Original Investigation

Sufficient niacin supply: the missing puzzle piece to

COVID-19, and beyond?
Dmitry Kats, Ph.D., M.P.H.1,*
1
Division of Epidemiology and Biostatistics, 3PIDEMIOLOGY, Cary, NC, USA
*
Correspondence: Dr@DmitryKats.com

Abstract: Definitive antiviral properties are evidenced for niacin, i.e., nicotinic acid
(NA), as coronavirus disease 2019 (COVID-19) therapy for both disease recovery
and prevention, to the level that reversal or progression of its pathology follows as
an intrinsic function of NA supply. This detailed investigation provides a thorough
disentanglement of how the downstream inflammatory propagation of ensuing
severe acute respiratory virus 2 (SARS-CoV-2) infection is entirely prohibited or
reversed upstream out the body to expeditiously restore health with well-tolerated
dynamic supplementation of sufficient NA (i.e., ~1-3 grams per day). Culmination of
this research leads to realization of the potentially ubiquitous therapeutic and
preventive powers of NA against inflammatory disease, in general.
Keywords: COVID-19; SARS-CoV-2; coronavirus; nicotinic acid; niacin; antiviral

1. Introduction

Despite continued intensive efforts to mitigate the spread and burden of

coronavirus disease 2019 (COVID-19) in populations, implications for the future
remain unclear. Encouraging nonetheless is the knowledge and understanding
specific to the disease gained as a result of the unprecedented level of collective
rigor dedicated by scientists across the globe. Recent advancements made from
such accelerated investigation augur, particularly dynamically supplied, sufficient
dosage of immediate-release nicotinic acid (NA) as a strikingly promising
therapeutic antiviral agent to overcome pending challenges.

Motivation for this original investigation into specifically NA supply as COVID-19

treatment was sparked by deduction of the possibility that the counterintuitive link
observed with (cigarette/tobacco-nicotine) smoking as being protective against
ensuing severe acute respiratory virus 2 (SARS-CoV-2) infection may be
explained by the fact that nicotine is oxidized into NA during the combustion
process [1], combined with realization—through elucidation by this research—of

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the exclusive ability of NA (upon which the human species continues dynamically
to be thoroughly deficient through diet) through its unique, intricate, endothermic
biochemical processing to induce a thermodynamic flush to ultimately reverse,
restore health from, and/or protect against ensuing inflammatorily-induced
disease. In turn, this may explain the consensus body of relevant literature that
points to the potent healing and/or protecting properties for sufficient dosage of
immediate-release NA across the disease spectrum, including but not limited to
consistently demonstrated successful application against cardio-
metabolic/vascular conditions [2-12], renal as well as hepatic damage [13,14],
pulmonary/lung injury [15], viral/infectious diseases including influenza [16] and
retroviruses like HIV/AIDs [17-21] as well as tuberculosis [21], cancers [22-25],
arthritic-related conditions [26] characterized with inflammatory damage to tissue
[27], neurodegeneration/dementia/unsuccessful aging [27-31], auto-immune
disorders [27,32,33], birth defects [33] and pre- or post-natal induced impairment
of immune and neurodevelopmental function [16,34,35], mental health disorders
[36-38], mast cell conditions [39,40], genetic disorders [33,40,41], among others.

Such conditions, disorders, and diseases pathologically manifested by ensuing

inflammation (i.e., downstream kinetic (heat) energy) can be hypothesized as
being governed by an underlying thermodynamic or bio-energetic (i.e., based on
balancing of energy transfer into, out, and through the body) mechanism [42-45],
which niacin works to modulate back towards a state of equilibrium, reflected in
terms of health and longevity. Implications from the NA-specific findings of this
research ultimately pave the way for not an ambitious promise, but rather an
established projection, for major mitigation and even potential eradication of
COVID-19, while further opening the opportunity for revolutionary advancement
to drive public health forward.

