By Dr. Allison Smith, ZRT Laboratory
I have been up to my elbows in melatonin research for a week now.
I always felt like I had a pretty good working knowledge of where melatonin came from in the body, roughly how it was synthesised, the signals that propagate its production, and where it acts. Like most clinicians, I tended to think of it for sleep problems in general and as an adjunct treatment for some of the comorbidities associated with different cancers.
I was also vaguely aware that there was a physical reason my colitis patients usually presented with depression and sleep problems — the gut really is the bigger of our two brains, after all. But I am not sure I was able to put it all together until this intensive synthesis of information.
Melatonin Is a Major Hormonal Player
While I am not ready to say that melatonin or any one hormone is a panacea, I will say it truly is a hormone with far-reaching potential to be a major player in resolving a myriad of health issues. If you thought melatonin was just a sleep hormone, consider this short list of its strengths:
- Resolving sleep disorders
- Decreasing pain in chronic pain conditions, including neuropathic pain
- Improving quality of life in depressed patients
- Reducing oxidative damage
- Acting as an anti-inflammatory agent by inhibiting 5-LOX and COX-2
- Ramping up both humoral and cellular immune responses
- Maintaining the circadian rhythm by day (from the gut) and by night (from the brain)
- Healing damaged tissues
This is all compelling, but to really understand melatonin’s importance and potential for improving health, we should start with what we know about its biochemistry and physiology.
If you are experiencing poor sleep, low mood, or persistent fatigue, our Sleep Balance Profile Test measures melatonin (as its urinary metabolite MT6s), cortisol and other key hormones involved in the sleep-wake cycle — giving you a clear biochemical picture of what may be driving your symptoms.
How Melatonin Is Produced in the Body
Where Melatonin Comes From
It might be surprising to hear that melatonin is synthesised from L-tryptophan at 500 times greater concentrations in the gastrointestinal tract than in the pineal gland of the brain. The gut is responsible for most of our daytime synthesis of melatonin, and its release increases significantly in response to food intake — particularly protein-rich foods with high tryptophan content. At night, the pineal gland takes over production by responding to light deprivation in the form of a huge surge of melatonin, peaking around 2am and dropping steadily until waking. The enzymes for synthesis of melatonin can also be found in the skin, lymphocytes, various epithelia throughout the body including airway passages, reproductive organs, endothelial cells, and in the thyroid.
The Melatonin Synthesis Pathway
The melatonin production pathway starts with tryptophan, an essential amino acid found in high-protein foods like chicken, fish, nuts and spinach. It is always important to remember that proper stomach acid and pancreatic function is required to break down and assimilate proteins into amino acids for absorption.
The first two steps in the pathway from tryptophan require the help of nutritional cofactors — niacin, iron, folate, zinc, B6, magnesium and vitamin C — resulting in serotonin. Once melatonin is formed, its versatile structure allows it to penetrate nearby and distant tissues very quickly for a near-immediate effect. Circulating melatonin is hydroxylated and conjugated with sulphate in the liver to form its primary metabolite, melatonin 6-sulphatoxy (MT6s), and excreted into urine.
Because serotonin is the direct precursor to melatonin, disruptions in serotonin production — whether from nutritional deficiencies, stress or gut dysfunction — will directly impair melatonin synthesis. Our Neurotransmitter Testing (Dried Urine Spot) measures serotonin, dopamine, GABA and other key neurotransmitters alongside melatonin metabolites — helping to identify whether a neurotransmitter imbalance is at the root of your sleep or mood difficulties.
Where Does Melatonin Act? Virtually Everywhere
Not surprisingly, melatonin has its own special membrane receptors — MT1, MT2 and MT3 — found in almost every cell and tissue in the body, from epithelia to neurons to smooth muscle.
“In humans, melatonin receptors were also detected in several organs, including brain and retina, cardiovascular system, liver and gallbladder, intestine, kidney, immune cells, adipocytes, prostate and breast epithelial cells, ovary/granulosa cells, myometrium, and skin.” The nuclear melatonin receptors, RZR/ROR, are as ubiquitous throughout the body as the membrane receptors and may be responsible for its apoptotic effects on cancer cells.
The Cortisol–Melatonin Relationship
One of the most clinically significant factors that suppresses melatonin production is elevated cortisol — particularly at night. Cortisol and melatonin operate on opposing rhythms: as melatonin rises in the evening, cortisol should be falling. When chronic stress keeps cortisol elevated into the night, melatonin production is blunted and sleep quality suffers. If you suspect adrenal stress may be interfering with your melatonin rhythm, our Adrenal Stress Profile (Saliva) measures cortisol at four time points across the day — including the critical evening reading — alongside DHEA-S.
References
- Dai J, et al. Transcriptional repression of RORα activity in human breast cancer cells by melatonin. Mol Cell Endocrinol. 2001;176:111–120.
- Ekmekcioglu C. Melatonin receptors in humans: biological role and clinical relevance. Biomed Pharmacother. 2006;60:97–108.
- Karasek M, Winczyk K. Melatonin in Humans. J Physiol Pharmacol. 2006;57 Suppl 5:19–39.
- Konturek SJ, et al. Role of melatonin in upper gastrointestinal tract. J Physiol Pharmacol. 2007;58 Suppl 6:23–52.
Originally by Dr. Allison Smith, ZRT Laboratory. Reproduced with permission. Last reviewed: May 2026.