Human beings spend around one-third of their lives sleeping, which is more than 25 years of sleep, assuming an average human lifespan. Why is sleep so essential to justify spending so much time in this inattentive and motionless state? Unfortunately, there’s still no clear answer to that question. Despite decades of research, the underlying mechanisms and functions of sleep are still shrouded in mystery. Yet, some of the functions of sleep can be inferred from the effects of its deprivation. In all mammals, sleep deprivation leads to lack of attention, emotional instability, heightened sensitivity to pain, metabolic and cardiovascular disorders, immune dysfunction, and, in extreme cases, death. Sleep certainly seems to be essential for good brain function. The scientific literature has thus far counted about 10,000 genes expressed in the brain during sleep. It is therefore not surprising that sleep affects all aspects of our lives.
In large parts of the developed world, sleep deprivation seems to become a major problem. Poor sleep, in terms of either quantity or quality, is a risk factor for several illnesses, including obesity, cardiovascular and neurodegenerative diseases, as well as metabolic and mental disorders. Moreover, lack of sleep is associated with higher all-cause mortality risk. Sleeping less than six hours per night is associated with a relative increase in mortality risk of 12%. This increased risk is carried by 9% of the population sleeping less than six hours per night in the U.S. On top of that, about one-third of Americans complain about sleep problems.
But not all sleep problems are alike. Sleep problems can be broadly categorized into primary and secondary sleep disorders. Primary sleep disorders are caused by endogenous disturbances that directly affect the ability to sleep well. Primary sleep disorders are relatively common. For example, 5% of the French population suffers from specific sleep disorders such as insomnia, apnea, and narcolepsy. In contrast, secondary sleep disorders are caused by other illnesses such as depression, asthma, or arthritis. Secondary sleep disorders are thus far more common. For example, the National Institute of Mental Health (NIMH) estimated that 17.3 million U.S. adults, about 7% of the population, had at least one major depressive episode in 2017. These numbers sound depressing yet reflect a tragic reality: a lot of people are living with chronic sleep problems.
What can be done about this? There are two kinds of therapy designed to treat sleep problems. First, lifestyle interventions such as ensuring healthy nutrition, sufficient exercise, and good sleep hygiene can improve sleep quality. Cognitive therapy, yoga, and meditation are also recommended. However, lifestyle interventions may not be suitable or effective for people suffering from serious diseases. In such cases, the second type of intervention, pharmacotherapy, or “sleeping pills,” seems more promising. The American Academy of Sleep Medicine offers and recommends a plethora of prescription drugs. However, these medications have substantial side effects, such as daytime sleepiness, cognitive impairment, dependency, and withdrawal. Due to these common adverse effects, researchers are looking for new promising treatment options. Melatonin is one of them.
Melatonin is a hormone and neurotransmitter that plays a crucial role in regulating sleep. Melatonin is secreted by the brain’s pineal gland (shown in Figure 1) in the evening hours, approximately two hours before bedtime. However, in our modern times, nocturnal melatonin secretion can be disturbed by excessive exposure to artificial lights such as smartphones, televisions, and indoor lighting. Furthermore, certain illnesses, such as depression, can negatively impact melatonin secretion. Thus, supplementation with exogenous melatonin could improve sleep quality.
The biological theory of melatonin’s usefulness has been backed by rapidly accumulating clinical evidence. The three most recent meta-analyses from 2015, 2016, and 2018 examined the efficacy of melatonin on primary and secondary sleep disorders. All three meta-analyses found that melatonin improved sleep quality significantly as assessed by the global PSQI score, total sleep time, and sleep latency onset, which is how long it takes to fall asleep. The current body of literature thus supports the use of melatonin to treat sleep disorders.
At first glance, the clinical evidence seems convincing. There are, however, three remaining caveats with melatonin. First, the observed effects were significant but small, and the results were often measured with suboptimal measures that assess only one or two dimensions of sleep quality. Second, the number of available RCTs is still low, and the existing studies often have short follow-ups and insufficient sample sizes. Third, the existing meta-analyses did not differentiate the different diseases that cause secondary sleep disorders. As a result, the American Academy of Sleep Medicine guidelines and the European insomnia guidelines do not recommend melatonin to treat sleep disorders based on the current evidence. In other words, the evidence exists, but is not yet convincing enough.
The present study was designed to fill this gap. The researchers meta-analyzed 23 RCTs that examined melatonin’s effect on sleep quality in 1,965 participants with different diseases. In contrast to previous meta-analyses, the present study focuses solely on RCTs that used the Pittsburgh Sleep Quality Index (PSQI), the most widely used and reliable subjective measure of sleep quality to date. The researchers also conducted subgroup analyses to assess whether melatonin is more effective in the context of some diseases than in others.
Sleep is essential for life, and insufficient sleep is a risk factor for several illnesses. As the hormone and neurotransmitter melatonin regulates sleep, supplementation may improve sleep quality. Due to insufficient evidence, however, professional societies are not recommending melatonin to treat sleep disorders yet. The present study was designed to meta-analyze the most recent high-quality evidence from RCTs to fill this gap.