Melatonin

Is Melatonin Safe?

by

What Is Peer Review?

Author: Dr. Stephen Chaney 

newspaper headlinesRecent headlines claim that long-term melatonin use may be risky. Specifically, the headlines claim that long term melatonin use may increase the risk of:

  • Heart failure by 90%.
  • Hospitalization for heart failure by almost 3.5-fold.
  • All-cause mortality by 2-fold.

Those statistics are frightening. But as Mark Twain said, “There are lies. There are damn lies, and then there are statistics.”

So, as someone who uses a melatonin supplement regularly, the claims about heart failure risk made me want to check out the study behind the headlines.

I set out to answer two questions:

  • Are the claims about melatonin use and heart failure risk true?
  • Are they significant?

How Was The Study Done?

clinical studyHere is what we know about the study:

  • The authors used a global data network of healthcare providers called the TriNetX Global Research Network and selected all patient records in the network of adults >18 who had a clinical diagnosis of insomnia.
  • They compared insomnia patients that had been prescribed melatonin for at least a year with non-melatonin users. Patients on heart failure drugs were excluded from the analysis.
  • Outcomes (new diagnosis of heart failure, hospitalization for heart failure, and all-cause mortality) were assessed 5 years after the patients were first prescribed melatonin.
  • A small subset of the two groups (414 in each group) were compared with respect to things like:
    • Demographics (things like age, sex, socioeconomic status, and income level).
    • Other diagnosed diseases.
    • Other medication use.
    • Healthcare utilization.
    • Blood and urine lab results.
    • Vitals (things like weight, height, blood pressure, heart rate, etc.

I said, “Here is what we know about the study” because this was not a published clinical study. It was a poster presented at a scientific meeting.

That means that a lot of details about design of the experiments and how the data were analyzed are missing. It also means the study has not gone through the peer review process that is required for publication in a scientific journal.

To help you understand why that is important, let me explain the peer review process.

What Is Peer Review?

SkepticPoster presentations at scientific meetings, like this one, have a couple of purposes:

  • They give graduate students and post-doctorate fellows a chance to learn how to present and defend their research. It also gives them a chance to form relationships with the leaders in their field who may become their next step up the career ladder.
  • They foster discussions with other experts in the field who may spot flaws or offer helpful suggestions for improving the research before submitting it for publication.

The ultimate goal, of course, is to get the research to the point where it is ready to be submitted to a high-quality, peer-reviewed scientific journal (It is still “publish or perish” in the academic world).

This is an area in which I have extensive experience, having published over 100 articles in peer reviewed journals during my career at the University of North Carolina. I was also a reviewer for hundreds of articles during my time at UNC.

Once the manuscript has been submitted to a peer-reviewed scientific journal, they send it to two or three peers (other experts in the same area of research). Some of the peers are your friends. Others are your competitors. In either case, their goal is to make sure the paper adheres to the highest scientific standards. They review the paper for:

  • Hypothesis to be tested: They ask, “Is the hypothesis credible and clearly stated?”
  • Experimental Design: They ask, “Are the experiments designed in such a way that they adequately test the hypothesis?”
  • Data Collection: They ask, “Was enough data gathered to test the hypothesis?” and “Were there gaps in the data that need to be filled?”
  • Statistical Analysis: They ask, “Was the statistical analysis of the data sufficient to test the hypothesis?” and “Were there any important controls missing from the data collected or the statistical analysis?”
  • Conclusions: They ask, “Are the conclusions of the authors adequately supported by the data collected and the statistical analysis?”

If the reviewers find defects in any of these areas, they have 3 options. They can:

  • Ask the authors to rewrite and resubmit the manuscript.
  • Ask the authors to perform additional experiments or use a more rigorous statistical method before resubmitting the manuscript.
  • Reject the manuscript.

Hopefully, this description helps you understand the power of the peer review process and why the lack of peer review for this study is significant.

I am not saying the claims in this poster presentation are inaccurate. I’m saying the headlines about them may be premature because the study has yet to be peer-reviewed.

What Did This Study Show? 

Question MarkThe abstract said that long-term (≥1 year) melatonin users had:

  • An 89% higher risk of developing heart failure.
  • A 3.44-fold higher risk of hospitalization for heart failure.
  • A 2.09-fold higher risk of all-cause mortality.

The authors concluded, “In a large, multinational real-world cohort rigorously matched on >40 baseline variables, long-term melatonin supplementation in insomnia was associated with an 89% higher hazard of incident heart failure, a three-fold increase in heart failure–related hospitalizations, and a doubling of all-cause mortality over 5 years. These findings challenge the perception of melatonin as a benign chronic therapy and underscore the need for randomized trials to clarify its cardiovascular safety profile.”

