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Melatonin: Understanding Indications, Dosages and Timing

Melatonin: Understanding Indications, Dosages and Timing

Deepak-Shrivastava-photo

Deepak Shrivastava, MD

The demand for over the counter melatonin continues to increase while the scientific research findings and clinical evidence remains relatively less than optimal for most indications.  Little was known about the pineal gland in until 1958 where Lerner reported that it secreted melatonin. However, the Greeks described it as the Realm of Thought; Descartes called it the Seat of the Soul. In Eastern medicine it has long been associated with the ‘Third Eye’ and intuition, and it is linked to an important energy chakra. While on one hand there are claims associating melatonin with delayed ageing, cancer fighting properties, improved sexual vitality and cure for insomnia; on the other concerns regarding possible side effects like headache, depression, dizziness, daytime sleepiness, irritability and stomach cramps are well documented.1 Melatonin is considered possibly unsafe to use during pregnancy and breast-feeding. Since melatonin interacts with other hormones in the body and might be unsafe to use in people who have bleeding disorders, high blood pressure, diabetes, seizure disorder, depression and organ transplantation.2

In the United States, melatonin is sold as a dietary supplement without need for a doctor’s prescription. Melatonin falls under the US Food and Drug Administration’s Dietary Health and Education Act as a ‘dietary supplement’. It can be purchased in any dose without a prescription. .Melatonin is commonly used for inducing sleep and to help reset internal body clock relative to the external time clock. Both conditions can present as insomnia; as an inability to fall asleep or inability to wake up when desired due to shifted sleep phase relative to the body’s internal clock.

Melatonin taken in afternoon moves body clock forward and promotes early sleep. Melatonin taken in the early morning causes opposite effect and moves body clock backwards and delays sleep.3 This physiologic effect called phase shift is successfully used to treat sleep-wake rhythm disorders also known as circadian rhythm disorders of delayed and advanced sleep phase.

This article addresses general information regarding melatonin and its recommended use in few specific sleep disorders. Since sleep disorders are complex and are influenced by medical and mental health conditions, it is advisable to discuss use of melatonin with a health care provider who is conversant with patient’s health history and current medications to avoid complications.

As melatonin is available over the counter, any dose can be used by people who intend to self manage their sleep problems. This clearly has potential for both under-dosing and overdosing.  Melatonin dose has remained a subject of curiosity for many patients and health care providers. Daily dosage of 0.5 mg to 5 mg is reportedly equally effective. Although there are no significant side effects reported with higher dosages, effective dose still remains low. Some recommend as small as 0.1 mg to 0.3 mg for inducing sleep and 0.3 mg to 0.5 mg for sleep phase shifting in jet lag and shift work sleep disorder. Higher does while equally effective as smaller dose do have more side effects including excessive daytime sleepiness, impaired mental and physical performance, low body temperatures and high levels of hormones like prolactin.  A dose taken 30-60 minutes before bedtime is likely to be effective. There is a possibility of some variability of response time from one person to the other. Many people will feel sleepy within 20 to 30 minutes of taking melatonin. Higher levels of melatonin are noted in blood of older individuals compared to the young.

Jet lag: A more complex dosing schedule is recommended while using melatonin to adjust the internal body clock. This is needed to improve disturbed sleep with travel related jet lag disorder. The benefits seemed to be greater when five or more time zones are crossed and the differential between the internal body clock and external time clock is larger. In this situation, Melatonin should be taken close to the target bedtime at the destination. To minimize the adverse effects of jet lag melatonin can be started on the day of departure and continued for up to four days after arrival. Further, beneficial effects of melatonin seem to be greater for eastwards travel verses westwards travel. For the eastward travel melatonin can be started after dark, 30 minutes before the destination bedtime during the overnight flight. For westward travel melatonin can be started on the evening of arrival, 30 minutes before the bedtime. It helps to change mealtimes and sleep time to the targeted destination times 2-3 days in advance. Minimum use of coffee, alcohol, sedatives and sleeping pills along with exposure to sunlight after arriving at the destination and exercise during daylight hours improve sleep. Many randomized controlled trials have documented the favorable effects of the melatonin in management of the Jet lag disorder. A systematic review of ten such trials reported that melatonin reduced jet lag in eight trials and showed more robust effect on eastward travel and more number of time zones crossed.4