2. COVID-19 follows an inflammatory melody

2.1. Hyper-inflammatory downstream mechanism of COVID-19

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Well-established to the COVID-19 pathology [46] is the integral role of the
cytokine release syndrome (CRS) in contributing to potentially lethal multiple
organ dysfunctions. Marked elevations in pro-inflammatory cytokines and
chemokines—including, most notably, interleukin-6 (IL-6), in addition to
interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and monocyte
chemoattractant protein-1 (MCP-1)—evidently so much as serve as hallmark
features [47] of pathological SARS-CoV-2. A commonly proposed effective
treatment of COVID-19 has thus involved targeting the blockage of IL-6, in
particular through inhibition of its most prominent transcription factor, nuclear
factor-kappa B (NF-κB).

2.2 Potent anti-inflammatory upstream properties of nicotinic acid

Experimentation [48] in vitro complemented by in vivo among both atherogenic

and control mice demonstrated direct attenuation of the inflammatory mechanism
of CRS (assessed via levels of IL-6, IL-1β, and TNF-α) to follow readily with
administration of (immediate-release) nicotinic acid (NA), or more habitually
referred to as niacin (a form of vitamin B3). In accordance with these findings,
sufficient doses of NA have been consistently shown to markedly reduce
production of pro-inflammatory cytokines (IL-6, TNF-α, MCP-1) in human
monocytes [49], substantially inhibit TNF-α-induced NF-κB activation along with
MCP-1 secretion in cultured human aortic endothelial cells [50], as well as
suppress TNF-α and IL-6 expressions through down-regulation of the NF-κB
pathway [51].

3. Underlying pathology of COVID-19

3.1. Synergy by bradykinin to induce COVID-19 respiratory complications

COVID-19 pathogenesis is further characterized by progression to pulmonary

damage, principally established as a pending hurdle that must be overcome with
worsening disease severity [52]. This sequelae of lung injury is hypothesized as
being explained by SARS-CoV-2 entering into host cells in the respiratory system
via the transmembrane protein, angiotensin-converting enzyme 2 (ACE2),

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thereby depleting ACE2 at the plasma membrane of infected cells, leading to
accumulation of des-Arg(9)-bradykinin and so its bioactive metabolite, bradykinin
(BK), in the extracellular environment of both infected and adjacent cells.

In turn, these emerging levels of BK promote both CNS inflammation by

triggering arterial dilation through the release of prostaglandin D2 (PGD 2), nitric
oxide (NO), and endothelium-derived hyperpolarizing factor, together with
vasoconstriction by promoting advancement of prostaglandin F2 2a, inducing
leakage into capillary beds from elevated capillary pressure and released
expression of neutrophil, monocyte, and eosinophil chemotactic activity from
alveolar macrophages [53]. Through this synergistic process of ACE2 down-
regulation leading to rising BK levels and concordant CNS up-regulation,
progression of COVID-19 pathology compounds stress on endoplasmic reticulum
(ER) while signaling mitochondrial destruction, which culminates into cell death.

Immediate-release NA administration has been reported as highly effective in

preventing the lung tissue damage involved in this bleomycin-induced pathology
[15]. As a matter of fact, authors of a March, 2020 paper in Nature [54] for this
very reason conclude with suggestion of niacin supplementation to COVID-19
patients as a “wise approach.”

3.2. Oxidative stress cascade

As the receptor for entry of SARS-CoV-2 into human hosts, ACE2 catalyzes
conversion of angiotensin (Ang) I to Ang II, which operates as a potent activator
of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, in turn
amplifying production of reactive oxidative species (ROS) [55-57]. Additionally
this increased expression of Ang II promotes damage from neutrophils and
macrophages flux to disturbed tissues, which further enables vascular injury by
inhibiting production of endothelial NO synthase (eNOS) [56,57].

3.3. Co-dependency of endolysosomal activity and endocytosis of SARS-CoV-2

Endocytic uptake of foreign pathogens like SARS-CoV-2 into the human body via
ACE2 leads to establishment of acidic environments as the CNS progresses

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through regions of endothelial cells [58]. In response to the downstream
inflammation, endolysosomic organelles emerge, which come equipped with two-
pore channels (TPCs) through which calcium (Ca2+) is released as mediated by
the availability of nicotinic acid adenine dinucleotide phosphate (NAADP).
Controlling Ca2+ release from endolysosomes and activation of TPCs, NAADP
functions as the focal mediator of spatiotemporal mobilization of Ca2+ [23].

