The Melatonin Mystery: Are Guidelines Wrong?

In this episode of Daily Value, we look at newer research on melatonin that challenges conventional wisdom. A recent meta‐analysis questions current clinical guidelines on melatonin use for sleep, suggesting there may be a dual (Dose X Time effect) secret to optimizing its effects. We’ll break down the scientific clues behind optimal dosing, timing, and formulation, leaving you to wonder if you've been taking melatonin all wrong.

Discussion Points:

• The clinical recommendations for melatonin may be “off”.
• What a recent meta-analysis (PMID: 38888087) suggests as better dosing and timing of melatonin.
• Formulation differences between fast-acting and extended-release melatonin.
• Practical tips for tailoring melatonin to boost your sleep quality.

https://pubmed.ncbi.nlm.nih.gov/38888087/ 

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Episode Transcript

Speaker 0 (00:00):
Melatonin is one of those compounds that tends to
split people into factions.
Either you are an advocate ofits use or people will
completely reject the idea of itbecause it's classified under
the hormone umbrella.
Well, there is new research tosuggest that recommendations for
its use for sleep may be off.
Hello everyone, and welcomeback to Daily Value.

(00:21):
I'm William Wallace, and todaywe're looking at new research on
melatonin, a hormone that'smuch more than a simple sleep
aid, although today's episodewill focus on its use as a sleep
aid.
Today we'll review the use ofmelatonin in insomnia.
We're going to look at commondosing strategies and protocols
and then focus on veryinteresting newer research that

(00:43):
has re-examined the optimal timeframe and dose for using
exogenous melatonin to promotesleep.
Melatonin is producedendogenously.
Actually, many differenttissues in our body produce it,
and it typically resides insidethe mitochondria, but its most
well-known place of synthesis inthe human body is the pineal
gland, in response to darkness.

(01:04):
Because melatonin is stimulatedby darkness, it is sometimes
referred to as the darknesshormone.
Think about the opposite of howwe refer to something like
vitamin D, which is also ahormone that's production is
stimulated by light, so there'sa relevant duality there.
Now it's very common to seesupplements ranging from as low
as 300 micrograms up to 10milligrams per serving.

(01:26):
That's the most common rangeand indeed it's a large range.
Interestingly, our pineal glandproduces between 100 and 900
micrograms of melatonin per day,depending on your age, with
younger people tending toproduce it on the higher end,
with children producing evenmore than that range on average
Because of this exogenous dosesof melatonin.

(01:49):
So doses from supplementsranging from 100 micrograms to 1
milligram so that's 0.1milligrams to 1 milligram of
melatonin being considered byclinicians a physiological dose
of melatonin, with larger dosesbeing considered unnecessary by
many.
Using that physiological rangelogic.

(02:10):
Now there are organizationslike the American Academy for
Sleep Medicine that currentlyrecommend the usage of
supplemental melatonin at 2 mgper day, taken 30 minutes before
sleep, for the treatment ofinsomnia.
I want you to remember thatdose in time.
Unfortunately, for treatingprimary insomnia, studies using

(02:30):
melatonin have produced mixedresults.
Clinical trials haveconsistently shown that
exogenous melatonin producesonly modest improvements in
sleep onset latency.
In some studies, benefitsappear to be more pronounced in
people with circadian rhythmdisruptions, like shift workers
or travelers, rather than inthose with chronic primary
insomnia.
However, what if we've beenrecommending supplemental

(02:52):
melatonin before bed the wrongway all this time.
Well, recent evidence showsthat a timing and dose mismatch
may blunt melatonin'seffectiveness.
May blunt melatonin'seffectiveness.
Recent research suggests thatboth the dose and, critically,
the timing of administrationplay pivotal roles in maximizing
its efficacy.
Major organizations, cliniciansand supplement companies have

(03:14):
been recommending melatonin 30to 60 minutes before bed.
But what if the time intervalfor melatonin to work needed to
be extended a little further?
That brings us to the centralstudy for today's episode, a
2024 systematic review andmeta-analysis by Cruz Sanabria
et al.
Their work examined 26randomized controlled trials

(03:37):
spanning over three decades andincluding 1,689 observations to
determine how both the dose andtiming of exogenous melatonin
administration influence two keyparameters, those being sleep
onset latency that's how long ittakes to fall asleep and total
sleep time.
The study showed that exogenousmelatonin gradually reduces

(03:58):
sleep onset latency andincreases total sleep time as
the dose increases, reaching apeak effect at around four
milligrams per day.
In other words, doses below twomilligrams were less effective,
and while three and fourmilligrams produced
significantly greaterimprovements than the
conventional two milligrams,going beyond four milligrams did

