58. Gender differences in sleep

11 September 2010 at 17:17 | Posted in Circadian rhythm | 2 Comments
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I’ve earlier seen hints that there are differences in men’s and women’s sleep timing.  Now a new study confirms that and has also found differences in the quantity of melatonin secretion and in the daily temperature amplitude.

The study participants were normal sleepers:  28 women and 28 men, ages 18-30, matched in pairs for age, habitual bedtime, habitual wake time and MEQ-results.  Under strictly controlled conditions, so-called constant routine, their core body temperatures and melatonin levels were measured.

The women reached higher levels of melatonin in the blood.

The men had a greater amplitude in body temperature throughout the day and night.

The illustration shows the significant differences in sleep timing between women and men, on average.  In each of the 28 matched pairs of participants, significant differences were found between the women and the men with regard to the intervals

  • between DLMOn and bedtime,
  • between wake time and DLMOff, and
  • between temperature minimum and wake time.

The women were sleeping and waking at the same clock time, but at a later biological time than the men.


  • MEQ = the Morningness-Eveningness Questionnaire by Östberg and Horne
  • DLMOn = Dim Light Melatonin Onset
  • DLMOff = Dim Light Melatonin Offset (Here, based on blood level, not offset of synthesis.)


Reference:  Cain, Sean W., Christopher F. Dennison, Jamie M. Zeitzer, Aaron M. Guzik, Sat Bir S. Khalsa, Nayantara Santhi, Martin W. Schoen, Charles A. Czeisler and Jeanne F.  Duffy.  Sex Differences in Phase Angle of Entrainment and Melatonin Amplitude in Humans.  Journal of Biological Rhythms 2010 25: 288.  DOI: 10.1177/0748730410374943


Next post: Coming soon


56. 2010: more sleep logs

16 August 2010 at 09:41 | Posted in Circadian rhythm | 5 Comments
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Uploading more sleep logs here, last half of 2010.   It’s looking like Irregular sleep-wake disorder which usually occurs after brain injury or in dement elderly.   I don’t seriously mean that I’ve earned that diagnosis and would rather blame the schedule on medication changes, the too-warm weather or something unidentified.

Sleep diary

Twice in this period (above) I’ve done my “36-hour trick”, that is stayed up for about 36 hours.  These just happen unplanned for some reason.   As a trial I’m using the expensive Circadin rather than the cheap melatonin for a while.   The effect is at least not negative, but not much else.  The hope was to get back to 8 uninterrupted hours a night.

More later!


Next post:  57. coming soon


53. Light therapy: white, blue or maybe green?

30 May 2010 at 14:00 | Posted in Circadian rhythm | 3 Comments
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It has long been known that light and dark affect the daily as well as seasonal rhythms of living things.  Early in the 1900s it was assumed that humans’ daily rhythms were less affected than those of “lower” beings, but that attitude was proved wrong.

In the 1980s it was noted that some totally blind people entrained perfectly to the 24-hour cycle while many did not.  Until some time in the 1990s, it was not known if entrainment occurred by light to the eyes or to the skin.  One research team claimed to have proven that light to the backs of the knees effected entrainment, but neither they nor other researchers could duplicate those results, which later were withdrawn.

It is now clear that we and other animals entrain primarily by light to the eyes, though secondary cues such as social activity, feeding times etc. also play a role.  It is also clear that our eyes contain not only rods and cones for vision but also the recently discovered light sensitive ganglion cells for the entrainment of circadian rhythms.  The light sensitive pigment in these cells is melanopsin.

There it stands, but there are always new questions to be answered.  One is: 

Do the light sensitive ganglion cells contribute to vision,

and do the rods and/or cones contribute to

the non-visual effects of light?

If the ganglion cells’ photosensitivity contributes to vision at all, it is very minimally.  But a study* published this month by well-known researchers suggests that the cones do affect entrainment, with variations dependent on the timing and intensity of the light.  The practical implications include the question of whether the use of blue-blocking goggles in the evening, so-called “dark therapy”, really does allow normal flow of melatonin as intended.  [An aside: mightn’t there be a more direct way to find this out?]   In addition, the jury is still out on what color light – white, blue or perhaps green – is best to use in light therapy.

In this study in Boston, more than 50 human subjects each spent 9 days in an laboratory environment free of time cues.  Semi-recumbent, totally confused about the time of day, and with their melatonin rhythms individually determined, half of them were exposed to blue (460nm) light and half to green (555nm) for 6.5 hours starting shortly after their own melatonin secretion started. 