3.4. Focal role of NAADP

During endocytosis, an extracellular proton pump operates to correspondingly

acidify the inside of endolysosomic organelles. Interestingly, SARS-CoV-2 entry
is completely obstructed through inhibition of this proton pump, which is only
capable of being explained by a deficiency in the supply and action of NAADP
needed to enable TPC activation. A specialized interplay involving changes in
endosomic acidity and TPC-mediated Ca2+ release drives both the endocytic
entry of SARS-CoV-2 as well as NAADP-mediated Ca2+ signaling [58] in that
sufficient NAADP supply is able to provide support against and push back
ensuing SARS-CoV-2-induced inflammatory propagation (i.e., the CNS).

Supplied NAADP furthermore prompts increased eNOS expression to efficiently

drive cell migration in these acidic environments [59]. The inflammation induced
from accumulation of ROS arouses expression of G protein-coupled receptor
109A (GPR109A) in adipose tissue and macrophages to promote the release of
prostaglandins from dendritic Langerhans and keratinocytes [60].

4. Exclusively sufficient dosage of immediate-release NA

Circulating levels of metabolites including amino acids, glucose, and free fatty
acids also correlate with inflammatory markers (namely IL-6 and C-reactive
protein) in patients with COVID-19 [61]. In fact, the major effects of COVID-19
are evidenced to involve tryptophan metabolism and the kynurenine pathway
towards depletions of these precursors of nicotinamide adenine dinucleotide
(NAD+), in addition to NAD+ (as has been reported with COVID-19 as well [61-

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63]), follow as a result of ensuing downstream inflammation (i.e., ROS
propagation).

Exclusively sufficient dosage of immediate-release NA—through its processing in

the mammalian body to form NAADP—leads to an inverse potential energy pump
back upstream, from the core up and ultimately out the body, of the downstream
ensuing propagation of such inflammatory disease that spreads into the cells.
This is made possible by the capability of NAADP to be readily formed by
sufficient NA supply to induce Ca2+ channeling back upstream out the body of
built-up or ensuing inflammation, representing kinetic energy (or ROS) that by
electron gradient, moves downstream into the body.

Attempting to restore NAD+ with other NAD+-precursors aside from NA (e.g.,

nicotinamide, nicotinamide riboside, nicotinamide mononucleotide) only actually
temporarily and in a sense, artificially, raises NAD+ levels, until they imminently
deplete back down with further ensuing inflammation. NA is in fact the only
compound to readily produce NAADP if needed in acidic environments (as is
characteristic to ensuing inflammatory disease pathology), which in turn provides
a potential energy/H+ pump-out action of its inverse, downstream kinetic (heat)
energy inflammation to ultimately restore NAD+ to normal, pre-inflammatory
levels [27], as well as other inflammatorily-depleted cofactors and biochemical
pathways towards a more thermodynamically homeostatic health status.

The decline in NAD+ observed with ensuing disease over the life course, or that
goes with ensuing inflammatory disease syndromes, is not actually restored by
simply trying to raise NAD+ levels. In fact, NA, which also processes to produce
NAD+, does not (markedly) restore NAD+ through its actual processing of NAD+
(as these other compounds do not likewise). Instead, a true NAD+ restoration
[27], accompanied as a result of reversal and/or protection against ensuing
inflammatory disease (made up of free radical electron/ROS damage) over aging
or an inflammatorily-induced disease pathology such as with SARS-CoV-2
infection/COVID-19, is achieved exclusively through the endothermic production
of NAADP by a sufficient level of NA. Mammalian bodies are evidently

6
engineered and designed—through their TPC channeling—to accommodate the
endothermic formation of NAADP in its bonds to in response, essentially potential
energy/H+ pump out ensuing downstream kinetic heat energy (i.e., ROS/free
radical electrons).

