Health - Melatonin and the Circadian Rhythm (Overview / Reference Guide)

[Bajeda]

Melatonin is an endogenous substance produced by the pineal gland. The current corpus of research suggests that it plays an essential role in the entrainment of the sleep-wake cycle by the circadian rhythm. Exogenous melatonin is used (unofficially) to help treat sleep problems such as Jet Lag, Advanced Sleep Phase Syndrome, Delayed Sleep Phase Syndrome, Shift Work Sleep Disorder, Non-Entrained Sleep Wake Disorder (also "non-24 hour sleep wake disorder"); and it is also being investigated for possible therapeutic effects on depressive disorders, which are increasingly considered to be highly interrelated with sleep patterns / disorders.

In this thread I aim to collect basic information on Melatonin's role in the sleep-wake cycle and research on its clinical / therapeutic for treatment of circadian rhythm disorders or even depressive symptomology. This is going to be more of a bibliography & basic reference guide at first, but hopefully once I get some spare time it will become more useful, especially to those having difficulties with circadian rhythm disorders.






Lavie, P. (2001). Sleep-wake as a biological rhythm. Annual Review of Psychology, 52, 277-303.

Evidence that the sleep-wake rhythm is generated endogenously has been provided by studies employing a variety of experimental paradigms such as sleep deprivation, sleep displacement, isolating subjects in environments free of time cues, or imposing on subjects sleep-wake schedules widely deviating from 24 hours. The initial observations obtained in isolated subjects revealed that the period of the endogenous circadian pacemaker regulating sleep is of approximately 25 hours. More recent studies, however, in which a more rigorous control of subjects’ behavior was exerted, particularly over lighting conditions, have shown that the true periodicity of the endogenous pacemaker deviates from 24 hours by a few minutes only. Besides sleep propensity, the circadian pacemaker has been shown to regulate sleep consolidation, sleep stage structure, and electroencephalographic activities. The pattern of light exposure throughout the 24 hours appears to participate in the entrainment of the circadian pacemaker to the geophysical day-night cycle. Melatonin, the pineal hormone produced during the dark hours, participates in communicating both between the environmental light-dark cycle and the circadian pacemaker, and between the circadian pacemaker and the sleep-wake-generating mechanism. In contrast to prevailing views that have placed great emphasis on homeostatic sleep drive, recent data have revealed a potent circadian cycle in the drive for wakefulness, which is generated by the suprachiasmatic nucleus. This drive reaches a peak during the evening hours just before habitual bedtime.


Useful Excerpts

• "Melatonin, which is a small molecule produced in the pineal gland in the depth of the brain, appears to play a critical role in the entrainment of the sleep-wake cycle by the circadian pacemaker. In all organisms, melatonin synthesis is limited to the dark period and is acutely inhibited by light. Although it can be entrained by the external light-dark cycle, melatonin production is under the control of the circadian pacemaker and it continues to oscillate under constant darkness conditions (Arendt 1995). Being responsive to light, the level of circulating melatonin provides an internal signal that is proportional to the length of the solar day. Lewy et al (1980), in a paper published back-to-back with Czeisler et al’s (1980a) paper on free-running rhythms in isolated subjects, was the first to demonstrate that exposing humans during the night to bright light suppresses melatonin production. Later it was demonstrated that illuminance well below typical indoor light can also suppress melatonin production (Brainard et al 1988)." (296)

• "In addition to light, exogenous melatonin also exerts phase-shifting effects on the endogenous melatonin production in humans (Lewy et al 1992). Administration of exogenous melatonin, close to the endogenous offset of its own production in the morning hours, causes phase delay of the endogenous rhythm and, conversely it phase advances the rhythm when administered before the onset of the endogenous production. These phase-shifting effects are a mirror image of the phase-response curve of melatonin to light (see recent review in Lewy & Sack 1997)." (296-297)

• "Daytime administration of melatonin modified the temporal pattern of sleep propensity in a time-dependent manner. When administered at 1200, it delayed the appearance of the sleep gate, whereas administration at 1700, 1900, and 2100 significantly advanced it. These changes resemble the phase-response curve of endogenous melatonin secretion to exogenous melatonin (Lewy et al 1992), and may be mediated by changes in the pattern of endogenous melatonin secretion. Possibly, the phase shifting effects of bright light on the sleep gate (Tzischinsky & Lavie 1997) may be also mediated by the delay in melatonin rhythm. Exogenous melatonin was also shown to be able to facilitate phase shifts of the sleep-wake rhythms. Facilitation of phase shifts has been reported both in field studies investigating adaptation to time zone changes, and in phase shifts induced under controlled laboratory conditions (see review in Arendt et al 1997). The soporific effects of exogenous melatonin were convincingly demonstrated when melatonin was administered during the daytime (Lavie 1997). Minimal effects, or none at all, were reported for nighttime administrations." (297)

ِ




Barion, Ana, & Zee, Phyllis C. (2007). A clinical approach to circadian rhythm sleep disorders. Sleep Medicine, 8, 566-577.

