Is Melatonin A Benign Supplement?

Before I get too carried away the answer to the question is most likely yes - it is a benign supplement.  That is based on all of the studies and reviews I have about melatonin used to treat insomnia and other sleep disorders.  Nobody seems to report any major side effect from even very high doses taken for periods of time.  Those same reviews have a lot of qualifiers.  As an example some will say that doses in the 4-6 mg per night range are unlikely to cause major side effects.  Others will suggest that even though melatonin use is widespread, there have not been any large clinical trials to assess long term safety.  There probably never will be.  When people ask me about the safety of melatonin that is exactly what I tell them.  Individual use of over-the-counter melatonin varies greatly.  The average self-administered dose that I encounter these days is 10 milligrams.  The range of outliers is to the high side.  Nobody uses the 1 mg or 3 mg tablets but there are people using 10-20 mg.

My concerns come from a number of perspectives.  First there is the issue of normal excretion of melatonin and pharmacokinetics.  Second there is the role of melatonin in other systems in the body. And third there is the question of the toxicology of melatonin.  In the case of supplements, the presumed toxicology is often based on the exposure of large numbers of people to the supplement and no alarming or immediate side effects.  Melatonin is ubiquitous in some tissues in the body and this gives the impression that it may be a benign compound.  On the other hand it is a metabolite of 5-HT (serotonin) and this has additional implications.  5-HT is a highly politicised molecule with unquestionable roles in human physiology and pharmacology.

When I start to think about the general approach to this problem - the first thing I look at is what the physiological levels of melatonin might be in both blood and CSF.  The published medical literature is scant. Normal levels are often determined as part of an experimental intervention like peripheral sympathectomy.  In one study (1), the normal diurnal fluctuations were noted with a peak ranges of peak plasma levels varied from 122-660 pmol/L, and the peak CSF levels from 94-355 pmol/L.   In this study the authors demonstrated that bilateral T1-T2 ganglionectomy abolished both the diurnal rhythms and resulted in lower levels of melatonin suggesting that the peripheral sympathetic nervous system has input into melatonin secretion.

Other studies have looked at the effects of melatonin supplementation on plasma and CSF levels.  This is always important because average natural melatonin secretion in humans is about 0.15 mg per day.  As I previously indicated supplementation is many times that.   An early study (2) showed that oral melatonin supplementation led to rapid increases in blood and CSF melatonin.  The authors also compared the ratio of CFS/blood melatonin and noted it was constant before and after supplementation suggesting that blood is the source of CSF melatonin.  Recent studies (4-6) suggest that melatonin is secreted directly into the third ventricle from the pineal recess or that there may be central or peripheral compartments of melatonin for different effects.

There was a recent comprehensive review of the pharmacokinetics of melatonin.  The authors reviewed 22 high quality studies looking at oral or IV  dose ranges of 0.1 mg  to 100 mg.   Cmax (maximum plasma concentration following the dose) ranged from 72.1 (10 ml/h; 0.02 mg, IV) to 101,163 pg/ml (100 mg, oral).  Tmax (time to peak plasma concentration) ranged between 15 (2 mg) and 210 min (10 mg).  T1/2 (half-life) ranged from 28 (0.005 mg, IV) to 126 min (4 mg, oral).  The response to melatonin for insomnia is unpredictable and no dose response curve has been determined. Of course there are a wide range of available melatonin preparations from pharmacies and health food stores.  Even in the research, it is often difficult to say what preparation was used, but the bioavailability is quoted as 15%.

The sleep research on melatonin shows that (as most clinician know) it has weak sleep effects but variability does exist.  Most people will notice very little effect.  Some will claim that they were "knocked out" and strongly sedated even the next day - an effect that is hard to reconcile with the short half-life.  The lack of a dose-response curve makes it difficult to determine dosing but a review in an authoritative sleep text (8) says that most studies use a dose of 4-6 mg and that the timing of the dose (1-3 hours before sleep) may be an important factor.  I have been advised myself by a sleep expert that a 1 mg dose of melatonin 3 hours before sleep may be optimal because it entrains the circadian rhythm of that individual and have seen that work in many cases.  The weak effects on sleep EEG to me suggest a strong placebo component.

