open access

volume 38 , number 1
published 30 JANUARY 2023

educational article

An Orthomolecular Protocol for Long COVID

Michael J Gonzalez; Jorge R. Miranda-Massari; Charles Simone; Jose Olalde; Miguel J Berdiel; Jorge Duconge;
Lourdes Amadeo; Jaime Claudio
Citation: Gonzalez MJ et al. (2023) An Orthomolecular Protocol for Long-COVID. J Orthomol Med. 38(1)

abstract return to the baseline health status. Many patients with

A significant number of COVID-19 patients suffer from a confirmed COVID-19 diagnosis are reported to con-
SARS-CoV-2 post-acute chronic sequelae, also known tinue having at least one symptom beyond two weeks
as post-COVID syndrome or long COVID. These patients following acute infection (Lopez-Leon et al., 2021). PASC
report a broad range of persistent and debilitating symp- is most prevalence among patients who experience
toms such as fatigue, brain fog, pain, breathlessness, and severe COVID infection, although many symptoms are
dysrhythmias. These chronic symptoms are believed to be still suffered by patients with a milder form of the dis-
a consequence of excessive production of reactive oxygen ease (Bell, 2021; Parker, 2021).
species (ROS), inflammation, tissue damage, and mito- The lack of a known etiology or pathophysiology, the
chondrial dysfunction. Patients at higher risk of long-term variability in the symptoms, and the lack of external
sequelae are those who experienced severe COVID-19 infec- physical signs of the illness contribute to difficulties
tion, are immunocompromised and likely have depleted in developing an effective therapeutic protocol or a
reserves of biological factors and micronutrients necessary rational, targeted, interdisciplinary approach. PASC has
for prompt recovery. Based on biochemical principles and often been referred to as an invisible disease, as people
studies in conditions that share common traits with long may appear healthy and well, but report feeling very ill.
COVID patients such as chronic fatigue syndrome and This means that there might be a significant number
fibromyalgia, symptom relief and sustained recovery can of people suffering from this condition without well-
be expected by administering an orthomolecular protocol defined solutions.
consisting of a combination of precursors, cofactors, and
biological response modifiers. discussion

introduction
In a population-based probability survey of 593 hos-
pitalized and non-hospitalized adult patients with
A significant number of patients are suffering from COVID-19, it was found that patients reporting very
Post-Acute Sequelae of severe acute respiratory syn- severe symptoms from initial infection had 2.25 times
drome Coronavirus 2 infection (PASC), also known as higher prevalence of 30-day and 1.71 times higher
post-COVID syndrome or long COVID. These patients prevalence of 60-day PASC (Hirschtick, 2021). In this
report a broad range of persistent and debilitating same study, hospitalized respondents had ~40% higher
symptoms centered around a general sense of fatigue, prevalence of PASC of both 30-day and 60-day COVID-
brain fog, pain, breathlessness, and dysrhythmias. These 19 (Hirschtick, 2021). In a recent systematic review of
symptoms can persist for several weeks to months 250,351 COVID-19 survivors, it was found that over half
post-infection period (Wood et al., 2021). of the survivors experienced PASC for 6 months after
There is a lack of systematic reporting on the long-term recovery (Groff, 2021). The most frequently reported
consequences of COVID-19 with relatively few studies on PASC consequences involved functional mobility impair-
the subject. However, based on the available evidence, ments, pulmonary abnormalities, and mental health
there seems to be a persistence of symptoms with delayed disorders. Since these long-term PASC effects are occur-

