Melatonin Overdose: Cause of Death?

According to a 2012 survey administered by the American Academy of Sleep Medicine (AASM), around 1.3% of U.S. adults (3.065M) had taken melatonin within the past 30 days. (R)

(This was more than a 2-fold increase from just 0.6% of U.S. adults who admitted to using melatonin within the past 30-days in a 2007 survey.)

A report from Business Insider, American consumers spent $825M on melatonin supplements in 2020 (a 42.6% year-over-year increase) and industry analysts expect the melatonin market to continue to grow. (R)

If so many people are taking melatonin, why haven’t we heard about melatonin overdoses?

For clarification, I’m going to define melatonin overdose – as many people assume “overdose” = death from a specific substance.

In reality, overdose just means taking more than a normal or recommended amount (i.e. over-dosing) regardless of whether intentional or unintentional.

Melatonin overdose (definition)

Administering more than a scientifically- or medically-recommended dosage of melatonin. An overdose may cause side effects, serious adverse reactions or death (i.e. fatality).

Note: Some people use the term “overdose” exclusively to refer to a lethal or toxic amount of a drug – not just “taking more than medically-recommended.”

Melatonin Overdose (Potential Effects, Symptoms, Reactions)

Included below is a list of symptoms that may occur with melatonin overdose.

Understand that these symptoms are NOT guaranteed to happen following melatonin overdose – and that there may be significant inter-individual variability in specific symptoms and respective severities.

These are merely symptoms that were documented in “case reports” and/or studies in which extremely high doses of melatonin were administered (R1, R2)

  • Abdominal cramps
  • Anxiety
  • Brain fog
  • Cutaneous flushing (sensation of warmth)
  • Depersonalization
  • Diarrhea
  • Disorientation
  • Drowsiness
  • Drunken appearance
  • Eye & vision changes (inability to focus eyes, scotomas, etc.)
  • Fatigue
  • Gastritis
  • Headache (migraine)
  • Hypotension (low blood pressure)
  • Insomnia
  • Lethargy
  • Memory loss
  • Nightmares
  • Orthostatic hypotension (abrupt low blood pressure after standing up)
  • Reduced arterial blood pressure
  • Reduced plasma noradrenaline levels
  • Reduced psychomotor activity
  • Sleepiness (i.e. somnolence)
  • Skin rash
  • Tingling sensations

Note #1: Not all of the effects documented in “case reports” of melatonin overdose may have been attributable (solely or even partially) to melatonin overdose (as co-administered substances may have played roles) – so it’s fair to remain skeptical of various effects listed.

Note #2: Some of these symptoms may have a “delayed-onset” if an extended-release, prolonged-release, or controlled-release melatonin are taken (as opposed to fast/instant-release formats).

Related: Can Melatonin Shrink Your Testicles?

Melatonin Overdose (Case Reports)

I conducted a search for “melatonin” and “overdose” in scientific databases and case reports were scarce.

(If you know of any additional case reports, feel free to share so that I can add/discuss them in this article.)

For some perspective: A standard melatonin dosage (for most people) ranges from 0.3 mg to 10 mg – taken 30-60 minutes prior to one’s ideal sleep time.

Severe Hypotension in an Adolescent After a Melatonin Overdose (R)

  • Date: 2019
  • Authors: Johnson et al.
  • Patient: 16-year-old girl
  • Medical conditions: Depression, Anxiety, ADHD, asthma
  • Melatonin (over)dose: 180 mg (20 tablets of 9 mg)
  • Other substances (urinalysis): Fluoxetine; Diphenhydramine; Dextromethorphan; Hydroxyzine metabolite; Trimethoprim.

What were the effects of melatonin overdose in this patient?

Day 1 (Hospital)

Patient was admitted to university hospital with lethargy and a Glasgow Coma Scale score of 15 – indicative of mild psychomotor impairment.

For those unaware, the Glasgow Coma Scale measures the level of consciousness and overall status of the CNS. (Glasgow Coma score of: 13-15 = mild; 9-12 = moderate; 3-8 = severe).

Vital signs were as follows: (1) blood pressure (126/99 mmHg); (2) pulse (82 BPM); (3) respiratory rate (14 breaths/minute); (4) pulse oximetry (100% on room air).

Laboratory results: unremarkable except mild leukocytosis (11.7 k/uL) – or slightly elevated level of leukocytes (i.e. white blood cells) in the blood.

Electrocardiogram (ECG): normal sinus rhythm & normal QTc-interval.

Co-administered substances: Patient also administered medically-prescribed fluoxetine (40 mg) & hydroxyzine (50 mg) and [2-fold her prescribed daily dose of] guanfacine (4 mg, immediate-release), methylphenidate (72 mg, extended-release) – all administered ~17 hours before arrival.

Urinalysis drug screen: Showed only fluoxetine, diphenhydramine, dextromethorphan/dextrorphan, hydroxyzine/cetirizine metabolite, and trimethoprim.

Discrepancies between what the patient reported taking and the urinalysis results indicate that the patient may have inaccurately reported the substances ingested in the 24 hours before hospital admission.

Day 2 (Hospital)

The patient was sent to the behavioral health unit and presented as drowsy, minimally responsive, and complained of tingling sensations and inability to focus her eyes.

Blood pressure was 68/50 mmHg which improved to 80/60 mmHg after ad lib oral fluid intake.

Orthostatic hypotension: ~10 hours after fluid intake, orthostatic vital signs revealed a 45/24 mmHg decrease in blood pressure from supine (107/69 mmHg) to sitting (62/45 mmHg).

Day 3 & 4 (Hospital)

Hypotension significantly worsened in this patient.

~3L IV saline was administered but standing blood pressure remained extremely low (50/21 mmHg) and she reported severe dizziness.

Thereafter, she was transferred to a pediatric hospital where she received continuous IV fluid therapy for 18 hours.

Blood pressure stabilized without vasopressor support after 24 hours.

What did the pharmacists and medical doctors (MDs) conclude from this case?