(04:20):
not add further benefits.
So going up to 10 milligramswas not better than 4 milligrams
and actually showed worseoutcomes here.
Next was the importance oftiming for sleep onset latency
reduction, advancing the time ofadministration.
Specifically, administeringmelatonin one to three hours
before sleep onset produced asteeper decline in sleep latency

(04:45):
compared to just taking it 30minutes before bedtime.
Taking melatonin three hoursbefore bed outperformed taking
it one hour before bedtime.
The authors conclude that thecurrent clinical practice, often
prescribing two milligramstaken 30 minutes before bedtime,
might be suboptimal.
Instead, optimizing melatonin'suse could involve administering

(05:07):
up to four milligramsapproximately three hours before
one's desired bedtime, thusallowing time for the drug to
reach plasma concentration andalign more naturally with the
endogenous melatonin profile andthe associated drop in core
body temperature as we approachsleep time.
So again, four milligrams a daywas significantly more

(05:28):
effective than two milligrams aday, while three milligrams per
day was significantly moreeffective than two milligrams
per day in increasing totalsleep time.
Their systematic review providesevidence that the
sleep-promoting efficacy ofexogenous melatonin is not
solely dose-dependent but iscritically modulated by timing.
The traditional 2 mg 30 minutesbefore bed approach may not be

(05:52):
ideal because it fails toaccount for the body's natural
kinetics.
The study shows thatmelatonin's hypnotic effects are
maximized when administeringearlier in the evening,
specifically one to three hoursbefore sleep onset, with the
most effective time appearing tobe around three hours before
bed.
One critical detail to consideris the formulation of melatonin

(06:13):
.
Fast-release melatonintypically reaches peak blood
concentration in about 50minutes, whereas
prolonged-release formulationscan take up to 167 minutes.
Since the majority of thestudies in this review paper use
fast-release melatonin,approximately 73% of them, the
observed optimal 2-3 hour windowmay apply primarily to fast

(06:35):
release formulations.
In other words, for prolongedrelease melatonin, the ideal
administration time might differ.
The safety of melatonin is acommonly raised concern, but
even at higher doses, studieshave reported doses as high as
100 milligrams withoutsignificant effects, although
that was in sepsis patients.
Adverse reactions are generallyuncommon.

(06:57):
Some studies have notedincreases in drowsiness,
dizziness, headaches and fatigueat higher doses and because of
these side effects that couldimpair activities such as
driving or operating heavymachinery, it's essential for
people taking melatonin to planaccordingly and avoid
potentially dangerous activitiesafter taking melatonin.
To plan accordingly and avoidpotentially dangerous activities
after taking melatonin.

(07:17):
Multiple studies spanning up tosix months have not reported
any significant long-term sideeffects from melatonin use.
Additionally, there's noevidence of dependence or
tolerance developing duringmelatonin supplementation, and
discontinuing or tapering thesupplement does not lead to
rebound insomnia or withdrawalsymptoms.

(07:38):
All of that is actually backedby clinical data.
While melatonin is widelyrecognized as a sleep aid, its
full potential as asleep-promoting drug depends on
both the dose and the timing ofadministration.
Traditional practices of taking2 mg 30 minutes before bed may
be less effective than a regimenof 4 mg taken approximately 3

(07:58):
hours before sleep onset.
The study by Cruz-Sanabria etal provides compelling evidence
that optimizing theadministration schedule can
significantly reduce sleep onsetlatency and modestly increase
total sleep time.
Modestly increased total sleeptime.
Even though exogenous melatoninappears less potent in primary

(08:19):
insomnia patients compared tohealthy individuals and its
effects may not rival those ofcognitive behavioral therapy, it
still offers a viable option,especially when combined with
good sleep hygiene practices.
As our understanding ofmelatonin's pharmacokinetics
evolves, it's clear that aone-size-fits-all approach is
outdated.
Personalizing melatonin'spharmacokinetics evolves, it's
clear that a one-size-fits-allapproach is outdated.
Personalizing melatonin therapyby considering individual

(08:40):
circadian phases, environmentallight exposure and inherent
sleep patterns may be the key tounlocking its full potential.
Thank you for joining me todayon Daily Value.
If you found today's episodeenlightening, please share it
with your friends and colleagues.
Stay curious, stay informed andremember that sometimes
optimizing your routine can beas simple as rethinking when and

(09:01):
how much you take yourmelatonin Until next time.
Stay asleep at night.
Stay healthy.