Chronobiotic use of melatonin improves DAT-binding in iRBD

[AkunaMatata]

Conference poster (not peer-reviewed) to be presented next month in Vienna at AD/PD 2025: cslide.ctimeetingtech.com/a...

Aims: Isolated REM-sleep behavior disorder (iRBD) is recognized as a prodromal state of clinical α-synucleinopathies such as Lewy-body dementia and Parkinson’s disease. A pathophysiologic hallmark of α-synucleinopathies is nigrostriatal dopaminergic impairment, with dopamine-transporter(DaT)-SPECT imaging considered best available prognostic and monitoring marker. DaT-binding is reported to decrease with healthy aging by 4-10% per decade, accelerated to 4-12% per year iRBD patients. We have introduced melatonin as a treatment option for iRBD. Aim of the study was to evaluate effects of melatonin on DaT-SPECT imaging in iRBD patients.

Methods: In a prospective, longitudinal, observational, single-center study we performed at least two DaT-SPECTs in 97 iRBD patients treated with melatonin as a chronobiotic (i.e. administration always- at-the-the-same-clock-time;10-11p.m.-corrected for chronotype); 28 patients were excluded mainly due to change of psychotropic drugs known to influence DaT.

Results: After mean follow-up of 3.6yrs, only 21/69 patients (11 female; mean age 71±6yrs) showed specific binding ratios (SBR) in most affected region (MAR, predominantly right posterior putamen) comparable to usually reported declines with iRBD. In contrast, 7 had declined SBR at a rate comparable to healthy aging, while 41 had actually improved SBR. Improvement after one year (SBR of MAR; F1,31=23.748;p>0.001) and two years was significant (F1,24=4.648;p=0.041). After four years half of the patients showed a higher SBR than baseline (23 vs. 24 patients), though this was not significant. 47/69 of our patients at baseline met established criteria for an advanced state.

Conclusions: To the best of our knowledge, present data give first evidence for a consistent increase in DaT-binding ratios in nigrostriatum over time in a cohort of patients with iRBD. In addition, the previously reported persisting effect of melatonin on RBD symptoms suggest that melatonin, when used as a chronobiotic, may have a disease-modifying effect in prodromal α-synucleinopathies.

In a previous authors argue that the dose and timing matter a lot: onlinelibrary.wiley.com/doi...

They use "2 mg, ≥6 months, always-at-the-same-clock time, 10-11pm, corrected for chronotype" because:

"Long-term medication with betablockers is likely to have changed melatonin receptor sensitivity, thus delaying response to initial melatonin. The same negative effect could be attributed to recommended increasing dosage of melatonin. Because melatonin influences its own receptor, it is important to have a melatonin-free period over the day. Supraphysiologic melatonin doses, especially in slow metabolizers, prevent the absence of melatonin during the day and could induce insensitivity in melatonin receptors the next evening."

"The rate of improvement of RBD symptoms with melatonin in previously reported case series varies, and two recent RCTs have shown no effect. Unfortunately, melatonin has been sold worldwide for the past 25 years as a hypnotic to be administered in connection with clock time independent events (eg, “after a meal,” “at bedtime”). Most people who took melatonin—including those in the two recent RCTs with negative results—will therefore not have adhered to a schedule based strictly on clock time. As an example, in our Clinic for Sleep & Chronomedicine, we precisely explain the chronobiotic protocol but even though, still some patients stuck to the aberrant leaflet prescription. Our study indeed demonstrates that beneficial effects of melatonin can easily be disrupted with improper timing of intake, which may well explain lower response rates reported by other groups. In those patients for whom we had a chance to reinstruct, melatonin improved RBD symptoms. On the other hand, melatonin should not be considered a harmless drug or being without side effects. Inadequate timing of melatonin seems likely not only to fail in improvement, but rather to worsen symptomatology due to desynchronization."

However, other papers suggest that the optimal timing is 3 hours before bedtime: onlinelibrary.wiley.com/doi...

[MarionP]

Melatonin is not a magic bullet. very interesting that the study did not compare that scan changes with known markers of concurrent disease progress and status. instead, what seems to be the assertion is "let's change the DAT picture, and then claim that means the disease doesn't exist anymore, even if all of the symptoms in the person's life actually continue on and continue to get worse. Oh and let's get paid and obscene amount of money for five or six years in the process so that we can have a second swimming pool."😜

[AkunaMatata in reply to MarionP]

Do you really think that German researchers get paid an "obscene amount of money" for studying a cheap old generic drug?

This is just a conference abstract where they looked at DAT binding. They didn't claim "the disease doesn't exist anymore". They will most likely publish a proper paper with other endpoints (UPDRS, RBD scale, quality of life, etc.).

As you can see, that's what they did in their previous papers: onlinelibrary.wiley.com/doi...