  • There’s a paucity of information on melatonin toxicology.
  • There are limited reports of overdose and reported cases ingested lower quantities than seen in this patient.
  • Symptoms in other cases of melatonin overdose included: drowsiness; dizziness; blurry vision; and confusion.
  • The patient’s symptoms were consistent with other cases of melatonin overdose – but differed in that this patient exhibited extreme orthostatic hypotension.
  • Possible mechanisms of melatonin-induced hypotension? Unclear. Possibly related to nitric oxide formation causing vasodilation, parasympathetic stimulation, or calcium metabolism.
  • Why the delay in hypotension onset (e.g. becoming more severe on Day 3)? Authors suspect potentially a “prolonged-release” formulation of melatonin was taken.
  • (In my opinion, it’s also possible that the patient was a slow CYP1A2 metabolizer – or that melatonin metabolism/excretion was slowed by concomitant substance ingestion.)
  • Thankfully, authors admit that the patient’s symptoms could’ve been due to an interaction between melatonin and reported co-ingested medications/other drugs.
  • The overall takeaway is that medical doctors should look out for similar signs (including orthostatic hypotension following melatonin overdose – and that onset of the hypotension may be delayed if prolonged-release melatonin is administered.

The problem with concluding that presenting symptoms were due to primarily to melatonin…

A variety of other substances were documented (in the urinalysis drug screening) as being present in the patient’s system: fluoxetine; diphenhydramine; dextromethorphan/dextrorphan; hydroxyzine/cetirizine metabolite; trimethoprim.

Let’s think logically about this case… Can any of the above medications cause orthostatic hypotension – along with lethargy, dizziness, drowsiness, inability to focus eyes? Yes.

Might the combination of substances (and respective dosages) taken by this patient have generated pharmacokinetic or pharmacodynamic interactions and/or subsequent synergistic effects irrespective of melatonin? Yes.

Could the high dose of melatonin have been solely or largely to blame for the patient’s symptoms? Yes.

Is it likely that melatonin was to solely blame for the patient’s symptoms? Unknown (too many co-administered substances as confounds).

Most likely: The combination of all substances taken by this patient – coupled with the high dose of melatonin (180 mg) – caused this patient’s symptoms (via synergistic/interaction-type actions).

What were the melatonin overdose symptoms for this patient?

This assumes that the patient’s symptoms were solely attributable to melatonin. Included below is a list just as a “recap.”

  • Dizziness (severe)
  • Drowsiness
  • Inability to focus eyes
  • Lethargy
  • Low blood pressure
  • Minimally responsive
  • Orthostatic hypotension (severe, delayed-onset)
  • Tingling sensations

Problems in Assessment of Acute Melatonin Overdose (R)

  • Date: 1997
  • Authors: Holliman & Chyka
  • Patient: 66-year-old man
  • Medical conditions: Insomnia (chronic) & Hypertension
  • Melatonin dose: 24 mg (8 tablets of 3 mg “Melatone” melatonin) – his usual dose was 6 mg (2 tablets of 3 mg)
  • Other substances: Chlordiazepoxide; Amitriptyline; Lisinopril; Diltiazem

Pharmacists wrote up a case report of an “acute melatonin overdose.”

General Information & Case Presentation:

In the past, this patient routinely took a combination of melatonin (6 mg) with chlordiazepoxide and amitriptyline as an evening sedative to enhance sleep.

This particular night, the 66-year-old man took 24 mg melatonin (4-fold his usual dose) because he thought it would aid in relaxation and sleep the night before his prostate surgery.

Within just 20 minutes of taking the melatonin, he felt lethargic and disoriented, became alarmed, and called the local poison center.

The man was verbally coherent with no complaints other than fatigue and sleepiness.

He denied drinking alcohol or using any drugs other than his usual medications (chlordiazepoxide & amitriptyline).

The patient was monitored at home through follow-up calls from the poison center to his spouse.

He was sitting up and reading but reported feeling sleepy ~1.5 hours after administering melatonin.

After ~5 hours of sleep, the patient awoke and [allegedly] appeared “drugged.”

He was [allegedly] unable to recall events of the previous evening [according to his spouse] – indicative of memory loss.

(It was not mentioned whether his memory of the previous evening eventually returned – such as 48-72 hours after the initial memory lapse.)

Because prostate surgery was scheduled just hours after the patient awoke, it was recommended that he inform his surgeon and anesthesiologist about the acute reaction to his recent melatonin use.

Spinal anesthesia for the surgery was successful and without complications.

The patient recovered rapidly and was discharged from the hospital a day early.

No other abnormal effects were reported by the patient from his larger-than-usual melatonin dose.

~48 hours after the melatonin incident, he resumed his melatonin at his usual (6 mg) dose with chlordiazepoxide and amitriptyline.

When asked why he uses melatonin, the patient claimed that melatonin potentiates the action of his sedative medications – making the combination more effective for chronic insomnia.

Authors of this report almost conveniently neglected to mention that the patient also had hypertension and was being treated with lisinopril and diltiazem.

What did the pharmacists mention & conclude from this case?

  • Melatonin has been shown to have a direct sedative-hypnotic effect.
  • Problems with assessing acute melatonin overdose include: (1) determination of therapeutic dosage range; (2) effects on comorbid conditions; (3) potential drug interactions; and (4) belief that melatonin is not a “drug.”
  • Doses of melatonin formally evaluated for sleep induction range from 0.1 mg to 1000 mg.
  • Melatonin between 10-50 mg has been investigated as a treatment for cancers – and melatonin at 300 mg daily has been studied as a potential oral contraceptive.
  • Several sources claim that 6 grams (6000 mg) can be taken with zero or minimal toxicity, the basis for this claim is a small observational study (11 subjects) – all of whom took at least 3 grams (3000 mg) for 15-35 days.
  • Reactions included: a few isolated but obvious episodes of: cutaneous flushing; abdominal cramps; diarrhea; scotoma lucidum (altered field of vision); and headaches (migraine).
  • It was further noted that melatonin supplement contents may not accurately reflect the label in terms of: (A) purity & (B) dosage.
  • Authors acknowledge that there are several problems in attributing observations in this case solely to an adverse effect of melatonin, including: (1) no formal medical evaluation (all hearsay from patient and spouse); (2) presence of other drugs; (3) medical conditions (chronic insomnia & hypertension).
  • It was hypothesized that long-term use of low-dose melatonin in concert with other sedatives may have triggered an acute reaction following a sudden increase in melatonin dosage.

