Jack

Melatonin is arguably one of the most important our body can make—but few people understand how it’s truly made, & its full capabilities. It boasts a wide range of benefits, including anti-inflammatory, anti-stress, anti-cancer, sleep-promoting, pro-bioenergetic, immune-boosting, neuroprotective, longevity-promoting, circadian-regulating, & mitochondrial-supporting properties. This is a deep dive into the mechanisms & practical ways to optimize your melatonin levels, so you can live your life disease-free & at your peak health:

Here’s just a short list of the magical benefits of melatonin: · controls autophagy & apoptosis. · enhances mitochondrial dynamics via TCA cycle, ETC & thus makes more ATP & metabolic H2O. · increases endogenous production of various antioxidant enzymes / proteins (NRF2, SOD, CAT, GPx, glutathione, TRx/PRx) · recycles vitamin C, E, glutathione & other redox molecules. · potent antioxidant properties of its own, except doesn't have to be recycled = very efficient. · controls photoreceptor regeneration. · heavily influences circadian biology & downstream hypothalamic/pituitary hormones. · chelates free transition metals. Let’s get into how we make it.

Melatonin is made from serotonin, which is made from the aromatic amino acid tryptophan, it loves interacting with light & absorbs 200-400nm—which is UVA, UVB, & UVC light. ~95% of serotonin is made in your gut lining inside enterochromaffin cells—this can later form melatonin. Tryptophan can be derived from your diet, or from a healthy gut microbiome via the shikimate pathway. Melatonin is also made locally in the skin, eyes, & brain. As well as every cell-line that infrared light reaches—which we will get into. We need UV light from the sun to photoactivate tryptophan into serotonin.

It goes L-Tryptophan → 5-HTP → Serotonin → N-acetylserotonin → Melatonin. There are various cofactors required, you can see them all in the diagram below. Calcium, magnesium, iron, zinc, BH4, vitamin C, B3, B5, B6, B9, & anything tied to methylation (thus, methionine, glycine, choline, B2, B12, & again—magnesium, zinc, B3, B6, B9).

Tryptophan can also form tryptamine, which can form DMT. I wrote a thread regarding these concepts: https://x.com/jack_schroder_/s...

The beauty of melatonin is the fact that it has hydrophilic & hydrophobic properties—meaning it is partly water-soluble, as well as party fat-soluble. This enables it to be transported in blood/cytosol, & bypass lipid membranes with ease.

Under the stimulation of infrared light—in particular near-infrared (750nm–2000nm)—it induces local mitochondrial melatonin synthesis at every cell it reaches, via absorption at cytochrome C oxidase (complex IV). Beyond infrared light’s beneficial effects on collagen synthesis, charge separation of water, oxygen utilization, & mitochondrial optimization—this is yet another HUGE benefit of infrared light.

And for the record, infrared light is present via sunlight from dusk-till-dawn—all you need to do is just be outside, or crack open a window. So easy. I have written a huge thread on infrared light here: https://x.com/jack_schroder_/s...

This is one of, if not the most potent antioxidant in the body—both being able to reduce free radicals in itself (due to its electron-rich indole ring) multiple times, with a long half-life (significantly more than glutathione, vitamin C & E). It can directly recycle vitamin E, vitamin C, glutathione, & NADPH. It also directly scavenges superoxide (O2*-), hydrogen peroxide (H2O2), peroxynitrite (ONOO-), lipid radicals, & even the most aggressive one of them all: hydroxyl radical (OH*-). And there’s more—it upregulates endogenous antioxidant enzymes: superoxide dismutase, catalase, thioredoxin reductase, glutathione peroxidase, glutathione synthesis (HUGE), as well as inhibition of both NLRP3 & NF-kappa-beta. This leads to suppression of inflammation, heightened redox, & optimized bioenergetics to ensure your ferrari engine is running like it should.

Once melatonin donates an electron to a free radical to neutralize it, it then forms various other metabolites (AFMK, AMK)—which are also efficient free radical scavengers. Unlike other antioxidants, melatonin & its downstream metabolites don’t become oxidants themselves, & instead just get removed via urine.

Melatonin also has a local effect on the mitochondria—it can enhance electron tunnelling by shrinking the respiratory proteins in the electron transport chain (ETC) to bring them closer. This leads to more ATP, more metabolic H2O, less ROS/RNS, more NAD+, & overall optimized mitochondrial function. Now, this is where it gets interesting…

Melatonin has also been shown to be a potent inhibitor of pyruvate dehydrogenase kinase (PDK)—what does this mean? It prevents pyruvate dehydrogenase from being inhibited by PDK, allowing pyruvate to form acetyl-CoA, which then can be shunted into the TCA cycle for increasing everything mentioned above. This leads to the INHIBITION of hypoxic cancer cell metabolism—known as warburg metabolism. Melatonin is your #1 ANTI-CANCER molecule.

Also to note, this acetyl-CoA can not only feed into the TCA cycle, but is also fundamental to acetylation of serotonin to make melatonin inside our mitochondrial matrix—a double whammy.