The “niacin red flush” in fact is this thermodynamic exfoliation of ensuing disease,
toxins, and (restoration of) free radical-damaged compounds being H+ (potential
energy) pumped out the body. It represents the anti-inflammatory or
thermodynamic (i.e., energy transfer-like) therapy in action that only and
exclusively sufficient oral intake of immediate-release NA is capable of (readily)
accomplishing with potency. As follows below provides thorough breakdown and
clarification behind the biochemical processing of NA to readily provide this
NAADP-induced Ca2+ channeling of downstream ensuing kinetic heat disease
free radicals/ROS back upstream out of the body.

4.1. Intracellular biosynthesis

Through its processing via hepatic metabolism, supplementation of (immediate-

release) NA into the body following oral ingestion [64,65] first undergoes
phosphoribosylation, catalyzed by the enzyme, nicotinic acid
phosphoribosyltransferase (NAPRT), to form nicotinic acid mononucleotide
(NAM). Subsequently, NAM is converted to nicotinic acid adenine dinucleotide
(NAAD) following catalyzation by nicotinamide mononucleotide
adenylyltransferace (NMNAT). Amidation of NAAD into NAD+ proceeds with
nicotinamide adenine dinucleotide synthase (NADSYN) as catalyst. From there,
some of this NAD+ is phosphorylated by NAD+ kinase to nicotinamide adenine
dinucleotide phosphate (NADP+).

4.2. Endolysosomic behavior

As disease-associated inflammatory environments manifest, connexin 43 (Cx43)

proteins are activated for transport of cytosolic NADP+ into the lumen of
endolysosomes that materialize in these conditions [66]. Meanwhile, free NA
remaining in cytoplasm following rate-limitation of its conversion of NA to NAM by

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NAPRT, transfers into endolysosomic lumen through reaction with
phosphoribosyl pyrophosphate. Both of NA’s catalytic enzymes, NAPRT and
NMNAT, are provided in endolysosomes to facilitate conversion of NA to NAM
and NAM to NAAD, respectively. Lastly, the type II membrane form of the cluster
of differentiation 38 (CD38) ecto-enzyme, delivered to the lumen of
endolysosomal through endocytosis, catalyzes synthesis of endogenous NAADP
in lumen by exchanging the nicotinamide moiety of NADP+ for the NA group of
NAAD.

5. NA as COVID-19 antiviral

5.1. Causative link between NA and SARS-CoV-2

NAADP-triggered endolysosomal Ca2+ release [23,58,59,66] is intensified by the

endoplasmic reticulum (ER) through the Ca2+-induced Ca2+ release
mechanism. Herein, Ca2+ supply in the ER is highly sensitive to the availability of
synthesized cyclic ADP-ribose (cADPR) and especially, inositol-1,4,5-
trisphosphate (InsP3), which activate receptors for InsP3 and ryanodine,
respectively. As InsP3 is provided, pH drops and Ca2+ is dumped from ER to
reestablish in acidic organelles. Liposomal production of NAADP stimulates this
Ca2+ transfer predominately through TPC2. Hence, SARS-CoV-2 invasion into
and further, its progression downstream through a human host, are dependent
upon whether or not NAADP-dependent Ca2+ signaling can proceed.

Adequate synthesis of endogenous NAADP in endolysosomes—accordingly

through a base-exchange reaction performed by luminal CD38—must proceed to
drive any needed Ca2+ signaling of SARS-CoV-2 out of or inhibit its entry into
host. Despite controversy surrounding whether (sufficient) NAADP+ can be
formed through a similar base-exchange reaction using NAAD that is (certainly
not miraculously) supplied in endolysosomes or by free NAM (which is too big for
entry into endolysosomic lumen [66]), investigation culminated into confirming
that this NAAD substrate is in fact only readily capable of being produced
exclusively by endolysosomal NMNAT [66-68].

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Ultimately, this means that free cytoplasmic NA supply is mandatory for NAADP
to form in endolysosomic organelles that arrive in these inflammatory
environments. Therefore, it follows that NAADP supply is a direct function that
follows exclusively with the level of free NA available in cytoplasm (for transfer
into endolysosomes), which in turn depends dynamically upon whether sufficient
supply of NA is available or needs to be supplemented (i.e., through oral
ingestion of immediate-release NA). In fact, nothing outside of sufficiently,
dynamically supplied NA is capable of readily leading to the NAADP supply
needed in these acidic environments for therapeutic action that counteracts
inflammatory disease progression to induce.

