A decade ago, melatonin was just considered a sleep hormone.
That all changed when scientists discovered as much as 95% of the body’s melatonin is NOT produced by the pineal gland, but rather to protect cells.
That’s right…
95% of the melatonin in your body has nothing to do with sleep!
Melatonin is a systemic supermolecule purported to:
- Deepen sleep
- Sync circadian ‘bioclocks’
- Shield mitochondria
- Modulate immunity
- Chelate heavy metals
- Defend against EMFs
- Supports gut-barrier integrity
- Enhances autophagy
- Bolsters antiviral defenses
In this guide I’ll explain everything you should know about megadosing melatonin, the benefits and drawbacks, and popular misconceptions.
Contrary to popular understanding, 95% of the melatonin produced by your body is for protecting your cells, while the other is for sleep. Not the other way around
Large doses show antioxidant, anti-inflammatory, and mitochondrial-protective effects, potentially useful in traumatic brain injury, stroke, etc.
Some studies suggest high-dose melatonin may slow tumor growth and improve survival in certain cancers
Outliyr considers anything over 50mg a melatonin megadose while other scientific studies have used well over 200mg
There are research institutes that consider melatonin as a longevity substance
Factors like age & metabolism naturally affect how long melatonin stays in your system
Melatonin as a Systemic Supermolecule
Melatonin is an indoleamine hormone (N-acetyl‑5‑methoxytryptamine) synthesized from serotonin not only in the pineal gland but also throughout the body.
Particularly in the gut, brain, immune cells, and mitochondria.
Enterochromaffin cells in the gut actually produce over 95% of your body’s melatonin, and it’s primarily used to support local redox balance and barrier integrity (N Engl J Med).
It binds MT1/MT2 receptors to regulate circadian rhythms and, importantly, also concentrates in mitochondria to scavenge free radicals (Trans Psych).
Why Megadose Melatonin & Why Do Biohackers Do It?
Megadosing refers to the process of consuming substances in far larger doses than traditional.
Standard supplemental doses (0.3-3mg) suffice for minor sleep issues or circadian re-alignment.
At ≥ 10mg melatonin floods intracellular compartments to act as an antioxidant and regulate genes (J Pineal Res).
While folks disagree on the exact threshold, I consider anything 50mg or greater a melatonin megadose.
Research has so far concluded up to 300mg/day to be safe with minimal serious adverse events (J Pineal Res).
High doses elevate tissue concentrations far above physiologic peaks, unlocking benefits unreachable by low-dose regimens (J Pineal Res).
As I’ll explain, unlike other hormones, ingesting exogenous melatonin doesn’t downregulate your natural production or receptor sensitivity.
Why I Take High Doses
For many years, I occasionally took 300mcg (micrograms, that’s 0.3mg) of extended release melatonin for sleep and circadian alignment.
When I came across Dr. John Lieurance’s book Melatonin Miracle and high-dose protocols (50-100mg+) for mitochondrial health and stress resilience, I looked into the research.
Eventually, I decided to test it out for myself.
I started with 20mg, and felt groggy the next day.
Paradoxically, I upped my dose to 50mg and felt less groggy. At 80mg, however, I woke up feeling totally refreshed and not groggy at all!
Immediately, I noticed:
- Faster workout recovery
- Fewer nighttime awakenings
- Greater stress resilience
- Lower resting heart rate
Over time, my digestions appears to have improved slightly, and I seem to get less disturbed by emotionally charged situations.
Energy levels were slightly more stable too, but that’s hard to quantify.
Fairly consistently, my lowest heart rate during sleep dropped by about 1 BPM. Not major, but interesting and worth noting.
Turns out, high-dose melatonin does all kinds of things.
Benefits & Uses of Megadosed Melatonin
This list is by no means comprehensive.
Nevertheless, these uses of megadosing melatonin should not be discounted due to its incredible potential benefit to safety ratio.
Most of the research has not been done on megadoses in healthy people likely due to stigma and funding reasons. Nevertheless, the mechanistic research appears to apply.
This 2024 systematic review of the evidence caught my eye (emphasis mine),
“The dose of melatonin supplemented in the trials ranged between 5mg to 100mg administered before or after exercise. The outcomes showed improvements in antioxidant status and inflammatory response and reversed liver damage and muscle damage. Moderate effects on modulating glycemia, total cholesterol, triglycerides, and creatinine were reported. Promising data were found regarding the potential benefits of melatonin in hematological biomarkers, hormonal responses, and sports performance”
The Impact of Melatonin Supplementation on Sports Performance and Circulating Biomarkers in Highly Trained Athletes
I do have a few concerns, however, that I’ll share later.