Abstract: Circadian rhythm sleep disorders are characterized by complaints of insomnia and excessive sleepiness that are primarily due to alterations in the internal circadian timing system or a misalignment between the timing of sleep and the 24-h social and physical environment. In addition to physiological and environmental factors, maladaptive behaviors often play an important role in the development of many of the circadian rhythm sleep disorders. This review will focus on the clinical approach to the diagnosis and management of the various circadian rhythm sleep disorders, including delayed sleep phase disorder, advanced sleep phase disorder, non-entrained type, irregular sleep–wake rhythm, shift work sleep disorder and jet lag disorder. Diagnostic tools such as sleep diaries and wrist activity monitoring are often useful in confirming the diagnosis. Because behavioral and environmental factors often are involved in the development of these conditions, a multimodal approach is usually necessary. Interventions include sleep hygiene education, timed exposure to bright light as well as avoidance of bright light at the wrong time of the day and pharmacologic approaches, such as melatonin. However, it should be noted that the use of melatonin is not an FDA-approved indication for the treatment of circadian rhythm sleep disorders.

Useful Excerpts

• "In humans, the propensity to fall asleep, as measured by multiple sleep latency tests, shows a biphasic circadian rhythm. In most individuals, there is a midday decrease in alertness occurring at around 2–4 p.m., followed by an increase in alertness that peaks during early to mid-evening hours, then it declines to its lowest levels around 4–6 a.m. During the early evening hours, when the homeostatic drive for sleep is high, the circadian alerting signal is also at its highest level. Thus, the circadian system plays an important role in determining the temporal distribution and duration of sleep and wakefulness." (566)

• "Circadian rhythm sleep disorders (CRSDs) arise from disruption of the circadian timing system or a misalignment between the endogenous circadian timing and the external 24-h social and physical environment, resulting in complaints of insomnia and/or excessive sleepiness and impairment in important areas of functioning and quality of life. The actual clinical presentation of CRSD is often influenced by a combination of physiological, behavioral, and environmental factors." (567)

• "Delayed sleep phase disorder (DSPD) is characterized by sleep times that are delayed three to six hours relative to the desired or socially acceptable sleep–wake schedules. Patients typically report difficulty falling asleep before 2–6 a.m. and, when free of social obligations, such as on weekends and vacations, would prefer wake times between 10 a.m. and 1 p.m. When following socially enforced sleep–wake times, patients will present with classical symptoms of chronic sleep-onset insomnia and difficulty waking up in the morning for work, school or social obligations. Quite often, DSPD patients report that this preference for delayed sleep–wake times remains stable for many years." (567)
  
  "It has been estimated that the prevalence of DSPD in the general population is between 0.13% and 0.17%. DSPD is more common in adolescents, with a reported prevalence of 7–16%, and may represent [approximately] 7% of patients presenting to sleep clinics with complaints of chronic insomnia." (567)
  
  "It is necessary to distinguish DSPD patients from ‘‘normal’’ delayed sleep patterns commonly seen in adolescents and young adults who have delayed sleep schedules without experiencing functional impairment or social distress." (567)
  
  "It is clear that successful treatment of DSPD requires an individualized approach using behavioral strategies, such as morning bright light exposure, avoidance of evening light, and/or appropriately timed melatonin." (570)

• "Advance sleep phase disorder (ASPD) is characterized by habitual and involuntary sleep times (6–9 p.m.) and wake times (2–5 a.m.) that are several hours early relative to conventional and desired times. Patients with ASPD typically present with complaints of sleep maintenance insomnia, early morning awakenings and sleepiness in the late afternoon or early evening. In general, individuals with ASPD tend to have less difficulty adjusting to their preferred earlier schedules schedules than those with DSPD." (570)
  
  "Non-age-related ASPD is believed to be rare, and there are only a few reported cases in the literature. However, the prevalence tends to increase with age, and has been estimated to be about 1% in middle-aged and older adults." (570)
  