6. The Flush

6.1. Exfoliation of disease-inducing agents out the body

As alluded to in prior, interactions of NA with GPR109A receptors on epidermal

Langerhans cells induce increases in cytosolic Ca2+, which actually advance the
processing of Ang2 and activation of its receptor (AT2) through a channel
counter to the direction of COVID-19 pathology, which runs along a different set
of lipopolysaccharide (LPS)-activated human monocytic cell lines to drive an anti-
inflammatory signal for downregulation of the expression of pro-inflammatory
cytokines (namely, TNF- α) as well as lipid mediators (e.g., prostaglandins,
prostanoids, leukotrienes, platelet-activating factor) out of (as opposed to as
before, which was downstream or into) cells and ultimately, the body, back into
the outside environment [7,36,60,70]. The notable flush response experienced
exclusive to the sufficient processing of higher doses (taken at-once) of beyond
~200 mg (if the first time) is in fact provoked here [7,69,70] through activation of
thermoregulatory transient receptor potential cation channel subfamily V member
1 (TRPV1) ion channels [69].

Ensuing vasodilation allows for further recruitment of NAADP, thereby opening

TPC1 and TPC2 exogenously to restore phagocytosis as well as facilitate a more
fluid, efficient upstream scavenging of ROS while simultaneously facilitating

9
clearance of infective pathogens out of the body [71]. In this way, the “red flush”
response is provoked when sufficient NA is supplied to address the following
conditions concordantly: (i) endolysosomes are emerging in acidic environments
but sufficient NAADP supply is not available or depletes to respectively initiate
and/or continue the counter-junction against disease progression, and (ii) a
sufficient amount of NA is not then readily available (usually not given the
recommended daily values of only 15-20 mg from diet) to reestablish NAADP.

6.2. Thermodynamically-induced response

The flush is the experience of the physical sensations involved in the kinetic
(heat) energy transfer from the core to utlimately out of the body during activation
of this endolysosomal NAADP/TPC pathway, induced by a potential energy/H+
pump that follows from introducing the significant amount of potential (work)
energy (the inverse or junction of kinetic heat energy) that is provided by the
favorable endothermic processing of NA to the much chemically bigger, more
intricate NAADP. As more potential energy is provided through the formation of
NA to NAADP, the downstream propagation towards increased expression and
activity of predominately the pro-inflammatory cytokines and chemokines,
NADPH oxidase, as well as ROS are eventually unregulated [72] out the body
until sufficient restoration of a state absent of such a progression into the body.

If NAADP is no longer needed (or sufficiently provided/available), any NA

supplementation beyond its rate limitation by cytoplasmic NAPRT will de facto
collect as free NA in cellular cytoplasm until it is gradually used up to prevent
progression of disease-related inflammatory environments (or more accurately,
any form of kinetic (heat) energy that emits or forms in the body to accumulate).
Any remaining free NA will eventually be cleared through the kidneys in urine.
With continued consistent dosage, flushing will not be as prominent as before
with each subsequent dose and ultimately reach a point where it will not occur,
which can be explained as energy flow and its modulation into/out of the body
approaching closer towards thermodynamic equilibrium as a result of previous
flushes having flushed out inflammatory free radicals/ROS so therefore less

10
remains to flush out with consecutive doses. This represents perhaps the ideal
state that should be worked up to and maintained thereafter—in terms of NA
dosing—to respectively reverse out and prevent inflammation, barring validation
through further experimentation and epidemiological surveillance.

7. Projected dosing regimen against COVID-19

To strategically address the pending concern of COVID-19 with limited

turnaround time and funding resources, NA capability as both COVID-19
prophylaxis and therapy was assessed using preliminary stoichiometric
estimations complemented with various “case study”-like communications
conducted over social media, email, telephone, and virtual meetings—all of
which are documented, filed, and can be made available upon request.