Deep sleep & circadian reset
Melatonin is among the powerful circadian reset agents available. This was one of its first discovered uses. Of course, it has become best known as a sleep aid.
Even in blind subjects, daily 10mg doses restore a normal 24 hour cycle and improve their sleep efficiency (N Engl J Med).
Higher dosages deepen slow-wave deep (N3) sleep, reducing awakenings and promoting restorative rest (J Pineal Res).
Most notably, shift-workers and travelers benefit from the phase-shifting effects. Minimizing jet lag and daytime fatigue (J Pineal Res).
The best time to take it for sleep enhancement appears to be 2-3 hours before bed and researchers recommend a higher dosage of 4mg (versus the clinical norm of 2mg) (J Pineal Res).
Note that dosing information on true high dose melatonin for sleep enhancement is sparse.
Apart from melatonin though, you can learn more about improving sleep here.
Cellular antioxidant defense
Melatonin concentrates in mitochondria, reducing cellular damage by scavenging reactive oxygen species/reactive nitrogen species (ROS/RNS).
As a paper titled Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas explains, it providing protection by upregulating superoxide dismutase (SOD) and glutathione peroxidase to preserve membrane integrity.
After neutralizing free radicals and losing its antioxidant properties, melatonin becomes other metabolites with antioxidant effects. Further protecting against prolonged stress.
This guards highly susceptible mitochondrial DNA (mtDNA) from damage during intense exercise or environmental exposures (J Pineal Res).
In a way, melatonin helps with cellular detox more specifically, protecting against the effects.
Immune & anti-inflammatory support
Megadosed melatonin powerfully downregulates a family of pro-inflammatory molecules, called cytokines (IL-1, IL-6, TNF-a).
It also alleviates chronic inflammation without heavy immunosuppression, promoting recovery from infections and workouts.
Melatonin balances immune activity of T-cells and macrophage responses (Cell Death & Dis).
This dual antioxidant-immune action helps with seasonal and travel-related illnesses (Int J Mol Sci).
Neuroprotection & cognitive clarity
Melatonin has multiple promising effects in the brain. It promotes the recycling of damaged parts of neurons (autophagy) and helps clear toxic proteins.
Functionally, melatonin guards against inappropriate cell death (apoptosis) and “brain fog” after sleep deprivation or injury (Trans Psych).
In a study titled, Melatonin’s neuroprotective role in mitochondria and its potential as a biomarker…, it says…
Melatonin stabilizes cell membranes and supports synaptic function, supporting cognition during stress
These effects make it a restorative nootropic agent and potential tool for brain-health protocols (Int J Mol Sci).
Heavy-metal protection
While it does not bind directly to heavy metals and help remove them from the body, melatonin does protect against the damage some of them cause (mercury, lead, and cadmium).
Melatonin helps reduce heavy metal damage by neutralizing free radicals, decreasing oxidative stress, and supporting detox pathways (J Pineal Res).
It also upregulates certain proteins (like metallothioneins) and antioxidant enzymes that bind heavy metals and reduce their toxicity (J Pineal Res).
Finally, melatonin alters how metals move throughout the body, by influencing metal transporter proteins.
EMF stress mitigation
The more technology and wireless signals pervade our life, the more we need intracellular protections.
Non-native electromagnetic radiation (EMR/EMF) impacts human physiology many ways, one of which is inducing oxidative damage.
Melatonin counters this oxidative damage by reinforcing cellular antioxidant defenses in various vital tissues throughout the body (neural, reproductive, etc.) (Curr Neuropharmacol).
It preserves the integrity of biological barriers and reduces skin damage from these sources of non-ionizing radiation (Curr Neuropharmacol).
Stacking with supplemental zinc, melatonin, and molecular hydrogen further amplifies protection against modern EMF exposures (J Pineal Res).
Gut-barrier & brain-gut axiss
Intestinal permeability (”leaky gut”) is among the major issues facing humanity. To varying degrees.
Megadosed melatonin strengthens the integrity of the gut (intestinal tight junctions) Share on XIt curbs endotoxin spillover into the bloodstream that then breaches the blood–brain barrier, causing neurological issues (N Engl J Med).
It alters the composition of the gut microbiota and local immune signaling to reduce gut inflammation (Int J Mol Sci). It becomes a factor in protecting and optimizing your gut health.
This is key to travel-related gut issues and healing from antibiotics and, since the gut is involved in all health, can help in many healing protocols (J Pineal Res).