It is well-known that blue light (including about 460 to 482nm) excites melanopsin leading to the suppression of  melatonin.  The question here is whether the green light may have similar or equal effects. Green was chosen because the human visual system is most excitable at green (555nm).

In the figure, A and B are two subjects.  Each person’s normal pattern of melatonin secretion is repeated on the left and on the right in black.  On the left, blue light acutely suppresses A’s melatonin, while green light only delays B’s for a good hour.  The next night, as we see on the right, the pattern of melatonin secretion has been phase-shifted by the previous night’s light exposure about equally for the two subjects (horizontal red line).  From previous knowledge, one would have expected an appreciably greater delay after the blue light than the green.

The authors write: 

“Our data … raise the possibility that activation of cone photoreceptors in the late evening by relatively low-illuminance light sources, such as liquid crystal display monitors, table lamps, and dimmable lamps, may delay the circadian clock and therefore contribute to the high prevalence of delayed sleep phase disorder.” [My emphasis.]


“[B]locking short-wavelength light with blue-blocking goggles may not always be effective in preventing undesired circadian responses based on our finding that longer-wavelength light is able to induce robust phase-shift responses.”


“Our findings have implications for the development and optimization of light therapies for a number of disorders, including circadian rhythm sleep disorders.…”

* Spectral Responses of the Human Circadian System

Depend on the Irradiance and Duration of Exposure to Light.

Joshua J. Gooley, Shantha M. W. Rajaratnam, George C. Brainard,

Richard E. Kronauer, Charles A. Czeisler and Steven W. Lockley

Science Translational Medicine, 12 May 2010 

See also these older posts: 

xliii. Blindfolding the blind   

xliv. Rods and cones and the “new” ipRGC 

 (posted by D )


Next post:  #54. Take a Nap!



51. Melatonin: Less Is (Sometimes) More

11 April 2010 at 20:31 | Posted in Circadian rhythm | 31 Comments
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Melatonin is often suggested as a remedy for those of us who have N24 or DSPS.  It works for some people, but not for others.  (So far I seem to be in the latter category.)  For some people it doesn’t work because — well because it doesn’t work for them — we can’t always tell why.  But for other people it does not work because they are using the wrong dose.  Melatonin dosing can be a bit tricky.

When speaking of hormone dosing, there are two terms that often arise: physiological dose and pharmacological dose.

The physiological dose of a hormone is the dose the replicates the level of the hormone normally found in the body.  For example, people with Addison’s disease, a deficiency of the hormone cortisol, will usually take 15 to 25 mg of cortisol a day, which results in a serum level of cortisol similar to that of a healthy person.  Another phrase to describe the physiological dose is the “replacement dose” which means essentially the same thing.

The pharmacological dose of a hormone is the dose required to produce a specific desired effect.  In some cases the pharmacological dose is much higher than the physiological dose.   Cortisol for example has an immune system suppressing effect at high doses, so people with auto-immune conditions are often prescribed cortisol (or cortisol analogs) in much higher doses than the replacement doses used for Adddison’s disease.  There is nothing necessarily wrong with using such high doses.  They are often the best treatment for a disease.   But they do have a much greater risk of side effects, since you are introducing a hormone at much higher doses than the body is used to.

Melatonin is a hormone produced at night, and in humans aids in consolidating sleep at night.  As such melatonin can have a sedative effect.  Melatonin levels during the day are very low, typically 1- 10pg/ml, and often undetectable.   At night melatonin levels rise to much higher levels, usually 40-100 pg/ml or roughly 10 to 40 times the daytime level.

You will often see recommendations to take melatonin doses at night of 3mgs.  Such a dose of melatonin will not only produce levels much higher than the daytime levels, but will produce levels much higher even than those found normally at night.   If the nighttime level of melatonin is around 10-40 times that found in the day, 3mg of melatonin will produce levels approximately 10-40 times higher than even the nighttime levels (or over 100 times that normally occurring during the day).  The serum level would be around 1000 pg/ml.

Why are such high doses suggested?  One reason is because this high dose maximizes the sedative effect of melatonin.   For most people the more you take the greater the immediate sedative effect. This is a pharmacological dose — it is maximizing the effect of a hormone by taking very large doses that produce a drug-like effect.

Well, what’s wrong with that?  If you want to get to sleep don’t you want to maximize the sedative effect?  Well, maybe, maybe not.   You see in the treatment of N24 or DSPS a sedative effect is not the whole answer.  If it were then any sedating pill could treat these conditions, and that is not the case.  Most sedatives in fact don’t work very well for circadian disorders.  What we are looking for in using melatonin is a phase shift in the timing of sleep, not just an acute sedative effect and for that too much melatonin can be harmful.

