Wake up… Melatonin Doesn’t Control Sleep

Part One: But it can affect your sexual physiology…

“Melatonin madness is everywhere! The media attention that melatonin has received recently is truly remarkable and has elevated the hormone to cult status.”

That was written 28 years ago, but it’s still true today. According to several analyses, the global melatonin market was valued at about one billion dollars in 2022, and it’s projected to be as high as $6.5 billion by 2032. That’s a lot of melatonin.

Where does all that melatonin come from?

Melatonin was discovered in 1958  by a research team headed by Dr. Aaron Lerner, Director of Dermatology at Yale University.  Previous research had demonstrated that feeding tadpoles pineal glands (harvested from cow brains) lightened their skin color. It did so by affecting the movement of melanin-containing pigment granules in the cells. Lerner used that color change reaction as a bioassay to confirm that he had successfully isolated the active ingredient from pineal extracts. Because it affected melanin, the chemical was dubbed “melatonin.” Two years later, the molecule was isolated and chemically characterized as 5-methoxy N-acetyltryptamine.

Since then, we’ve learned that melatonin is an ancient molecule, ubiquitous among organisms, with an evolutionary history that can be traced back to the beginnings of life on earth. Physiologically, melatonin is derived from serotonin (a well-known human neurotransmitter) which is synthesized from the amino acid tryptophan. This biochemical pathway — from tryptophan to serotonin to melatonin — has been extensively studied in bacteria (and other single-celled organisms), animals, (vertebrates and invertebrates), fungi, algae, and plants (wherein it’s called phytomelatonin).

Originally, both experimental and clinical melatonin were derived from pituitary glands (harvested from animal brains), and animal urine, with all of the associated risks of viral transmission. These sources were all but abandoned once melatonin could be synthesized, and chemical synthesis is currently the source for all industrial, agricultural, and pharmaceutical melatonin.

However, chemical synthesis is not without risk. In the 1980s, seven different toxic contaminants were found in three commercial preparations of melatonin synthesized from L-tryptophan. Six of the contaminants were associated with the eosinophilia-myalgia syndrome epidemic and several deaths in 1989. Although chemical synthesis of melatonin is much safer now, there are still a number of undesirable byproducts that can occur during the most commonly used synthetic procedures.

The chemical synthesis of melatonin may soon be replaced by two safer, eco-friendlier processes. The first is extraction of phytomelatonin from plants. Unfortunately, cost is currently a deterrent. It’s estimated that phytomelatonin would be about 2000 times more expensive to produce at scale than chemically synthesized melatonin, and that’s without considering the cost of plant harvesting, handling, and extraction.

The second, more promising method is bio-manufacturing. That’s how we produce insulin, for instance. In this process, genetically engineered (but harmless) E. coli bacteria living in huge fermentation vats produce the compound naturally, each bacterial cell acting like a tiny melatonin factory.

So, what’s in those gummies I give to my kids?

The most recent and thorough biochemical analysis of melatonin supplements that I’ve found analyzed 31 products — 16 different brands — purchased from local grocery stores in Ontario Canada. The brand names were not revealed (for obvious legal reasons), but the results were remarkable, nonetheless.

First, the actual melatonin content of the supplements varied wildly between individual samples and lot numbers with no pattern between brands, forms of the supplements, or labeled value. Chewable tablets were the most variable with one sample containing 478% more melatonin than labeled (~9 mg versus the 1.5 mg label claim), and individual lots varied by as much as 465%. Capsules varied both in dosage and content. One sample had 83% less melatonin than labeled, and contained lavender, chamomile, and lemon balm. Other capsules contained a variety of herbal extracts including valerian root, passion flower, chamomile, skullcap, and hops.

Tablets were the least variable (-71% to +38% different than labeled), and contained the simplest mix of ingredients, generally melatonin added to cellulose-derived or silica fillers.

The dose variability is concerning for a couple of reasons. First, there are large individual differences in the bioavailability of melatonin. In other words, the amount of melatonin that gets into the circulatory system after taking a fixed dose varies considerably between people. So, swallowing 1 mg of melatonin for me is not the same as it is for you, even if we’re the same size. Second, the normal nocturnal concentration of circulating melatonin can vary more than 10-fold between healthy individuals. Consequently, 1 mg of melatonin may be far too much for you, but perfectly normal for me.

More concerning than the dose variability is that the scientists found 1.2 to 74.3 micrograms of the neurotransmitter serotonin (from which melatonin is derived) in eight of the supplements. As you may know, serotonin is a strictly controlled chemical used to treat neurological disorders. However, when taken in excess, it can lead to serotonin syndrome, which ranges from mild to fatal, and can be worsened by interactions with medications such as selective serotonin reuptake inhibitors (SSRIs), and analgesics such as tramadol.

Sex and melatonin… think about this carefully

In the late 1950’s, melatonin was investigated as a possible dermatological medication. However, it proved ineffective in treating human skin disorders. And, in the original paper, the authors admitted that, “The physiological role of melatonin in animals is not known at the present time.”

Then, in the early 1960s, melatonin was shown to have a strong effect on sexual development and reproductive physiology, and was referred to as an antigonadal hormone. For instance, injecting melatonin into female lab rats decreased estrus (sexual receptivity and fertility), and shrunk their ovaries. It also reduced testicular size in male hamsters and suppressed ovulation in females.

Now we know that melatonin has a very complex relationship with reproductive physiology. For instance, melatonin can increase fertility in sheep and is administered as a veterinary medicine to do so. Melatonin also suppresses estrus cycles in cats, and alters seasonal reproductive behavior in stallions, rams and hamsters. Even more remarkable is the fact that a small daily dose of melatonin that simply extends the normal nighttime concentration into the daylight hours will advance the onset of puberty in rhesus monkeys by as much as by 5 months (their total lifespan is only 25 years).

Speaking of primates — that includes you and me — melatonin also affects human reproduction. In the 1990s, melatonin was investigated as a possible contraceptive to be used in conjunction with progestins. A more recent review concluded that melatonin plays a key role in ovarian function, and may influence parturition time, oocyte (egg) maturation, embryo development, and fertility in humans.

Although you have to be thoughtful when comparing animal studies to human physiology, one reviewer noted that in proportion to body weight, the doses used in rodent and primate experiments are below the doses usually administered to children with sleep disorders, and, in another reviewer’s words:

“Considering the pronounced effects of the pineal gland and melatonin on reproductive physiology in these nonhuman mammals, to assume they would not have some sexual effects in humans would almost seem naive. Whereas only 30 years ago the pineal was generally considered to be vestigial, it now appears it may be functionally involved with every organ system in the body.”

Well, like I’ve said before, biology is complicated. It’s never as simple as it seems…

And, it’s never as simple as it seems when someone’s trying to sell you a bottle of pills.

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coming next… Part Two: What about that sleep thing?