7.1. As health restorative therapy

Administration (through oral intake) of a 500 mg, working up as the flush

response becomes milder and more pleasant, to a 1,000 mg dose, two-to-three
times a day (depending on subject age, weight, body composition, and previous
medical history; note that individuals with body mass >125 kg may require even
higher dose to induce flush response and dose can be halved for children <30 kg
as long as it still induces flush) of immediate-release NA offers what could be
considered to represent health restorative therapy—as indicated from
stoichiometric calculations by sufficient levels of decrease (i.e., to pre-infection
ranges) in the antioxidant metabolites and inflammatory proteins characteristic of
COVID-19 pathology and further via report back from individuals of health
restoration—to follow within two days for those with recently detected (i.e., within
the past 48 hours) SARS-CoV-2 infection and within four days for individuals with
more severe stages of live, ensuing COVID-19 disease progression. For the
subgroup of patients still suffering with high cytokines profiles from deep,
remnant damage of previously experienced SARS-CoV-2 infection—termed the
“long-haulers”—alleviation from ailment(s) towards complete health restoration to
pre-infection state from initiating and maintaining the aforementioned dosage

11
regimen has consistently been reported to assume within two days and to
incrementally follow further over the course of weeks.

7.2. As prophylactic management

As aforementioned, by readily providing sufficient NAADP, this same NA dosage

regimen is capable of serving as prophylaxis, which can be interpreted as the
physical/biochemical inability of sufficient progression of SARS-CoV-2 in order to
enter into the body and/or thereafter induce replication, infection onset, or
disease progression in a previously uninfected host. Through social media
communications, no individuals have reported back detection or suspicion of viral
infection (or illness/malady in general) since maintaining such a dosage regimen.

7.3. Safety considerations

The Council for Responsible Nutrition (i.e., CRN) identifies a lowest-observed-

adverse-effect level (LOAEL) of 1,000 mg/day corresponding to oral intake of
immediate-release NA [73]. Estimated regimens established in this report to
provide health restoration and/or to protect against COVID-19 infection onset are
more than just well tolerated. Given the water solubility of NA and its ability to
readily dump (up to 4-5 g at-once) through the liver to then spread ubiquitously
through the cellular systems [73], maintaining higher dose/dosage of immediate-
release NA eclipsing the LOAEL (i.e., working up to 1 g at-a-time, two-to-three
times a day) could and—together with the implications gathered from this report
along with the extent of information from others [74]—even should be considered
as potent preventive and therapeutic medicine against COVID-19 and
inflammatory disease, in general. Given the marked deficiency in available NA
from diet, these what many misinterpret to be “mega” doses more likely actually
more appropriately represent sufficient doses.

As the flush response is indeed safe and should be sought when needed for its
anti-inflammatory properties, it is important to administer (via oral ingestion)
exclusively the immediate-release form of NA, preferably as a tablet/pill or
straight powder. If the immediate-release NA happens to be provided in a

12
capsule, then it would be advantageous—as to not impede the flush response—
for the capsule material to not contain any gelatin-like components like aloe vera
and to dispense the powder to take with water. Similarly, administration of
immediate-release NA should be accompanied with abstinence from compounds
that may inhibit the flush response, such as aspirin, inositol, and potentially the
pectin in apples, and that may contradict the therapeutic and/or protective effects
of NA (notably N-acetyl cysteine, glutathione, and 5-hydroxytryptophan). To
concordantly ensure balanced metabolic function when supplementing with NA, it
is also noteworthy to remain hydrated as well as to maintain a diverse, non-
processed as possible, and sufficient calorie diet. Lastly, although not absolutely
necessary, the added supplementation (per recommended supplementation
doses) of other B-vitamins (particularly B1, B2, and B6), zinc, vitamin C, vitamin
D3, magnesium, selenium, alpha-lipoic acid, and quercetin to the NA regimen
may help expedite recovery from and ensure protection against COVID-19
(among other diseases and conditions characterized by inflammation).
Nevertheless, dynamically maintaining (with use of the flush response as
guidance) a sufficient NA supply, of which we are remarkably deficient from diet,
presents as the obvious primary prophylactic and therapeutic treatment option.

Alternative medications that should ideally be spaced apart from (though can be
safely eventually curtailed and replaced with NA) to facilitate efficient absorption
of NA or prevent interactions that may hinder NA absorption with each dose
include: antibiotics (particularly tetracycline), anticoagulants/thinners, aspirin,
proton pump inhibitors, blockers, and isoniazid.