 Getting back to the side effect issue - I was surprised to find a few pages on melatonin in last week's New England Journal of Medicine in their Clinical Implications of Basic Science Research section (9).   These authors discuss the implications of the MTNR1B variant as a risk factor for Type 2 diabetes mellitus.  This variant leads to an overexpression of MT2 melatonin receptors on pancreatic beta cells.  Melatonin in this case leads to a G-protein-coupled receptor (GPCR) initiated cascade that inhibits insulin secretion.  They reviewed the epidemiology of diabetes and the facts that Type 2 diabetes is typically a combination of insulin resistance in muscle and fat cells, increased hepatic glucose output and no compensatory insulin release.  They reference an experiment where the daily melatonin (4 mg dose) for 3 months reduced first phase glucose induced insulin secretion in an oral glucose tolerance test compared with baseline before melatonin secretion.  They point out that there has been some epidemiological work that associates shift work with susceptibility to diabetes mellitus.  They conclude that typical doses of melatonin of 4 mg/day or less are not likely to be associated with decreased insulin release and talk about the application of melatonin in jet lag with dosing for a few days.  They also point out in the 3-month long study that overall glucose tolerance was hardly affected and baseline glucose levels returned after 2 hours of dosing.  That may not be as assuring to psychiatrists who are seeing their patients take 5-10 mg indefinitely along with other medications that may cause metabolic syndrome.

To me this is also further evidence of just how crude many of our clinical trials are that look at the issue of metabolic syndrome and diabetes in clinical populations.  Whenever I discuss consent for atypical antipsychotics and the metabolic issues, I always tell people that weight gain and increased appetite is common.  I also tell them that I have seen people develop diabetes from these medications who were rail thin and never gained an ounce.  The 150 risk alleles for Type 2 diabetes mellitus, the thousands of associated intracellular signalling proteins, and the 300 GPCRs expressed in pancreatic beta cells probably has something to do with that.

Biological complexity rarely leads to simple answers.

I will probably encourage a lot of insomniacs from taking melatonin when there has been no clear benefit.  I will probably also discourage the practice of taking high dose (> 5 mg) of melatonin for the same reason.                


George Dawson, MD, DFAPA




References:

1:  Bruce J, Tamarkin L, Riedel C, Markey S, Oldfield E. Sequential cerebrospinal fluid and plasma sampling in humans: 24-hour melatonin measurements in normal subjects and after peripheral sympathectomy. J Clin Endocrinol Metab. 1991 Apr;72(4):819-23. PubMed PMID: 2005207.

2: Young SN, Gauthier S, Kiely ME, Lal S, Brown GM. Effect of oral melatonin administration on melatonin, 5-hydroxyindoleacetic acid, indoleacetic acid, and cyclic nucleotides in human cerebrospinal fluid. Neuroendocrinology. 1984 Jul;39(1):87-92. PubMed PMID: 6205317.

4: Leston J, Harthé C, Mottolese C, Mertens P, Sindou M, Claustrat B. Is pineal melatonin released in the third ventricle in humans? A study in movement disorders. Neurochirurgie. 2015 Apr-Jun;61(2-3):85-9. doi: 10.1016/j.neuchi.2013.04.004. Epub 2014 Jun 26. PubMed PMID: 24975205.

5: Leston J, Harthé C, Brun J, Mottolese C, Mertens P, Sindou M, Claustrat B. Melatonin is released in the third ventricle in humans. A study in movement disorders. Neurosci Lett. 2010 Jan 29;469(3):294-7. doi: 10.1016/j.neulet.2009.12.008. Epub 2009 Dec 11. PubMed PMID: 20004701. 

6: Skinner DC, Malpaux B. High melatonin concentrations in third ventricular cerebrospinal fluid are not due to Galen vein blood recirculating through the choroid plexus. Endocrinology. 1999 Oct;140(10):4399-405. PubMed PMID: 10499491.

