You start counting, hoping that you will fall asleep before the number of sheep becomes an uncountable herd. Before you know it, you reach number 1,000 and you are still awake. You get out of bed, go to the living room and try to fall asleep on the couch, while watching TV. You manage to finally close your eyes around 4:30 in the morning, just to wake up – with great difficulty – at 7:30, feeling exhausted.

Does this scenario sound familiar? If you have ever experienced insomnia, you know the agony of trying to fall or stay asleep when your body seems unwilling to cooperate. The solution in this case may very well come in the form of a health supplement containing melatonin.

Melatonin is considered by the American Academy of Family Physicians (AAFP) the first-line pharmacological therapy for the treatment of insomnia, jet lag and sleep disturbances due to shift work. Melatonin is the main hormone secreted by the pineal gland in your brain, and it regulates the circadian sleep-wake cycle. Melatonin’s peak production is during the night, whereas when there is adequate light, the hormone’s production rapidly declines. Melatonin is generally considered safe and well-tolerated in healthy adults, with very few – if any, in most cases – side effects.

However, do you know which melatonin supplement is best for you? Consumers are bombarded by dozens of TV commercials relating to sleeping aids/melatonin supplements. Which is most suited to your particular needs?

There are three important questions we need to explore before choosing:

Does the supplement you wish to buy, contain the amount of melatonin it advertises?

In a 2017 Canadian study, a total of 31 supplements were analyzed, in order to quantify melatonin and serotonin. Melatonin content was found to range from −83% to +478% of the labelled content. It is easily understood that this can have serious health implications. Additionally, even products under the same brand name did not show consistency in their content: there was a lot-to-lot variability within a particular product of nearly 465 percent! Furthermore, serotonin, a related controlled substance used in the treatment of neurological disorders and certainly not supposed to be included in such products, was identified in 8 out of the 31 supplements analyzed. This practically means that consumers need to be very careful when purchasing their health supplements. It is always best to trust respected and well-known companies, and take melatonin after consulting your family doctor or your pharmacist. Avoid buying health supplements over the internet, especially from untrusted sources.

What is the route of administration and the pharmaceutical form of your supplement?

a. Oral administration through pills/tablets/soft gel capsules/syrup: in this case you simply swallow a pill, tablet, soft gel capsule (enclosing a liquid fill) or syrup. Keep in mind though, that there are different types of pills/tablets: Immediate release tablets dissolve in the stomach and release melatonin very quickly: in these dosage forms upward of 85% of the labeled amount is released within 30 minutes. On the other hand, there are controlled/modified-release tablets — extended-release (ER) and delayed-release (DL) — where the active ingredient is released over a more prolonged period of time, providing a more sustained, and long-lasting action. These dosage forms are able to prolong and maintain therapeutic effect in order to improve patient outcomes.

If you prefer an oral dosage form, you need to be aware of the following: Oral administration of melatonin has low bioavailability: only a small fraction of the administered melatonin will manage to reach your bloodstream. With oral administration, before melatonin enters systemic circulation, it undergoes metabolism during its first pass from the liver. This metabolism reduces the actual quantity of melatonin that manages to finally enter the blood stream. It has been estimated through clinical studies that the absolute bioavailability of oral melatonin with doses of 2mg and 4mg in humans, is approximately 15 percent. So, the oral route of administration will not allow much of the original melatonin to enter into your bloodstream.

b. Oral mucosa absorption [in part] through gel gummies: This is a melatonin dosage form that has become very popular recently. In gel gummies the active ingredient [melatonin] is released when the product is dissolved in the mouth and/or chewed. Melatonin is absorbed first through the lining of the mouth, i.e. the oral mucosa (for the part that gets slowly dissolved in the mouth) and then by the digestive tract (for the part that gets swallowed and goes through the gastrointestinal tract). So, part of the supplement will get absorbed by the oral mucosa, which is highly vascularized. This means that this portion of the supplement will directly enter systemic circulation, bypassing the gastrointestinal tract and thus avoiding first-pass metabolism in the liver. As a result, a larger percentage of the original melatonin will reach the blood stream.