Discussion

The unequivocally potent mechanistically-demonstrated properties of NA as

COVID-19 as well as all-around inflammatory disease therapy (and similarly, its
prophylactic/preventative function), can be conceptualized as an upstream
process of thermodynamic regulation occurring directly as a function of NAADP
supply in endolysosomes over the course of molecular progression towards the
junction of an increasingly acidic, inflammatory, disease-associated environment.

13
A favorable production of the significantly larger, more intricate NAADP
compound as product that follows readily and ubiquitously through the human
body with sufficient oral supplementation of (immediate-release) NA, so as
reactant, implies increased potential energy into the body as NAADP forms.

According to thermodynamic law, the (human and essentially, any) body sub-
system connected to (i.e., dependent on energy transfer from and back out to)
the outside-world, functions predominately under the assumption of sustaining a
constant volume and temperature. Hence, it follows that the extra potential
energy formed by the endothermic processing of NA to NAADP must transfer out
as the NAADP subsequently breaking down. Herein lies the flush: temperature
drop, which represents the transfer from the core to endothelial system up to out
of the skin back to the outside environment system, of free radical electrons,
ROS, toxins, damaged organic compounds—essentially inflammatory disease
progression (downstream kinetic (heat) energy).

Inducing potential (work) energy as through physical activity/exercise to protect

against or pump the downstream-ensuing disease (such as SARS-CoV-2
infection) back upstream out the body as has been growingly reported in the
developing literature [44,75] is essentially what orally-ingested immediate-release
NA supplementation by its processing through the liver via hepatic metabolism
introduces in the mammalian body but considerably more efficiently (and of
course, without the physical labor).

Conclusion

As evidenced in this report, safety and effectiveness of NA as both a short- and

long-term therapeutic and prophylactic agent against COVID-19 is
mechanistically established. Taken together, the findings from this investigation
along with those from recent Network Pharmacology and bioinformatics analyses
[76] point directly to NA—particularly its substantial deficiency—as the causative
agent explaining COVID-19. However, further confirmation as to whether major
mitigation and potentially even eradication of COVID-19 follow accordingly in a

14
real-world setting requires more extensive experimentation (e.g., wide-scale
randomized controlled trial (RCT) conduct) in live humans [76].

Further, the findings of this investigation establish inference that reversal of and
protection against inflammatory disease progression, as a bioenergetic
conceptualization of disease under an umbrella, follows as a causally-linked,
dynamic function of NA supply. Exclusively sufficiently and properly supplied NA,
upon which we are anywhere between 1/50 th to 1/200th deficient from daily diet,
provides the processing ability to readily exfoliate out and protect against ensuing
inflammatory disease. Given the ubiquitous, powerful therapeutic and
preventative properties consistently evidenced across the disease spectrum [2-
40], advancement and wide-scale RCT confirmation of NA treatment offers not
just safe and rapidly effective opportunity for eradication of COVID-19 but also
merits further exploration through its mechanistically established capacity as a
paradigm-shift level way to drive individual- and population-level health forward.

Hypothetically, if the global population was sufficiently supplied with NA

dynamically (per the 1-3 g per day regimen)—instead of the only 15-20 mg from
diet set by the U.S. Food and Drug Administration and other public health
agencies worldwide—then no one may have ever experienced COVID-19.
Nevertheless, even after the fact, we still evidently have the opportunity to
efficiently mitigate and even potentially eradicate the pandemic by simply filling
this drastic NA void through its supplementation (and maintaining sufficient
supply by continuing with the dosage as per described in this paper). A strong
case can be made through digestion of these findings that the immune system is
not functioning to its full potential (and in turn health is not sustained) with only
15-20 mg of NA daily. Unfortunately, our species as a whole has been
undersupplied with NA (most likely as a result of the lack of this knowledge), to a
causative level for not just COVID-19 but perhaps comprehensively in terms of all
inflammatory-related disease progression. A fundamental hypothesis can be set
forward that human beings should always remain sufficiently, even amply,
supplied with NA for disease reversal (if needed) and/or prevention (thereafter).

15
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