Autophagy & cellular rejuvenation
Cellular health requires the replacing of damaged cellular components (organelles) to work effectively.
Melatonin regulates two key pathways (mTOR and sirtuins) to enhance this process (autophagy) under stress.
Unlike some powerful autophagy inducers, melatonin fine-tunes nutrient-sensing signals, promoting cleanup without excessive breakdown (Cell Physiol Biochem).
Some scientists believe this may underlie melatonin’s lifespan-extending effects (Int J Mol Sci).
Anti-pathogenic
Rapid melatonin administration disrupts viral “factories” which enhances innate immunity against RNA viruses (Int J Mol Sci).
Plus, infection models show that it lessens cytokine storms and supports mitochondrial health, including that of SARS-CoV-2 (Int J Mol Sci).
Back in 2021, it was one of multiple things I used to get over sickness symptoms in 24 hours.
The antiviral effects, combined with antioxidant and immunomodulatory actions, make it an interesting compliment to most longevity strategies (Cell Death & Dis).
Growth hormone boost
Growth hormone (GH) is sometimes touted as the “fountain of youth.”
Yet injections are expensive, require a prescription, and have trade-offs. Melatonin can help.
Melatonin seems to stimulate GH levels mainly by inhibiting a hormone that suppresses GH (somatostatin).
In men, a study showed that 5mg of melatonin administered 60 minutes before a workout significantly amplified the GH response by 157% to exercise (J ISSN). Good news for GH secretagogue peptide users.
Melatonin also enhances responsiveness to growth hormone-releasing hormone (GHRH), 2X’ing GH release when administered before GHRH stimulation (Science).
Cancer defense & adjunctive action
High dose melatonin reduces the proliferation of unhealthy cells, inducing apoptosis and interfering with tumor cell cycles.
Savvy doctors use melatonin as an adjunctive, because it enhances chemotherapy tolerance and may slow the progression of various cancers (breast, prostate, and colorectal) (Oncotarget).
It helps fix damaged DNA in cells, and it also stops tumors from growing new blood vessels to feed themselves (angiogenesis) (Cell Physiol Biochem).
Doctors & Experts Advocating High-Dose Melatonin Protocols
Currently, only several popular figures research and widely educate on high dose melatonin: Dr. Russel Reiter, Doris Loh, Dr. John Lieurance, and The Life Extension Foundation.
Most of them advocate larger doses to manage medical conditions and acute issues.
Dr. John Lieurance’s Melatonin: Miracle Molecule also mentions 100-200mg+ regimens for mitochondrial and endocrine rehab.
Especially for patients with chronic Lyme, mold illness, autoimmune disease, or cancer.
Doris Loh’s work on viral phase separation shows melatonin prevents “viral factories” in early infection specifically, with dosing of ‘tens of milligrams’ (20–80mg daily) (Int J Mol Sci).
Dr. Russel Reiter, author of 1,400+ studies, likes melatonin for its neuroprotective and oxidative stress regulating effects (Cell Death & Dis). He mentions dosages of 20–200mg+ (Front Med).
The editorial team and medical advisors of The Life Extension Foundation have long promoted the use of higher-dose melatonin for immunity, neuroprotection, and longevity purposes.
They sometimes use doses of 50mg, and write about research on dosing protocols of up to 1,000mg per day (Life Extension).
Safe Megadosing Strategies
Melatonin appears safe when used at high dosages, at least over the short-term (J Pineal Res).
Research shows:
- No evidence of clinically significant toxicity (organ damage, cardiovascular effects, etc.) in published studies up to 1,000mg/day for short periods
- No increase in serious adverse events or withdrawals due to adverse effects, even at very high doses; again, in short-term studies
Long-term, high-quality safety data are lacking. Most studies are small, short term, and/or do not rigorously report adverse events.
There are some populations that are even less studied and should be cautious with chronic high dosing:
- Children
- Pregnant women
- Autoimmune disease patients
A small crossover clinical study of 12 healthy male volunteers investigated the effects of high-dose (100mg) intravenous melatonin and found no adverse effects.
This study, Pharmacokinetics of high-dose intravenous melatonin in humans, did not find a greater sedative effect with the 100mg intravenous melatonin relative to a 10mg dose.
Indole melatonin (50mg) administered intravenously to 3 male narcoleptics dramatically increased the amount of REM sleep and decreased REM sleep latency (Peptides).
Oral administration of 1,000mg of melatonin daily to 5 adults resulted in, unsurprisingly, drowsiness reported as a side effect.
