The efficacy and safety of the melatonin agonist beta-methyl-6-chloromelatonin in primary insomnia: a randomized, placebo-controlled, crossover clinical trial.
BACKGROUND
While melatonin agonists are known to regulate circadian sleep rhythms, it is not clear whether melatonin agonists have a direct soporific effect. It has been suggested that melatonin's soporific effect is secondary to its ability to induce hypothermia. beta-Methyl-6-chloromelatonin is a high-affinity melatonin receptor agonist that is not associated with hypothermia. The purpose of the present study was to determine if the melatonin agonist beta-methyl-6-chloromelatonin has a direct soporific effect in subjects with primary insomnia.


METHODS
A double-blind, placebo-controlled, crossover safety and efficacy study of 20 mg, 50 mg, and 100 mg of beta-methyl-6-chloromelatonin and placebo was conducted in subjects with DSM-IV-TR primary insomnia. Of 84 subjects screened, 40 progressed to randomly receive each of 3 beta-methyl-6-chloromelatonin doses or placebo on each of 2 consecutive nights with 5-day washout periods between treatments. The effect of treatment on both polysomnographic and subjectively measured sleep parameters, next-morning psychomotor performance, and safety measures was determined. The primary outcome measure was latency to persistent sleep measured by polysomnography.


RESULTS
A significant effect of beta-methyl-6-chloromelatonin on the primary efficacy variable, latency to persistent sleep, was observed (p = .0003). The 20-mg dose resulted in a significant 31% improvement in sleep latency compared with placebo, while significant 32% and 41% improvements were observed at the 50-mg and 100-mg doses, respectively (20 mg, p = .0082; 50 mg, p = .0062; 100 mg, p < .0001). Similarly, a significant effect of beta-methyl-6-chloromelatonin on subjective measures of time to fall asleep occurred (p = .0050), with significant improvement observed at both the 50-mg and 100-mg doses (p = .0350 and .0198, respectively) and a trend toward improvement observed at the 20-mg dose (p = .0582). Adverse events were mild to moderate in severity and did not differ in frequency between beta-methyl-6-chloromelatonin and placebo treatments.


CONCLUSIONS
beta-Methyl-6-chloromelatonin significantly decreases both objective and subjective measures of sleep latency in subjects with primary insomnia. Thus, these data suggest that mel-atonin agonists may exert a direct soporific effect, as previous research indicates that beta-methyl-6-chloromelatonin is not associated with changes in body temperature, heart rate, or blood pressure.
Zemlan
Frank P
FP
Phase 2 Discovery, Inc., Cincinnati, OH 45219, USA. Fzemlan@phase2D.com
Mulchahey
J Jeffery
JJ
Scharf
Martin B
MB
Mayleben
David W
DW
Rosenberg
Russell
R
Lankford
Alan
A
D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008550:Melatonin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D008875:Middle Aged; D010919:Placebos; D017286:Polysomnography; D011597:Psychomotor Performance / Q000187:drug effects; D007319:Sleep Initiation and Maintenance Disorders / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D016896:Treatment Outcome
D010919:Placebos; C489883:beta-methyl-6-chloromelatonin; D008550:Melatonin