© 2023 International Society for Orthomolecular Medicine ISSN 0317-0209

An Orthomolecular Protocol for Long COVID

ring on a very significant scale; it is important to develop This article will focus mostly on the use of nutritional
a rational, safe and affordable protocol that can provide concepts, pharmacologic nutritional biochemistry, and
relief and effectively address the pathogenetic causes of metabolic optimization to improve post-COVID syn-
this condition (Groff, 2021). drome outcomes. Careful selection and consumption
of food at optimal intervals, combined with nutrient
According to other studies, risk factors for PASC include
supplementation in amounts that are established as
having more than five initial symptoms in the orig-
safe and potentially effective, may provide a solution
inal infection, severe COVID-19, increased D-dimer,
for many people. Some anti-inflammatory agents are
increased C-reactive protein, increased interleukin-6,
known cause mitochondrial dysfunction and adenosine
decreased lymphocyte count, pre-existing comorbid-
triphosphate (ATP) depletion by a variety of mechanisms
ities, prior psychogenic disorder, and old age among
such as an increase in ROS, damage of mitochondrial
others (Yong, 2021).
membrane lipids, and a decrease in glutathione (Salimi,
management of post covid - 19 fatigue and
2019). The role of pharmaceuticals is not within the
scope of this article.
long covid
Mitochondria are organelles that are present in most
Persistence of some of the acute illness physical symp- cell of the body and produce a substantial portion of
toms, including dyspnea, fatigue, post-exertional the body’s total energy. Viral infection triggers mito-
malaise, chest pain, and cough, are the most common chondrial damage, accompanied by increased ROS
manifestations of long COVID-19 (Carfi et al. 2020). production. ROS, in turn, damages the mitochondrial
Patients can also experience gastrointestinal and neu- membranes, mitochondrial deoxyribonucleic acid
rological symptoms (Yong, 2021). Fatigue has been the (mtDNA), and proteins, including those comprising the
most common complaint. The mechanisms underlying electron transport chain (ETC), thereby decreasing ATP
this post-viral fatigue syndrome in COVID-19 have been production. There are dysfunctional pathways that can
proposed to be similar to that of chronic fatigue syn- develop that are related to chronic fatigue. Moreover,
drome (CFS) (Komaroff, 2021). an increase in glycolysis causes further mitochondrial
There seems to be a persistent inflammatory and exces- damage and contributes to other cellular dysfunctions
sive reactive oxygen species (ROS) production that (Boothet et al., 2012). There are a variety of nutrition-
affects mitochondrial function among other things al-related, or analogs of endogenous substances with
(Tereshin, 2021; de Las Heras, 2020; Piotrowicz, 2021). biochemical and biological actions that improve phys-
Thus, our proposed protocol concentrates primarily on iology. Molecules are mostly of natural origin, have the
neutralizing excessive ROS, re-establishing mitochon- correct structure and form, and are supplied at the cor-
drial function, and reducing excess inflammation. rect amount are termed orthomolecular substances.
These orthomolecules may reduce inflammation and
orthomolecular nutrition mitochondrial damaging ROS, provide lipids for mem-
and supplementation brane repair and precursors and cofactors needed for
the production of oxidative phosphorylation (energy).
Since patients who have more severe COVID are more In individuals experiencing with illness, some of these
likely to have post-covid syndrome (Hirschtick, 2021), orthomolecules are frequently scarce; thus,providing
it is likely that they have more extensive tissue dam- individuals with orthomolecules at sufficient quantities
age and therefore have a longerrecovery and repair and form often facilitates and enhances mitochondrial
period. Having more extensive damage is potentially functioning (Gonzalez et al., 2018).
the reason for extended inflammation, increased gen-
eration of ROS, and mitochondrial damage (Yong, Two other aspects of the post-COVID syndrome man-
2021). Correcting mitochondrial function has produced agement are to: 1) address excessive inflammation; and
improved outcomes in other conditions such as chronic 2) minimize free radical formation and propagation.
fatigue syndrome and other energy-related Illnesses These two aspects are interrelated, and their control is
(Nicolson, 2004). It is also hypothesized that improv- critical in the healing process.
ing mitochondrial function may in the alleviation of a COVID-19 infection and post-COVID syndrome are
variety of symptoms ranging from pain to mobility and associated with the involvement of diferent organs
energy in post-COVID syndrome. and systems, such as lung, liver, kidney, heart, and

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An Orthomolecular Protocol for Long COVID

