‍Reviewed by Sahil Chopra MD and Stacey Gunn MD.

Research by Savit Malhotra.

This article marks the sixth installment of our insomnia series. This week, we will be continuing on the topic of medications that are available to help those struggling with insomnia sleep at night. Last week, we looked specifically at DORAs (Dual Orexin Receptor Antagonists), a specific class of insomnia medications. This week, we will be looking at melatonin receptor agonists and their role in helping you get a better night's rest.

Introduction

For the majority of our insomnia series, we’ve talked about and done in-depth analysis on the different medications that are available to treat insomnia. The reason why we’ve spent so much time on this topic is that there are so many different types of medications available, and it wouldn’t make sense to fit them all into one article. We want to make sure that our readers are very well informed about the different types of medications available to them, and for this reason, we’ve broken it down into much easier and manageable chunks. This week, we will be concluding our discussion on medications by talking about melatonin, a name that is likely quite familiar, and the class of medications known as melatonin receptor agonists. 

What is Melatonin?

You’ve likely heard of or seen melatonin gummies behind the counter of many drug stores or pharmacies. However, what is lesser known is the actual mechanism behind how this drug works. To begin, melatonin is one of many naturally occurring hormones that the brain produces, and that melatonin’s role is in helping people sleep. Based on this information alone, it is not uncommon for people to think that melatonin itself is what causes people to go to sleep, which isn’t necessarily true. Melatonin is a hormone that is produced and released every night based on a person’s circadian rhythm, or their internal clock.[1] Light suppresses melatonin from being released, and darkness allows for it to be released on schedule.  Interestingly, most people’s internal clocks can actually turn out to be a little longer than 24 hours in the absence of cues like light. We need to make this very important distinction in the function of melatonin: it is most useful in helping the body time when it needs to sleep, rather than creating sleep itself. (Walker, M. (2018). Why We Sleep. Penguin Books).

This may start to raise some questions then on the practical use of melatonin. If our body naturally produces melatonin, why do some people take supplements for it? Typically, melatonin is recommended for those who are struggling with short-term sleep problems. For example, those who are jet-lagged can take melatonin to help reset their internal clock. While the body will naturally adjust its melatonin levels, this process can take some time, and a dosage of melatonin can help a person quickly resolve their temporary lapse in sleep. The melatonin supplement will create a temporary rise in melatonin levels that the body normally would not experience at that time, thus leading to one’s internal clock being reset.[2]

However, melatonin can also be used in the treatment of some sleep disorders. Take, for example, delayed sleep phase syndrome. This is a condition where a person has trouble falling asleep, staying asleep, or waking up due to their circadian rhythm gradually falling behind or ahead by increments of one to two hours, or longer.[3] Melatonin can successfully help in the treatment of this disorder because of its role in sleep regulation.[4] Additionally, melatonin can also help in the treatment of other circadian rhythm disorders. Take, for example, those who are partially or totally blind. These individuals are unable or struggle to receive visual cues from their environment in regard to what time of day it is, and may develop a disorder called a Non-24 Hour Rhythm, in which their sleep and wake timings are out of sync with the world around them. Melatonin has been shown to be an effective treatment in managing and regulating the circadian rhythm of those who are blind.[5]

In the end, the most important conclusion to draw from this discussion of melatonin is that the hormone itself (and any supplements) are not very good at directly putting a person to sleep. Instead, melatonin regulates the body's internal clock, and this regulation is what aids a person in managing their sleep timings. 

Figure 1.   Shows how melatonin is regulated by light and darkness. The presence of darkness (or absence of light) during the biologic night allows the suprachiasmatic nucleus in the brain to stimulate the pineal gland to produce melatonin. Melatonin then starts the cascade of all the processes of the biological night in the respective organs (adrenal glands, thyroid, heart, etc).

Melatonin Receptor Agonist 

We’ve previously talked about melatonin receptor agonists (ramelteon/Rozerem) in our medications article. As a quick summary, these medications work by mimicking the effects of melatonin and binding to and stimulating the MT1 and MT2 receptors, which are important for inducing sleep and regulating its timing.[14] Currently, there are only two FDA-approved melatonin receptors. We will be focusing on the newest of the two. 

Melatonin receptor agonists are often a preferred choice by many sleep physicians because not only are the medications effective, but they are also relatively low risk. However, these medications may not be as effective as some other choices that carry more risk. Melatonin receptor agonists are generally well tolerated and are not associated with dependency or withdrawal symptoms. The most commonly reported side effects include dizziness, fatigue, and nausea. Compared to other sleep aids, they have less risk of impairing next-day functioning or cognition.[6]

Hetlioz (Tasimelteon)

Tasimelteon, sold under the brand name Hetlioz, was first approved for use on January 31st, 2014, and it is primarily used to treat Non-24-Hour Sleep-Wake Disorder (Non-24).[15][16] Non-24 is a condition where a person’s internal clock progressively gets disrupted, causing their sleep and wake time to shift by one to two hours over time, gradually more and more each day, with their sleep schedule “moving around the clock.” As a result, their sleep and wake times no longer align with the environment, which leads to a whole host of issues. Those suffering from non-24 are likely to experience fluctuations in the following: mood, alertness, and appetite. This condition tends to commonly affect totally blind individuals due to them not being able to perceive light from their environment, but even those who aren’t blind can suffer, though the reasoning for this is not fully understood. [17]

