Rational Prescribing Article Series

First extracted from the pineal glands of cows by dermatologist Aaron Lerner in 1958, melatonin (N-acetyl-5-methoxytryptamine) is a hormone that regulates the sleep-wake cycle in many species, including plants. In humans, it is mainly produced by the pineal gland, a tiny gland that is shaped like a pinecone, in a part of your brain that some call the third eye. When light strikes the retina of your eye, specialized nerves send a message to the suprachiasmatic nucleus of the hypothalamus, which tells the pineal to stop making this hormone.

In terms of human physiology, melatonin does many things. Rather than thinking of it as a hormone that induces sleep, consider it as the signal that turns on repair systems in the body and the brain that take place while you sleep. Melatonin receptors activate many white blood cells to regulate the immune system, microglial cells that perform housekeeping duties in the brain, and even endothelial cells that regulate blood pressure. Studies have reported effects of melatonin on oxidative stress and immune regulation in the brain and body.

There is clear evidence that melatonin can be an effective tool for improving sleep. This comes from a 2021 systematic review of 23 randomized, controlled trials, which reported that melatonin improved sleep quality as measured by the Pittsburgh Sleep Quality Index.

There are many different formulations of melatonin, and this can affect how it is absorbed and how long it lasts. Melatonin is made from tryptophan, one of the 22 amino acids that are the building blocks of protein. Enzymes turn melatonin into serotonin, and then turn serotonin into melatonin. The liver breaks down melatonin into 6-hydroxymelatonin, and from there it is sulphated so it can be excreted in the urine.

Different providers use different approaches, but thankfully melatonin has no known toxicity, even at very high doses. The main side-effect of melatonin is sedation, drowsiness or sleepiness. While this may be a concern in terms of the risk of falls in the elderly, some research suggests that melatonin use may help prevent these falls.

Anyone who has trouble sleeping knows how it can affect memory and concentration. While sedatives can help with sleep, they can also impair these cognitive functions. In a systematic review of 11 trials in healthy subjects, melatonin did not affect these skills. The same study reported that melatonin improved the mini-mental state examination (MMSE) score in nine clinical trials in patients with Alzheimer’s disease. Melatonin not only improved sleep in these patients, it made their brains work better.

Several lines of evidence also suggest that melatonin might even help prevent Parkinson’s disease. While it is not clear why, low levels of melatonin in the cerebrospinal fluid (CSF) are strongly correlated with Alzheimer’s disease, and it has been proposed as a biomarker that might help identify those at risk. Because of its safety profile, it has also been advocated as a potential treatment for high blood pressure during pregnancy, a condition known as pre-eclampsia.

In some cases, it may be worthwhile to consider laboratory testing of melatonin levels. The most widely used test is a 24-hour urine collection, and while these tests have not yet been validated for widespread use, an experienced provider can help interpret these results as part of a broader panel of hormone testing.

While there is still a need for more research to clarify the best forms of melatonin and optimal dosing, it makes sense to consider using it as a natural sleep aid. That’s especially true given that all the prescription medications available come with risks like addiction, falls and impaired memory and concentration.

Doctors typically only recommend treatments that have been proven effective in randomized controlled trials. This approach is called evidence-based medicine, and while it has major benefits, patients find themselves on their own when these options don’t work. Randomized controlled trials can provide evidence that a treatment is better than a placebo in a large group of people, but it does not confirm that it will work for you. If you are struggling to get a good night’s sleep, you can use a process that the World Health Organization (WHO) calls rational prescribing to find out if magnesium works for you.

First you should clarify what you want to improve and what improvement looks like. This is about goal-setting, so choose a specific, measurable, achievable, realistic and time-based (SMART) goal. An example of a SMART goal would be more total hours of sleep with fewer night-time wakings. You may also make note of whether it makes you feel less drowsy and more rested during the day.

You can choose to try melatonin once you have considered your other options. It is hard for most people to do this on their own, and the internet is a big place filled with lots of information that can be hard to interpret without clinical experience or medical knowledge. If you have a good relationship with your doctor, consider asking them to supervise your trial. If you are working with a wellness provider, they will know a lot about the natural options available to you, but their advice will likely be based on the specific therapies they use most often and those they know best.

Do your homework.

Next you need to find the right melatonin. It is still unclear whether long-acting melatonin is better than the short-acting form, and what the optimal dose should be. While doctors often seek guidance from clinical trials, every person is different, and melatonin absorption is very different from one person to the next. For this reason, I recommend a sublingual spray and tell patients to use one spray every 15 minutes until they fall asleep.

How much to take? As always, this depends. While studies in cancer have used 20-50mg per day, the dose used to improve sleep is much lower. As little as 0.5mg may be enough for some, but you may need a higher dose. A knowledgeable provider can help with this part, but trial and error is not a bad approach, as the toxicity of melatonin is low.

Once you have figured this part out, you can start your trial. Take your melatonin regularly, and if you are really keen, consider keeping a daily record of your progress. You can use paper and pen, or find a smartphone app to help you track this information. For some people, remembering to take their medicine is a challenge, but for most people melatonin quickly becomes part of a nightly ritual.

By the end of your trial, you should know whether melatonin has helped you or not. Many people don’t respond to proven therapies, but many people have also reported major benefits from unproven treatments. In a rational prescribing approach, your experience and your preferences are important and you are the only expert on these.

If you feel that melatonin has helped you make progress on your goal, you can keep things as they are, or you can try increasing the dose or adding something else. If it hasn’t, you may choose to try a different dose, a different formulation, or simply try something else.