7: Harpsøe NG, Andersen LP, Gögenur I, Rosenberg J. Clinical pharmacokinetics of
melatonin: a systematic review. Eur J Clin Pharmacol. 2015 Aug;71(8):901-9. doi: 10.1007/s00228-015-1873-4. Epub 2015 May 27. Review. PubMed PMID: 26008214.

8:  Krystal AD.  Pharmacological Treatment: Other Medications.  in Kryger MH, Roth T, Dement WH.  Principles and Practice of Sleep Medicine, 5th Edition.  Elsevier Saunders, St. Louis, 2011. p. 916-930.

9: Persaud SJ, Jones PM. A Wake-up Call for Type 2 Diabetes? N Engl J Med. 2016 Sep 15;375(11):1090-2. doi: 10.1056/NEJMcibr1607950. PubMed PMID: 27626524. (to full text link).


Attribution:

Serotonin metabolism graphic is from VisiScience.

Will Sitting Really Kill You?

This question should strike fear into the hearts of psychiatrists everywhere.  We do after all spend practically all day sitting.  I easily spend 8-10 hours, 5 days a week sitting in a chair and another 5 or 6 hours on the weekend.  Not all of that time is as comfortable as it sounds, but it certainly does not require a great deal of physical exertion.  This situation only got worse with the placement of computer terminals in every office.  When I first started working, I would walk down the hallway and randomly glance into office doors.  In order to look busy, the people in those offices would typically stare at a paper or papers on the desk or in their hands.  Now everyone is staring at the obligatory computer screen.  I won't digress into the massive problems associated with the computerized model but only point out how people have been immobilized by it.

Several years ago, I started to see stories about people who were exercising while they did their work.  I remember the first story showed an office where the person at the desk lost a significant amount of weight by walking on a 1 mph treadmill while he worked the phones and used his computer.  That was followed by the idea that it was healthier to stand all day than sit.  Suddenly there were people in my clinic standing at work instead of sitting.  And then I started to see the news stories suggesting that it was dangerous for person to sit at work.  Sitting at work could actually lead to a shorter life.  It could kill you.   They were the type of news stories that lead you to an immediate search of your memories to see if this could possibly be true.  Does it have face validity?  Has there been a hidden epidemic of deaths due to - (gasp) sitting.  I rapidly dismissed the idea as a combination of marketing and hysteria.  But the stories persisted.  There was an article from a reputable clinic that described how enzyme activation changed from the sitting to the standing position and that this had an effect on metabolism.  The usual concept for public consumption is that higher metabolic rates lead to more calories burned and weight loss.  It appeals to the American obsessions with calories, food, appearance, and weight loss.  Is there an easy way to trick the metabolism into burning off all of those calories I ate today?  Is there a hack?  Is it as easy as standing up at work all day?

I decided take a two pronged approach to look at this problem - review the whole idea of activity monitoring and examine the available literature.  The following graphic is the display of a Garmin vivofit2 activity tracker.  This tracker plots all activity in terms of steps.  If you are walking too slowly it does not count those steps.  During the setup phase it asks you to select a fitness level and it plots the number of steps per day based on the level you choose and your height and weight.  I chose the level at the 75% percentile or about 7500 steps per day.  So far it has not been much of a problem doing that especially because I work on a campus that requires a fair amount of walking.  The step plot only tells part of the story, because I also cycled 19 miles today, but that is not really indicated in the hour to hour plots - only steps.

Notice the red zones below the graphs.  The tracker emits a soft beeping sound and an extending red bar across the display if you have been "idle" for an hour.  You have to get up and expend about 200 steps to cancel the visual alarm.  The overriding question is whether a warning for inactivity is valid, especially in the case of a guy who just biked 19 miles the same day.  The graphic of that cycling is illustrated below.

It may not be readily apparent but during the time I was cycling, the activity monitor went into a mysterious mode of counting steps.  Not nearly enough to account for covering 19 miles, but it did put a green mark below the line indicating a high activity period.

