Long COVID ME/CFS patient recovers to 80-90% using high-dose melatonin at 3 x 5 mg daily, taken morning, afternoon and night

[Hip]

This Reddit post details an 80-90% recovery from long COVID ME/CFS, achieved from melatonin at a high dose of 15-20 mg daily. In a PM he told me he takes three divided doses of 5 mg in the morning, 5 mg in the afternoon, and 5 mg at night.

He said he was drowsy and sleepy for 3 days when he first started daytime melatonin, but then started getting used to it. He said he drank coffee to counter the sleepiness, and that helped.

His ME/CFS was between moderate and severe, but after following this melatonin protocol for three months, he went into near remission.


However, his long COVID ME/CFS was somewhat unusual, in that he was constantly catching colds and infections, which hit him severely, and were always setting his ME/CFS back to square one.

Before melatonin, he would get a new cold every 2-3 weeks, and this meant he would be in bed for 7-10 days due to the infection, and then have 1-2 weeks to recover, until a new infection would come along and put him back to being bedridden again.

But after starting melatonin, this protected him from severe colds, so his ME/CFS was not being constantly set back by these viral infections. When he catches a cold, he says he increases his melatonin dose to 30-60 mg daily, and finds he now recovers from the cold within 1-3 days, and finds the colds are now very mild and barely noticeable.

He thinks these constant severe colds were preventing his recovery from ME/CFS, and he credits the high-dose melatonin taken day and night with preventing these colds from becoming severe.

He says the severe colds he was constantly getting were definitely due to COVID, because before catching COVID, he only caught colds once or twice a year.



So this melatonin treatment might be good for the sort of ME/CFS patients who are always catching colds, and who find these colds hit them very hard, and cause lingering ill effects which constantly set back their ME/CFS.

According to a poll, most ME/CFS patients are the type who have ramped up immunity, so that they rarely catch colds (Rich Van Konynenburg had a theory of why this subtype of ME/CFS is immune to colds).

But the poll indicates that 15% of patients are the opposite, the type that has weakened immunity that makes them catch colds all the time, with each cold hitting them extremely hard, and with it taking them weeks or months to fully recover and get back to baseline.

It is for this latter subtype that this very high-dose melatonin protocol might work.



Melatonin is synthesised in the brain's pineal gland at night for the purpose of inducing sleep, but it is also synthesised in the rest of the body, where its benefits include its potent antioxidant capabilities and immune regulation.

Note that melatonin has a short plasma half-life of only 40 minutes, so it leaves the body quickly. Thus if taken only at night before bed, melatonin will have mostly disappeared from the body after about 3 hours.

Thus the key feature of this protocol may be that he takes melatonin three times daily, which exposes his body to melatonin for longer periods.



He lists the following studies as those he read about the benefits of melatonin:

General benefits:
https://pmc.ncbi.nlm.nih.gov/articles/PMC6453953/
https://pmc.ncbi.nlm.nih.gov/articles/PMC3645767/

Specific benefits for COVID:
https://pmc.ncbi.nlm.nih.gov/articles/PMC10043401/
https://pmc.ncbi.nlm.nih.gov/articles/PMC9687267/
https://pmc.ncbi.nlm.nih.gov/articles/PMC10852014/
https://pmc.ncbi.nlm.nih.gov/articles/PMC7985934/

General antiviral effects:
https://pmc.ncbi.nlm.nih.gov/articles/PMC7169144/
https://pmc.ncbi.nlm.nih.gov/articles/PMC7405774/


I asked perplexity.ai to summarise the benefits mentioned in these studies, and this is the response:

Immunomodulatory Effects​

Melatonin acts as an immune buffer, providing both immunostimulant and anti-inflammatory properties depending on the immune conditions. This dual action allows melatonin to:

• Stimulate the immune system under basal or immunosuppressive conditions
• Act as an anti-inflammatory compound during exacerbated immune responses, such as acute inflammation

Antiviral Properties​

Melatonin has shown promising antiviral effects against various viral infections:

