Interesting. Thank you.

Vitamin D is also correlated with exposure to ultraviolet light, i.e. sunlight. In that case, exposure to sunlight is a direct cause of vitamin D synthesis.

Exposure to sunlight causes other things to happen. One of those things is that trans-urocanic acid—a substance synthesized by the body and found on the skin—is converted to the cis isomer, so into cis-urocanic acid, which induces immune suppression by activating serotonin receptor 5-HT2A. Sunlight reduces inflammation through the end result of activating a serotonin receptor! (This is wild!)

Source:

• Cis-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT2A receptor, Proceedings of the National Academy of Sciences, 2006 — https://doi.org/10.1073/pnas.0603119103

It's all very interesting. I'm super curious.

(As far as I know, the 5-HT2A receptor is unusual among serotonin receptors in that it causes immune suppression; As I understand it, most of the other serotonin receptors cause immune system activation in the context of the immune system. And afaik serotonin receptors are widely purposed in the immune system.)

Now. COVID-19 is a disease of inflammation and clotting. As far as I know, plasma serotonin is greatly elevated in COVID illness. Platelets have both serotonin transporters and serotonin receptors – type 5-HT2A. (In platelets, that receptor happens to induce clotting, not immunomodulation.) There is a strong correlation between SSRI use—serotonin reuptake inhibitors—and people faring much better with a COVID-19 infection.

Randomized clinical trials have shown this:

• Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial – The Lancet, October 17, 2021: https://www.thelancet.com/journals/langlo/article/PIIS2214-1...

Observational studies have shown a correlation. Here's a recent, large one:

• Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants – Journal of the American Medical Association, November 15 2021: https://jamanetwork.com/journals/jamanetworkopen/fullarticle...

And there are plausible mechanisms of action:

• Fluvoxamine: A Review of Its Mechanism of Action and Its Role in COVID-19 – Frontier in Pharmacology, April 2021: https://www.frontiersin.org/articles/10.3389/fphar.2021.6526...

The following preprint on the proposed mechanism of action is super interesting. It's a preprint but as far as I know the mechanisms have shown to hold true.

• COVID-19 Pathophysiology: Are Platelets and Serotonin Hiding in Plain Sight?, preprint dated February 5, 2021:
https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3800402

Frankly, I'd be willing to bet real money that at least part of the correlation between having little vitamin D and faring poorly with COVID-19 is a reflection of a causative relationship: Little exposure to sunlight causing less than usual 5-HT2A-receptor immunomodulation causing more severe disease.

How? Not exactly sure. But the papers try to present the case (and do so much better than a HN rando). I'm thinking receptor up/downregulation might have something to do with it maybe. And what seems to be the role of the 5-HT2A receptor as a negative feedback point in general in the immune system.