I make a great example of the immobilized white collar worker who counters that problem with a lot of exercise away from work.  But I go into the endeavor with my eyes wide open.   I can see it now - the guy who thought he was going to live longer than anyone else.  I have already experienced this attitude.  One day I was walking down the hallway eating a granola bar and and one of my colleagues came up to me and said: "Do you think you are going to live longer than me?"  He was using the Socratic method to get at my unconscious motivations for eating a granola bar.  I tried to emphasize to him that sometimes a granola bar is just that and some people like me happen to like the way they taste.  But he wasn't buying that idea.

So if I do keel over, I apologize in advance to my widow and hope that my family will understand  that I present this data with the best of intentions.  I think that it is good data because it involves actual measurements rather than the usual epidemiological data that most of these studies provide.  I have been sitting behind a desk for at least 6 hours a day over the past 35 years.  In that time, I have had 4 exercise stress tests (one was a stress echocardiogram) and a CT scan of the heart.  All of them were negative.  On the CT scan of the heart my calcium score was 0.  For the first 20 years of that period, I was cycling about 200-250 miles per week between the months of May and October and either riding the equivalent time on an indoor trainer or speedskating the rest of the year.  The last ten years, the mileage figure has gone down to 100-150 miles per week with additional strength training.

What about the new sedentary science?  The early data is well summarized in a 2011 review by Proper, et al (2).  The authors reviewed the quality of the evidence and concluded that the evidence is strong for all-cause and cardiovascular mortality, moderate for diabetes mellitus Type 2, and poor for body weight/BMI, obesity, waist circumference, and endometrial cancer.  A very detailed epidemiological study (1) of five different categories of sitting time was very interesting because it showed a correlation of sitting time dose on mortality and it showed that effect persisted even if controlled for BMI, smoking status, and activity level when not sitting.  Suggested mechanisms included lipoprotein lipase activity and the effect of being sedentary on cardiac stroke volume and output.  The effect on lipoprotein lipase activity was not trivial with one study showing that activity restriction resulted in a 10 fold elevation decrease of lipoprotein lipase activity in red oxidative muscle fibers.   Subsequent studies show that breaking up sitting time has the expected positive effects on metabolic markers including triglycerides, waist circumference, and fasting blood glucose.  Some recent studies have looked at measures of endothelial function (3) and demonstrated that there is a measurable decline with 3 hours of sitting that can be countered by walking for 5 minutes at 2 mph every hour.  If replicated that has important implications for office workers who think they need to stand or walk on a treadmill continuously in order to prevent the problems associated with a sedentary work environment.  It also has implications for the kinds of exercise that we recommend to patients for prevention of metabolic syndrome and cardiovascular disease.  Although I am aware of no clear guidelines it may mean at some point that our sedentary patients may just need to get up and move around in a low intensity manner on an hourly basis and plan a more high intensity exercise at least once a day.  It also has implications for the patients we see who have not been moving much and have significantly abnormal lipids profiles like people who are admitted to hospitals and residential treatment centers who have been immobilized for weeks or months.  It may mean that medical therapy for dyslipidemia is not necessary until the patient is up and moving about for a while.  It may also have implications for the cognitive dysfunction noted with many psychiatric diagnoses.  In the past year I saw Roger S. McIntyre, MD present data on cognitive problems in bipolar disorder and major depression patients that were correlated with obesity and metabolic syndrome (5).  Impaired executive function persisted during periods of euthymia.  Interventions that impact those metabolic factors may have an effect in improving cognition.   A more recent review takes a look at the variables that may be important in the types of exercise used to break up prolonged sitting times (4).