• It exhibits antiviral activity against respiratory syncytial virus (RSV) by suppressing RSV-induced inflammation and oxidative stress
• Melatonin can inhibit viral infections by reducing virus-induced oxidative stress and inflammatory responses
• It has been shown to have antiapoptotic effects, potentially protecting cells from virus-induced cell death
• Melatonin can modulate autophagy, a cellular process that plays a role in viral replication and host defense
• Its ability to cross physiological barriers, including the blood-brain barrier, allows for potential neuroprotective effects during viral infections affecting the nervous system

COVID-19 Potential​

Several studies have explored melatonin's potential in combating COVID-19:

• Melatonin may help reduce the severity of COVID-19 by suppressing cytokine storms and oxidative stress
• It has been suggested as a potential adjuvant therapy for COVID-19 due to its anti-inflammatory, antioxidant, and immune-enhancing properties

Oxidative Stress Reduction​

One of melatonin's key benefits is its potent antioxidant activity:

• It acts as a free radical scavenger, protecting cells from oxidative damage
• Melatonin enhances the production of antioxidant enzymes, further bolstering cellular defenses against oxidative stress

Anti-inflammatory Action​

Melatonin's anti-inflammatory properties contribute to its potential therapeutic effects:

• It can suppress the production of pro-inflammatory cytokines
• Melatonin modulates the NF-κB signaling pathway, which plays a crucial role in inflammation

Sleep Regulation​

As a well-known sleep aid, melatonin's benefits extend to immune function:

• Proper sleep is essential for maintaining a robust immune system
• Melatonin's sleep-promoting effects may indirectly support the body's ability to fight viral infections

I also came across this study showing how in mice, very high-dose melatonin was able to ameliorate coxsackievirus B myocarditis infection. This mouse study used 14.4 mg/kg of melatonin as a coxsackievirus B3 myocarditis treatment. The equivalent human dose would be 100 mg of melatonin.

 

[bad1080]

i don't know how one tolerates such high doses of melatonin. i am having after-effects (drowsiness) the next day from just a single dose of 1-2mg in the evening.
maybe such high doses (15-60mg) have paradoxical effects? otherwise idk if i'd even be awake for my next dose...
if anybody here has experience with high doses and is willing to share i'd be interested to hear about it!

 

[Wishful]

Of course, N=1 doesn't prove that melatonin was the causative agent for the improvement. It could have been some factor he was unaware of. Also, it doesn't mean that melatonin will work the same way for anyone else, since his immune system might have a quirk regarding melatonin.

At least it's not an expensive or risky treatment to try, unless grogginess is a serious problem (driving, etc).

 

[pamojja]

Don't have bad effects from melatonin, sometimes can't sleep even despite. Tried to increase the dose. So far use LEFs 3mg, Swansons 10mg and Sunday's 1 mg, for a total of 14 mg/d until now (the only melatonin available to me in Austria to get sent from within the EU. From abroad, it would be illegal). Still no effects to report . Maybe one of those providers isn't accurate in their dose?

 

[hapl808]

Thus the key feature of this protocol may be that he takes melatonin three times daily. Also, possibly taking melatonin during the day may have beneficial effects that you don't get when taken before sleep?

My brain is a bit fried, but where did you see that he takes it three times daily?

Nice to see someone who at least sounds like they really were moderate-severe (bedridden, couchbound, etc). As opposed to the stories, "I was moderate-severe for months. I would be exhausted for days after even a 5 mile bike ride at a relaxed pace." Ummm, yeah.

I catch a cold as soon as I am among people, even though I mask up.

I wonder about this, because I thought that in my first 10-15 years of MECFS symptoms. I got sick so easily. Yet now that I'm housebound or bedbound, I've realized that I was likely mistaking sick for severe PEM. If someone comes to visit me, I have a sore throat and exhausted for a week or so. However, I also get the exact same symptoms from a video chat - and I think it unlikely I'm getting sick through Zoom.

The symptoms of 'sick' and PEM are identical for many, so how would you tell them apart unless you are able to get a positive influenza or Covid test or culture or something? Someone visited me for 10 mins a few weeks ago, and I had a sore throat for a week. I wore an N95, windows open, air purifier running. I think it's very unlikely that I got 'infected' with anything.