The problem with concluding that the presenting symptoms were due to melatonin…

Although technically the patient “overdosed” (i.e. took more than his normal or recommended amount), a 24 mg dosage of melatonin is not generally regarded as high enough to induce medically concerning or problematic reactions.

Furthermore, we must take into account that no urinalysis screening was conducted to determine whether the patient had consumed alcohol or other drugs – or larger-than-usual amounts of other medications (chlordiazepoxide, amitriptyline, lisinopril, diltiazem).

The respective administration timings of each medication and potential interactions/synergies of these substances (e.g. slowing melatonin/drug clearance or potentiating a sedative/hypnotic effect).

The patient had an upcoming surgery (potentially stress/anxiety-inducing) – which may have contributed to certain symptoms (to some extent).

The patient was also formally diagnosed with chronic insomnia; hypertension; and had a prostate issue (which required surgery).

Specific melatonin supplement taken was not documented nor chemically analyzed for impurities.

Metabolism and excretion rates of melatonin and other drugs for in this individual remain unknown. (CYP1A2 expression, liver & kidney function influence metabolism/elimination).

Most likely: There was some sort of interaction between higher-than-usual melatonin dosage (24 mg), chlordiazepoxide, amitriptyline, lisinopril, diltiazem.

This case report has glaring limitations:

  1. The patient was NOT evaluated by a medical professional
  2. Symptom reports were from the patient and his wife
  3. There may have been overreaction/panic due to upcoming surgery (thinking too much melatonin will exacerbate anesthesia or surgery)
  4. Unknown as to whether dosages of other drugs were increased (and maybe not mentioned by the patient)
  5. Unknown as to whether other substances (e.g. alcohol) were ingested
  6. Unknown to what extent medical conditions (e.g. chronic insomnia, hypertension) may have played in symptom presentation
  7. Specific melatonin supplement not chemically analyzed for dosing accuracy and impurities

My thoughts on this specific case…

My analysis here is that the patient took more melatonin than usual and, coupled with his other medications, it made him feel disoriented and mentally foggier than usual.

He likely panicked due to the combination of: (1) perceptual change (i.e. disorientation) & (2) upcoming surgery concerns (thinking melatonin may somehow interfere with it or increase risk of death via anesthesia) – and called the poison center.

He maybe told his wife about taking a bunch more melatonin than usual and she may have also panicked and been worried (particularly given his upcoming surgery).

It would’ve been beneficial to follow-up with this patient a few days post-surgery to determine whether his memory returned of the night on which it lapsed.

This case wasn’t concerning enough to the poison center to send this patient to a hospital for immediate medical evaluation, his surgery was carried out successfully (on schedule), and he returned to normal within ~48 hours of the “melatonin overdose.”

What were the effects of melatonin “overdose” for this patient?

  • Lethargy
  • Disorientation
  • Anxiety (enough to call the poison control center)
  • Fatigue
  • Sleepiness
  • “Drugged” appearance (according to his wife)
  • Memory lapse/loss (inability to recall the previous night’s events) (according to wife)

The Importance of Melatonin Detection in Pediatric Deaths (R)

  • Date: 2019
  • Authors: Labay et al.

In the journal Academic Forensic Pathology, researchers underscore the importance of melatonin detection in pediatric deaths.

Recent news reports suggest that melatonin is often administered without appropriate authorization and oversight in daycare centers.

Although lethal outcomes have not been solely attributed to exogenous melatonin overdose – it may have been a contributing factor in 2 cases.

Case #1 (9-month-old female)

  • Found unresponsive after co-sleeping with an obese adolescent sibling (250-300 lbs.).
  • The mother had a longstanding history of drug abuse, diabetes mellitus, and placenta previa.
  • The baby was last known to be alive at ~9 PM and found unresponsive at ~10 AM and declared dead at 10:12 AM.
  • Caretaker was out partying the night before and was quoted as saying: “I was so drunk I do not remember my babies last night.”
  • Additional neglect allegations including: (1) pesticide exposure; (2) dextromethorphan ingestion (afternoon prior to death ~2 PM) when baby drank from her sister’s cup; (3) nicotine ingestion from consuming ½ cigarette; (4) rubber band in mouth.
  • The caretaker also admitted to providing melatonin to the child. Sleeping environment was also unsafe: co-slept in prone position in adult bed with overstuffed bedding.
  • Evidence of physical injury: Trauma to the right-side of the scalp, a nasal plume, blanched livor on right face and abdomen, and right temporalis hemorrhage with focal subscapular and subgaleal hemorrhage.
  • LC-MS analysis of blood and gastric fluid revealed melatonin concentrations of 13 ng/mL (blood) and 1200 ng/mL (gastric fluid).
  • Toxicology results were negative for organophosphate pesticides, nicotine, and dextromethorphan.
  • Cause of death was ruled undetermined, but melatonin may have played a role.

Case #2 (13-month-old male)

  • Found unresponsive in a room shared with brother. A space heater was located between 2 playpens.
  • Melatonin was found within some of the empty “sippy cups” and bottles.
  • The baby was checked on throughout the night but found unresponsive in the morning.
  • First responders noted the baby was “extremely warm to the touch” and the room temperature was above 80 F (26.7 C).
  • Anatomic and clinical findings revealed: early decomposition with superficial skin slippage, evidence of medical intervention, a large amount of white particulate/granular matter in stomach, partial burns to the lower extremities, petechiae over the thymus and heart, impacted stool within the rectum, and gastric aspiration.
  • There was no evidence of blunt or penetrating trauma or skeletal injury.
  • Toxicological analysis via LC-MS determined melatonin concentrations of 210 ng/mL.
  • Cause of death was determined to be acute melatonin ingestion and complications of thermal injuries to the body. Manner of death was ruled a homicide.

What did the authors conclude from these cases?

  • Severe adverse events and lethal outcomes as a direct consequence of melatonin administration have not been reported – even in overdose.
  • For this reason, melatonin is not included in routine toxicology panels designed for postmortem investigations.
  • It was noted however, that pediatrics are vulnerable to mistreatment and abuse – and that care providers may be tempted to use something like melatonin to get them to sleep for an extended period of time.
  • Although not always intentionally nefarious, regular forced induction of sleep (such as with melatonin) could be indicative of infant/pediatric neglect.
  • Moreover, even older children that are capable of more advanced communication may lack cognitive ability to recognize a poor care environment.
  • Providing melatonin to induce sleep without appropriate authorization in daycare settings has been reported in multiple cases – and postmortem analyses reveal the importance of melatonin detection in forensic pediatric death investigations.
  • LC-MS is effective for successfully determining level of exogenous melatonin ingested – and may indicate secretive, inappropriate administration to pediatrics.