Melatonin taken in the evening produces a phase advancing effect, while melatonin taken after the midpoint of sleep (roughly) produces a phase delaying effect.   Keep in mind that melatonin taken orally has a half-life in the blood that can range from 30 minutes to 2 hours (depending on the individual and the study method).  If you take 3 mg you are getting blood levels in the evening that are extremely high and it’s going to take many hours for those levels to get back down.  And that’s the problem.  You will still have melatonin in your system the next morning, when it will produce a phase delay.  This spillover effect is nicely illustrated in a graph produced by Lewy et al in a study which showed the advantages of lower doses of melatonin.  They found they could entrain a blind patient to 24hrs with 0.5mg of melatonin but not with 10mg.  As one can see from the graph this is because the 10 mg dose caused melatonin levels to remain elevated during the phase delay portion of the  phase response curve (PRC).

(Graph from Lewy AJ, Emens JS, Sack RL, Hasler BP, Bernert RA. Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period. Chronobiol Int. 2002 May;19(3):649-58.)

In addition to the spillover effect from high doses of melatonin, the immediate sedative effect of a large dose can cause other problems.  With any kind of sedative the phenomenon of acute tolerance can occur, which means as the sedative effect wears off later in the night the person may find themselves awakening again in the middle of their normal sleep period.

To achieve physiologically normal levels of melatonin in the blood an oral dose should be around 0.1 to 0.2 mg (100 – 200 mcg).   This will produce levels mimicing those normally present in the body.  For N24 or DSPD we don’t necessarily want very high levels, we just need the melatonin to be produced at an earlier time.   For N24 you should take this low dose at the same time each night, about an hour or two before you want to fall asleep — possibly even several hours earlier.  The aim is to stabilize the time of sleep onset.  For DSPS (aka DSPD) you will want to take it a several hours ahead of your normal bedtime to try to pull your sleep to an earlier time.  (The timing of melatonin is complex as well so I can’t cover it in detail today. In general earlier melatonin produces greater phase advances, but may also cause sleepiness immediately after the dose, which can be problematic during the day.)

There may be some individuals who need high doses of melatonin because they are insensitive to its effects or they require an acute sedative effect.  I would not discourage anyone from trying higher doses.  But if a higher dose doesn’t work or causes problems, consider going low dose.  That’s the point of this post.

Will these lower doses of melatonin work for you if you have N24 or DSPS?  I wish I could promise they will.  For some people they do work or at least help.  They are often helpful for blind people with N24; less so for sighted people.  But for many others melatonin does not work.   There are several possible reasons.  Taking melatonin early in the evening produces the equivalent of a very long winter night and this can result in depression-like symptoms in many people.  It may also be that the spillover effect of melatonin is more pronounced in some people.  It also may be that the underlying cause of N24 or DSPD in many people has nothing to do with melatonin itself, and therefore manipulating melatonin levels accomplishes nothing for them.

I know that melatonin often makes me feel very tired and lethargic the next day — not what I am trying to achieve, needless to say.   Lately I’ve been experimenting with even smaller doses. I put around 125mcg (0.125mg) of melatonin in liquid form in a glass of water and sip small amounts of it for an hour or two before bed.  I probably get only around 25-50mcg (less than half a glass) in total.  I’m not sure if this is helping yet (and even such a low dose may have made me more lethargic  at times).

But while I can’t promise melatonin will work, if you are going to try it you are better off trying the right dose.   At the right dose it may work, and at least if it does not you work will know that melatonin is not the answer for you, not that you just took the wrong dose.

Remember, for melatonin less is (sometimes) more.

Posted by LivingwithN24 (James Fadden).


Next post: #52.  2010: sleep logs


xlix. 2009: sleep logs

4 February 2010 at 22:53 | Posted in Circadian rhythm | 18 Comments
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As “D” gets the forms filled out, her (my) sleep logs will appear here.  They are of interest primarily to myself and my sleep specialist, Prof. Holsten.  But if you see a long-term pattern, do let me know.  What I see for sure is that I am affected by melatonin and/or bright light.  Next experiment will be to cut the melatonin and see what just morning bright light does.

Sleep Diary

Sleep Diary

The doctor said: "WHAT happened here?"

Umm, I just tried a couple of weeks without melatonin and light therapy, is all.  

More weeks free of melatonin

Back on track

Back on track, such as it is.  My “normal” with the help of melatonin and light therapy.

Posted by Delayed2Sleep (aka “D”).  Updated 22 February 2010.


Next post:  l.  A Man with Too Long a Day (by L)


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