A drug that binds to brain-cell receptors for the hormone melatonin helps to prevent jet-lag-type sleep disturbances, according to the results of a large-scale clinical trial. The drug, tasimelteon, would not be the only melatonin-mimicking drug on the market, but it could become the first FDA-approved drug specifically for the treatment of insomnia related to jet lag, shift work and similar “chronobiological” disturbances. Whether it works better than melatonin itself is an open question.
“The results look good to me,” says Josephine Arendt, a researcher at the University of Surrey in the U.K. who works in this area.
In the clinical trial, more than 400 healthy volunteers, in 19 sleep clinics with controlled light conditions, were asked to try to sleep five hours earlier than normal, to simulate night-shift work or jet lag. Those who took tasimelteon a half-hour before going to bed slept about 75 percent of the time, versus about 66 percent for those who took a placebo. The tasimelteon group also spent less time getting to sleep, spent less time awake after initially falling asleep and then waking up, and showed improvements on other observed and self-reported measures of sleep quality. A cognitive skills test given to all subjects after they slept showed no significant changes from the baseline.
Reported side effects were minor and did not differ significantly between the tasimelteon and placebo groups, although melatonin-like drugs have been known to increase levels of prolactin in some women, potentially leading to lactation and menstrual irregularities.
The study was run by a team from the division of sleep research at Brigham and Women’s Hospital in Boston, assisted by researchers at Rockville, Md.–based Vanda Pharmaceuticals, which owns the rights to tasimelteon. (Charles Czeisler, the veteran Harvard researcher who directs the division of sleep research, also chairs Vanda’s scientific advisory board.)
In the same paper, the researchers described an earlier study of tasimelteon in 39 people. Results were similar to those for the larger study, but throughout the smaller study, the researchers also measured levels of melatonin (which they could biochemically distinguish from tasimelteon) in subjects’ blood. They found that the normal, 24-hour (circadian) rise and fall of melatonin levels shifted by two to three hours after a single dose of tasimelteon. The tasimelteon group also had more rapid-eye-movement (REM) sleep than the placebo group.
“We used those two measures to show that we had shifted the circadian pacemaker to an earlier time,” says Elizabeth Klerman, the physician whose laboratory in the sleep research division led the study.
The circadian pacemaker, which controls the sleep/wake cycle and a host of other functions in the body, is a cluster of neurons in the suprachiasmatic nucleus (SCN), which sits astride the optic nerves. It keeps its rhythm aligned with the day/night cycle by receiving ambient-light readings from special cells in the retina, and it also makes use of neuronal and hormonal inputs originating from the cortex and other regions.
Melatonin, a hormone chemically related to serotonin, is secreted by the pineal gland, under control of the SCN, and has two major effects. First, it influences other brain systems to induce drowsiness and maintain sleep, a “soporific” effect. Second, it feeds back to the SCN, helping to maintain the circadian clock time, a “chronobiotic” effect. Tasimelteon, which binds to melatonin receptors on brain cells in the SCN and elsewhere, probably also influences these effects.
“This experiment could not differentiate between those two effects,” says Klerman.
It is not clear whether Vanda Pharmaceuticals, a small biotech company with financial troubles, will be able to bring tasimelteon to market. It had hoped to gain FDA approval for the drug to treat chronic insomnia, which has a much larger market, but in a recent clinical trial in chronic insomniacs, tasimelteon’s advantage over placebo seemed to wear off over several weeks. In any case, tasimelteon would not be the first melatonin mimic, or “agonist,” on the market. The first melatonin agonist, ramelteon (brand name Rozerem) is already FDA-approved and widely prescribed for chronic insomnia. “We haven’t done a head-to-head study of ramelteon with tasimelteon,” says Klerman.
Tests also needed on melatonin
The major question hanging over this field is whether either of these drugs works better than melatonin itself. The drug is available cheaply over the counter as a health food supplement in the United States and many other countries. Because such products are only lightly regulated by the U.S. Food and Drug Administration, there have been concerns over product quality. Nevertheless, melatonin in this form is widely used by travelers and shift workers. In Europe, ordinary melatonin is regulated by the European Medicines Agency and approved for alleviating insomnia in blind people whose circadian pacemakers cannot entrain to ambient light.
In the United States, commercial researchers have not sponsored large trials for ordinary melatonin. It cannot be patented, so there likely would be little profit in it. Most melatonin trials that have occurred have had fewer subjects and therefore less statistical power. Some of these trials also haven’t been performed under conditions that accurately simulate time-zone shifts, Klerman says. The results of these clinical trials have been mixed, although sleep researchers generally believe that melatonin does work both as a sleep inducer and a circadian clock resetter.
“At some point there should be a direct comparison between melatonin and agonists such as tasimelteon and ramelteon,” says Arendt. Unless research proves that the agonists are more efficient than melatonin, she adds, “I would see no strong reason to use them instead of melatonin.”