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/ 

Chapters

• 0:00 Optimizing Melatonin Dose and Timing
• 8:30 Personalized Melatonin Therapy Optimization

Transcript

Speaker 0: 0:00

Melatonin is one of those compounds that tends to split people into factions. Either you are an advocate of its use or people will completely reject the idea of it because it's classified under the hormone umbrella. Well, there is new research to suggest that recommendations for its use for sleep may be off. Hello everyone, and welcome back to Daily Value. I'm William Wallace, and today we're looking at new research on melatonin, a hormone that's much more than a simple sleep aid, although today's episode will focus on its use as a sleep aid. Today we'll review the use of melatonin in insomnia. We're going to look at common dosing strategies and protocols and then focus on very interesting newer research that has re-examined the optimal time frame and dose for using exogenous melatonin to promote sleep.

Speaker 0: 0:50

Melatonin is produced endogenously. Actually, many different tissues in our body produce it, and it typically resides inside the mitochondria, but its most well-known place of synthesis in the human body is the pineal gland, in response to darkness. Because melatonin is stimulated by darkness, it is sometimes referred to as the darkness hormone. Think about the opposite of how we refer to something like vitamin D, which is also a hormone that's production is stimulated by light, so there's a relevant duality there. Now it's very common to see supplements ranging from as low as 300 micrograms up to 10 milligrams per serving. That's the most common range and indeed it's a large range. Interestingly, our pineal gland produces between 100 and 900 micrograms of melatonin per day, depending on your age, with younger people tending to produce it on the higher end, with children producing even more than that range on average Because of this exogenous doses of melatonin. So doses from supplements ranging from 100 micrograms to 1 milligram so that's 0.1 milligrams to 1 milligram of melatonin being considered by clinicians a physiological dose of melatonin, with larger doses being considered unnecessary by many. Using that physiological range logic. Now there are organizations like the American Academy for Sleep Medicine that currently recommend the usage of supplemental melatonin at 2 mg per day, taken 30 minutes before sleep, for the treatment of insomnia. I want you to remember that dose in time.

Speaker 0: 2:26

Unfortunately, for treating primary insomnia, studies using melatonin have produced mixed results. Clinical trials have consistently shown that exogenous melatonin produces only modest improvements in sleep onset latency. In some studies, benefits appear to be more pronounced in people with circadian rhythm disruptions, like shift workers or travelers, rather than in those with chronic primary insomnia. However, what if we've been recommending supplemental melatonin before bed the wrong way all this time. Well, recent evidence shows that a timing and dose mismatch may blunt melatonin's effectiveness. May blunt melatonin's effectiveness.

Speaker 0: 3:07

Recent research suggests that both the dose and, critically, the timing of administration play pivotal roles in maximizing its efficacy. Major organizations, clinicians and supplement companies have been recommending melatonin 30 to 60 minutes before bed. But what if the time interval for melatonin to work needed to be extended a little further? That brings us to the central study for today's episode, a 2024 systematic review and meta-analysis by Cruz Sanabria et al. Their work examined 26 randomized controlled trials spanning over three decades and including 1,689 observations to determine how both the dose and timing of exogenous melatonin administration influence two key parameters, those being sleep onset latency that's how long it takes to fall asleep and total sleep time. The study showed that exogenous melatonin gradually reduces sleep onset latency and increases total sleep time as the dose increases, reaching a peak effect at around four milligrams per day. In other words, doses below two milligrams were less effective, and while three and four milligrams produced significantly greater improvements than the conventional two milligrams, going beyond four milligrams did not add further benefits. So going up to 10 milligrams was not better than 4 milligrams and actually showed worse outcomes here.

Speaker 0: 4:28

Next was the importance of timing for sleep onset latency reduction, advancing the time of administration. Specifically, administering melatonin one to three hours before sleep onset produced a steeper decline in sleep latency compared to just taking it 30 minutes before bedtime. Taking melatonin three hours before bed outperformed taking it one hour before bedtime. The authors conclude that the current clinical practice, often prescribing two milligrams taken 30 minutes before bedtime, might be suboptimal. Instead, optimizing melatonin's use could involve administering up to four milligrams approximately three hours before one's desired bedtime, thus allowing time for the drug to reach plasma concentration and align more naturally with the endogenous melatonin profile and the associated drop in core body temperature as we approach sleep time. So again, four milligrams a day was significantly more effective than two milligrams a day, while three milligrams per day was significantly more effective than two milligrams per day in increasing total sleep time.

Speaker 0: 5:37

Their systematic review provides evidence that the sleep-promoting efficacy of exogenous melatonin is not solely dose-dependent but is critically modulated by timing. The traditional 2 mg 30 minutes before bed approach may not be ideal because it fails to account for the body's natural kinetics. The study shows that melatonin's hypnotic effects are maximized when administering earlier in the evening, specifically one to three hours before sleep onset, with the most effective time appearing to be around three hours before bed. One critical detail to consider is the formulation of melatonin. Fast-release melatonin typically reaches peak blood concentration in about 50 minutes, whereas prolonged-release formulations can take up to 167 minutes. Since the majority of the studies in this review paper use fast-release melatonin, approximately 73% of them, the observed optimal 2-3 hour window may apply primarily to fast release formulations. In other words, for prolonged release melatonin, the ideal administration time might differ.

Speaker 0: 6:42

The safety of melatonin is a commonly raised concern, but even at higher doses, studies have reported doses as high as 100 milligrams without significant effects, although that was in sepsis patients. Adverse reactions are generally uncommon. Some studies have noted increases in drowsiness, dizziness, headaches and fatigue at higher doses and because of these side effects that could impair activities such as driving or operating heavy machinery, it's essential for people taking melatonin to plan accordingly and avoid potentially dangerous activities after taking melatonin. To plan accordingly and avoid potentially dangerous activities after taking melatonin. Multiple studies spanning up to six months have not reported any significant long-term side effects from melatonin use. Additionally, there's no evidence of dependence or tolerance developing during melatonin supplementation, and discontinuing or tapering the supplement does not lead to rebound insomnia or withdrawal symptoms. All of that is actually backed by clinical data.

Speaker 0: 7:41

While melatonin is widely recognized as a sleep aid, its full potential as a sleep-promoting drug depends on both the dose and the timing of administration. Traditional practices of taking 2 mg 30 minutes before bed may be less effective than a regimen of 4 mg taken approximately 3 hours before sleep onset. The study by Cruz-Sanabria et al provides compelling evidence that optimizing the administration schedule can significantly reduce sleep onset latency and modestly increase total sleep time. Modestly increased total sleep time. Even though exogenous melatonin appears less potent in primary insomnia patients compared to healthy individuals and its effects may not rival those of cognitive behavioral therapy, it still offers a viable option, especially when combined with good sleep hygiene practices.

Speaker 0: 8:30

As our understanding of melatonin's pharmacokinetics evolves, it's clear that a one-size-fits-all approach is outdated. Personalizing melatonin's pharmacokinetics evolves, it's clear that a one-size-fits-all approach is outdated. Personalizing melatonin therapy by considering individual circadian phases, environmental light exposure and inherent sleep patterns may be the key to unlocking its full potential. Thank you for joining me today on Daily Value. If you found today's episode enlightening, please share it with your friends and colleagues. Stay curious, stay informed and remember that sometimes optimizing your routine can be as simple as rethinking when and how much you take your melatonin Until next time. Stay asleep at night. Stay healthy.