Is Melatonin Safe? 

The TruthAt the beginning of this article I said I wanted to answer two questions:

  • Are the claims about melatonin use and heart failure risk true?
  • Are they significant?

The first question (Are the claims about melatonin use and heart failure risk true?) is difficult to answer.

  • This is an abstract instead of a publication. That means I have no access to the data, statistical methods, and controls that went into the Author’s conclusions. So, I have no basis for analyzing the accuracy of the authors’ statements.
  • This has not gone through peer review. The conclusions of the authors may be modified or may be rejected based on peer review.

There are several questions I and others who have discussed this study would like to see answered. For example:

  • How can hospitalizations for heart failure be greater than the number of people with heart failure? Normally, between 20-80% (average = 45%) of people with congestive heart failure end up in the hospital. The discrepancy between hospitalizations and heart failure patients in this study suggests that:
    • Some hospitalizations were for another reason and were mischaracterized as being due to heart failure…or…
    • The same individual(s) were hospitalized multiple times during the 5-year follow-up.
    • In either case hospitalizations for heart failure would be overcounted.
  • How did they accurately distinguish between melatonin users and non-users since their study drew on data from both England and the United States?
    • In England, melatonin is only available by prescription, so the distinction is clear.
    • But in the United States a prescription is not required. Melatonin is infrequently prescribed. Most melatonin users obtain their melatonin over the counter and are not recorded in any database.
  • Were the controls sufficient?
    • The author’s conclusion states the data were “…matched on >40 baseline variables…”, but the Methods section states that only a small subset (414) of melatonin users were matched for those variables. That is less than 5% of the melatonin users in the study.
  • Are the data on the relationship between melatonin use and all-cause mortality accurate?
    • Again, the increase in all-cause mortality was greater than the number of melatonin users.
    • That suggests that the increase in all-cause mortality may be due to some characteristics of severe insomniacs who choose to take melatonin rather than to melatonin itself.

These are the kinds of questions that need to be answered during the peer review process and might alter the conclusions or prevent the study from being published.

  • So, the answer to the first question (Are the claims about melatonin use and heart failure risk true?) is, “We don’t know. The study has not gone through the peer review process and is unpublished.

Relative Risk Versus Absolute Risk 

ProfessorThe answer to the second question (Are the claims about melatonin use and heart failure risk significant) is much clearer. It has to do with the difference between relative risk and absolute risk.

Simply put:

  • Relative risk is the change in risk caused by an intervention (melatonin in this case) relative to the risk without the intervention.
    • Relative risk is generally used in describing the results of clinical studies because it gives much larger numbers and is, therefore, more newsworthy. It is more likely to generate the headlines you see and grab your attention.
  • Absolute risk is the actual change in risk that you experience.
    • This is the risk that matters to you.

With those simple definitions, let’s review the claims of this study:

  • The study said that long-term melatonin use increased the risk of heart failure by 90%. That sounds horrible, but it is an increase in relative risk!
    • To calculate the absolute increase in the risk of heart failure, you need to first ask what the baseline risk is in non-melatonin users. In this study it was 2.7%.
    • With that information, we can do some simple math. A 90% increase would increase the risk to 4.6%. 4.6% – 2.7% = 1.9%.
    • That means the absolute increase in risk caused by long-term melatonin use is less than 2%.
  • The study said that long-term melatonin use increases the risk of hospitalization 3.44-fold.
    • On average, 45% of heart failure patients are hospitalized. Since the risk of heart failure in this study was 2.7%, that means the baseline for hospitalization should be 45% of 2.7% or around 1.2%.
    • A 3.44-fold increase would increase that to 4.2% which means that the absolute risk of being hospitalized if you are a heart failure patient is around 3% (4.2% – 1,2%).
  • Finally, if the increase in all-cause mortality is solely caused by melatonin use (which is unclear), melatonin use increases mortality risk from 4.3% to 7.8%, for an absolute increase in risk of 3.5%.

In short, if the claims about melatonin use and heart failure are true (which is uncertain) the absolute increase in risk is very small for the average, healthy adult.

What Does This Study Mean For You? 

ConfusionIf you are an average, healthy adult you probably do not need to be concerned about the headlines linking melatonin use with heart failure.

  • It is not yet clear whether the claims are accurate.
  • And, if they are accurate, your increased risk is very small.

There are, however, some caveats.