Did melatonin cause death in either of these babies?

It probably was a contributing factor – particularly in the second case.

It’s difficult to know whether either baby would’ve “died” solely from standalone melatonin administration – as there were many confounding variables.

  • Confounds in the first case: Unsafe/improper sleeping position in an inappropriate/unsafe bed (with an obese sibling); potential: pesticide exposure, dextromethorphan ingestion, nicotine ingestion; a rubber band within the mouth; evidence of significant physical injuries.
  • Confounds in the second case: Space heater & extremely hot room temperature; physical burns; impacted stool; gastric aspiration.

In the first case, it’s difficult to know whether the baby died from: sleeping in an improper position; perhaps being smothered (even accidentally) by an obese sibling; physical abuse; and/or melatonin.

In the second case, the space heater may have played a role in causing death, however, it seems as though melatonin overdose is the most likely cause.

Levels of melatonin were 210 ng/mL and the white granular matter (melatonin) probably accumulated to such an extent that it caused both impacted stool and gastric aspiration – and ultimately death.

The sheer content of melatonin within the second baby’s stomach is likely what caused the death – not necessarily the biological effects of that melatonin (e.g. within the CNS), but this can’t be ruled out.

What did case reports and scientific literature tell us about melatonin overdose?

I was able to find 4 total reports of “melatonin overdose” in the scientific literature: (A) a 66-year-old man; (B) 16-year-old female; and (C) 2 infants (9 months & 13 months).

Below is a summary of what I learned from these reports.

Melatonin overdose might cause death in infants

Particularly if a nefarious adult intends to kill (as was documented in a homicide wherein concentrations of melatonin reached 210 ng/mL in the body of a 13-month-old).

13-month-old

In the one case wherein melatonin was a likely contributor to or cause of death – the pharmacodynamic actions of melatonin may not have been as much to blame as the sheer accumulation of melatonin granules in the body (causing stool impaction, gastric aspiration, probable breathing difficulties and subsequent asphyxiation, etc.).

9-month-old

In another case wherein melatonin may have played a role in causing death – there are so many confounding variables (e.g. improper sleeping position/environment, neglect, physical abuse, potential ingestion of other drugs/pesticides, etc.) that it’s impossible to know what the role melatonin played in the death – or if it played any role at all.

Even in case reports of “melatonin overdose,” there are so many confounds that it’s difficult to know whether the presenting symptoms were legitimately due to melatonin overdose, other variables (co-ingested substances, medical conditions), or a combination of melatonin plus other substances/medical conditions.

16-year-old girl

Had other medications in her system including: fluoxetine, diphenhydramine, dextromethorphan, hydroxyzine metabolite, trimethoprim – and had ADHD, anxiety, and depression.

Melatonin dose (180 mg) was high and likely interacted with other substances in her system to cause severe orthostatic hypotension.

66-year-old man

Took other medications with melatonin including: chlordiazepoxide, amitriptyline, lisinopril, diltiazem – and had hypertension, chronic insomnia, and upcoming prostate surgery.

(None of his symptoms were concerning enough to poison control to recommend that he seek emergency medical care).

His melatonin dose wasn’t considered dangerously high (only 24 mg). None of his “overdose” symptoms were medically-verified.

Any deaths confirmed from just melatonin?

There are zero medically-documented adverse reactions or deaths in which melatonin overdose is confirmed to be the sole cause.

Overdosing on melatonin while under the influence of other substances (e.g. medications, supplements, etc.) – particularly CNS depressants (e.g. alcohol; benzodiazepines; nonbenzodiazepines; opioids; various antidepressants; antipsychotics; antihypertensive agents; antihistamines) – could increase risk of adverse reactions and death.

  • Why? A melatonin overdose could probably potentiate the effects of and/or interact with other substances.
  • In both the 16-year-old and 66-year-old cases, I think potentiation or interaction type effects (from melatonin + a cocktail of other drugs) probably explained the presenting symptoms.
  • Do I think these symptoms would’ve happened with standalone melatonin (and no other drugs)? Likelihood is considerably less – but I can’t make guarantees.

There are zero reports of “melatonin overdose” occurring in completely healthy individuals (all had multiple medical conditions and some were also being abused by caregivers).

Important to understand: Adverse reactions to melatonin do NOT always mean “melatonin overdose.” Some people won’t tolerate melatonin well regardless of the dose. (Don’t always assume “overdose”).

Reiterating: “Overdose” does NOT automatically mean “death.” It simply means taking more than an intended dose or overshooting the amount. Most people who use the term “overdose” refer to an amount taken that generally results in death.

Since melatonin usage continues to increase (according to the latest data), we’ll see maybe more case reports of “melatonin overdose” in the future.

My main issue with current case reports is that they seem to overemphasize the potential role of melatonin in causing adverse events – while underemphasizing the potential roles of other medications in systemic circulation.

Instead, case reporters should discuss potential roles of: (A) other medications/substances in systemic circulation (along with melatonin); (B) medical conditions; and (C) the combination of melatonin + other substances + medical conditions (and how the combination may alter physiology to cause adverse reactions and/or death).

One might argue that instead of emphasizing “melatonin overdose” – the case reports should’ve instead emphasized potential adverse events stemming from “melatonin interactions” with other medications (e.g. antidepressants, antihypertensives, benzodiazepines, etc.).

I would argue that interactions would be more valuable to study melatonin interactions with commonly used medications (prescription & OTC) – than suggesting high-dose melatonin is somehow dangerous as a standalone agent.

There’s some potential risk with any dietary supplement, including melatonin (supplements are NOT regulated by the FDA) – so there’s potentially dangerous impurities and/or dosing discrepancies (between listing and actual contents).

That said, there are “bad batches” of pharmaceutical medications on occasion wherein people end up with impure or tainted pharmaceutical drugs and experience serious adverse events, etc. (Then you read about FDA recalling a certain drug and subsequent lawsuits).

I happen to think that, when used responsibly, melatonin is one of the safest supplements on the market with an extremely low risk of adverse events – even from an overdose.