Just my guesses.

I don't get groggy from melatonin, so I'm interested in trying it. When I take it every night it seems to lose some effectiveness, but I usually take 750mcg to 1.5mg before bed. I've only tried 3mg maximum dosage, once per day.

Since there is a lot of interesting research on melatonin, I am interested in experimenting.

 

[Judee]

This lady does a lot of research on high dose melatonin. Her site is very interesting but a bit above my understanding. https://doris-loh.com/home?fbclid=I...pZmQ899s3xwOPxqhb0_aem_ZmFrZWR1bW15MTZieXRlcw

I know she does talk about ATP which is mentioned often in ME/CFS circles so it made me wonder if it could be helpful to us.

​

 

[Hip]

My brain is a bit fried, but where did you see that he takes it three times daily?

I started a PM with him to ask a few further questions.

Melatonin has a short plasma half-life of only 40 minutes. Thus melatonin will have mostly disappeared from the body after about 3 hours. So maybe taking it three times a day will give the body greater exposure to melatonin, and this may be the secret to his success.

 

[Mary]

@Hip - this is really interesting - thanks for posting! I take 10 mg. melatonin for sleep every night (in addition to a bunch of other stuff) and am not sure at this point if it's helping or not. Years ago I'd feel its effects the next day after a 3 mg. dose, but not any more.

I've come across the use of high-dose melatonin in reading about cancer treatment. Here's a 2021 review of the research: https://pmc.ncbi.nlm.nih.gov/articles/PMC8123278/

(btw, I don't have cancer - it's just our cancer treatments cause so much damage, I'm alert to things that can help with cancer that don't kill you or cause severe harm.)

I would be nervous about high doses of melatonin during the day for fear of becoming extremely woozy or getting knocked out, but apparently people are able take quite high doses during cancer treatment without getting knocked out, and now the Reddit poster - it certainly seems worth a try - I've just skimmed this very quickly, need to read more about it.

 

[Mary]

From this study linked above in the opening post: https://pmc.ncbi.nlm.nih.gov/articles/PMC10043401/

Endurance exercise consumes glucose, resulting in a decrease in muscle and liver glycogen stores (Trefts et al., 2015[150]). For ATP synthesis, melatonin can partly shift glucose metabolism from anaerobic glycolysis to aerobic mitochondrial oxidative phosphorylation, and consequently result in decreased lactate production (Mazepa et al., 1999[100]; Sayed et al., 2018[133]). Therefore, pre-exercise melatonin administration can enhance lipid utilization as a substrate energy source (Mazepa et al., 1999[100]; Souissi et al., 2022[136]; Trionfante et al., 2017[151]). Future studies should investigate the relationship between melatonin secretion/supplementation and the body mass index, and why not considering melatonin as a potential way to help patients with obesity to optimize the outcome of their exercise programs.

Maybe this is part of why melatonin helped Redditer spicyrosary?

 

[Hip]

Melatonin can partly shift glucose metabolism from anaerobic glycolysis to aerobic mitochondrial oxidative phosphorylation

https://pmc.ncbi.nlm.nih.gov/articles/PMC10043401/

Interesting finding. So melatonin might work well combined with other mitochondrial oxidative phosphorylation boosters, such as oxaloacetate, dichloroacetate (DCA), and sodium phenylbutyrate.

 

[datadragon]

Many in vitro and in vivo studies have proved that melatonin alleviates NLRP3 inflammasome activity via various intracellular signaling pathways. https://pmc.ncbi.nlm.nih.gov/articles/PMC8300798/ This NLRP3 activation would naturally have led to increase of ER Stress, WASF3 levels and Exercise Intolerance/PEM. NLRP3 increases IL-1b/IL-6, INF-y which leads to that WASF3 increase. Heavy exercise, high glucose and fructose and infection all can also increase INF-y. Remember that I found and mentioned how infections, high glucose and fructose, heavy exercise and IFN-y which can increase from inflammation all happen to converge to increase WASF3 levels which is currently shown to cause exercise intolerance/fatigue from research at the NIH. Blocking WASF3 allowed mitochondria to produce energy at normal levels. Glucose deprivation strongly inhibited IFN-gamma (IFN-y) gene expression for example. IFN-y increases expression of GRP78, which is the same GRP78 that increases WASF3 levels. We were discussing in this thread. https://forums.phoenixrising.me/thr...s-chronic-fatigue-syndrome.90582/post-2469256