  • If you suffer from severe, chronic insomnia you should consult your healthcare provider first.
    • Your insomnia may be caused by an underlying health condition.
    • Your healthcare provider may suggest more effective treatments. Some of these treatments may have more side effects than melatonin use, but it always useful to know what your choices are.
  • If you have been diagnosed with heart failure, you should avoid melatonin.

Finally, even though this study is very preliminary, there are also some individuals who may wish to consult with their healthcare provider before taking melatonin. These include people with conditions that increase the risk of heart failure such as coronary heart disease, heart attacks, diabetes, obesity, and high blood pressure.

The Bottom Line 

Recent headlines have suggested that long-term melatonin use substantially increases the risk of heart failure, hospitalizations due to heart failure, and premature death.

However, these headlines were based on an abstract of a poster presented at a scientific meeting. That means:

  • There is not adequate information available to analyze the data behind the claims.
  • The study has not yet gone through the peer review process, so we don’t know whether the claims are accurate.

Based on my evaluation of the available information, my analysis is:

If you are an average, healthy adult you probably do not need to be concerned about the headlines linking melatonin use with heart failure.

  • It is not yet clear whether the claims are accurate.
  • And, if they are accurate, your increased risk is actually very small.

For more information on the study and who should consult with their healthcare provider before using melatonin, read the article above.

These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure or prevent any disease.

_____________________________________________________________________________

My posts and “Health Tips From the Professor” articles carefully avoid claims about any brand of supplement or manufacturer of supplements. However, I am often asked by representatives of supplement companies if they can share them with their customers.

My answer is, “Yes, as long as you share only the article without any additions or alterations. In particular, you should avoid adding any mention of your company or your company’s products. If you were to do that, you could be making what the FTC and FDA consider a “misleading health claim” that could result in legal action against you and the company you represent.

For more detail about FTC regulations for health claims, see this link.

https://www.ftc.gov/business-guidance/resources/health-products-compliance-guidance

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About The Author 

Dr. Chaney has a BS in Chemistry from Duke University and a PhD in Biochemistry from UCLA. He is Professor Emeritus from the University of North Carolina where he taught biochemistry and nutrition to medical and dental students for 40 years.

Dr. Chaney won numerous teaching awards at UNC, including the Academy of Educators “Excellence in Teaching Lifetime Achievement Award”.

Dr Chaney also ran an active cancer research program at UNC and published over 100 scientific articles and reviews in peer-reviewed scientific journals. In addition, he authored two chapters on nutrition in one of the leading biochemistry text books for medical students.

Since retiring from the University of North Carolina, he has been writing a weekly health blog called “Health Tips From the Professor”. He has also written two best-selling books, “Slaying the Food Myths” and “Slaying the Supplement Myths”. And most recently he has created an online lifestyle change course, “Create Your Personal Health Zone”. For more information visit https://chaneyhealth.com.

For the past 54 years Dr. Chaney and his wife Suzanne have been helping people improve their health holistically through a combination of good diet, exercise, weight control and appropriate supplementation.

 

What Is The Truth About Melatonin?

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Why Are There So Few High-Quality Melatonin Studies? 

Author: Dr. Stephen Chaney

Insomnia is a major problem in our world. The reasons are not hard to see:

  • We live in troubled times. Conflicts abound and the days of reasoned discussions and compromise have become distant memories.
  • We live in difficult times. Many of us have lost jobs or loved ones. We have all lost our freedoms. We live in forced isolation. The consoling hug of a friend or neighbor has become a distant memory.
  • We live in fast-paced times. We are constantly “on” from the moment our feet hit the floor in the morning to the moment our head hits the pillow at night. We are also on our devices until the time we go to bed, and most of the news on those devices is bad.

The reasons are also physiological:

  • When we turn off the lights our pineal gland produces a hormone called melatonin that calms our brain and prepares us for sleep.
  • However, as we age our body produces less melatonin because:
    • Our pineal gland produces less melatonin.
    • Many medications commonly prescribed to older Americans suppress melatonin synthesis.

Whatever the reason, insomnia has become a major problem for millions of Americans.

  • One third of all Americans and 69% of older Americans suffer from insomnia. That is a concern because severe insomnia:
  • Affects their quality of work.
  • Affects their quality of life.
  • Increases the risk of accidents.

Medications abound, but they have a long list of side effects. Plus, long term drug use can result in tolerance (the drug loses its effectiveness) and/or dependence (sleep without the drug becomes impossible).

It is no wonder melatonin supplements have become popular among people who have trouble getting a good night’s sleep.

People have been asking me about melatonin supplements. “Do they work? Are they safe?”

It turns out that these aren’t easy questions to answer. Most published studies on melatonin are poor quality and/or have been performed by the company that wants to sell you their melatonin supplement. This raises the question, “What is the truth about melatonin?”

