What a Melatonin Study Found About Heart Failure

Okay, I want to get into this next deep dive because it's a really important one. Many people have asked me questions about it, not only in this Q&A but also friends of mine and people on social media. I've seen this question come up time and time again, so I definitely want to get to it. The question has to do with a recent quote-unquote study that found an association between long-term melatonin use and an increased risk of heart failure. ConsumerLab covered this.

Every science and health press outlet seemed to cover it. There are a lot of related questions.

Karen, Lee Turner, Sam, all of these people are wanting me to address the recent hype about this new study claiming that long-term melatonin use is associated with chronic heart failure. First thing I want to emphasize here is that this study has not been peer-reviewed. It has not been published yet. Right now, what we are going off of is preliminary results that were presented in a presentation at the American Heart Association Scientific Sessions last November.

So last month, whenever findings like this are shared before going through the rigorous peer-review process, we need to be very cautious about interpreting them.

That also means that I cannot break down all the methods, all the statistical analyses, all the details that I usually like to cover because those have not been released. This was a conference presentation. Okay. The second point that I absolutely want to hammer home and I will get into this in more detail is that this is an observational study.

Observational studies can highlight associations and sometimes these associations can be quite striking, but they cannot tell us whether one thing causes another. There are always potential confounders, other lifestyle factors that especially when we're dealing with very large databases and real world populations that play a role here.

So keep this in mind when we are talking about correlations. It is not proving causation. So with that said, let's talk about what the researchers found, what they talked about in this study. They used a very large international database and pulled five years of electronic health records from several different countries.

So for this they focused on adults with chronic insomnia who had melatonin use documented in their health records and had been using it for more than a year. Then those individuals were matched with their peers who also had chronic insomnia but had no record of melatonin use. Importantly, this is very important.

Anyone who had a previous diagnosis of heart failure or who had been prescribed other sleep medications was excluded from the analysis. So researchers could isolate this very specific comparison. When we look at the main analysis, researchers reported a very big difference between these two groups. Among adults with insomnia who had long-term melatonin use, meaning more than a year, documented in their health records, the incidence of heart failure was 4.6% versus 2.7% in the group that did not have melatonin recorded in their health records.

In other words, melatonin users had about a 90% higher chance of developing heart failure over a five-year period.

They also ran a similar analysis when they looked at participants who had at least two melatonin prescriptions filled at least 90 days apart. So, in some countries like the UK, melatonin is actually a prescription medication. Here, the increased risk was about 82%. So it was very similar to the first analysis.

There were also secondary findings. Additional outcomes were explored, and they fit the same general pattern. Again, these were participants who had melatonin documented in their health records. You're going to understand why later because many people are taking melatonin that's not in their health records.

Okay. But anyways, with that said, participants that were taking melatonin were nearly 3. 5 times more likely to be hospitalized for heart failure than those not taking melatonin in their health records. Right.

The hospitalization rates were 19% versus 6.6%. And when researchers looked at deaths from any cause over the 5-year period, the people that were taking melatonin according to their health records had almost double the rate compared to the control group. And I think if we just look at these numbers, everything is sounding very concerning and it's very alarming.

However, there are several very important limitations here that we have to discuss.

One of the biggest limitations here is that the database combines countries where melatonin is a prescription medication such as the UK as I mentioned and countries where it is available over the counter such as the United States and the researchers could not separate these populations because there's just no way to do that. So, as a result, for example, anyone in the United States who regularly takes melatonin as an over-the-counter supplement would not appear in the melatonin group unless it happened to be documented by a clinician. Instead, they would actually appear in the control group that was defined as not taking melatonin.

That introduces a very important potential misclassification bias. So this is basically we have no way of knowing how many people in the control group were actually regular melatonin users, right? And as we'll talk about in a minute, let's talk about how many people are actually taking melatonin. We have at least in the United States, we have some documentation here about melatonin use.

