Melatonin Inhibits COVID-19-induced Cytokine Storm by Reversing Aerobic Glycolysis in Immune Cells

[at140]

The pathogenesis of a COVID-19 respiratory infection, in a major way, is related to what is referred to as the cytokine storm [cytokine storm syndrome (CSS, hypercytokinemia, etc.], i.e., it is a hyper-inflammatory response. During this response, an explosive production of proinflammatory cytokines such as TNF-? IL-1?, and others occurs, greatly exaggerating the generation of molecule-damaging reactive oxygen species (free radicals) [1]. In severe cases, the cytokine storm is responsible for the most obvious signs of a COVID-19 infection including fever, lung injury which causes cough and shortness of breath (and the long-term complication, lung fibrosis) and in death.

A causative factor related to the hyper-inflammatory state of immune cells is their ability to dramatically change their metabolism. Similar to cancer cells in many solid tumors, immune cells such as macrophages/monocytes under inflammatory conditions abandon mitochondrial oxidative phosphorylation for ATP production in favor of cytosolic aerobic glycolysis (also known as the Warburg effect) [2]. This switch is driven by the transcription factor HIF-1? (hypoxia inducible factor-1? and the serine/threonine kinase, mTOR (mammalian target of rapamycin) and other proteins The change to aerobic glycolysis allows immune cells to become highly phagocytic, accelerate ATP production, intensify their oxidative burst and to provide the abundant metabolic precursors required for enhanced cellular proliferation and increased synthesis and release of cytokines (Fig. 1 ).




https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211589/?fbclid=IwAR3EKCn7MtmGk3GxhLboOhUCDIEtDbxEnJe8sBJWXHjc7velVxJAAlYOB2Q

[Roland99]

1. Here's the best part

Given the above information, the use of supplemental melatonin as a treatment to overcome a COVID-19 infection is justified. Exogenously administered melatonin reverses aerobic glycolysis by repressing both HIF-1? and mTOR thereby disinhibiting PDC activity and allowing acetyl-coenzyme A synthesis which also ensures locally-produced melatonin production [13]. The functionally re-instated mitochondria-generated melatonin in combination with the parenteral melatonin provides a formidable weapon to reduce the cytokine storm as well as its damaging consequences thereby relieving the signs of a COVID-19 infection.

The anti-inflammatory and antioxidant actions of melatonin in protecting the lungs from damage in many experimental models that involve inflammation or oxidative stress (or both) is well documented [14]. Moreover, melatonin has anti-viral actions against viruses other than COVID-19 [15,16]. The collective data, in addition to its very high safety profile, indicate that melatonin would be effective as a treatment for COVID-19 and support the recommendation of the published reports that encourage its use for this purpose [[3], [4], [5], [6], [7]]. Melatonin is inexpensive, non-toxic over a very wide dose range, has a long shelf-life and can be self-administered which is a major advantage when large numbers of individuals are involved. Thus, the use of melatonin to mitigate the COVID-19 pandemic would be feasible and a socially-responsible measure to attempt.

[Thekaspervote]

4. Thx for the detailed explanation!!

[niyad]

11. Melatonin?? The stuff I get from the vitamin wall? Or the health food store? No scrip, no vaccine?

Ohhh desr, donnie bodybags and big pharma are not going to like that!!

[at140]

15. Exactly my first thought as well

Big profits Big Pharma would prefer meds costing thousands of dollars.

[Faux pas]

2. Translation?

[Moostache]

13. If you use Melatonin as a sleep aid, better go buy up all you can NOW...

Very rough simplification:

The bug (COVID) causes your immune cells to utilize and generate energy (ATP) differently to fight infection. That change in energy source allows for benefits in fighting some disease, but comes with a cost - harder for the cells to regulate or act 'normal'.

Not 100% of the story - it also has to do with the way the cells trigger the immune response and gets more complicated from there, but that's the high-level gist of it.