Most trials included in this review had used 5 mg melatonin dose. The higher dosages have not shown any added therapeutic effect except better sleep quality and sleep latency. One comparative study indicated slow release melatonin preparations to be less effective than fast release forms.5

Shift work: Shift work is known to be associated with disturbance of circadian rhythm and sleep-time misalignment.  It causes difficulty in sleep initiation, or awakening from sleep, need to take naps during work shifts especially in the night, impaired mental ability, and irritability. Other recognized consequences are reduced performance capacity and increased adverse safety.  In addition, various adverse health conditions and outcomes are associated with shift work sleep disorder. Almost up to one third of the shift workers experience these impairments. Night shift workers need sleep during the daytime. Many studies failed to show any strong evidence that melatonin improved daytime sleep or sleep latency that is the time it takes to fall asleep.6

According to the current American Academy of Sleep Medicine guidelines, the night shift worker if suffering from insomnia during the day and is unable to fall asleep then a 1.8 to 3 mg dose of melatonin should be taken 30 minutes prior to the desired onset of daytime sleep.7

Delayed Sleep Phase Syndrome: In the adolescence population Delayed sleep phase syndrome (DSPS) is one of the most common sleep disorders. The habitual sleep time and wake time are delayed compared to conventional bedtime and wake times. This results in chronic sleep insufficiency and daytime impairment. It is estimated that about seventy percent of adolescents get insufficient night school night sleep.8

Initial therapy for Delayed sleep phase syndrome is behavior modification and sleep-wake scheduling. Timed melatonin is recommended for patients who fail to respond. In the absence of strong consensus due to lack of data, current recommendation are to use 3 to 5 mg daily dose of melatonin taken in the early evening, at least 90 minutes prior to the desired bedtime. Few randomized, placebo controlled trials have shown significant advancement of sleep onset by almost 60 minutes and sleep latency by 30 minutes.9 Other more complex therapies are available as well.

Insomnia: Nighttime melatonin plasma levels decline with age; many older individuals develop age associated insomnia (waking up at night and diminished sleep efficiency).  Physiologic doses of melatonin may be beneficial for these individuals suggesting the use of low, physiologic doses (0.1 to 0.5 mg melatonin) for insomnia.

Melatonin seems to be ineffective in typical cases of insomnia though other than delayed sleep phase syndrome. Insomnia is a symptom that may represent many contributing causes. A thorough medical and mental health evaluation must follow before a trial of melatonin use. Since melatonin is a hormone that influences the sleep-wake cycle, its dose amount and timing of the dose can have significant effects that may sometimes be counterproductive. For age related insomnia, likely due to reduced levels of melatonin in the body, dosages of 0.1 to 5 mg melatonin two hours before bedtime for many months has been recommended.10 One study compared melatonin in older insomnia patients verses controls. It showed improved sleep efficiency and increased plasma levels of melatonin in insomnia patients.11

REM behavior disorder (RBD):  Typical RBD is common REM parasomnia or abnormal behavior mostly occurring in middle age men during sleep. Typical manifestations are disruptive and violent behaviors emerging during rapid eye movement sleep with potential risk of injury to patient itself or the sleep partner. According to the clinical practice guidelines of the American Academy of Sleep Medicine, melatonin is one of the options for the treatment. Although the clinical evidence for efficacy is less strong compared to other choices like clonazepam, low side effect profile favors use of melatonin. It is however better than many other alternate agents. Melatonin in the dosage of 3 to 12 mg at bedtime has been effective in the treatment of RBD.12 Interestingly, melatonin related suppression of REM sleep motor activity persists for weeks after melatonin is discontinued. Melatonin can be started at a 3 mg dose and titrated up in increments of 3 mg according to the patient response. Highest recorded dose has been 18 mg without any significant side effect according to one study.