It's become very popular. So data from the National Health and Nutrition Examination Surveys have shown that melatonin use rose from about 0.4 percent of the population in 1999 to about 2.1 percent in the year 2018.

Other statistics show sales more than doubled between 2017 and then 2020. So there's a substantial number of people in the United States outside of a clinical setting that are actually using melatonin just as an over-the-counter supplement. It's not going to be documented in any electronic health record and therefore those melatonin users are actually going to be in the control group. Now when we think about the control group in this observational study, the possibility that many participants are actually taking melatonin and are classified as non-users becomes a very important source of potential bias and very much can change the results here.

Another limitation has to do with how hospital data is recorded. When someone is hospitalized, doctors enter several codes to describe what is going on. These codes aren't always specific. So, if a patient is hospitalized and heart failure is involved, the system might not label it as a new case.

Instead, it might only record the broader medical issue. So this means that the study could be counting a lot more hospitalizations related to heart failure than actual new diagnoses which could inflate the data. It also seems like the researchers did not actually have data on insomnia severity or co-occurring psychiatric conditions both of which meaningfully influence health outcomes.

So, for example, individuals with more severe insomnia are going to be prescribed melatonin or they're going to seek out professional care that results in electronic documentation that they're taking melatonin because they're having a much more severe case of insomnia. So this would create an association that's actually reflecting the documented melatonin users as people with more severe chronic insomnia and comorbidities as well. We know that insomnia itself increases the risk of heart failure. And that is in a dose-dependent manner.

It worsens the prognosis of heart failure. It raises all-cause mortality in people who already have heart failure.

So separating these effects of chronic insomnia and the severity of chronic insomnia is very important and that was not done and I'm saying here that the electronic records of melatonin use might also be the more severe patients that have more severe chronic insomnia who are now seeking out melatonin. Because they are so desperate and their insomnia is so severe. So that is a very important point. Another issue is that over-the-counter supplements are usually unregulated in terms of dose and formulation and so you have all kinds of melatonin products that vary widely in the actual dose of melatonin.

Many are contaminated with other things like serotonin. There's a lot of things to consider here. So to put this new study in perspective, I think it helps to look at what controlled clinical trials have found in people who already have heart failure who are taking melatonin. There aren't that many studies available, but earlier this year, a systematic review and meta-analysis came out that pulled together results from three different randomized controlled trials.

They lasted between 8 to 24 weeks. They used daily melatonin doses ranging from three to 20 milligrams per day. Across these three trials, melatonin improved quality of life, which is obviously an important outcome in people living with heart failure.

One of the studies reported an increase in ejection fraction. So, this is a measure of how well your heart can pump blood with each beat. That often declines in chronic heart failure patients. So, you are seeing an improvement in one study.

Another study didn't see any change. So, it did not find a change. And when we looked at all the data combined, the overall effect was neutral. In other words, chronic heart failure patients supplementing with melatonin, even a high dose up to 20 milligrams a day for up to 24 weeks, did not have any adverse effects on chronic heart failure.

The two trials had enough information to look at something called the New York Heart Association class.

This is a scale clinicians use when they're describing how limited someone is by their chronic heart failure symptoms to do daily activities. In both those studies, melatonin users, so these are people with chronic heart failure using melatonin actually had a trend towards less severe New York Heart Association classification. So in other words, they were actually improving and when pooled together, that data almost reached statistical significance. So the sample sizes were probably not large enough.

But in other words, what we're talking about here is a beneficial effect in chronic heart failure patients that were taking melatonin.

There was also some other biomarkers that were looked at that melatonin lowered biomarkers of physiological stress. In other words, everything is showing melatonin supplementation is actually benefiting people with chronic heart failure. I would say, this is an important piece of data because this is randomized controlled trials when we have a placebo versus melatonin in people with actual chronic heart failure and we're not seeing negative effects on melatonin. If anything, we're seeing beneficial effects.

So, very important to keep in mind. There was also a 2022 review concluding that melatonin has shown heart protective effects in both human trials and also pre-clinical studies using animals.