There were no severe and/or irreversible impacts on clinical parameters like:
- Blood pressure
- Heart rate
- ECG
- Serum chemistry
- Urine analysis
Not in these people taking a massive 1,000mg dose of melatonin each night for 25 to 30 days (J Clin Endoc Metab).
Some rumors claims that high doses of melatonin (>75mg) cause contraceptive effects, but this does not appear to be supported by evidence unless coadministered with synthetic birth control (J Clin Endoc Metab).
Myth-Busting Common Melatonin Concerns
Below are answers to frequently asked questions on melatonin.
Does melatonin desensitize receptors?
No human data show that melatonin desensitizes MT1/MT2 receptors at high doses. These receptors recycle rapidly after pharmacological exposure (J Pineal Res).
Unless treating a chronic condition, it still may make sense to cycle off melatonin supplementation occasionally. When following a high dose protocol, I will take 1 day off every 3 days or so.
Does melatonin shut down endogenous production?
No. Endogenous melatonin production rebounds within days of stopping use, even with 100mg/day for weeks (J Pineal Res). This suggests mild suppression during use, but not a complete shutdown.
Is melatonin safe?
Trials of up to 300mg, even up to 1,000mg/day, report only mild, self-limiting adverse events (drowsiness, headache, dizziness) (J Pineal Res).
Melatonin is not subject to the same negative feedback loops as other hormones.
Will supplementing melatonin reduce my testosterone levels?
Melatonin supplementation does NOT suppress testosterone and may actually boost it (J Sex Med, J Mens Health).
In women with PCOS (a condition classified as high testosterone) melatonin supplementation significantly reduced it, bringing it back into the optimal range (Front Endocrinol).
How do I stop melatonin grogginess?
Next morning melatonin grogginess is one of the most common adverse effects of any melatonin supplementation.
There are 3 main ways to combat it:
-Try changing dose
-Receive immediate morning light upon waking
-Some people report that consuming lemon water helps
Dose response to melatonin is very bioindividual and often biphasic. Doses of 3-20mg make me feel groggy, but lower dosages <3mg and above 20mg do not.
Does melatonin have side effects?
Yes, but melatonin side effects are generally rare and mild. Common side effects include:
-Headache
-Daytime sleepiness
-Dizziness
-Vivid dreams or nightmares
-Stomach cramps
-Mood changes like irritability or brief bouts of depression
Serious allergic reactions are very rare. Side effects tend to be more likely with higher doses or extended release forms, and older adults may experience prolonged sleepiness the next day.
Can I overdose on melatonin?
Yes, it is possible to overdose on melatonin, especially by taking an excessive amount well beyond recommended doses.
Research shows up to 300mg/day is safe, with very few serious side effects (J Pineal Res). I recommend consulting your doctor for doses higher than 300mg.
Symptoms of overdose can include:
-Extreme drowsiness
-Irritability
-Stomach pain
-Nausea
-Fatigue
-Hypotension
-Tachycardia
-Hypothermia
Life-threatening overdose is rare but may require emergency care if severe symptoms like difficulty breathing, seizures, or loss of consciousness occur. Treatment is supportive with close monitoring.
How long does melatonin stay in my system?
Melatonin typically stays in your system for about 4 to 5 hours.
Its half-life is around 20 to 60 minutes, with most of the hormone cleared within this timeframe. Extended-release forms may last slightly longer.
Factors like age and metabolism can affect this duration. It takes longer for older populations and those with slower metabolism to clear melatonin.
Megadosing Melatonin: The Cheap, Accessible, & Forgotten Health Tool
Melatonin is colloquially known as ‘the sleep hormone’. Which makes sense, given its intricate role in circadian rhythm and sleep architecture.
The new science of human biology, however, clearly shows that the vast majority of the body’s melatonin isn’t in the brain and isn’t used for sleep. Instead…
Cutting-edge research suggests melatonin’s main role is as the body’s master antioxidant. Shielding every cell from damage and the harmful byproducts of the mitochondrial energy generation process
Whether you’re seeking immune regulation, healing from various conditions, or just greater performance, melatonin is a powerful full-spectrum therapeutic tool (Cell Death & Dis).
In fact, some research institutes like Life Extension Foundation categorize melatonin as a longevity substance.
Especially when used in megadoses.
Remember that it follows a biphasic dose curve. You’ll likely notice improved sleep from very low dosages (<1mg).
For me, standard melatonin doses of 1-20mg make me feel groggy the next day.
Superdoses of 20-80mg are my sweet spot, where I saturate intracellular melatonin and amplify my bodily protection. Paradoxically, without the next day melatonin hangover.
What about you? Have you tried high dose melatonin?
Drop a comment below and share your experience!
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