Isn’t melatonin toxic at high doses?

Guardiola-Lemaitre (1997) suspected that melatonin (high-dose, chronic dosing, or improper time of administration) could potentially adversely affect:

  • The reproductive system
  • Photoreceptors in the eye: Causing: deprivation myopia; intraocular pressure glaucoma; increase phagocytosis retinal pigment epithelium to induce age-related maculopathy).

However, there are no data from this report suggesting that melatonin is actually toxic – just hypotheses that it could be in certain circumstances (e.g. regular administration of extreme doses taken at improper circadian times).

According to Melatonin StatPearls (2021): (R)

“The acute toxicity of melatonin, as observed in both animal and human studies, is remarkably low. Melatonin may cause minor adverse reactions such as headache, insomnia, rash, gastritis, and nightmares at supraphysiological doses.”

Researchers could NOT discover an LD50 (lethal dose for 50% of the subjects) for melatonin in animals. (This is pretty crazy considering that nearly all substances have documented LD50s.)

What are the highest dosages of melatonin taken in human research?

The highest documented dosage of melatonin in human research is 6.6 grams – taken for 35 days.

An observational study by Papavasiliou et al. (1972) comprised of 11 patients with Parkinsonism received high doses of melatonin – below are the dosages and durations of treatment. (R)

Melatonin dosages & durations (11 patients)

  • 3 grams (15 days)
  • 5 grams (31 days)
  • 6 grams (35 days)
  • 4 grams (34 days)
  • 3 grams (16 days)
  • 6 grams (27 days)
  • 9 grams (21 days)
  • 1 grams (28 days)
  • 2 grams (26 days)
  • 2 grams (25 days)
  • 5 grams (23 days)

5 of the 11 patients also received Levodopa (ranging from 0.36 to 5 grams per day) with the melatonin – whereas the other 6 received standalone melatonin.

The highest dosage of melatonin administered in this study was 6.6 grams (6600 mg) per day for 35 days… that is pretty crazy.

The lowest dosage of melatonin administered in the aforementioned study was 3 grams (3000 mg) per day.

And what were the adverse effects from such large doses? A few isolated but definite episodes of cutaneous flushing, abdominal cramps, diarrhea, scotoma, and migraine-like headaches.

Keep in mind that concomitantly administered Levodopa may have played a role in causing or intensifying some of these reactions.

The 2 highest dosed patients in the study (5.4 grams & 6.6 grams) reported somnolence during the day – as did 4 more patients taking lower doses.

According to Holliman & Chyka (1997):

  • Various sources cite that 6+ grams of melatonin have no or minimal toxicity.
  • Melatonin in doses of 10 mg to 50 mg has been studied as a treatment for a variety of cancers with or without concomitant interleukin 2 (IL-2).
  • Melatonin at 300 mg/day or 75 mg/day with norethindrone has been studied as a potential oral contraceptive.

A mini review by Dawson & Encel (1993) discussed various studies in which high-dose melatonin was administered.

(No serious adverse events were reported from doses that at-present day would be considered “overdoses”).

  • Arutyunyan et al. (1964): Large oral doses (200-1200 mg melatonin) reduce oral temperature and block amphetamine-induced increases in core body temperature.
  • Anton-Tay et al. (1971): IV Infusion with 100 mg melatonin. Profound hypnotic effects reported.
  • Cramer et al. (1974): IV Infusion with 50 mg melatonin. Significantly increased sedation, reduced psychomotor activity, and reduced sleep onset latency.
  • Lerner & Norlund (1975): 1 gram (1000 mg) melatonin administered for 28 days. Increases in sedation across waking periods were reported.
  • Carman et al. (1976): 200-1200 mg/day melatonin administered from 3-24 days to 6 moderately-to-severely depressed patients. (Effect: Weight gain, reduced total sleep time, worsening depression).
  • Lieberman et al. (1986): 240 mg melatonin (oral) administered during daytime produces sedative effects similar to those following the ingestion of other hypnotic drugs.
  • Valcavi et al. (1987): 500 mg (oral) melatonin significantly increased plasma GH & GH response to GRF.
  • Waldhauser et al. (1987): 80-240 mg melatonin (during the daytime). No effect on prolactin was observed.
  • Waldhauser et al. (1990): 80 mg melatonin (oral) at 21:00 significantly improves measures of sleep onset latency and sleep fragmentation while increasing sleep maintenance.
  • MacFarlane et al. (1991): “When supraphysiologic levels of melatonin were administered to 13 chronic insomniacs at 22:00, subjects reported a subjective increase in total sleep time.”

Dawson and Encel noted that, in studies in which melatonin significantly altered the endocrine system, it was administered at dosages 50-1000 times normal physiologic levels.

It was also suggested that, at high plasma concentrations, melatonin may interfere with serotonergic or noradrenergic systems – and therefore have an indirect effect on neurotransmission.

Note: What most would consider a melatonin “overdose” these days was commonly utilized in research throughout the 1970s, 1980s, and early 1990s – without serious adverse effects.

What would increase risk of melatonin overdose & adverse events?

Drugs & substances

Any drugs (medications, illicit substances, supplements) in systemic circulation (such as substances administered before, along with, or within a specific time window post-melatonin administration).

This could increase risk of interactions (pharmacokinetic & pharmacodynamic) or potentiate/be potentiated by melatonin and thus induce serious adverse reactions following “melatonin overdose.”

Note: This includes legal substances like alcohol and caffeine (I’m stating this because many fail to consider that these are drugs – albeit legal and commonly used).

Melatonin (even at high doses) is unlikely to cause “death” in most individual when ingested as a standalone agent.

However, combining high-dose/overdose of melatonin with CNS depressants might exacerbate certain neurochemical actions of the CNS depressants such as to increase risk of adverse reaction (e.g. hypotension, respiratory depression, death).

The specific additional substances in systemic circulation (beyond melatonin) AND the systemic concentrations of those substances – can determine whether interaction effects are likely to occur, as well as the respective magnitudes (i.e. severities) of those effects.

CNS Depressants & other substances

These are just some substances that I suspect may increase risk of serious interactions & death in the event of a melatonin overdose.

(Obviously specific substances ingested, concentrations, and melatonin levels will determine the reactions).

