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Melatonin Update - Does It Really Work To Optimize Sleep?

08/01/2017 - Product Newsletter #304

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INTRODUCTION

For years, we've been hearing about the many attributes of supplemental melatonin.  At first, about 25 years ago, melatonin gained popularity primarily due to its purported positive impact on various sleep issues ranging from jet-lag to insomnia to poor quality sleep.  Later, we learned about melatonin's tremendous versatility as an antioxidant due to its unique and somewhat rare ability to quench both water- and fat-soluble free radicals.  Nevertheless, despite the dozens of published papers on the value of melatonin as an antioxidant, clinical use over the years has almost exclusively been driven by its reported impact on sleep.

Unfortunately, as time passed, we began to hear increasingly frequent anecdotal reports from individuals who were having trouble falling asleep or staying asleep that "It didn't work for me" or "It worked but I felt groggy upon waking in the morning."  Of course, when we hear that we need to ask some questions:

  • Was it a dosage issue?
  • Was melatonin used long enough?
  • Are all the positive reports nothing more than placebo with the reality being that the purported effect of melatonin on sleep is nothing more than hype?

To find out what is behind the inconsistent findings our usual approach is to read published research on the melatonin/sleep relationship.  Disturbingly, nearly all of the studies on the subject are animal research.  Furthermore, the human studies are highly conflicting with some reporting a positive impact and others demonstrating poor results. 

Fortunately, to make sense of it all, a paper was recently published that considered virtually all the studies on the subject to see if the preponderance of studies suggested any clearly defined trends in terms of efficacy when supplementing melatonin for sleep issues.

MELATONIN AND SLEEP - WHAT CAN WE RELIABLY CONCLUDE?

To answer this question Auld et al, in their paper "Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders" (Auld F et al.  Sleep Medicine Reviews, Vol. 34, pp. 10-22, 2017), conducted the following investigation:

"An electronic literature view search of MEDLINE (1950-present) Embase (1980-present), PsycINFO (1987-present), and Scopus (1990-present), along with a hand-searching of key journals was performed in July 2013 and then again in May 2015.  This identified all studies that compared the effect of exogenous melatonin and placebo in patients with primary insomnia, delayed sleep phase syndrome, non-24-h sleep wake syndrome in people who are blind, and rapid eye movement-behaviour disorder.  Meta-analyses were performed to determine the magnitude of effect in studies of melatonin in improving sleep."

In all 5030 studies were identified.

To begin my review of this paper, I would like to feature a quote which highlights the history of melatonin and the initial claims of efficacy:

"Melatonin was first described in 1958 by dermatologist, Aaron Lerner, as a hormone produced by the pineal gland from the essential amino acid tryptophan (N-acetyl-5-methoxytryptamine).  Exogenous melatonin has no reported tolerance, dependence, or 'hangover effect', and no adverse effect on alertness or mood the following day, as well as minimal side-effects (e.g., headache, dizziness, nausea, drowsiness) if administered at a low dose.  Melatonin has a short half-life of only 30-50 min and can induce phase shifts in the circadian timing system (both central and peripheral clocks) and when administered acutely, reduces core body temperature and lowers alertness, encouraging sleep propensity."

As you can see, the early reports clearly suggested that supplemental melatonin was a true panacea in terms of sleep issues.  Did later reports continue with this suggestion of panacea or were they more reflective of some of the less than shining anecdotal feedback I outlined in the beginning of this monograph?  Before I answer this question, I feel it is important to understand the reality of endogenous melatonin production and function.  Auld et al state:

"In humans, the primary physiological function of melatonin is to reinforce darkness-related behavior, such as sleep propensity."

The authors continue:

"Endogenous melatonin synthesis is finely regulated by visual light cues received by the hypothalamic suprachiasmatic nucleus in the brain, the site of the major circadian oscillator.  During daylight hours, perceived light signals inhibit melatonin production.  Conversely, at night when no light signals are received, melatonin synthesis and release occur with levels peaking in the early hours of the morning.

Melatonin is metabolized by the liver, which processes >90% of the circulating hormone and together with it metabolites, is excreted in the urine.  There is vast inter-individual variability in the quantity of melatonin produced depending on pineal gland size.  Despite this, each person will have a similar bell-shaped production curve, which is reproducible from day to day.  Melatonin production declines as we age due to several factors.  The lower peak levels of endogenous serum melatonin may be due to decreased pineal melatonin synthesis at night, or gradual pineal gland calcification.  Endogenous melatonin synthesis may be further reduced by drugs (e.g., benzodiazepines, non-steroidal anti-inflammatories (NSAIDS), and calcium channel blockers which many elderly patients are likely to be prescribed.  Beta-blockers, such as albuterol, have also been shown to oppose the sympathetic stimulation of melatonin synthesis."