A recent 2020 study on individuals who experienced jet lag due to a shift of 8 hours earlier looked at the effects of tasimelteon on these individuals. Since the individuals were jet lagged, their natural sleep-wake cycle had been shifted, mimicking the effects of non-24. In the end, the study found that total sleep time had increased by 85.5 minutes and sleep latency was shortened by 15.1 minutes. Additionally, next day alertness and sleepiness had improved.[18] As we can see from these results, tasimelteon is indeed effective in the treatment of shifting one’s circadian rhythm back on track. The broader effects of tasimelteon on insomnia are still being studied, but there is great potential for this medication to be able to treat more forms of insomnia. 

The most common side effects associated with tasimelteon are pain in the bladder region/lower back, or pain or difficulty urinating. These side effects are among the more serious, and anyone experiencing these should consult with their doctor. However, other side effects that may occur do not necessarily require immediate medical attention. These side effects include body aches/pain, chills/fever, nightmares, headache, ear congestion, or a runny/stuffy nose. If these side effects are continuous or bothersome, though, then checking in with a doctor is a strong suggestion.[19]

Conclusion

With so many different medications to choose from, it can become overwhelming deciding which medication is the right one for you. Generally speaking, melatonin and melatonin receptor agonists are a good first line against fighting sleep disorders because of their strong efficacy and minimal risk. However, no medication is a “one drug treats all” solution, and the best medication does depend on the individual scenario that a person presents with. For this reason, the best choice always remains seeing a professional to help you figure out what treatment option is best for you. Oftentimes, you may not even need a medication if the underlying cause of your insomnia can be targeted. Next week, we will be taking a look at cognitive behavioral therapy for insomnia (CBT-I) and why, for many people, this may be a better option than medications. 

References

  1. “Can’t Fall Asleep? It Might Be Delayed Sleep Phase Syndrome.” Cleveland Clinic, 8 Feb. 2025, my.clevelandclinic.org/health/diseases/14295-delayed-sleep-phase-syndrome-dsps.
  2. “Hetlioz (Tasimelteon) FDA Approval History.” Drugs.Com, www.drugs.com/history/hetlioz.html. Accessed 14 May 2025.
  3. J;, Skene DJ;Arendt. “Circadian Rhythm Sleep Disorders in the Blind and Their Treatment with Melatonin.” Sleep Medicine, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/17420154/. Accessed 14 May 2025.
  4. “Jet Lag Disorder.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 19 Nov. 2022, www.mayoclinic.org/diseases-conditions/jet-lag/diagnosis-treatment/drc-20374031.
  5. Lankford, Alan. “Indiplon in the Treatment of Sleep Disorders.” Neuropsychiatric Disease and Treatment, U.S. National Library of Medicine, Dec. 2007, pmc.ncbi.nlm.nih.gov/articles/PMC2656319/.
  6. “Melatonin.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 10 Aug. 2023, www.mayoclinic.org/drugs-supplements-melatonin/art-20363071#:~:text=Melatonin%20can%20be%20used%20to,it%20under%20your%20doctor’s%20supervision.
  7. “Melatonin: What You Need to Know.” National Center for Complementary and Integrative Health, U.S. Department of Health and Human Services, www.nccih.nih.gov/health/melatonin-what-you-need-to-know#:~:text=Melatonin%20is%20a%20hormone%20that,in%20the%20body%20beyond%20sleep. Accessed 14 May 2025.
  8. “Non-24-Hour Sleep Wake Disorder.” Sleep Foundation, 16 Nov. 2023, www.sleepfoundation.org/non-24-sleep-wake-disorder.
  9. Polymeropoulos, Christos M, et al. “Efficacy of Tasimelteon (HETLIOZ®) in the Treatment of Jet Lag Disorder Evaluated in an 8-H Phase Advance Model; a Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.” Frontiers in Neurology, U.S. National Library of Medicine, 9 July 2020, pmc.ncbi.nlm.nih.gov/articles/PMC7381312/#s3.
  10. “Tasimelteon Side Effects: Common, Severe, Long Term.” Drugs.Com, www.drugs.com/sfx/tasimelteon-side-effects.html. Accessed 14 May 2025.
  11. Walker, Matthew P. Why We Sleep: The New Science of Sleep and Dreams. Penguin Books, 2018.
  12. “Welcome to HETLIOZ® (Tasimelteon).” HETLIOZ® (Tasimelteon) Is the First and Only FDA-Approved Treatment for Non-24-Hour Sleep-Wake Disorder (Non-24) and Nighttime Sleep Disturbances in Smith-Magenis Syndrome (SMS), hetlioz.com/. Accessed 14 May 2025.
  13. “What Are Melatonin Receptor Agonists and How Do They Work?” Synapse, synapse.patsnap.com/article/what-are-melatonin-receptor-agonists-and-how-do-they-work. Accessed 14 May 2025.