  "Current treatment options for ASPD include chronotherapy, timed exposure to bright light in the evening and pharmacotherapy with hypnotics or melatonin. Chronotherapy progressively advances sleep time by two hours every day until the desired sleep time is achieved." (571)

• "Non-24-h sleep–wake syndrome is characterized by a steady daily drift of the major sleep and wake times. Because the endogenous circadian period in humans is usually slightly longer than 24 h, patients will report a progressive delay in the timing of sleep and wake times. Attempting to maintain a regular sleep–wake schedule can lead to the development of symptoms of insomnia, early morning awakenings and excessive sleepiness that varies in intensity periodically. At times when the endogenous pacemaker is not in phase with the conventional sleep and wake times, patients will report symptoms that cause impairment in social, occupational or other areas of functioning. When the endogenous circadian rhythm is in phase with sleep times, sleep is usually normal." (571)
  
  "It has been estimated that 50% of totally blind people have non-entrained circadian rhythms and about 70% have complaints of chronic sleep disturbances. In addition to non-entrained rhythms, advanced or delayed circadian rhythms with a period of 24 h have also been reported in the blind. Although rare, non-entrained sleep and wake patterns have also been reported in sighted individuals." (571)
  
  "Melatonin 10 mg given 1 h before bedtime has been shown to synchronize sleep–wake behaviors to a 24-h period in blind people with non-entrained circadian patterns. Entrainment can be maintained with lower doses of 0.5 mg of melatonin given nightly." (572)
  
  "Much less is known regarding treatment approaches for sighted patients with non-24-h sleep–wake disorder. Attempts should be made to increase the regularity of work and sleep–wake schedules, as well as the intensity and duration of bright light exposure during the day. Very little is known regarding the use of melatonin in sighted persons. In a recent case report, administration of melatonin in the evening to a sighted adolescent with non-24-h sleep–wake schedule disorder restored a normal sleep–wake cycle." (572)

• "Shift work disorder (SWD) typically presents with complaints of unrefreshing sleep, excessive sleepiness and insomnia that vary depending on the work schedule.... SWD is most commonly seen in association with night and early morning (before 6 a.m.) shifts. Patients usually report decreased total sleep time, poor sleep quality and excessive sleepiness at work." (572-573)
  
  "Approximately 20% of the workforce in industrialized countries is estimated to work non-standard hours. A recent study suggests that the prevalence of shift work sleep disorder is 10% in night and rotating shift workers."
  
  "Melatonin has also been studied in SWD. In night shift workers, melatonin administered in the morning can accelerate re-entrainment by delaying the timing of circadian rhythms, and also improve sleep with its hypnotic effects. Although melatonin taken during the day can improve daytime sleep, it has not been shown to significantly increase nighttime alertness." (573)

• "Jet lag is the result of the external environment being temporarily altered in relation to the timing of the endogenous circadian rhythm by rapid traveling across time zones. It is characterized by symptoms such as daytime fatigue and sleepiness, nighttime insomnia, mood changes, difficulty concentrating, general malaise and gastrointestinal problems [110]. During eastward travel, difficulty falling asleep is more prominent, and during westward travel complaint of sleep maintenance is most common. Symptoms are transient and should resolve as the traveler’s circadian clock re-establishes a normal phase relationship with the local time." (574)
  
  "A combination of approaches to accelerate circadian alignment, including timed light exposure and melatonin and/or behavioral strategies, has been used to improve sleep and daytime function. Travelers should be instructed to wear loose fitting clothes, drink plenty of fluid, and avoid alcohol and excessive caffeinated beverages or foods during the flight to minimize travel fatigue. Upon arrival, all efforts should be made to eat meals at local times, exercise and maintain good sleep habits to decrease the severity of the symptoms.
  
  Independent of the direction of travel, travelers should remain awake while it is daytime at the destination. Eastward travelers should avoid bright light in the early morning, and increase exposure to bright light in the evening while westward travelers should get as much exposure to bright light as possible in the early morning and try to sleep when it gets dark, avoiding bright light in the evening." (574)

Circadian Rhythm Sleep Disorders - Features, Evaluation, Treatment.

CRSD - Treatment.jpg





Additional References in Archive

Revell, V.L., Burgess, H.J., Gazda, C.J., Smith, M.R., Fogg, L.F., & Eastman, C.I. (2006)Advancing Human Circadian Rhythms with Afternoon Melatonin and Morning Intermittent Bright Light. The Journal of Clinical Endocrinology & Metabolism, 91(1), 54-59.

