will take 5 mg of melatonin (or placebo). Volunteers
will wake up at 7 am-10:30 am (local time) and take 25 mg hydrocortisone (or placebo).
Subjects will repeat these dosages for 3 days for a total of four days. Participants also
will obtain salivary samples of cortisol and melatonin on awakening and at bedtime on one day
before travel and at the new destination for days 1 - 4, 7 and 10 after arrival. The primary
outcome measure will be subjective rating of jet lag and components or correlates of this
such as fatigue and daytime tiredness. Subjects will keep sleep logs and fill out a symptoms
questionnaire daily for 3 days before and 4 days after the flight and on days 7 and 10.
Secondary outcomes will be the measurement of salivary cortisol and melatonin. The data
obtained from this study will provide an assessment of effective treatment of jet lag
syndrome and will provide a better understanding of the role of hormones in the disruption of
the circadian rhythm.
- INCLUSION CRITERIA:
- Age greater than or equal to 18, but less than or equal to 65, men or women.
- Normal blood pressure, BMI within 20-30 and normal laboratory results.
- Negative urinary pregnancy test 1 week prior to travel (pre-menopausal women).
- Planned non-stop eastward flight crossing 6-8 time zones between 30n and 50n
- A minimum stay of 4 - 10 days abroad.
- Willingness and anticipated ability to comply with study procedures, including sleep
and wake hours, saliva collection and questionnaire completion.
- Written informed consent.
- BMI less than or equal to 20 or greater than or equal to 30 kg/m.
- Current psychiatric or seizure disorder.
- Current sleep disorder as assessed by presence of sleep apnea, daytime napping of more
than 20 minutes, chronic fatigue.
- History of Cushing's syndrome.
- Serious chronic medical condition.
- Current drug or alcohol abuse.
- SGOT or SGPT greater than three-fold normal.
- Current pregnancy or lactation.
- Current use of CPAP.
- Chronic use of beta-blockers (which inhibit melatonin secretion), anti-epileptic
agents, anticoagulants, fluvoxamine, nifedipine or soporific or sleep-inducing agents
(including benzodiazepines, melatonin), or glucocorticoids (including nasal or inhaled
- Fasting blood glucose greater than 110 mg/dL or known diabetes.
- Exclusion of individuals who have not experienced jet lag on previous flights.
- Use of medications known to interact with melatonin or hydrocortisone.
- Use of prescription, over-the counter, or alternative medications known to cause sleep
- Use of prescription, over-the counter, or alternative medications that commonly cause
insomnia or excessive drowsiness.