    • Alcohol
    • Antihypertensive agents
    • Antidepressants (TCAs, MAOIs, SSRIs, etc.)
    • Barbiturates
    • Benzodiazepines
    • Gabapentinoids
    • Opioids/Opiates
    • Nonbenzodiazepines (i.e. Z-Drugs)
    • Sedating supplements: 5-HTP, CBD, Glycine, Hops, Magnesium, Lemon balm, Passionflower, Kava, Theanine, Valerian, etc.
    • Various antibiotics

Medical conditions

The specific medical conditions that a person has could determine what he/she experiences during a melatonin overdose.

Having specific medical conditions may increase (or in some cases decrease) risk of adverse events following excessive melatonin administration.

The severities of specific medical conditions may also play some role in determining how someone reacts to melatonin.

  • Renal (kidney) impairment: Could increase risk of adverse events from melatonin overdose due to insufficient excretion of melatonin.
  • Hepatic (liver) impairment: Could increase risk of adverse events from melatonin overdose due to insufficient metabolism of melatonin.

Genetics

Gene expression may determine how someone responds to a melatonin overdose (in terms of specific effects and the respective severities/durations of those effects).

CYP1A2 metabolism: Melatonin is primarily metabolized by CYP1A2 enzymes and expression differs throughout the general population. A slow/poor CYP1A2 metabolizer will probably have a worse reaction to melatonin overdose than a rapid CYP1A2 metabolizer.

Melatonin receptors: It’s also possible that there are interindividual differences in genetically-mediated melatonin receptor expression/activation that could influence how someone responds to a melatonin overdose.

Pre-melatonin neurobiological expression

The specific state of someone’s entire neurobiology (e.g. brain chemistry, ANS activation, peripheral chemistry, hormonal profile, blood flow, etc.) may determine how he/she responds to a melatonin overdose.

Melatonin details (dose, purity, additives, release format)

Certain melatonin supplements are higher quality than others in terms of “purity” and label accuracy – whereas others are lower quality, impure (potential toxins or unadvertised ingredients).

Dose: Total dose obviously matters a lot in the case of melatonin overdose. Taking 10 mg instead of your usual 5 mg isn’t a big overdose. Taking 1000 mg instead of your usual 5 is a big overdose.

Purity, additives, toxins: How pure is the melatonin that was administered? Does it contain any additives (e.g. serotonin, B-vitamins, etc.) – or toxins (e.g. arsenic, lead, etc.).

Release format: The release format of melatonin may have some impact on response to an overdose. Delayed, prolonged, or extended release formats tend to generate delayed onset “adverse events” following an overdose – relative to immediate-release.

Extreme age (young/old)

Those who are extremely young (e.g. months to years) may be prone to serious adverse reactions and death via melatonin supplementation – especially when administered by a nefarious caretaker (such as with malicious intent).

Elderly may also be prone to serious adverse events due to declining organ function/general health and coadministered medications.

Smaller body size

It’s likely that the smaller one’s body size relative to the dosage of melatonin taken – the higher the risk of adverse events.

In summary, a recipe for “melatonin overdose” disaster (e.g. serious adverse reactions & possible death) would be something like:

  • Cocktail of other substances (e.g. CNS depressants at high doses that interact with or are potentiated by melatonin)
  • Extreme melatonin dose (e.g. 1+ gram)
  • Extreme end of age spectrum (e.g. very young or very old)
  • Poor CYP1A2 metabolism
  • Small body size
  • Various medical conditions

What should you do if someone you know overdoses on melatonin?

Contact emergency medical care.

Why? Because you don’t know whether they have any other substances in systemic circulation that may potentiate, be potentiated by, or interact with melatonin in some serious way(s).

You also don’t know whether the person has any serious medical condition that may put him/her at risk for serious adverse reactions following melatonin overdose.

Moreover, the motto “better safe than sorry” applies here.

Why risk someone’s life and health when you can have them under professional medical care to ensure swift recovery?

Should you be concerned if you take too much melatonin?

It depends (on many variables).

  • Specific melatonin dosage & product (purity, additives, toxins)
  • General health & medical conditions
  • Other substances in your system (with melatonin) & respective concentrations
  • CYP1A2 metabolism
  • Age & body composition
  • Vitals post-overdose
  • Subjective symptoms & severities post-overdose

Given the fact that millions of people regularly use melatonin and there have been ZERO reports of death from melatonin overdose – most people probably shouldn’t be too concerned as long as otherwise healthy AND no other substances are in systemic circulation with melatonin.

If other substances are in systemic circulation during/after melatonin overdose – all bets are off… interaction/potentiation risk increases dramatically along with risk of adverse events and fatality.

If we’re assuming standalone melatonin administered to a healthy adult (and no other substances in systemic circulation) – I personally wouldn’t be too concerned unless a behemoth dosage (e.g. 1-10+ grams) was administered.

Even then, 11 individuals [with Parkinsonism] safely administered melatonin at dosages above 3 grams per day for 15-35 days (one person took 6.6 grams for 35 days).

Most modern “melatonin overdoses” don’t even involve 1 gram (i.e. 1000 mg).

An entire bottle of “NOW Melatonin 5 mg” (180 capsules) contains a total of 0.9 grams (i.e. 900 mg).

An entire bottle of “NOW Melatonin (Extra Strength) 10 mg” (100 capsules) contains just 1 gram (i.e. 1000 mg).

This is still a lower dosage than the lowest dosage taken in the referenced 11-patient study.

Most people will probably be just fine with that concentration of melatonin.

That said, if you feel unusual or are concerned – don’t hesitate to contact emergency medical services and get yourself checked out!

High-dose melatonin vs. mega-dose melatonin vs. supraphysiologic dose melatonin vs. melatonin overdose?

High-dose melatonin

Any dosage that is arbitrarily considered to be “high.”

Most consider low-dose melatonin to be 100-300 mcg (micrograms).

Others might consider low-dose melatonin to be between 300 mcg and 1 mg.

Most people consider 5 mg to be a “standard dose” (as this is the most common dose sold).

Most products list 10-20 mg as “extra strength” or “high dose.”

Mega-dose melatonin

“Mega-dose” is also subjective – but usually orders of magnitude beyond a standard “high-dose.”

For example, you might consider 10-20 mg to be a high-dose whereas a mega-dose might be something like 50-100 or even 100-1000 mg of melatonin.