The activation of the NLRP3 inflammasome, results in the processing and secretion of active Interleukin 1 (IL-1b) and IL-18. IL-1β induces IL-6 and a Th-17 immune response, whereas IL-18 induces IFN gamma (IFNγ) production by Th-1 lymphocytes An IL-1/IL-6 signature increases neutrophils and C-reactive protein (CRP), whereas an IL-18/IFN-y signature is characterized by hyperferritinemia (excess of an iron storage protein called ferretin in the blood) and cytopenia. https://www.pnas.org/doi/10.1073/pnas.2009017117 There are additional effects of NLRP3 activation such as the lowering of nutrients such as Zinc availability that can lead to many of the other reported downsteam effects. It will be interesting to see if combined with something like solgar chelated zinc would see further benefits.

Melatonin (100 μM) markedly alleviated the M1 microglia phenotype shifting and abnormal mitochondria morphology. Melatonin attenuated prorenin-induced ΔΨm increasing and ROS overproduction https://pmc.ncbi.nlm.nih.gov/articles/PMC6370243/

i don't know how one tolerates such high doses of melatonin. i am having after-effects (drowsiness) the next day from just a single dose of 1-2mg in the evening.

Yes its a balance when to use higher doses such as in a CURRENT inflammatory state. The patent is on 1mg or less of Melatonin by MIT, because Professor Wurtman discovered that small doses of melatonin (0.3 MILLIgrams) (.3mg = 300 mcg micrograms) worked better. 300 mcg not milligrams versions of life extension are on places like amazon. https://news.mit.edu/2001/melatonin-1017 When the melatonin receptors in the brain are exposed to too much of the hormone, they become unresponsive. I've read that occurs in about 3 days. As a result, many people don't think melatonin works at all. To get around paying for the patented version, companies sell the higher doses but these many find do not work well especially trying to take it more than just a few times in a row. Of course it may work well in certain situations like inflammation and infection in higher doses taken short term only during that period or when inflammation is chronic, but maybe should be avoided for preventative use when not in those states (except the very low dose for sleep as needed).

 

[bad1080]

When the melatonin receptors in the brain are exposed to too much of the hormone, they become unresponsive.

thanks for your input! i wonder if this also leads to reduced production/release of the hormone by the body?

if i understand you correctly, the higher doses are being used because people notice the reduced efficacy due to tolerance build up and increase their dose, yet a much smaller dose can have the same or even better effect as it doesn't result in the same problems with tolerance?

 

[pamojja]

Though receiving only slightly noticeable effects, I don't experienced down regulation of endogenous melatonin production upon discontinuation.

Guess has to do with the short half-life of oral doses.

Melatonin has a short plasma half-life of only 40 minutes. Thus melatonin will have mostly disappeared from the body after about 3 hours.

 

[Dysfunkion]

I started a PM with him to ask a few further questions.

Melatonin has a short plasma half-life of only 40 minutes. Thus melatonin will have mostly disappeared from the body after about 3 hours. So maybe taking it three times a day will give the body greater exposure to melatonin, and this may be the secret to his success.

Yeah but the effects can be felt into the next day for me, some other people get the same. What specifically causes that? I have a long while back taken it for sleep and I'd also in short time after 5 mg doses gain tolerance and then I'd hit 10 mg which would lead to further tolerance in my case and do nothing but make me feel dull and groggy into the next day with no sleep benefits.

With extremely high doses there could be a paradox effect in some people. Maybe the spread of the doses leads to down regulation of production if dosed on half life for long enough though would that really increase overall energy? I'd think doing so would only cause crippling insomnia unless the chain reaction off the down regulation would lead to improvements but then you'd need to get endogenous production levels back online.