Attenburrow ME, Cowen PJ, Sharpley AL. (1996) Low dose melatonin improves sleep in healthy middle-aged subjects (1996). Psychopharmacology (Berl), 126(2), 179-81.

Melatonin for the Treatment and Prevention of Jet-Lag (Herxheimer and Petrie, 2007)

Melatonin For Treatment of Sleep Disorders (Buscemi et al)

Melatonin, The Hormone of Darkness: A Ray of Hope for Many Diseases (Shakar et al, 2006)





There are numerous other works of interest on melatonin. Below is a list of articles that I haven't yet retrieved (or couldn't access) that may be of use:

Cajochen C, Krauchi K, Wirz-Justice A. 2003. Role of melatonin in the regulation of human circadian rhythms and sleep. Journal of Neuroendocrinology 15(4): 432-437.

Dagan Y, Eisenstein M: Circadian rhythm sleep disorders: toward a more precise definition and diagnosis . Chronobiol Int 1999 Mar; 16(2): 213-22.

Gorfine T, Assaf Y, Goshen-Gottstein Y, et al. 2006. Sleep-anticipating effects of melatonin in the human brain. Neuroimage 31(1): 410-418.

Hardeland R, Poeggeler B, Srinivasan V, et al. 2008. Melatonergic drugs in clinical practice. Arzneimittel-Forschung-Drug Research 58 (1): 1-10.

Lewy AJ. (2006). The circadian basis of winter depression. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 103 : 7414 DOI 10.1073/pnas.0602425103

Lewy AJ, Ahmed S, Jackson JM, Sack RL. 1992. Melatonin shifts human circadian rhythms according to a phase-response curve. Chronobiol. Int. 9: 380– 92.

Lewy AJ, Sack RL. 1997. Exogenous melatonin's phase-shifting effects on the endogenous melatonin profile in sighted humans: a brief review and critique of the literature. J. Biol. Rhythms 12: 588– 94.

Schrader H, Bovim G, Sand T: The prevalence of delayed and advanced sleep phase syndromes. J Sleep Res 1993 Mar; 2(1): 51-55.

Skene DJ, Lockley SW, Arendt J. 1999. Use of melatonin in the treatment of phase shift and sleep disorders. TRYPTOPHAN, SEROTONIN AND MELATONIN 467: 79-84.

Suhner A, Schlagenhauf P, Johnson R, Tschopp A, Steffen R. 1998. Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag. Chronogbiology International 15(6): 655-666.

SRINIVASAN V. 2006. Melatonin in mood disorders. WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY 7 : 138 DOI10.1080/15622970600571822

Yazaki M, Shirakawa S, Okawa M, et al: Demography of sleep disturbances associated with circadian rhythm disorders in Japan . Psychiatry Clin Neurosci 1999 Apr; 53(2): 267-8.

Zhdanova IV, Wurtman RJ, Morabito C, Piotrovska VR, Lynch HJ. 1996. Effects of low oral doses of melatonin, given 2-4 hours before habitual bedtime, on sleep in normal young humans. 19(5): 423-431.



As for drugs-forum threads....

Experiences With Melatonin: Please post them Here!

Taking Melatonin During the Day

Mixing Melatonin With Kava-Kava

Can Melatonin really be the answer to "Cannabis Fatigue"?

Melatonin as a potentiator? (Codeine)



Thats all for now, but this will be added to over time. Feel free to add your input / commentary.

[Richi]

Thanks for the excellent thread Bejeda, especially the attached table. Is the table also by Barion, Ana, & Zee, Phyllis C. (2007).?

[Bajeda]

Yes, it is from the same research article. It is a quite good overview, so I thought I'd attach it directly as its too much to type out yet well worth viewing.

[MountainDeW]

Nice read. Last night, after a quick trip to the local bar, I returned home and got into bed. I quickly drifted off to sleep and was out for approximately 3 hours. I was ripped from sleep by a horrible nightmare about two mob bosses shooting each other in the neck at a funeral. Don't ask me about the dream, I don't know where it came from, but the consequences of terror and alcohol induced dry-mouth left me laying in bed miserable. Not wanting anything other than sleep, I walked to my goodies drawer and popped a couple melatonin tabs chased with a big glass of water. Needless to say I feel refreshed this morning and no worse for the wear. What a wonderful supplement we have in melatonin.