EXTENSIONS AND COMMENTARY : This is a difficult drug to try to determine the active level. It is late. You want to sleep. You take a tab of melatonin and you sleep well. Or you don't take a tab of melatonin and still you sleep well. Or perhaps you sleep badly -- what connection can be drawn from the melatonin usage? The end-point of these studies is not the enhancement of consciousness but the loss of consciousness. I truly cannot say what the active level might be, because I do not know what positive experience might be expressed with an active level. In my notes is a report of a person who took 80 milligrams, orally. "Apparently I drifted quite quickly and smoothly into sleep, which was sound and which felt natural. On awakening, both my mood and performance seemed enhanced over my usual state." Is that a positive response? Melatonin has been espoused as a cure for jet-lag. But when I try to record the doses and times and effects, there is quite a bit of looseness. It is being sold in tablets (sometimes for sublingual use, why, I do not know) at dosage units from 300 micrograms to 10 milligrams. I know of one very modest i.v. trial (with 25 micrograms, at 0.10 micrograms / minute). "No subjective effects were noted."
Melatonin is found in many areas of many animals. It is involved in the skin coloration of amphibians, and in the thermal or motor regulation in some higher animals. Its major regulatory role is in response to light and, in man, is the major hormone produced by the pineal gland. This popular gland in the brain (incidentally the only unpaired site in the brain) has long been the darling of the new-age set as it is the so-called third eye. Its primary hormone, melatonin, has been the subject of many studies related to brain function. It has effects on other brain bodies that are themselves involved in hormone secretion. It has been implicated in behavioral and emotional changes in man, including anxiety, seasonal depression, and delayed sleep-phase syndrome (DSPS, with a delay in getting to sleep, and delay in coming awake). Its function is strongly affected by exposure to light, and it has been referred to as the body's hormone of darkness. And there is no question but that the biochemistry of the brain allows it to know what time of day it is. Studies with the pineal in the rat have shown that the enzymatic activity needed to run the acetylation reaction (using N-acetyltransferase, which produces melatonin from its original serotonin precursor) is 45 times more active at 10:00 PM than it is at 10:00 AM.
There has been no satisfactory pharmacology ascribed to melatonin. At low dosages it certainly decreases sleep latency. It is not a sedative at the low milligram levels (which achieves blood levels in the physiological range) but rather is a factor that might guard the user from the disruptions known as jet-lag, which is certainly a close cousin to the DSPS. Here the dosages usually explored are in the 2 to 10 milligram range. It is invariably offered as a dietary supplement rather than a sleep aid (which would be a medical claim) but a side-effect that the user is warned against is drowsiness. One popular brand I know of is available in 2.5 milligram tablets recommended for sub-lingual use. I inquired of them to learn what studies were available that indicated any virtue the sublingual route might have over direct oral use, and I learned nothing. Just a few days ago I was shown a fascinating sham offering in the OTC world. Alice brought home from the local branch of a national chain drug store a container containing 120 tablets that contained 300 micrograms each. The label said, "University Tested Strength" and "Preferred Dosage." The recommendation was for the user to take from one to three tablets (still less than a milligram). This is an example of drug-abuse at the corporate level. At relatively large dosages (75-80 milligrams) it appears to produce an increase in total sleep, along with a decrease in daytime sleepiness. This is all without hangover. It appears to be a sleep catalyst at modest levels, and a soporific at higher levels, where it can be administered chronically (75 mg/day) for a couple of weeks. with satisfactory effects. There is a paucity of reports at intermediate dosage levels. Whatever the effective dosage might be, the sales of melatonin are truly booming in the health food stores. Genzyme, a major manufacturer of melatonin, estimates that 20 million people in the United States bought melatonin for the first time in 1995, and it places the retail sales at between $200 million and $350 million per year.
-shulgin;TIHKAL