Melatonin is a HUGE player when it comes to controlling autophagy & apoptosis. It regulates these processes, allowing for the removal of damaged cells & dysfunctional proteins, promoting cellular repair & renewal, as well as preventing the accumulation of harmful debris that can contribute to aging & disease. By optimizing autophagy & apoptosis, melatonin plays a fundamental role in maintaining healthy tissue function, reducing the risk of cancer & slowing the aging process overall.

The best explanation of autophagy & apoptosis from Jack Kruse’s blog—Hypoxia #18:

In terms of sleep architecture, melatonin is a HUGE player. The synthesis of this form of pineal melatonin instead influenced by absence of light—AKA darkness—which allows for the conversion of serotonin into melatonin in the pineal gland. This melatonin is KEY to sleep architecture, regulating ALL circadian hormones (leptin, prolactin, growth hormone, etc.), clearance of toxins/metabolic wastes via the glymphatic system, & mopping up any excess free radicals. Look at the graphic below—you’ll see pineal melatonin acts like a domino effect for enhancing the release of all circadian hormones.

Melatonin production can be suppressed by artificial light & natural light by various degrees. This is why I’m such a stickler for doubling down on your light-dark cycles. https://x.com/jack_schroder_/s...

Both noradrenaline & dopamine act as the ignition & brakes of melatonin synthesis/release, melanin may have an influence here: https://x.com/jack_schroder_/s...

Btw, you also need optimal levels of melatonin & dopamine (as well as adenosine) to properly regenerate ALL photoreceptors in your body—found most in eyes, skin, subcutaneous fat, brain, & arteries. These photoreceptors are fundamental to absorbing the external information of photons from sunlight, to determine what to do internally to best run optimally. This is how we best optimize circadian biology, bioenergetic/redox factors, hormone signals, neurotransmitter release, immune modulation, gut function, detoxification, & more.

Touching on serotonin quickly—it has a number of benefits when it’s in optimal amounts. It is a very complex neurotransmitter & hormone—it has 14 receptor subtypes, & has several heterodimers with other neurotransmitters—these are not only found in the brain, but peripheral body. I’ll be sure to write a big thread on serotonin someday soon.

If there’s any presence gut dysbiosis (infections, permeability, inflammation, digestive issues, etc.), it has the potential to elevate serotonin, which inevitably leads to lower melatonin systemically. Enterochromaffin cells have calcium (Ca2+) channels/vesicles, & if they’re chronically activated due to a nnEMFs/loss of charge—this leads to excess serotonin release. Alongside the many more potential consequences from chronic exposure to nnEMFs.

As I mentioned before, serotonin gets acetylated to form N-acetylserotonin (which then gets methylated to form melatonin) N-acetylserotonin may also have neurogenic effects. https://x.com/photobiogenesis/... Now, let’s get back to melatonin.

Now, circling back to light, it’s important to note that melatonin activity is incredibly sensitive to artificial blue light. Blue light photons (~460-480nm) that are found in unnatural amounts in tech devices, LED downlights, fluorescent bulbs, etc. have the power to completely INHIBIT melatonin—this is a BIG deal. It also raises cortisol, sympathetic drive, & induces melanopsin/mitochondrial dysfunction—leading to chronic inflammation, metabolic chaos, cellular dehydration, & decoherence to your system—nothing works well in this state.

Cortisol works on a see-saw with melatonin. Alongside leptin, they are 2 of the main circadian hormones that are strongly attuned to light-dark cycles, temperature, feeding cues, & exercise. As cortisol is a stress hormone, it also increases when one is under any form of stress—whether that’s light, metabolic, emotional, mental, or physical.

Acute stress, or for the better term—quantized pulses of stress hormones, are fundamental to life. It’s when this stress becomes chronic is where issues start to arise, it induces inflammation & hypoxia via HIF1a. If you are pseudohypoxic due to fear/stress, blue light/nnEMF, mitochondrial dysfunction, or malnutrition—then NAD+ levels drop.

What does this do? This pushes more tryptophan down the kynurenine pathway to make more NAD+. This means you make less serotonin/melatonin.

What’s interesting is that there is a circadian mechanism regarding NAD+ biosynthesis & recycling via NAMPT. So optimizing your circadian biology through respecting your local light-dark cycles, exposure to your outdoor environment, eating seasonally, & exercise/feeding at sensible times is key to driving proper NAD+ status, which indirectly improves melatonin. This NAD+ also acts a precursor to NADPH (via NAD kinase), which is key to antioxidant defence, recycling various metabolites, steroidogenesis, fatty acid & cholesterol synthesis, detoxification pathways, & more.

So to summarize above: if one has low dopamine, noradrenaline, melanin, & dysregulated cortisol—on top of low melatonin/serotonin (as well as various other neurotransmitters/hormones becoming dysregulated). There is complete dysregulation in sleep-wake cycles. You’ll feel wired at night, making it hard to get to sleep. As well as struggling to wake up in the morning. How many people do you know have this problem?

Before I summarize how to optimize melatonin status, let’s share some more cool stuff melatonin can do for you:

Melatonin acts as an aromatase inhibitor, leading to regulated estrogen status, thus increasing testosterone/DHT in men, as well as alleviating excess estrogen in women