Supraphysiologic dose melatonin

A supraphysiologic dose of melatonin is any amount that exceeds standard physiological concentrations of melatonin (100-300 mcg per night).

Melatonin overdose

There’s no formal threshold dose agreed upon by the scientific/medical community as criteria for a “melatonin overdose” (such as: (A) doses beyond 50 mg + other substances OR (B) doses beyond 1 gram without other substances – qualify as an overdose).

What is the lethal dose of melatonin (LD50)?

According to Melatonin StatPearls (R):

  • “The acute toxicity of melatonin, as observed in both animal and human studies, is remarkably low.”
  • “Researchers could NOT discover an LD50 (lethal dose for 50% of subjects) in animals.”
  • “Melatonin is not fatal even at a dose of 800 mg/kg in animal studies.”

This is not to say that there’s no lethal dose of melatonin for animals or humans – but it is suggesting that researchers were unable to discover one.

In animal studies, melatonin was administered at a dose of 800 mg/kg without causing death – this is an insanely high dose.

The average body weight globally is 62 kg – and the average body weight in North America is about 82 kg.

Assuming doses of 800 mg/kg were administered – this would be ~49.6 grams (62 kg person) and ~65.6 grams (82 kg person).

Although it’s unethical to test such high doses on humans, many suspect that, taken alone, melatonin isn’t inherently toxic (even at monstrous doses).

I’d hypothesize that there is likely a threshold dosage at which susceptible individuals (preexisting conditions) would die from melatonin overdose (but I might be totally off-base with this hypothesis).

I’m somewhat surprised melatonin researchers didn’t evaluate dosages beyond 800 mg/kg in animals to find the LD50 – but perhaps they thought it was futile given that most humans won’t come close to administering such a massive quantity (even in cases of overdose).

How could melatonin cause death? (Theoretically)

To be clear, there are ZERO official reports of death in which melatonin overdose was deemed the sole cause with 100% confidence.

Accumulation of granules/powder

Sheer ingestion of too much powder could cause melatonin granules to accumulate so rapidly – that the body cannot excrete them efficiently.

Stool becomes impacted, person experiences gastric aspiration and literally chokes to death on melatonin powder causing asphyxiation and/or organ dysfunction and subsequent death.

Aspiration, Choking, Asphyxiation (after powder/granule accumulation)

  • There’s probably some threshold of melatonin powder at which the entire stomach contents would be full and you’d literally aspirate the powder, choke, and die via asphyxiation.
  • (Think of this like filling the stomach all the way up with sand until the sheer quantity of sand causes choking and suffocation).
  • Odds of this would increase with dehydration and impaired melatonin excretion.

CNS actions (?)

Melatonin overdose is unlikely to cause death via actions within the central nervous system – but the possibility should be acknowledged.

  • Hypotension: It’s possible that a melatonin overdose might induce severe hypotension in susceptible individuals such as to trigger: dizziness, fainting, and subsequent death via cardiac arrest. Hypotension was documented in one case report of melatonin overdose (but there were too many confounds to know what role melatonin played here).
  • Organ dysfunction: It’s possible that an insane amount of melatonin could directly cause organ dysfunction and subsequent death (but this hasn’t been substantiated by any science).

It’s likely that some people have died following a “melatonin overdose” – but my guess is that “melatonin overdose” was NOT ruled the primary cause of death – and may not have even contributed to any extent (e.g. presence of melatonin may have been a mere correlation).

In the event of death following melatonin overdose, it’s important to ask:

  1. Were any other substances found in systemic circulation? (If so, could they have been the cause of death instead of, or along with, melatonin?)
  2. Might this death be better explained by a medical condition (rather than the melatonin overdose) or an interaction between melatonin and said medical condition?

Technically, melatonin overdose may have played a role in killing a 13-month-old male wherein the nefarious caregiver was charged with homicide – but even here, the extent to which melatonin contributed to death remains unclear.

In said case, melatonin overdose may not have been the sole inducer of death – as there were confounds of: (1) abnormally warm room temperature – coupled with burns to the baby’s thymus and heart (from a proximal space heater), (2) potential dehydration/improper diet, and (3) intentional neglect.

Melatonin concentrations reported via LC-MS toxicological analysis in this case were 210 ng/mL (probably abnormally high for a 13-month-old – but I could be wrong).

In this case, it is unclear as to whether melatonin’s actual pharmacologic actions resulted in physiologic changes that caused death – or whether the sheer quantity of melatonin particulate/granular matter ingested is what may have contributed to or caused death.

I’m suspecting that the sheer amount of melatonin granules is what may have contributed to or caused death given the fact that there was evidence of impacted stool (possible effect of excessive granules) and gastric aspiration – wherein stomach contents enter windpipe/lungs (another possible effect of excessive granules).

Gastric aspiration may have been substantial as a result of massive amounts of melatonin in the stomach – and may have been exacerbated by the baby’s body position prior to death.

I’m thinking the baby may have choked on the powder via aspiration – leading to subsequent asphyxiation and death (but this is just my amateur, post-hoc hypothesis).

Melatonin Overdose Signs, Symptoms, Effects (Common)

Each person will have slightly different reactions depending on the dosage, whether they take other substances with melatonin, genetics, age, medical conditions, and general health.

  • Sleepiness, drowsiness, tiredness
  • Fatigue & lethargy
  • Disorientation, depersonalization, dissociation (this may cause anxiety)
  • Feeling “drunk”
  • Brain fog & cognitive impairment
  • Cutaneous flushing (warmth sensation)
  • Stomach aches & cramps, gastritis, diarrhea
  • Eye & vision changes (difficulty focusing)
  • Low blood pressure (particularly when standing up)
  • Memory lapses or memory loss
  • Skin rash
  • Tingling sensations
  • Nightmares & vivid dreams

The most dangerous potential effect is probably severe hypotension – but sleepiness, drowsiness, tiredness, etc. could be dangerous if the individual decides to drive a motor vehicle or operate machinery.

Who is most likely to “overdose” on melatonin?