The authors of this review article report that melatonin might help prevent cardiac hypertrophy. Right? So that would be the enlargement of the heart muscle which is an early step towards chronic heart failure. Mechanistically, there's all sorts of reasons why melatonin would be beneficial on the cardiovascular system.

It has antioxidant properties. It influences mitochondrial function. It also has anti-inflammatory properties. So, there's a lot of evidence that really seems to show that melatonin seems to be beneficial for chronic heart failure patients, for cardiovascular function in general, including randomized controlled trials, including animal studies as well.

So, I think we don't fully understand what's going on here because this observational study did have quite compelling findings. I mentioned it's limited for many reasons including the fact that's not peer-reviewed yet and we don't really know what's going on because it was only documenting electronic records documenting melatonin supplementation use which could actually be a biomarker for severity of insomnia. Right? I think overall these new results are interesting, but at the end of the day, we have conflicting data here.

Randomized control trials are not showing the same thing. And if anything, they're showing beneficial effects.

So I don't think that we can make a strong statement that melatonin supplementation is bad for the heart or will cause chronic heart failure. I do think that this needs to be studied in more depth, and I'm definitely going to follow the publication of this study. When it comes to treating insomnia, as I discussed in my podcast with Dr. Michael Grandner, many lifestyle habits can improve insomnia. Good sleep hygiene and cognitive behavioral therapy for insomnia, or CBT-I, are important first-line treatments to identify and work on before turning to melatonin. Long-term melatonin supplementation is never really the answer.

But again, I still am not sure that it's actually causing chronic heart failure based on the totality of evidence here. With randomized controlled trials being the strongest evidence, it doesn't mean we should ignore the observational data that has not been peer-reviewed. It is something that we need to consider and keep an eye on because sometimes observational data can pick up real-world signals. I just don't know that this signal is necessarily pointing to melatonin or is it pointing to severity of insomnia.

There are a few more melatonin-related questions that I'm going to go through. Hillary asks, "Would you address the long-term safety and maybe even benefits of taking melatonin one to three milligrams nightly for sleep?" And this is, of course, we're not talking high dose here.

I have discussed both the long-term and potential benefits of taking melatonin beyond sleep in great detail. Please go back and listen to Q&A episode number 54 and Q&A episode number 45. I've talked about, any concerning problems with melatonin and the potential benefits as well. So, I'll just give you a little bit of a summary.

So, there is some evidence that melatonin is a hormone. It's changing the expression of over 500 different genes in the body many of these genes are antioxidant genes and in that context it does show some beneficial antioxidant effects and there's even some interesting data and early promising data in the context of people with cancer undergoing radiation and chemotherapy where melatonin seems to help buffer some of the negative oxidative stress damage induced by radiation.

I've also talked about how important it is to maintain, the balance between pro-oxidant and antioxidant systems in the body before. You don't want too much of an antioxidant effect because something called reductive stress can happen, right? Where it's just it's a different type of oxidative stress where it's actually reductive stress, right? And so I've talked about that before where you want that balance to be right.

And that's just one reason why you don't want to go overboard with supplementing with all these antioxidants. Beyond melatonin's antioxidant properties, it also has important effects on sleep.

Beyond its important effects on sleep, it has been shown to lower blood pressure and improve metabolic disorders. It has been studied in some cancers and for improving fertility. I think all the research in these areas is still very preliminary.

They're in their early stages. They are encouraging. We do need more, long-term evidence and stronger evidence to really make strong claims in all those areas. But I do think it's encouraging when it comes to safety.

Many studies have looked at daily doses of melatonin up to 20 milligrams a day for several months. Across those studies, melatonin has been shown to be safe with only rare and mild adverse effects.

So these rare and mild effects are things like daytime sleepiness, dizziness, headache, mild hypothermia, melatonin can lower core body temperature. But again, these are sort of I would say mild adverse effects and they are rather uncommon with the exception of sometimes people getting the daytime sleepiness when they're supplementing with a really high dose.