[Faux pas]

41. Thank you

I used to take it, then I switched to ashwagandha. Guess I'll switch back.

[Cha]

52. You just introduced me to ashwagandha..

Mahalo, Faux pas.. it sounds like just what I need!

I just ordered it

[Faux pas]

53. Your welcome

for sure Cha. It's great stuff!

[Cha]

59. Good information exchange on DU!

[Faux pas]

60. Glad

I could be of some assistance. It's done wonders for me.

[Cha]

61. I'm happy it's helped you.. I'm anxiously awaiting my bottle..

[Faux pas]

42. PS

Just read ashwagandha may help too.

[Eliot Rosewater]

3. So any melatonin supplement from the drug store or

https://images.costco-static.com/ImageDelivery/imageService?profileId=12026540&imageId=1206867-847__1&recipeName=350

for example?

[Thekaspervote]

6. The best way to take melatonin is sublingual, faster better absorption

[qazplm135]

10. for the vast majority of folks who have no idea what that means

it means under the tongue.

[awesomerwb1]

23. Oh so no submarine needed? nt

[Nevilledog]

43. That's what I take. Get it at Costco.

[Cha]

51. That's how I take it.. spray melatonin every other

night for awhile now.

Thanks, Kasper.

[Miguelito Loveless]

8. Costco is probably safe

Others, not so sure.

[Miguelito Loveless]

22. Had to look for this link

Brands you can trust

https://www.consumerlab.com/m/reviews/melatonin-supplements/melatonin/

[Ilsa]

29. Of course, one must pay for results. nt

[Miguelito Loveless]

34. My apologies

Their policies have changed since i was last on their site. As they do not accept ads, they are now behind a paywall.

[Miguelito Loveless]

36. I posted the top picks

in this thread.

[Ilsa]

37. Thank you. You're a mensch! nt

[Eliot Rosewater]

33. Did you pay to get the results? What are the results?

please

[Miguelito Loveless]

35. Sorry, they placed them behind the paywall

which was not the case the last time I was there.

Low dose: Swanson Melatonin 1mg
Moderate dose: Trader Joe’s chewable 3mg
Timed Release: CVS 5mg

Consumer Labs tests for the actual presence of ingredients and the absence of harmful impurities or adulterations.

[Kahuna]

24. That's what I use, the Natrol but 10mg....

I have 2 new unopened bottles and just ordered 4 more.

[ChazII]

55. This is what I use as well. n/t

[Kahuna]

57. That's the good stuff. I tried other brands and dosages before I settled.

[ChazII]

58. My neurologist is the

one who recommended it to me.

[Thekaspervote]

5. Really good news!

[Stallion]

7. I Use Melatonin to Help me Sleep

hope I'm safe

[Goodheart]

12. So do I. Love it.

[Stallion]

14. Leaves You a Little Foggy in the Morning-but after 30 Minutes I'm good

I know I take it too late but I'm out usually within :30 minutes and I'm a nightowl

[a kennedy]

17. Only problem I've had with it is, my eyes are a tad dry when I wake up.....

other then that I love it. What’s your dose? I’m doing 2.5 milligrams. I cut a 10 milligram in half and then in half again.....so it’s 2.5 when I use it UNDER MY TONGUE.

[Goodheart]

21. I do much less than that. 3/10 of a milligram

A single 300 mcg tablet helps me sleep like a baby.... EXCEPT:

I have noticed that it's a potent diuretic. When I take it I get up about four times per night to pee... and I'm not talking little drips, either. Doesn't really bother me, though, because it makes me feel skinnier and I fall right back asleep.

[EllieBC]

9. Bookmarking. Should we be taking melatonin supplements

now? Or no is it just as a treatment?

[at140]

18. More as a treatment but taking it could make you less susceptible

to inflammation if you do come down with infection.

[triron]

40. Melatonin is good for you in many ways. Just research it.

[LeftInTX]

16. Sounds more scientific than kimchi!

[leftyladyfrommo]

19. I take it every night to help me sleep.

If I take too much I have really weird bad dreams.