 

[BrightCandle]

I buy the 3mg capsules, I break them apart and mix it with glycine and put it into capsules for a dose of .3mg due to this research. I have been doing this and taking melatonin this way for years. When my symptoms back off a bit I can stop taking it and get no ill effect, if I struggle to sleep I might be on 2-4 but always feel rougher the next day when I do. 300mcg is the right dose or at least its as high as I want to routinely go and its been confirmed in a number of studies now.

Its a pain to buy it that way unfortunately so you have to own a capsule maker and do your own calculations for the mix and its all a bit more work than ideal for a moderate to severe ME patient but it also really helps with the sleep. No idea if it helps with anything else, seems as a dose its likely too low for these other benefits and I wouldn't take it through the day as it makes me drowsy within 30 minutes (the point of it!).

One other benefit is that one normal 60 bottle becomes 600 days of treatment. It does cost a bit more because of the capsule maker and the capsules (capsule prices are really high at the moment, £20 for a 1000)

 

[datadragon]

f i understand you correctly, the higher doses are being used because people notice the reduced efficacy due to tolerance build up and increase their dose, yet a much smaller dose can have the same or even better effect as it doesn't result in the same problems with tolerance?

Yeah but the effects can be felt into the next day for me, some other people get the same. What specifically causes that? I have a long while back taken it for sleep and I'd also in short time after 5 mg doses gain tolerance and then I'd hit 10 mg which would lead to further tolerance in my case and do nothing but make me feel dull and groggy into the next day with no sleep benefits.

For sleep use only the 300 mcg (micrograms) was found to work better. Melatonin at a much higher level has anti-inflammatory effects so that can potentially be used when in a current high or chronic inflammation state to bring it down although inflammation is a balance so may not be a good idea to use high levels of melatonin when not currently in that high inflammatory state. For sleep, when the melatonin receptors in the brain are exposed to too much of the hormone, they become unresponsive. This link again showed why they use the low dose for sleep https://news.mit.edu/2001/melatonin-1017

 

[Hip]

Yeah but the effects can be felt into the next day for me, some other people get the same. What specifically causes that? I have a long while back taken it for sleep and I'd also in short time after 5 mg doses gain tolerance and then I'd hit 10 mg which would lead to further tolerance in my case and do nothing but make me feel dull and groggy into the next day with no sleep benefits.

Just found this study which speculates that people who experience rapid loss of effect from melatonin are slow metabolisers of this hormone. Apparently melatonin is metabolised almost exclusively by the liver enzyme CYP1A2.

Some inducers and inhibitors of this enzyme detailed in this article.

 

[bad1080]

I buy the 3mg capsules, I break them apart and mix it with glycine and put it into capsules for a dose of .3mg due to this research.

i found melatonin is available as liquid, should be easier to handle small doses

 

[Dysfunkion]

Just found this study which speculates that people who experience rapid loss of effect from melatonin are slow metabolisers of this hormone. Apparently melatonin is metabolised almost exclusively by the liver enzyme CYP1A2.

Some inducers and inhibitors of this enzyme detailed in this article.

Oh yeah never considered that but I didn't know what enzyme was specifically responsible, even more interesting that it also metabolizes other toxins and PUFA (which I benefited from consuming as little of as I can help). there is a lot that gets pushed through that enzyme.

"Vegetables such as cabbages, cauliflower and broccoli are known to increase levels of CYP1A2. Lower activity of CYP1A2 in South Asians appears to be due to cooking these vegetables in curries using ingredients such as cumin and turmeric, ingredients known to inhibit the enzyme." - Wow that is interesting too because those veggies to me are crucial, I wouldn't go a week without them and cumin/turmeric make me worse, if I had them for than one night in a row I'd likely crash hard and upon first consumption of them I feel extremely turned off and weak. I completely gave up on them and eating indian food because of it. CBD will do almost the exact same thing and it's on the same list. Didn't know any of this before.

 

[bad1080]

i am still unclear on one thing: are the higher doses necessary or can the same be achieved with smaller doses? (but i guess the answer is "it depends")