12-week melatonin intake attenuates cardiac autonomic dysfunction and oxidative stress in multiple sclerosis patients: a RCT, 2024, Jallouli

[Dolphin]

https://link.springer.com/article/10.1007/s11011-024-01428-2

12-week melatonin intake attenuates cardiac autonomic dysfunction and oxidative stress in multiple sclerosis patients: a randomized controlled trial

• Research
• Published: 04 December 2024

• Volume 40, article number 52, (2025)
• Cite this article

Metabolic Brain Disease

• Sonda Jallouli,
• Dana Jallouli,
• Mariem Damak,
• Salma Sakka,
• Sameh Ghroubi,
• Chokri Mhiri,
• Tarak Driss,
• Giovanni de Marco,
• Fatma Ayadi &
• Omar Hammouda

• 
  17 Altmetric
  

Abstract

Multiple sclerosis (MS) can induce cardiac autonomic dysfunction identified by a decreased heart rate variability (HRV) which was linked to oxidative stress, vitamin D deficiency and sleep disturbance.

Previous MS studies revealed the antioxidant and anti-inflammatory effects of exogenous melatonin, as well as its benefits on sleep and vitamin D.

We aimed to investigate the change in HRV, oxidative stress, systemic inflammation and sleep following melatonin supplementation in MS patients.

Participants were randomly allocated to either a melatonin group (MG, n = 15) or a placebo group (PG, n = 12) (3 mg/night during 12 weeks).

Pre- and post-tests included HRV analysis (Kubios software), sleep dairy and biological analysis [oxidative stress biomarkers (malondialdehyde (MDA), advanced oxidation protein products (AOPP) and reduced glutathione (GSH)); 25-hydroxyvitamin D; C-reactive protein and cholinesterase Gen.2 (CHE2)].

Based on the pre-post supplementation change (Δ (T1₋T0)), melatonin increased the root mean square of successive differences between normal heartbeats [ΔMG (14.17 ± 16.93) vs. ΔPG (₋8.61 ± 12.67), p = 0.0007] and the HRV high-frequency band [ΔMG (6.86 ± 14.85) vs. ΔPG (₋12.58 ± 13.30), p = 0.0016] comparatively with placebo. MG showed a decrease in the HRV low-frequency band [ΔMG (₋4.96 ± 10.08) vs. ΔPG (10.22 ± 13.54), p = 0.003] as well as in the MDA [ΔMG (₋2.27 ± 1.92) vs. ΔPG (0.22 ± 2.30), p = 0.005] and AOPP levels [ΔMG (₋113.97 ± 137.72) vs. ΔPG (156.46 ± 230.52), p = 0.0008] compared with PG.

Melatonin enhanced the GSH [ΔMG (10.51 ± 14.93) vs. ΔPG (₋5.05 ± 10.18), p = 0.004] and CHE2 levels [ΔMG (407.07 ± 723.26) vs. ΔPG (₋22.92 ± 506.52), p = 0.029] as well as sleep quality [scores: ΔMG (1.50 ± 1.28) vs. ΔPG (₋1.05 ± 2.05), p = 0.0006] and quantity [weighted total sleep time: ΔMG (0.74 ± 1.14) vs. ΔPG (₋1.04 ± 1.00), p = 0.0003] comparatively with placebo.

Caregivers may recommend 12-week nocturnal melatonin intake to attenuate cardiac autonomic dysfunction, oxidative stress and sleep disorders in MS patients.

Clinical registration This study was prospectively registered in the Pan African Clinical Trial Registry database (PACTR202007465309582) on 23 July 2020 (https://pactr.samrc.ac.za/.).

Graphical abstract

Highlights
• 12-week melatonin supplementation (3 mg per night) alleviated cardiac autonomic dysfunction (i.e., it increased heart rate variability) in multiple sclerosis patients.

• Exogenous melatonin had benefits on oxidative stress biomarkers (reduced glutathione, malondialdehyde and advanced oxidation protein products).

• Chronic nocturnal melatonin intake enhanced sleep quality, efficiency and quantity.

https://twitter.com/user/status/1865227207754342474

 

[Hutan]

There's a paywall.
Tunisian study

I have been quite dismissive of the idea that melatonin helps much - I think the evidence to date has supported that stance. And I'm still feeling pretty skeptical, although perhaps I have no reason to be.

I can't find any evidence of conflicts of interest. But it's a small study and the abstract is not completely clear about the data. For example:

Based on the pre-post supplementation change (Δ (T1₋T0)), melatonin increased the root mean square of successive differences between normal heartbeats [ΔMG (14.17 ± 16.93) vs. ΔPG (₋8.61 ± 12.67), p = 0.0007] and the HRV high-frequency band [ΔMG (6.86 ± 14.85) vs. ΔPG (₋12.58 ± 13.30), p = 0.0016] comparatively with placebo.

The abstract says that the HRV high-frequency band increased more with melatonin than with the placebo, but the change with melatonin was 6.86 while the change with the placebo was 12.58.

 

[bobbler]

There's a paywall.
Tunisian study

I have been quite dismissive of the idea that melatonin helps much - I think the evidence to date has supported that stance. And I'm still feeling pretty skeptical, although perhaps I have no reason to be.