Fortunately, I came across a recent study (F Auld et al, Sleep Medicine Reviews, 34: 10-22, 2017) which is a review and meta-analysis that included only high-quality studies in its analysis. This is the one I will discuss today.

How Was This Study Done?

Clinical StudyThe scientists in charge of this review and meta-analysis started by identifying 5030 studies of the effect of melatonin on various aspects of sleep that had been performed between 1990 and May 2015. Next, they excluded all poor-quality studies from their analysis.

I will list the exclusion criteria below with comments on why these exclusion criteria are important.

#1: Commercially sponsored research: You will often see clinical studies of melatonin supplements reported on their company’s website. The graphs look impressive. The website will say something like. “Our scientists found…” My question is, “If the scientists had not found that their company’s product worked, would they have a job tomorrow?”

Sometimes the research has been done by outside scientists who were supported by funding from the company. These studies are sometimes biased in favor of the company’s product.

#2: Unpublished research: Many companies will cite unpublished “white papers” showing their products work. Often these studies have been done by scientists not directly affiliated with the company. While that sounds impressive, my questions are, “What weaknesses in the study are they trying to hide? Why are they afraid to submit their study to the rigors of peer review so it can be published?”

#3: Research that did not use well established criteria and measurements of sleep disorders: There is an international classification system and rigorous protocols for evaluating sleep disorders. Studies using subjective measurements of sleep quality instead of internationally- recognized protocols are considered low-quality. [For example, a subjective measurement of sleep quality would be to ask subjects, “Did you sleep better?” Whereas, the gold standard objective protocol for sleep quality measures brain waves, heart and breathing rates, and eye and leg movements.]

#4: Research design that was not placebo-controlled. Many of the published clinical studies just gave melatonin to their subjects and asked if sleep quality improved. The placebo effect for something as subjective as sleep quality can be huge. Without a placebo control those studies are worthless.

#5: Research design that was not blinded: The investigators only included double- and single-blinded studies in their analysis. In the single-blinded studies the subjects did not know whether they got melatonin or the placebo. This is the most important aspect of blinding because it avoids the placebo effect.

In double-blinded studies, neither the subjects nor the investigators know who got melatonin and who got the placebo. This is considered the “gold standard” of clinical studies, but investigator blinding is only important when investigators are using subjective criteria to measure outcomes.

#6: Research design that was not randomized. Randomization simply means that the subjects were randomly assigned to the melatonin and placebo groups. This assures that the two groups are alike in every characteristic except whether they received melatonin or placebo.

Once they had excluded all low-quality studies, the investigators were left with 12 high-quality studies. [You didn’t misread that. They started by identifying 5030 studies on melatonin and, after carefully analyzing those studies, ended up with only 12 high-quality studies.] I can’t resist making two comments here.

  • Now you understand why many scientists are skeptical about the value of melatonin. There are too many low-quality studies.
  • Now you understand why I chose this particular paper to report on in today’s “Health Tips From the Professor”.

Most of the high-quality studies were small (had relatively few subjects), so the investigators combined studies of similar design in their meta-analysis.

They were able to assess the effect of melatonin supplements on something called sleep latency (the time it takes to fall asleep). This can be a problem at any age but is most common in the elderly.

What Is The Truth About Melatonin?

The TruthThe investigators identified five high-quality randomized, blinded, placebo-controlled clinical studies with a total of 1,113 subjects that addressed sleep latency (the time it takes to fall asleep). Subjects were given 2-3 mg of melatonin and the studies lasted 4-5 weeks.

When they combined the data from all 5 studies, there was a highly significant reduction in the time to fall asleep for melatonin-treated subjects compared to placebo. The p value was 0.004 (For comparison, p values <0.05 are considered significant, and p values <0.01 are considered highly significant.)

There were a few high-quality studies addressing the effect of melatonin on other sleep disorders. There appeared to be a beneficial effect of melatonin on some of those disorders, but there were not enough subjects in these studies for the effect of melatonin supplementation to be statistically significant.

The investigators concluded, “These findings highlight the potential importance of melatonin in treating certain sleep disorders. Meta-analysis of the data emphasized in particular the improvement in sleep latency [time it takes to fall asleep] with melatonin in these patients.”

Why Are There So Few High-Quality Melatonin Studies?

ConfusionThe investigators went on to say, “The development of large-scale, randomized, placebo-controlled trials is recommended to provide further evidence for therapeutic use of melatonin in a variety of sleep difficulties.” However, they acknowledged that future large-scale studies of melatonin supplements are unlikely.

