This document discusses melatonin's role in regulating sleep-wake cycles and circadian rhythms. It describes how melatonin is produced in the pineal gland and responds to light exposure, activating receptors involved in sleep regulation and circadian phase shifting. Studies show that oral melatonin supplementation can effectively treat jet lag when taken around bedtime at the destination for 2-5 days after long-haul flights. Melatonin doses from 0.5-5mg are similarly effective for this use and have a good safety profile when used short-term. However, melatonin did not demonstrate sleep benefits versus placebo in patients with primary insomnia.

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6. Sleep Stage Eye Movements Motor
Movements
HR, BP,
Respirations
Cerebral
Activity
Stage 1 Slow, rolling
movements
Moderate
activity
Slows Decreases
Stage 2 Slow, rolling
movements
Moderate
activity
Slows Decreases
Stages 3 & 4
(i.e., deep sleep)
Slow, rolling
movements
Moderate
activity
Slows Decreases
REM Sleep Clusters of rapid
eye movements
Suppressed w
loss of muscle
tone
Increases,
variable
Increases
Chart adapted from: Porth CM, Sleep and Sleep Disorders. In: Pathophysiology:
Concepts of Altered Health States. 8th edition. Porth CM, Matfin G, eds.
Philadelphia: Wolters Kluwer Health; 2009.

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8. SCN
Forebrain/Thalamus
Attention, memory,
emotion, psychomotor
performance,
sensorimotor integration
Hypothalamus
Anterior pituitary Hormone levels
Hypothalamus
Body temperature,
metabolism, ANS
function, sleep-wake
cycles
Brain stem reticular
formation
ANS function, sleep-
wake cycles
Pineal gland Melatonin
Light impulses through
retina a,b
Chart adapted from: Porth CM, Sleep and Sleep Disorders. In: Pathophysiology:
Concepts of Altered Health States. 8th edition. Porth CM, Matfin G, eds.
Philadelphia: Wolters Kluwer Health; 2009.
a Light = inhibitory signals
b Dark (i.e., lack of light) = stimulating signals

9. https://www.researchgate.net/figure/40454967_fig1_ Figure- 1-Physio log y-of-Melaton in-Secre tion-Me lat onin

11. MT1 Receptors in
SCN
Forebrain/Thalamus
Attention, memory,
emotion, psychomotor
performance,
sensorimotor integration
Hypothalamus
Anterior pituitary Hormone levels
Hypothalamus
Body temperature,
metabolism, ANS
function, sleep-wake
cycles
Brain stem reticular
formation
ANS function, sleep-
wake cycles
Pineal gland Melatonin
Melatonin
Activation of MT1 receptors is
the likely mechanism of how
melatonin regulatessleep2

12. Activation of MT2 receptors is
the likely mechanism of how
melatonin influences circadian
rhythm phase shifts2
Adapted from: http://www.brightenyourlife.info/images/slide4.jpg
Phase Response Curve

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23. Jet-Lag SWSD 1o Insomnia DSPS
Dose 0.5-8mg on
arrival day,
continue for 2-5
days
2-12mg for up
to 4 weeks
2-3mg prior to
bedtime for up
to 29 weeks
5mg prior to
bedtime for up
to 1 week
0.3-5mg for up
to 9 months
Formulation IR IR, CR, FR, SR CR, FR, SR IR
ROA PO PO PO PO

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32. Design N patients Intervention Results
Randomized,
double-blind,
placebo-controlled
crossover trial
22 Melatonin or
placebo 5mg PO
QD x 4 weeks
between 1900 and
2100 hours, 1 week
washout period,
received other
treatment x 4
additional weeks
20/22 patients
finished the study à
sleep onset latency
was significantly
reduced while
subject were taking
melatonin as
compared with
both placebo and
baseline

33. Strengths Limitations Conclusion
• No ADEs noted
• Study design allowed
patients to select their
baseline bedtime and
duration of sleep à
permitting investigators the
ability to compare their
natural sleep pattern with
that of the imposed sleep
period (2400 to 0800 hours)
• No evidence that melatonin
altered total sleep time
• Melatonin did alter
subjective measures of
sleepiness, fatigue or
alertness
• Small sample size
• Crossover design – each
patient served as his or her
own control
• Not well controlled
• Dose response relationships,
possibility of relapse after
discontinuation, not
explored
• Melatonin 5mg 3-4 hours
prior to bedtime was an
effective treatment for
patients with DSPS

34. Design N trials Results
Cochrane Systematic
Review
10 8/10 trials found that
melatonin, taken closeto
the target bedtime at
destination time of 2200 –
0000 hours, decreased jet-
lag from flights crossing 5+
time zones.

35. Other findings Conclusion
Daily doses of melatonin
ranging from 0.5-5mg were
shown to be similarly
effective; however, patients
fell asleep faster and better
after 5mg vs. 0.5mg
2mg slow-release melatonin
suggested a relative
ineffective short-lived
higher peak concentration
vs. 0.5-5mg (NNT = 2)
Start taking two nights prior
to flight and continue for 4
nights after arrival
Reports suggested that
patients with epilepsy, and
patients taking warfarin
may be harmed by
concurrent administration
with melatonin
Melatonin was remarkable
effective in preventing jet
lag
Safety and efficacywas
proven for occasional short-
term use
Should be recommended
to adult travelers flying
across 5+ time zones,
particularly on an eastward
flight

36. Design N patients Intervention
Randomized, double-blind,
placebo-controlled crossover
trial
10 Random order of 0.3mg, 1.0mg
melatonin or placebo 60
minutes prior to bedtime for 7
days.
Study was setup for patient to
receive each intervention dose
with a 5-day washout period in
between
After each 7 day treatment,
nighttime EEG records were
collected

37. Results
Treatment; mean (and SD)
Sleep variable Placebo MT 0.3mg MT 1.0mg
% waking stage in
total recordingtime
15.7 (15.6) 15.5 (15.9) 17.3 (18.8)
No. of awakenings 6.4 (5.1) 6.5 (4.2) 5.9 (2.4)
Total time waking
stage, min
73.8 (74.1) 72.1 (76.4) 83.0 (90.7)
There were no significant differences in sleep EEG, the amount or subjective quality of sleep or side effects
between the placebo, 0.3-mg melatonin or 1.0-mg melatonin treatments.

38. Strengths Limitations Conclusion
• Exclusion criteria ruled
out confounders at
baseline (e.g., all other
sleep disorder diagnoses
were excluded)
• Small sample size
• Findings are difficult to
interpret because of the
variability of the same
(e.g., age)
• Crossover study – each
patient served as his or
her own control
• Melatonin did not
produce any sleep
benefit in this sample of
patients with primary
insomnia

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HTTP://DX.DOI.OR G/10.1016/S0025-6196(11)63555-6
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0.1021/TX970202H
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