51. Melatonin: Less Is (Sometimes) More11 April 2010 at 20:31 | Posted in Circadian rhythm | 26 Comments
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 (aka “L”).
Next post: #52. 2010: sleep logs