[Voltaire2]

20. Well at least FLOTUS is good for something.

[niyad]

25. ??????

[MissB]

26. Some folks call her melatonin

Instead of her name.

[niyad]

28. Ahh. Much more polite than what I call her.

[MissB]

31. Same.

I’ve used melanoma before though.

[niyad]

32. melanoma and malaria are the polite terms.

[jmbar2]

48. I thought she was Melanomia

[gristy]

27. hmmm. I googled "melatonin covid treatment" (without the quotes)

And I found articles at least as far back as April. So I worry that efficacy may not be all that is hoped, or we would have been hearing a lot more of this by now.

[oswaldactedalone]

30. I've had to increase to 10 mg

about 2 hours before I hope to be asleep and I don’t use the sublingual tablets. I found that the effects of the quick dissolving tablets wear off too fast and I wouldn’t get more than 2 hours of sleep.

Last night, I wanted some extra sleep so took 5 add’l mgs just before going to bed. Had the unusual experience of getting 9 uninterrupted hours of sleep. However, I wouldn’t recommend more than 3-5 mgs at first, and I won’t take more than 10 often at all.

Did I miss the mention of a recommended dosage?

[triron]

39. Many doctors say 10 mg is fine. I usually take anywhere from 5 or 6 mg up to about 10.

[triron]

38. This is great news. I and my gf take melatonin every night. I take more than she.

[myccrider]

44. I also use it for sleep some nights

but have odd side effects if I take more than 4 or 5 mg or use it every night...severe headaches, hours-long grogginess the next morning. I now take a combo of approx. 3mg melatonin, 20 mg CBD and 5mg THC (which is legal here in California, thankfully) 3 or 4 nights a week. That lets me sleep well 4-6 hours with minimal side effects.

I use prescription meds other nights usually with some CBD. If I use anything every night it becomes less effective over time and/or I start having more severe side effects.

I have had a weird relationship with sleep for a long time.

It would be wonderful if melatonin turns out to be a therapeutic treatment for Covid. It’s cheap and readily available OTC. Are there any trials going on with it, I wonder?

Looks like there is one in Spain. Started April 2020, results by Dec 2020.
https://clinicaltrials.gov/ct2/show/NCT04353128

[triron]

45. This is from the description of the study:

"SARS-CoV 2 seems to relatively spare younger children and those who are infected develop the severe forms of the disease very rarely. Peak melatonin serum levels are higher in younger children and decrease with age. These levels are also higher in women, specially during pregnancy, who also seem to be less affected by the virus when compared to men.

The investigators hypothesize that elevating peak melatonin levels to a range similar to that of children by administering 2 mg of melatonin daily might prevent the infection with SARS-CoV 2 among exposed healthcare workers. The investigators also hypothesize that among those who develop the disease melatonin might prevent the more severe forms."

[myccrider]

47. Thanks for the info

Seems it’s being tested as a prophylactic, not necessarily as a treatment. Hope the results will be positive. We need all the tools we can get to fight this thing.

[mvd]

46. Cool. I used to take it for insomnia

It stopped being as effective for sleep after a while, but maybe I will try it again.

[Raine]

50. Same thing with me, it quit working but

I'll give it another try.

[helpisontheway]

49. Already taking Vitamin D,Vitamin C immunity boost and Zinc everyday

Guess it will not hurt to add Melatonin. Anything to prevent or lessen the severity of this awful disease.

[triron]

54. Me too. Sometimes add astragulus. Also take an immune senescence formula (by Life Extension)

[helpisontheway]

56. This is the immune booster I take

https://www.amazon.com/gp/aw/d/B086MWXW3B?psc=1&ref=ppx_pop_mob_b_asin_image

It has a few other things plus vitamin C.

Now gonna research the things that you are taking..

[LAS14]

62. Never did I ever expect to see a post like this on DU! But thanks! I think.... nt