Clocking on to `miracle' drug

John Emsley discusses the hyped but versatile melatonin molecule

A report last week by the Institute of Management shows many executives to be overworked, under stress, and suffering symptoms such as insomnia. A growing number are looking to melatonin to help them sleep, or cope with jet lag. Companies who make the drug report record demand.

Melatonin (chemical name: N-acetyl 5-methoxy-tryptamine) is a hormone produced by the pineal gland, a pea-sized organ at the centre of the brain. It regulates sleep by releasing melatonin molecules at night, in response to changes in light entering the eye. Levels of this chemical in the bloodstream peak in the small hours at around 80 parts per billion (ppb), and then decline slowly, falling sharply at dawn to 10 ppb. As we reach old age, our ability to produce melatonin decreases.

A 3 milligram capsule of melatonin is enough to raise the blood level quickly, and send you off to sleep in about five minutes. It can be bought from health food shops, although the Committee on the Safety of Medicines has now banned its sale as a non-prescription drug.

The European Pineal Society, while admitting that melatonin is useful in treating sleep disorders, has issued a warning: "There is insufficient scientific evidence for ... therapeutic uses in humans. There is no information on possible harmful long-term side effects. Melatonin may be dangerous if [its consumption is] incorrectly timed and should not be taken without medical supervision."

In the US it is being touted as a cure-all, with claims that it can ward off cancer, heart disease, Alzheimer's disease, cataracts, Aids, depression and old age. Melatonin mania has been fuelled by best sellers such as The Melatonin Miracle by Walter Pierpaoli and William Regelson, who say it prevents ageing, and Melatonin: your body's natural wonder drug by Russel Reiter and Jo Robinson, who claim it can counter cell damage caused by free radicals.

There is as yet no convincing support for either theory, but that has not slowed demand, and in some American states melatonin now outsells aspirin.

A more scholarly work is Melatonin and the mammalian pineal gland by Josephine Arendt of the University of Surrey, who has researched the effects of melatonin on human biological rhythms, and developed sophisticated methods of measuring the chemicals in the body.

Meanwhile, in the Department of Anatomy at Cambridge University, Dr Mike Hastings and Professor Francis Ebling are carrying out research into how melatonin controls the body's internal clock: "We have discovered that the brain has two mechanisms related to time," says Dr Hastings. "One regulates the daily, or circadian, rhythm of our lives, the other controls our response to seasonal changes. Both are sensitive to melatonin at the very low concentrations found naturally." The body clock is located in the hypothalamus, the body calendar in the nearby pituitary gland.

Melatonin can be manufactured easily, and when pure is pale yellow, with leaf-like crystals which melt at 117C. The pineal gland synthesises it from serotonin, the brain chemical that regulates mood, and this in turn is made from the essential amino acid tryptophan. They are all derivatives of indole, a simple molecule which has two rings of atoms closely joined together; one with six carbon atoms, the other with four carbons and a nitrogen.

The dermatologist Aaron Lerner discovered melatonin in 1958. He reported that in frogs it caused dramatic changes to the colour of skin cells known as melanophores, and consequently named it melatonin. Since then it has been found to occur in organisms ranging from single cell algae to mammals. In humans it helps us to adjust our sleep patterns to the daily rotation of the planet and its annual cycle round the sun, and also controls our body temperature, reducing it slightly during the hours of sleep. In sheep and deer, melatonin signals the breeding season, while in other animals it causes moulting.

There are proper uses for melatonin; in helping those who frequently travel across time-zones, or suffer abrupt changes in sleeping patterns due to shift work. Melatonin has also been used to treat children suffering from disturbed sleep patterns. Allowing over-stressed managers to get a good night's sleep may also be another legitimate use.

Dr John Emsley is science writer in residence at Imperial College, London.