I can't find any evidence of conflicts of interest. But it's a small study and the abstract is not completely clear about the data. For example:

The abstract says that the HRV high-frequency band increased more with melatonin than with the placebo, but the change with melatonin was 6.86 while the change with the placebo was 12.58.

as a side note I was intrigued years ago when I looked into it and realised there seemed to be big differences in availability/access to melatonin. In the UK I think maybe children or the elderly might be able to be prescribed it more, but for 'adults' it is never suggested and got the impression that (putting aside ME/CFS where I'm not sure it has been listed for that) it would require a specialist and even then to be prescribed with strong reasons and have a management plan beyond just sending someone back to the GP with it listed etc.

I'm not completely sure why this is the case.

and yet I get the impression this isn't the case in other countries and in some it is more freely available and I guess tried more often for that reason.

 

[Hutan]

The effect of melatonin on irritable bowel syndrome patients with and without sleep disorders: a randomized double-blinded..trial, 2023,Dinevari et al
There was that study that found melatonin was useful in IBS. That was an Iranian study.

Maybe melatonin really is a wonder drug, and of course good science can be done anywhere. But, if you were a melatonin manufacturer, perhaps getting a range of studies published showing it does amazing things for a wide range of diseases would be a smart plan. And perhaps Tunisia and Iran are relatively cheap places to get such studies done.

 

[Hutan]

This is when I wheel out my previous post about the fact that melatonin may not be completely safe, especially in children and adolescents:

There have been questions raised about its safety particularly for adolescents e.g.
https://www.adelaide.edu.au/news/news76502.html

Warning on use of drug for children's sleep
Wednesday, 25 February 2015

Sleep researchers at the University of Adelaide are warning doctors and parents not to provide the drug melatonin to children to help control their sleep problems.
...
In a paper published in the Journal of Paediatrics and Child Health, Professor David Kennaway, Head of the Circadian Physiology Laboratory at the University of Adelaide's Robinson Research Institute, warns that providing melatonin supplements to children may result in serious side effects when the children are older.
...
"Melatonin is registered in Australia as a treatment for primary insomnia only for people aged 55 years and over, but it's easily prescribed as an 'off label' treatment for sleep disorders for children."
...
Professor Kennaway says there is extensive evidence from laboratory studies that melatonin causes changes in multiple physiological systems, including cardiovascular, immune and metabolic systems, as well as reproduction in animals.
...
Professor Kennaway, who has been researching melatonin for the past 40 years, says these concerns have largely been ignored throughout the world.
...
"Considering the small advances melatonin provides to the timing of sleep, and considering what we know about how melatonin works in the body, it is not worth the risk to child and adolescent safety," he says.

 

[Hutan]

My contemplation of the implausibility of 'big melatonin' led me to this article:
Melatonin from Microorganisms, Algae, and Plants as Possible Alternatives to Synthetic Melatonin

Melatonin (N-acetyl-5-methoxytryptamine) is widely used around the world as a dietary supplement. In general, melatonin is used as a sleep aid supplement, a mild tranquilizer, a generalist antioxidant, and an anticancer and anti-aging component, among others [1]. According to the American Psychiatric Association (APA), approximately one-third of adults suffer from insomnia during their lifetime [2]. It manifests itself in incessant problems falling asleep and staying asleep. Therefore, it is very likely that the use of synthetic melatonin will spread. In 2019, the global production of synthetic melatonin, which was around 4000 tons, accounted for around 1.3 billion USD. This vast market is fully assisted by chemical melatonin, whose synthesis process is very cheap, effective, and, therefore, lucrative.

The melatonin market is expected to grow at a CAGR (compound annual growth rate) of >10% over the next 5 years. With this considerable increase in demand, the insomnia problems generated by the COVID-19 pandemic have been of great relevance [3]. North America has the highest consumption by far, followed by Europe. The global melatonin market is mainly controlled by a few major companies, such as BASF, Aspen Pharmacare Australia, Nature’s Bounty, Pfizer Inc., Natrol LLC, Aurobindo Pharma, and Biotics Research Co. Note that the consumption of melatonin for medical purposes involves about 50% of the synthetic melatonin produced; the rest has chemical and industrial applications [2,4].

So a substantial and growing market although evidence of effectiveness for the many things it is supposed to fix is still weak.

However, even though melatonin is a molecule that has been widely studied since the 1950s, the studies carried out require more clinical and extensive double-blind trials in order to clarify its sometimes confusing pleiotropic action [33,34].

It has been supplied by synthetic melatonin. However, this has issues.