c. Sublingual administration through film/granules/pill/spray: With these different melatonin dosage forms, the supplement is allowed to dissolve slowly under the tongue or is administered in the form of a sublingual spray, with most of the active ingredient rapidly being absorbed via the blood vessels under the tongue (a small portion, however, may always escape and be swallowed). Keep in mind that the blood vessel network under the tongue is highly developed. The great advantage of this route of administration, is that the active ingredient avoids the first pass metabolism through the liver; instead, it enters systemic circulation directly, providing a much better bioavailability than oral administration.

d. Transdermal administration through patches: Unlike most melatonin health supplements, which aim to deliver the melatonin quickly to help you fall asleep faster, melatonin patches are formulated with an extended-release system, in order to help you stay asleep longer. The patch should be applied in an area as hair-free as possible, about an hour before bed time. The patch is designed for one-time use, and should be removed in the morning. The great advantage of this route of administration is that the concentration of plasma melatonin is increased for an extended period of time and its action lasts until the patch is removed.

Even though different supplements contain the same active ingredient (melatonin), and in the same concentration, they are not bioequivalent due to the different routes of administration and different pharmaceutical forms. Gummies, sublingual sprays and transdermal patches present a much higher overall bioavailability, due to the fact that a large portion (and, in some cases, all) of the active ingredient avoids the first pass metabolism through the liver.

What other substances are contained in the supplement you are taking?

Is melatonin the sole ingredient in the supplement you are taking, or is it combined with other substances in a formula? Let us examine three (among many) rather “innocent” companions of melatonin in some health supplements.

a. Valerian: Valerian is a rather safe and effective herb, used to treat anxiety, stress, nervous tension, and sleeping disorders. But is valerian that “innocent”? Are there no possible side effects? Well, there are! Common side effects include headache, upset stomach, sleeplessness, dry mouth, strange dreams, and/or daytime drowsiness. Serious side effects like nausea, vomiting, stomach/abdominal pain, dark urine, itching, and jaundice (yellowing eyes/skin) indicate a serious liver problem, and if you notice any of these side effects, you should stop taking valerian immediately. Lastly, in some rare cases a very serious allergic reaction may appear, with symptoms including rashes, itching, swelling of the face, tongue and/or throat, along with severe dizziness and difficulty in breathing. In such a case, you should seek medical care immediately.

b. Cannabidiol: Recently great hype has been surrounding health supplements that contain cannabidiol [CBD], a non-intoxicating cannabinoid. Although CBD is considered relatively safe, it can cause certain side effects like nausea, diarrhea, fatigue, vomiting, drowsiness, lightheadedness, and dry mouth. One should be very cautious, when receiving a formula that contains two substances that both induce sleep: taking CBD with melatonin may cause increased sedation, tiredness and fatigue, leading possibly to accidents when driving and/or accidental falls. As a result, you should be very cautious with the combination, because it may double the side effects!

c. GABA: If you have a personal or family history of breast cancer, it would be advisable to avoid supplements containing GABA. GABA is a neurotransmitter in your brain, known for its calming effect. However, at the same time it has been discovered that GABA feeds metastatic breast cancer cells that migrate to the brain and masquerade as neurons! These cancer cells express a receptor for GABA and a transporter protein, to ensure they receive enough GABA, to use it as an energy source. Although it has been thought that GABA cannot easily cross the Blood-Brain Barrier, recent studies have shown that liposomal formulations can manage to encapsulate and deliver GABA to several sites within the brain.

So, be careful with sleeping aids where melatonin is not the only ingredient. Avoid “heavy” formulations with substances that can intensify side effects, like CBD. In case of a medical history involving breast cancer, simply avoid GABA. And remember: no health supplements should be consumed without the necessary approval of your doctor. Select wisely the best sleeping aid for you and have the sweetest dreams!

* Dr. Lentis is Assistant Professor of Biomedical Sciences at Deree – The American College of Greece