Below are the individuals that I suspect are most likely to “overdose” on melatonin intentionally…

  • Neuropsychiatric disorders: Those with neuropsychiatric disorders who are (A) suicidal (this may be intended as self-harm or a cry for help); (B) extremely stressed (taking a crazy dose in attempt to calm down); (C) struggling with insomnia (thinking a monster dose might actually help).
  • Illicit drug users: These individuals may or may not have neuropsychiatric disorders. Nonetheless, I suspect that some illicit drug users may take high-dose melatonin in attempt to offset various effects of illicit drugs or to counteract illicit drug withdrawal symptoms, etc.
  • Psychonauts: Those who explore alternate or states-of-consciousness as an adventure or for fun. Think Erowid vault. I suspect some psychonauts may just want to try mega-dosing melatonin for the experience.

Those who are most likely to “overdose” on melatonin unintentionally…

  • CYP1A2 slow metabolizers: Those with slow/poor CYP1A2 metabolism may be more likely to experience symptoms in the aftermath of melatonin overdose (i.e. administering more than a usual amount) due to inefficient melatonin metabolism/elimination.
  • Organ dysfunction: Those with hepatic (liver) and/or renal (kidney) impairment may be susceptible to “melatonin overdose” even following modest dosage increases (due to impairment-associated inefficiencies in melatonin metabolism/excretion.)
  • Users of medications, supplements, caffeine/alcohol: Persons who regularly take medications (pharmaceutical and/or OTC); dietary supplements; caffeine; and/or alcohol – may not realize that even slight melatonin overdoses may cause serious adverse events due to interactions or synergisms (between melatonin and co-circulating substances).
  • Medical conditions: Various medical conditions (e.g. autonomic dysfunction, hypotension, etc.) may increase susceptibility to noticeable or severe adverse reactions following even mild melatonin overdose.

Why isn’t melatonin toxic at high doses?

Melatonin is not directly toxic to the cells in your body and does not influence neurons in such a way as to produce lethal effects.

In other words, even at high doses, melatonin doesn’t drastically alter bodily systems that regulate life-sustaining functions like breathing, blood pressure, etc.

If you take melatonin with other agents – there may be some synergistic pharmacodynamic or pharmacokinetic effects wherein melatonin might contribute to death, but probably won’t be the sole cause.

For example, it’s possible that taking an array of CNS depressants simultaneously like alprazolam, oxycodone, alcohol, diphenhydramine, and melatonin would cause respiratory depression and inevitable death (depending on the doses).

Hypothetical: 0.25 mg (alprazolam); 5 mg (oxycodone); 25 mg (diphenhydramine); 1 beer might not cause death… but then add in some mega-dose of melatonin like 100 mg – and this might tip the scales and cause death. (Admittedly, I could be totally incorrect in this hypothesis).

Perhaps melatonin might contribute (to some degree – even if minuscule) in inducing death when administered with other substances (such as via kinetic/dynamic) synergisms.

(Don’t take this as a challenge to see if you can overdose on melatonin.)

There is probably some dosage and threshold concentration at which melatonin becomes lethal in humans.

Thankfully this dosage/threshold is a much higher amount than most people are typically willing to administer, or capable of administering.

And although melatonin’s central effects are unlikely to cause death following overdose, you might end up with: (A) some sort of organ damage or blockage OR (B) interactions between symptoms of a preexisting medical condition (e.g. hypotension) and effects of melatonin (exacerbation of hypotension) that could lead to death.

What is the highest dosage of melatonin I’ve taken?

I think ~30-40 mg at once and like 50 mg within 12 hours.

I was extremely stressed and kept popping melatonin because I thought that: (1) it was safe, and that (2) “more” would finally knock me out and “turn off” my brain (such as to promote and sustain sleep).

I’ve also taken 20-30 mg in combination with a cocktail of CNS depressants: (A) low-dose diphenhydramine (12.5 mg); (B) low-dose alprazolam; (C) low-dose clonidine; and (D) mega-dose magnesium (8-10 grams) (citrate, threonate, glycinate).

Would I recommend this combination to anyone? Absolutely not. (Relevant reading: Melatonin & Xanax combination).

I believe I experienced similar symptoms to the case of the 66-year-old man who administered high-dose melatonin along with his amitriptyline and benzodiazepine.

I felt disoriented, drowsy, sleepy, spaced out (like in some twilight zone) – but also developed anxiety (fearing that the combination might induce respiratory depression) – so I actually had a difficult time falling asleep (as a result of the anxiety regarding: fear of respiratory depression and the altered state of consciousness).

Had I not developed anxiety over potential respiratory depression and disorientation, I probably would’ve fallen asleep easily.

Unlike the 66-year-old man, I did NOT have any memory issues/lapses and was able to recall everything from the previous day/night fine (unlike the man in the case report).

Is melatonin safe as a supplement?

In most cases – yes. Obviously there are caveats (dosage, specific supplement, use of other substances, medical conditions, etc.).

Generally speaking, melatonin taken at normal/appropriate dosages, from a trustworthy supplement manufacturer will be safe for most people. Risk of fatal overdose at normal dosages is pretty much zero.

Whether it provides legitimate health benefit however, is an entirely different debate – and likely varies significantly in the general population based on myriad variables.

Potential danger may ensue if a specific melatonin supplement contains dramatically more melatonin than is listed on the label along with impurities (e.g. toxins, additives, etc.) – but I’ve yet to read about adverse events from an impure melatonin supplement in the scientific literature.

Personally, I think melatonin is among the safest supplements on the market and its antioxidant action makes it extremely protective against toxin-induced neuronal/cellular insult.

Antioxidant potential seems to increase between 5 mg and 20 mg – relative to extremely low doses.

Have you “overdosed” on melatonin?

If you’ve overdosed either intentionally or unintentionally and want to leave a comment, feel free.  If you’re not sure what to write, just provide some details about your experience, including:

  • Melatonin dosage & format: What dosage did you take? What was the format? (Immediate-release or prolonged-release?)
  • Other substances: Whether you were under the influence of any other substances (e.g. alcohol, drugs, medications, supplements) along with melatonin
  • Effects: What were the effects that you experienced?
  • How long did the effects last?
  • What dosage of melatonin do you normally take? (Assuming you normally take it)
  • What was your age when this happened?
  • Do you have any medical conditions that may have influenced your reaction to a melatonin overdose?

Parting thought…

I got a bit longwinded with this article, but enjoyed researching and writing it and hope that you found it helpful in learning about melatonin overdose.

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