Initially, melatonin was obtained for experimental and clinical studies from animal sources (mainly from the pineal gland and urine), with the consequent risk of viral transmission [98,99]. These techniques were withdrawn when melatonin could be obtained by chemical synthesis [100]. Currently, all melatonin used for industrial and medical purposes is obtained by using chemical synthesis methods. These methods, which presented serious problems in the 1980s, including deaths due to the presence of by-products of synthesis from tryptophan [101], are much safer and more efficient today. However, melatonin preparations have described the presence of a whole set of undesirable by-products due to their toxic nature. Figure 3 shows three of the most commonly used chemical synthesis routes for melatonin and the by-products that are generated in its synthesis [102]. The synthesis of melatonin from tryptophan derivatives (Figure 3, Scheme A) generates toxic by-products that have sometimes caused significant diseases, such as eosinophilia myalgia syndrome [101,103,104], while the most current methods (Figure 3, Scheme B) for the synthesis of melatonin from phthalimide [105] raise important doubts about the toxicity of several of the by-products that are generated [106]. In addition, Fischer indole reactions from allylamine (Figure 3, Scheme C) present dangerous and toxic reactants [107].

Obtaining melatonin from plants and other non-animal sources would be quite a coup (although there could still be the problem of toxic contaminants). There has been progress but it doesn't yet seem to be commercially viable. There are suspicions that companies selling non-synthetic non-animal melatonin are adding synthetic melatonin to their products to get the concentration up.

After reading all that, I am less skeptical about the idea of an organisation paying for fraudulent studies that show melatonin works for a range of diseases. As I said, apart from the size, I can't see any problems with this particular study from the abstract, so it might be totally fine.

 

[Ryan31337]

Circadin (prescription melatonin) is something i've been keen to get off after being prescribed it post sleep study, maybe 6 years ago - at the time Neurology stuck to guidelines and suggested I come off it after a few months but the GP hasn't blinked.

I don't need it to initiate/maintain sleep anymore now that I'm pacing better and my wider issues (POTS/AS) are treated. If I really overdo it or flare i'm going to have a disrupted night regardless. I had wondered if part of my increased orthostatic intolerance in the AM might be due to the melatonin, and with the lack of data on long-term effects I figured i'd be safer coming off and started that process a week ago.

Subjectively my sleep hasn't been much worse, but boy did I forget how much daytime lower leg pain I experience without taking melatonin. Have no idea if there's some direct explanation for that or if its simply because I'm having worse quality sleep. Either way I will probably just go back on melatonin, otherwise I think i'd need to start chronic pain meds to manage it instead and that seems like a bad deal.

 

[bobbler]

This is when I wheel out my previous post about the fact that melatonin may not be completely safe, especially in children and adolescents:

Do you think there is something of the same fallacy you see with people these days (which is strange/due to marketing into the culture because it wasn’t this way in the past) assuming therapist-based can’t harm and doesn’t need yellow card , even when it’s CBT that is pretty combative and targeting ‘thoughts’ without proof either the one they are replacing is wrong or the change will help, or pushing through on an illness watching people get worse long term.

ie that combo of it ‘not adding in some chemical the body doesn’t already have’ fallacy (as melatonin is produced in body) just like people tend to give vitamins more leeway (although interestingly they rarely think that with steroids even if some ‘are close to those produced naturally’) or will use eg skincare ‘based in natural ingredients’ that might be actually as likely to cause allergies or issues but you see it coming less ‘because it’s natural’

and… the obsession with ‘training people to behave right’ rather than seeing it as a symptom (or maybe even not wrong just not what society wants - I’ve seen a few videos on neurodiversity that make this point on the ‘tyranny/fallacy of normal’ which is of course different to healthy or able to be useful or productive (just not under the conditions society wants to base things round)?

I ASSUME for trials melatonin would come under drugs licensing eg yellow card and side effects

but .. all I know about sleep research is a grim feeling it doesn’t move on from assuming it’s all about sleep hygiene. And it hasn’t expanded its knowledge. And I think it tends to separate off sleep from the rest of the body and the rest of someone’s health in a weird way. Unless it’s doing crap correlations about shift workers getting more illness (when how much if that is societal eg not making life easy at all in so many ways if you aren’t 9-5, like cafes being closed during shifts, often less staff and then these days imagine trying to sleep at home whilst everyone is doing building work or other noisy things - not to mention the shifts where people do different times of different days).

 

[sb4]

@Ryan31337 You can buy melatonin from an American online store like iHerb and get it delivered to the UK without prescription.

 

[oldtimer]

My own experience over the years, from having tried it (via iHerb) at different doses for periods of weeks and months at a time, is that it hasn't helped my insomnia at all. I won't be taking it again because of the potential risks.
I know nothing about biochemistry but it seems to me that for a hormone that is produced by the body at around 30 to 80 micrograms per day in an adult (depending on which article you read), the quantities in supplements are extreme. Because it's a supplement, proper safety studies haven't been done as far as I'm aware (?).

 

[Ryan31337]

@Ryan31337 You can buy melatonin from an American online store like iHerb and get it delivered to the UK without prescription.

Thanks - all the time I can get prescription circadin I think that's the better option. The sleep clinic Neurologist said the supplement versions are less likely to be controlled and reliable doses.

@oldtimer clinical trials for Circadin (prescription melatonin) were done and it is approved for use in the NHS. But the trials were fairly limited so recommendations are patchy for certain age groups and not beyond 13 weeks use. I have seen a couple of literature reviews suggesting it seems safe and non-habit forming but no robust research on long-term use has be done.