"With melatonin, RBD symptom severity gradually improved over the first 4 weeks of treatment (Ikelos-RS: 6.1 vs. 2.5; CGI Severity: 5.7 vs. 3.2) and remained stably improved (mean follow-up 4.2 ± 3.1years; range: 0.6-21.7years). Initial response was slowed to up to 3 months with melatonin-suppressing (betablockers) or REM sleep spoiling co-medication (antidepressants) and failed with inadequately timed melatonin intake. When melatonin was discontinued after 6 months, symptoms remained stably improved (mean follow-up after discontinuation of 4.9 ± 2.5years; range: 0.6-9.2). When administered only 1-3 months, RBD symptoms gradually returned. Without any melatonin, RBD symptoms persisted and did not wear off over time. Clock-timed, low-dose, long-term melatonin treatment in patients with iRBD appears to be associated with the improvement of symptoms. The outlasting improvement over years questions a pure symptomatic effect. Clock-time dependency challenges existing prescription guidelines for melatonin."

They showed in another paper that "Most RWA metrics correlated significantly with DAT-SPECT ratios (eg, Montreal tonic vs most-affected-region: r=−0.525; p<0.001).": jnnp.bmj.com/content/94/7/5...

So this paper is massive and, if the results are confirmed by other markers of the disease (questionnaires, sleep recordings, etc.) then melatonin (following their protocol and not at random doses taken "30 minutes before bedtime") might be a magic bullet.

[MarionP in reply to AkunaMatata]

Be serious yourself. Didn't know they were German. Apparently that makes some difference to you though. What if they were South African, would that have made a difference? Talk about your non sequitur. At least they weren't Irish.

How about...When you put something up put up an explanation or the point you're trying to make don't just leave it naked light somebody skipping a flat rock over the lake. And yes, German scientists are no different than any other scientists, the first order of business is to make a good living, the second order of business is to contribute something, but only if convenient to the first order. Maybe you're a little young to notice the real world. So I'll be serious if you do first. In the meantime maybe you should learn something about melatonin, and also learn something about competent consumption of research, which is a degree level skill in itself. And while you're at it maybe even something about Parkinson's, might be helpful. All these guys did was change the channel, not what's being broadcast.

[AkunaMatata in reply to MarionP]

Your reaction confirms your inability to assess the scientific relevance of this study. Have a good day!

[CPT_Katelyn Partner]

Just a note that a few replies to this post have been flagged. Please remember to be kind and understanding when speaking to one another, as per our community guidelines. To review these, please read our post on this: healthunlocked.com/cure-par....

[AkunaMatata]

 park_bear : I'm curious to know your thoughts on these papers (the protocol, the DaT SBR improvements, and the correlation between DaT SBR and RBD metrics).

[park_bear in reply to AkunaMatata]

Firstly, I appreciate it that you provided the relevant text rather than making me go hunt for relevant parts in a link. I did not see any obvious problems. I did not do a really deep dive but based on my read through it looks good to me. I agree that allegations of researcher dishonesty do not fit here, and you effectively answered the criticism regarding measurement of symptoms.

[AkunaMatata in reply to park_bear]

Thanks. It also looks surprisingly good to me. A 2021 RCT used "25 mg of melatonin or placebo at noon and 30 min before bedtime for three months" and found improvements of some biomarkers but they didn't report UPDRS... onlinelibrary.wiley.com/doi...

[Fireside15]

Taking melatonin at the same time/s every day (as well as the specific times chosen) is an interesting issue. I wonder if this is emphasized in trials of melatonin for PD, specifically.

[AkunaMatata in reply to Fireside15]

Previous trials of melatonin for PD used a different protocol (the typical "30 min before bedtime" that seems suboptimal).

[BlockRuys]

Interesting. Thanks for sharing. I've been taking melatonin 25 mg at the exact same time every day for over a year now. Things have been pretty stable. There's some evidence melatonin is a drug that is very powerful, especially for people like us. Something that can be relatively risk-free added to our protocols.

[Esperanto]

For many individuals, adopting a more balanced and moderate approach may be wise. Research indicates that even lower doses of melatonin, starting at 0.5 mg, can effectively promote sleep without significant side effects. This makes it a preferable option for those who experience headaches or other adverse effects from higher dosages.

Moreover, spending ample time outdoors and in natural sunlight can greatly enhance sleep quality. Exposure to natural light plays a crucial role in regulating the circadian rhythm, which is essential for a healthy sleep-wake cycle. This, in turn, supports improved melatonin production in the evening.

By combining a moderate melatonin dosage with healthy lifestyle choices—such as increasing outdoor activity—I have experienced further improvements in my sleep regimen even after more than a year.

[AkunaMatata in reply to Esperanto]

The benefits of melatonin go way beyond sleep. Namely: DNA damage repair ( oem.bmj.com/content/early/2... ) and potential SBR decline reversal (the present paper). For these additional benefits, such a low dose might not be enough.

[Esperanto in reply to AkunaMatata]

Combining a moderate melatonin dosage with sunlight exposure could produce effects similar to the used 2 mg. Sunlight regulates the circadian rhythm and boosts melatonin production. This approach allows for benefits with lower doses, but individual responses may vary.

[AkunaMatata in reply to Esperanto]

People with PD seem to have lower melatonin production and/or disregulated released so exogenous might still be needed.