In the words of the authors, “Future research may be hindered by the…lack of financial incentives that may decrease motivation to undertake such trials. Funding agencies are more likely to support research on novel medications, which leads to new treatments and increased revenue for pharmaceutical companies, than to supply funding for a supplement (melatonin) that has been easily purchased over the counter since the 1990’s.”

Finally, someone has pointed out the elephant in the room. There is a good reason that it is so hard to find large, high-quality studies on supplements – and it is called money. It takes lots of money to fund large high-quality clinical studies. Companies don’t make enough money from supplement sales to justify those kinds of studies.

Let me give you an example. There is a sleep disorder called “Non 24-hour sleep wake syndrome” in blind patients. Simply put, the pineal gland relies on the transition from light to darkness to regulate when melatonin is released. If a blind person cannot distinguish between light and darkness, they have no signal for melatonin release. They have no physiological signal that it is time to sleep.

Sometimes they can overcome this with a set bedtime every day. However, some blind people really struggle falling asleep and waking up on a regular schedule.

In the review I described above, two very small high-quality studies were identified that suggested melatonin supplementation may help blind people normalize their sleep and wake times. However, the studies were too small to be statistically significant.

On the other hand, a drug company spent hundreds of thousands of dollars developing and testing a drug which mimics the effect of melatonin. Because the drug does not occur in nature, they could patent it. And because they could afford to pay for large-scale, randomized, placebo-controlled clinical trials of the drug, the FDA approved it. They will probably make millions from this drug. You may have even seen it advertised on TV.

How Can You Get A Good Night’s Sleep?

SleepThe study described above confirms that melatonin is effective at reducing sleep latency (the time it takes to fall asleep). It may be useful for other sleep disorders, but the evidence to support those uses is inconclusive at present.

However, holistic approaches are always best. If you toss and turn at night, you might want to start by trying these “sleep hygiene” tips from the CDC:

  • Be consistent. Go to bed at the same time each night and get up at the same time each morning, including on the weekends.
  • Make sure your bedroom is quiet, dark, relaxing, and at a comfortable temperature.
  • Remove electronic devices, such as TVs, computers, and smart phones, from the bedroom.
  • Avoid large meals, caffeine, and alcohol before bedtime.
  • Get some exercise. Being physically active during the day can help you fall asleep more easily at night.

You may also want to try relaxation techniques like yoga before bedtime.

When sleep hygiene fails, try melatonin to help you fall asleep. Here are a few things to know:

  • Melatonin is cleared from the body very rapidly (usually within 1-2 hours).
    • That means melatonin is much less likely to cause drowsiness the next morning than many of the insomnia drugs.
    • It also means that melatonin helps you fall asleep, as the review and meta-analysis described above confirmed. However, it doesn’t stick around long enough to help you stay asleep. Other herbs like valerian are more effective for that purpose.
  • Our ability to clear melatonin from our system declines as we age.
    • Therefore, doses of 2 or 3 mg are usually recommended for people over 50, while 5 or 10 mg are sometimes used for teenagers and young adults.
    • However, we are all different, so you may need to experiment to find the best dose for you.
  • Melatonin has remarkably few side effects compared to the widely prescribed insomnia drugs. It also appears less likely to create dependence.
  • Melatonin is often considered an occasional use supplement.
    • That is fine if you only have trouble falling asleep occasionally.
    • If you suffer from insomnia on a regular basis, you will be comforted to know that clinical studies have reported no side effects or dependency with daily use of low-dose melatonin for up to 6 months.
    • However, if you do have chronic insomnia, it is always a good idea to discuss your situation with your health professional to make sure it is not caused by an underlying medical condition.

The Bottom Line

Insomnia is a major problem in our world. Medications abound, but they have a long list of side effects. Plus, long term drug use can result in tolerance (the drug loses its effectiveness) and/or dependence (sleep without the drug becomes impossible).

It is no wonder melatonin supplements have become popular among people who have trouble getting a good night’s sleep. People have been asking me about melatonin supplements. “Do they work? Are they safe?”

It turns out these are not easy questions to answer. Most published studies on melatonin are poor quality and/or have been performed by the company that wants to sell you their melatonin supplement. This raises the question, “What is the truth about melatonin?”

Fortunately, I came across a recent review and meta-analysis that included only high-quality studies in its analysis. This study concluded that melatonin is effective at reducing sleep latency (the time it takes to fall asleep). It may be useful for other sleep disorders, but the evidence to support those uses is inconclusive at present.

For more details about this study, how to use melatonin, and a holistic approach to improve your quality of sleep read the article above.

These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure, or prevent any disease.

Health Tips From The Professor