High Dose Melatonin Side Effects


  1. Why are we taking megadoses of melatonin?
  2. Melatonin Dose-Response Curves
  3. Persistently Elevated Melatonin Plasma Levels
  4. Melatonin and Depression
  5. High-Dose Melatonin Side Effects

Why are we taking megadoses of melatonin?

What happens if you take an irresponsibly high dose of melatonin? Would you just be a little disoriented or sedated for a couple of hours and then make a full recovery, no harm done? Actually, some people have pointed out that the standard 3-5mg dose of melatonin is already a megadose.

Because dietary supplements are not subject to the same regulatory scrutiny by the FDA as prescription drugs, there is actually very little known about the long-term effects of melatonin use. Despite this lack of oversight, most physicians and scientists will (correctly) tell you that melatonin is a pretty innocuous substance.

Melatonin Dose-Response Curves

As it turns out, even recommended (1-5mg) doses of melatonin can result in plasma levels of melatonin that are 10-20 fold higher than normal physiologic levels of melatonin.

In the plot below, circadian time (CT) is plotted on the x-axis against plasma melatonin levels (expressed as pg/mL) on the y-axis. Circadian Time (CT) = 0 corresponds to 7am, whereas CT 15 is 11PM – when most folks are headed to bed. Hence, the interval from CT 0 to CT 15 is wake, while CT 16 to 23 is sleep.

You’ll notice that even a modest 0.5 mg dose of melatonin results in a spike in melatonin plasma concentrations that is more than 5x the normal, physiologic levels of melatonin.

A 10mg dose of melatonin results in a peak melatonin plasma concentration of over 20,000 pg/mL, compared to 150 pg/mL for a 0.5mg oral dose of melatonin. This is about a 133-fold difference in plasma levels of melatonin.

This graph begs the question: is it really safe to increase your endogenous melatonin levels to this extent by taking melatonin? We should restrain our health anxiety by recalling that most evidence has confirmed the widely-held view that melatonin is a benign substance at these doses.

Persistently Elevated Melatonin Plasma Levels

From the above plot, a 10mg dose of melatonin results in persistently elevated melatonin plasma levels that are an order of magnitude higher than “normal”, physiologic levels during the day. In other words, despite melatonin’s rapid half-life (~45 minutes), a large dose of melatonin will still elevate next-day plasma melatonin concentrations far above normal levels.

What is the effect of persistently elevating melatonin in this fashion? Little research has been done, but we can speculate that chronically elevated melatonin could blunt your natural, diurnal circadian rhythms. The melatonin receptors MT1 and MT2 in the hypothalamus (and elsewhere) are exquisitely sensitive to melatonin, sensing the increase that naturally occurs about 2 hours before bed. But if melatonin levels are constantly elevated, we would expect tachyphylaxis to result in receptor desensitization. To have a robust circadian rhythm (which is an important determinant of general wellbeing), we want to have big differences in our peak melatonin at night and trough levels during the day.

Melatonin and Depression

While melatonin can be helpful for patients struggling with depression-related insomnia, melatonin has also been reported to be depressogenic. The pro-depressant effects of melatonin are probably related to melatonin’s tendency to suppress catecholamine release in the brain. We can speculate that chronically elevated plasma melatonin concentrations from excessive doses might be the cause of the depression side effect that is sometimes reported.

High-Dose Melatonin Side Effects

The side effects of high-dose melatonin are really just an extension of the side effects of melatonin at lower doses. These adverse effects include:

  • Headache
  • Confusion
  • Fragmented Sleep
  • Dizziness
  • Somnolence
  • Nausea

These side effects are also associated with the melatonin agonist, Ramelteon, and possibly other melatonergic drugs like Agomelatine.

Despite being essentially unregulated in the US, melatonin ingestion in excessive doses does not appear to result in any clear pattern of adverse effects.

Studies where 1 g to 6.6 g were administered to human subjects daily concluded that, aside from drowsiness, all findings were unremarkable at the end of the test period. This does not rule out the possibility of negative long-term effects, but it is at least suggestive that melatonin is relatively safe in overdose.