All right.
So let's move on to the last question I will address in this episode, which has to do with
melatonin.
The question is, what are your thoughts on melatonin being a potential factor to impacting
the severity of the virus via its effect on inflammation and oxidative stress?
Before we dive into this, I want to emphasize there is no data to suggest that melatonin
may prevent or lessen the severity of COVID-19 illness.
There was an article published in March of 2020 discussing the potential role of melatonin
as an adjuvant treatment for COVID-19.
We can discuss some of the rationale behind that publication.
So as we've previously discussed, you know, some of the COVID-19 disease pathology includes
excessive inflammatory and immune responses that may activate a cytokine storm, and this
could result in cell death of epithelial cells and endothelial cells, disrupting the vascular
endothelial barrier and leading to vascular leakage, abnormal T-cell and macrophage responses
and these can induce acute lung injury acute respiratory distress syndrome.
A common clinical feature in COVID-19 patients is low albumin levels, low lymphocyte numbers,
low neutrophil numbers, and decreased percentage of CD8-positive T cells.
So let's talk a little bit about melatonin.
Melatonin is actually a hormone.
It controls the activity of over 500 genes, many of them involved in circadian rhythm,
inflammation, immune function, antioxidant activity, and more.
In mammals, melatonin is synthesized in the pineal gland with a rhythm regulated by an
endogenous circadian clock, the most important factor for regulating its metabolism, being
the light-dark cycle.
So melatonin is inhibited with blue light and melatonin production starts in the evening
hours as the light goes away.
Melatonin production in the pineal gland declines with age, starting around 40 years old.
Besides being produced in the pineal gland, melatonin is also synthesized in many other
organs like the gastrointestinal tract, retina, and also leukocytes, both in the peripheral
blood and in the bone marrow.
For example, human lymphoid cells are an important physiological source of melatonin since resting
and activated human lymphocytes synthesize and release large amounts of melatonin with
melatonin concentration in medium increasing up to five times the nocturnal physiological
levels in human serum.
T-lymphocytes, natural killer cells, and mast cells possess melatonin receptors.
Melatonin has the capability to regulate leukocyte function and contributes to the control of
inflammation in tissues, acting as both an activator of the immune system and an inhibitor
of the inflammatory and immune responses, depending on the biological context.
So melatonin seems to play a homeostatic role in regulating the immune system, activating
it when it's needed or reducing inflammation when levels are too high.
So let's go into a little more detail on the immune system.
Melatonin administration increases the proliferative response of rat lymphocytes, increases the
number of natural killer cells, stimulates the release of proinflammatory cytokines,
tumor necrosis factor, it enhances phagocytosis, and it modulates apoptosis.
So it can have immune-activating functions.
But on the other hand, in other experimental systems, melatonin can inhibit the translocation
of nuclear factor Kappa B, NF Kappa B as it's called, to the nucleus, which then blondes
the production of many different proinflammatory cytokines, which are regulated by that NF
Kappa B.
Melatonin's immune-stimulating versus immune dampening effect really depends on the biological
context.
So the immune dampening effect occurs in circumstances where inflammation is elevated.
So melatonin has anti-inflammatory and antioxidant properties in the lungs.
It has been shown to be protective against acute lung injury and acute respiratory distress
syndrome caused by other viral pathogens in preclinical animal studies.
Melatonin ameliorates RSV-induced lung inflammatory injury in mice via inhibition of oxidative
stress and proinflammatory cytokine production.
RSV is a very contagious and common virus that infects the respiratory tract of most
children by two years of age.
Two clinical studies have shown that melatonin has antioxidant and anti-inflammatory actions
in the lungs in newborns born with respiratory distress syndrome.
Melatonin treatment reduce proinflammatory cytokines and an improved clinical outcome.
So melatonin can decrease pro-inflammatory cytokines as we've been discussing.
Several clinical studies have found that melatonin can reduce circulating levels of proinflammatory
cytokine levels in people with higher circulating levels.
A meta-analysis of randomized control trials suggested that the use of melatonin is associated
with a reduction of TNF alpha and IL-6 levels.
In chronic inflammatory conditions like in an eight-week randomized controlled trial
with patients with diabetes and also periodontitis, supplementation with six milligrams of melatonin
per day decreased serum levels of il-6, TNF alpha, and high sensitivity C reactive protein,
which are all biomarkers of inflammation.
In another trial in patients with multiple sclerosis, supplementation with 25 milligrams
of melatonin per day for 6 months promoted the reduction of serum concentrations of a
variety of different proinflammatory cytokines, as well as biomarkers of oxidative stress.
Also, during the acute phase of inflammation, for example, during surgical stress, brain
reperfusion, and coronary artery reperfusion, melatonin intake for less than five days reduce
the level of proinflammatory cytokines.
Some evidence suggests that melatonin modulates the NLRP3 inflammasome.
Inflammasomes are large intracellular complexes that detect and respond to internal and external
threats.
Activation of inflammasomes have been implicated in a host of inflammatory disorders.
SARS CoV-1, the virus responsible for the original SARS outbreak activates the NLRP3
inflammasome, triggering NF Kappa B and a cytokine storm in the lungs.
During a cytokine storm, the excessive immune response ravages healthy lung tissue and drives
acute respiratory failure.
Melatonin has been shown to reduce the infiltration of macrophages and neutrophils into the lung
in acute lung injury animal models due to the inhibition of the NLRP3 inflammasome.
Melatonin is commonly taken to improve sleep.
Sleep is very important for regulating the immune system and lack of sleep can significantly
dampen immunity.
A meta-analysis of 19 randomized control trials demonstrates that melatonin decreases sleep,
onset latency, increases total sleep time, and improves overall sleep quality.
Trials with longer duration and using higher doses of melatonin demonstrated greater effects
on decreasing sleep latency and increasing total sleep time.
Melatonin has a pretty high safety profile.
Short-term use of melatonin is safe even at high doses.
There's no adverse effects that have been seen at doses, even as high as one gram of
per day for a month.
In patients in the ICU, doses of 3, 6, or 10 milligrams were shown to be safe compared
to placebo.
Also in animal models for acute lung injury, acute respiratory distress syndrome, there's
been no adverse effects of melatonin supplementation.
But even though melatonin has been considered safe in many, many human studies, there are
currently no studies with, you know, melatonin supplementation in COVID-19 patients.
So that needs to be carefully monitored.
In summary, melatonin seems to be beneficial for a variety of respiratory and inflammatory
disease models.
It's been shown in clinical studies to dampen inflammation, it regulates the immune system,
lowers oxidative stress as well, and it does dampen the cytokine storm.
It's also been shown to improve sleep and that is associated with a decrease in anxiety.
While there's no direct evidence that melatonin use could prevent or treat COVID-19, it's
plausible that melatonin may possibly have some beneficial role.