As I hope you can see from the above quote, it is very possible that reports of lack of efficacy may be largely related to inadequate dosing due to a failure to take into account age- or medication-related decreases in endogenous melatonin production.  Furthermore, reports of grogginess in the morning may be due to excessive dosing that occurred because the consumer may have possessed a higher level of endogenous melatonin production than the usual norm.    

With the above in mind, what were the findings of the study?  The first quote presents overall conclusions:

"This review has shown evidence that melatonin has a role in the treatment of some primary sleep disorders, namely primary insomnia, delayed sleep phase syndrome (DSPS), non-24h sleep-wake disorder and in people who are blind.  There is some evidence that melatonin may be beneficial for those with rapid eye movement-behaviour disorder (RBD), but more research is required to draw this conclusion.  Melatonin facilitates achieving better sleep for these patients by reducing the sleep-onset latency or by regulating sleep-wake times to coincide with the natural circulatory cycle, as well as reducing sleep episodes without muscle atonia."

It was also found that the vast majority of studies were conducted on older individuals:

"This review has focused on the effects of melatonin on adult patients with much of the insomnia work carried out in those aged 55-80 y, as sleep disorders have increased prevalence in this age group."

Reasons were also discovered for the reports of lack of efficacy:

"Studies have shown exogenous melatonin can lack effectiveness depending on the circumstances relating to timing and amount of dose administration, if there is neuroanatomical deterioration, if there are co-morbid clinical disorders (e.g., Alzheimer's disease), and if the formula is extended release or fast acting."

Is there a risk of adverse effects or withdrawal due to long-term use?  Unfortunately, the vast majority of studies do not answer this question due to the fact they only examined short term use.  However, one study did evaluate the impact of a six month term of use:

"Wade et al. performed a trial over six months of daily melatonin use and demonstrated no adverse effects or rebound withdrawal symptoms."

Still another study considered 3-6 months of usage:

"Two studies investigated the treatment of primary insomnia of older people (aged ≥55) with melatonin (2 mg 1-2 h before bedtime orally) and concluded long-term use of melatonin (for 13-24 wk) is well tolerated, safe, and effective."

Concerning the many studies on short-term use, the following was concluded in relation to dose, efficacy, and potential side-effects:

"In terms of the soporific effect of acutely administered melatonin, studies have indicated healthy volunteers receiving a single dose (0.3 mg and 1.0 mg orally) of melatonin had significantly improved sleep efficiency and there are no observable toxicological or side-effects in the short-term daily use of melatonin (10 mg for 28 d)."

With all of the above in mind, Auld et al conclude:

"In summary, exogenous melatonin administration can be used to mimic the physiological functions of endogenous low level melatonin when administered in a specifically timed manner (i.e., to correct abnormalities in circadian timing), or be used as a soporific/other agent when given in high doses for other types of sleep disorders since melatonin does not appear to suppress rapid eye movement (REM) sleep nor does it delay the onset of REM.  Recent reviews in the medical literature have demonstrated exogenous melatonin is safe with short term use..."

FINAL THOUGHTS ON USE OF SUPPLEMENTAL MELATONIN TO OPTIMIZE SLEEP

Based on the above review, I hope you have a better understanding of why some people say "It didn't work for me" or "It worked but I felt groggy in the morning."  To reduce the incidence of these comments from your patients in the future, I would like to offer the following observations on how to use supplemental melatonin most efficaciously with patients desiring to improve sleep quality:

  • Based on current research, for the vast majority of healthy individuals with minor, short-term sleep issues, ingestion of 0.3 - 1.0 mg before bedtime should be both effective and free of side effects.  Anecdotal reports I have received for years suggest that higher doses may be needed for many patients.  This is why our Moss Nutrition Melatonin product contains 3 mg per cap.
  • Lack of effectiveness or grogginess in the morning with healthy individuals with short-term sleep issues probably indicates endogenous melatonin production outside the norm, either high or low.  The solution would be to adjust the dosage accordingly.
  • A history of medication use of many different types will both reduce the likelihood of efficacy and increase the risk of side effects.  Therefore, under these circumstances the decision to use supplemental melatonin at all should be weighed carefully.
  • Pre-existing behavioral or neurodegenerative conditions will also reduce the likelihood of efficacy and increase the risk of side effects.  Again, under these circumstances the decision to use supplemental melatonin at all should be weighed carefully.

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