It is important to recognize melatonin’s drug interactions. Blood thinner medication like warfarin and antiepileptic medications are reported to have side effects with concomitant melatonin use. Alcohol consumption should be avoided while taking melatonin due to unpredictable and unknown circadian adaptation. Sedatives and hypnotic agents have more side effects than melatonin. A short acting benzodiazepine may be used to induce sleep in jet lag disorder. Non- benzodiazepine can be similarly used. However, these both are controlled substances and require physician’s evaluation and prescription.

There have been theoretical concerns regarding the use of melatonin in children on growth hormone regulation and reproductive function and development.13, 14  A few long-term studies in children with delayed sleep phase syndrome with comorbid ADHD and neurodevelopmental disabilities described no adverse events with higher dosages of melatonin over almost four years of trial period.

There are many other indications suggested in the medical literature regarding the therapeutic usage of melatonin. It however requires a meticulous patient evaluation, dosing and timing of melatonin administration to achieve successful results. In any case, one must realize that there may be dose, strength and quality inconsistencies across various melatonin brands.

  1. Safety in melatonin use. Morera AL, Henry M, de La Varga M. Actas Esp Psiquiatr. 2001;29(5):334.
  2. http://www.webmd.com/vitamins-supplements/ingredientmono-940-melatonin.aspx?activeingredientid=940
  3. Lewy AJ, Sack RL, Blood ML, et al. Melatonin marks circadian phase position and resets the endogenous circadian pacemaker in humans. In: Circadian clocks and their adjustment, Ciba Foundation Symposium 183, Wiley, Chichester 1995. p.303.
  4. Herxheimer A, Petrie KJ, Cochrane Database Syst Rev. 2002
  5. Chronobiol Int. 1998; 15(6):655.
  6. Pharmacological interventions for sleepiness and sleep disturbances caused by shift work. Liira J, Verbeek JH, Costa G, Driscoll TR, Sallinen M, Isotalo LK, Ruotsalainen JH; Cochrane Database Syst Rev. 2014;8:CD009776.
  7. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report. Morgenthaler TI, Lee-Chiong T, Alessi C, Friedman L, Aurora RN, Boehlecke B, Brown T, Chesson AL Jr, Kapur V, Maganti R, Owens J, Pancer J, Swick TJ, Zak R, Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep. 2007;30(11):1445-59.
  8. Prevalence of insufficient, borderline, and optimal hours of sleep among high school students – United States, 2007. Eaton DK, McKnight-Eily LR, Lowry R, Perry GS, Presley-Cantrell L, Croft JB J Adolesc Health. 2010; 46(4):399-401. 2010.
  9. Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline. Auger RR, Burgess HJ, Emens JS, Deriy LV, Thomas SM, Sharkey KM. J Clin Sleep Med. 2015 11(10):1199-236. 2015.

10.http://www.mayoclinic.org/drugssupplements/melatonin/dosing/hrb-20059770

  1. Melatonin treatment for age-related insomnia. Zhdanova IV,Wurtman RJ,Regan MMTaylor JAShi JPLeclair OU. J Clin Endocrinol Metab. 2001;86(10):4727-30.
  2. Melatonin stimulates growth hormone secretion through pathways other than the growth hormone-releasing hormone. Valcavi R, Zini M, Maestroni GJ, et al, Clin Endocrinol (Oxf). 1993;39:193.
  3. Melatonin administration alters semen quality in healthy men. Luboshitzky R, Shen-Orr Z, Nave R, Lavi S, Lavie P

J Androl. 2002 Jul-Aug; 23(4):572-8.

 

  1. Aurora RN; Zak RS; Maganti RK; Auerbach SH; Casey KR; Chowdhuri S; Karippot A; Ramar K; Kristo DA; Morgenthaler TI. Best practice guide for the treatment of rem sleep behavior disorder (rbd). J Clin Sleep Med 2010; 6(1):85-95

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