  
My preliminary take on all of this data is that sitting may be dangerous to your health, especially if your BMI is high and you have other risk factors.  In many of these studies the effect size of sitting seem relatively robust independent of other risk factors.  The measurements of rapidly deteriorating endothelial function over a period of hours raises a lot of questions.  For example, most people are going to be sleeping at least 7 hours per night.  Is there the equivalent amount of deterioration over that time period, or are there protective mechanisms during sleep that prevent that problem.  The 2001 review classifies sleep as a sedentary behavior that does not raise energy level substantially above rest.  And what about the idea that these periods need to be broken up by low level exercise every hour?   What are the optimal times and exercises for doing this?  The validation studies for these measures seem daunting.  And finally what about the technology.  It is obvious from what I have posted here that it is at a primitive stage.  Different manufacturers are marketing different features.  One manufacturer has a device that claims to wake you up in non-REM sleep in the morning.   I chose my device as the only one that has a one year battery life.   Practically every other equivalent fitness monitor battery lasted from 4-30 days.  I could use a monitor that tracks more than steps.  My guess is that my current device picks up some other accelerations based on the fact that it characterized my 20 mile bike ride as "high activity" but gave me a negligible number of steps.  It also needs to do a better job detecting sleep instead of using my specified sleep hours as a way to not count inactivity.  The best example of that is my attempts to catch up on sleep on Saturday and Sunday mornings being counted as inactivity.  And finally, if I am logging into a manufacturer's web site to log activity on all of the devices I have purchased,  that interface  should do a good job of integrating all of that data in a logical manner and showing the relevant scientific parameters.  A few references would not hurt.  I understand that a move to using software on your personal computer is a step away from the domination of internet cloud enamored device companies but I can't imagine there is not a market for that and the best possible display of data.

All things considered, it looks like there might be something here.  One of my colleagues stated her opinion that these devices might be useful for people who don't do much exercise.  But is there is a separate effect of being sedentary on your metabolism that prevents you from getting all of the effects of high intensity exercise?  There are reports of long time endurance athletes and high intensity athletes either sustaining heart attacks or having clear coronary artery disease at angiography.  A basic study that I could not find was the effect of interrupted sitting on lipid profiles and BMI.  That would be a difficult study to do because of the effort it would take in a community sample.

For now, I will add activity monitoring to my other exercise routines and see what I can learn from it.


George Dawson, MD, DFAPA


References:

1:  Katzmarzyk PT, Church TS, Craig CL, Bouchard C. Sitting time and mortality from all causes, cardiovascular disease, and cancer. Med Sci Sports Exerc. 2009 May;41(5):998-1005. doi: 10.1249/MSS.0b013e3181930355. PubMed PMID: 19346988.

2:  Proper KI, Singh AS, van Mechelen W, Chinapaw MJ. Sedentary behaviors and health outcomes among adults: a systematic review of prospective studies. Am J Prev Med. 2011 Feb;40(2):174-82. doi: 10.1016/j.amepre.2010.10.015. Review. PubMed PMID: 21238866.

3:  Thosar SS, Bielko SL, Mather KJ, Johnston JD, Wallace JP. Effect of prolonged sitting and breaks in sitting time on endothelial function. Med Sci Sports Exerc. 2015 Apr;47(4):843-9. doi: 10.1249/MSS.0000000000000479. PubMed PMID: 25137367.

4:  Benatti FB, Ried-Larsen M.  The effects of breaking up prolonged sitting time: a review of experimental studies.  Med Sci Sports Exerc. 2015 February 4, 2015, published ahead of print.

5:  Bengesser SA, Lackner N, Birner A, Fellendorf FT, Platzer M, Mitteregger A, Unterweger R, Reininghaus B, Mangge H, Wallner-Liebmann SJ, Zelzer S, Fuchs D, McIntyre RS, Kapfhammer HP, Reininghaus EZ. Peripheral markers of oxidative stress and antioxidative defense in euthymia of bipolar disorder-Gender and obesity effects. J Affect Disord. 2014 Oct 22;172C:367-374. doi: 10.1016/j.jad.2014.10.014. [Epub ahead of print] PubMed PMID: 25451439.

Attribution:

The chair photo at the top of this post is by Humanscale (shop.humanscale.com) [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], via Wikimedia Commons.