gastrointestinal, hematological, and nervous system The angiotensin-converting enzyme (ACE2) has mul-
with a high rate of mortality and induction of multi- tiple physiological roles. ACE2 is a negative regulator
organ failure. A recent cohort study of German patients of the renin-angiotensin system; a facilitator of both
(n=10) who recently recovered from severe COVID-19 amino acid and SARS-CoV transport; and a SARS-CoV-2
infection, found that cardiac involvement was apparent receptor. It has been shown that ACE2 expression and
in 78% of patients and ongoing myocardial inflamma- activity are associated with obesity (Tejpal et al. 2020),
tion presented in 60%, irrespective of infection severity suggesting the role of diet and cardiometabolic health
(Puntmann et al., 2020). Fortunately, lung damage with in COVID-19 infection. Dietary patterns have a strong
acute respiratory distress syndrome (ARDS), including effect on ACE2 levels (Bousquet, 2020). Antioxidant
post-severe acute respiratory syndrome (SARS), tends to activity and ACE2 inhibition have been found in many
improve over time and often resolves (Salamon, 2020). foods. Moreover, ACE2 levels in the blood are highly and
rapidly sensitive to food intake. There are natural ACE2
Post-viral brain involvement presents a temporary
inhibitors such as pomegranates, flaxseed, beets, apples,
brain fog that does not manifest as long-term brain
prunes, dark chocolate, garlic, kiwis, and blueberries.
injury. Rather it involves persistent free radical irrita-
tion, a decrease in cerebral blood flow probably due proposed orthomolecular protocol
to microglial activation, and alterations in temporal
blood flow. Nutraceutical support of mitochondrial function is
associated with a reduction in long-term fatigue and
proposed dietary protocol inflammation (Hamilton and Jensen, 2021).
Follow a diet rich in whole foods, high in antioxidants, High-Dose Intravenous Vitamin C (IVC): 25-50 grams,
and colorful phytonutrients with anti-inflammatory 2x per week for 4 weeks
and detoxifying properties (i.e. organic berries, citrus
fruits, spinach, garlic and onions, ginger, broccoli, red The redox, anti-inflammatory, endothelial-restoring, and
bell peppers, etc.). The diet should be low or minimal in immunomodulatory effects of high-dose intravenous
refined carbohydrates and processed foods. Eat more (IV) vitamin C might be a suitable treatment option
vegetables, fruits, and nuts. Merino et al. 2021 showed (Riordan, 2003). The pathophysiology of COVID-19 is
that a dietary pattern characterized by healthy plant- characterized by inflammation and oxidative stress
based foods was associated with an overall 9% lower leading to vascular and organ damage, as well as the
risk of COVID-19 infection and a 41% lower risk of severe suppression of adaptive immune responses (Vollbracht
COVID-19. Additionally, hydration is critical. It is recom- and Kraft, 2021). It is likely that the post-acute recovery
mended to consume 10–15 cups (2.5–4L) of water per phase is also accompanied by oxidative stress, inflam-
day. A good sign of adequate hydration can often be mation, and thus a deficiency of antioxidants such as
increased frequency of urination, approximately four to vitamin C. It is therefore clinically plausible that vitamin
six times per day, and improved energy levels. C administration could alleviate fatigue by treating vita-
min C deficiency symptoms, and by neuroprotective
Hyperglycemia in COVID-19 patients is a frequent com- and vasoprotective effects due to its antioxidant and
plication. High blood glucose has been identified as an anti-inflammatory properties.
important risk factor for poor outcomes such as inten-
sive care unit (ICU) admission, acute respiratory distress Vitamin C: 1000 mg, 3x per day (oral)
syndrome (ARDS), and death (Kitt, 2021). Hyperglycemia
Scavengers of reactive oxygen species, such as vitamin
may result in vitamin C depletion possibly related to
C can play an important role in minimizing the cytokine
inhibition of ascorbic acid transport across the cell
storm and preventing tissue damage. In doing so, the
membrane of the leukocytes (Chen, 1983). It has been
level of vitamin C can be rapidly depleted if not replen-
shown that prolonged hyperglycemia can cause signifi-
ished (Gonzalez et al. 2020b; Miranda-Massari et al.
cant decreases in chemotaxis, a fundamental biological
2020; Toro et al .2021; Rs et al. 2022). Oral intake should
process in which a cell migrates following the direction
commence after intravenous therapy in order to main-
of a spatial cue. These results are consistent with the
tain optimal physiological levels (Gonzalez, 2020a).
hypothesis that chronic hyperglycemia may be asso-
ciated with impaired acute inflammatory response,
increased susceptibility to infection, and altered wound
repair (Pecoraro, 1987).

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An Orthomolecular Protocol for Long COVID

Magnesium Citrate: 500 mg, 2x per day ubiquinol (reduced form). Ubiquinol supplementation
has been shown to improve fatigue in juvenile fibromy-
Magnesium (Mg) is a cofactor for over 300 metabolic
algia (Miyamae, 2013).
enzymes that regulate multiple essential functions in
central nervous system, endocrine system, and mus- Alpha Lipoic Acid (ALA): 300 mg, 2x per day
culoskeletal system among others. Magnesium is
insufficient in about 50% of the United States popula- Alpha lipoic acid, also known as thiotic acid, is a sul-
tion (Reider, 2020). The supplementation of this mineral fur compound widely distributed in all human cells
has been shown to prevent or treat a variety of disor- with important oxidation-reduction (redox) activity
ders or diseases related to the respiratory system (Tang that contributes to the regeneration of vitamins C and
et al., 2020). SARS-CoV-2 may induce a cytokine storm E and participates in the aerobic energy production
that drains ATP whose regeneration requires phosphate (Podda, 1994). ALA has several beneficial effects such
and Mg. Available data show that phosphate and Mg as glucose control, excess ROS control, and antioxi-
levels are depleted in COVID-19 patients, with phos- dant regeneration. These effects may help reduce cell
phate showing a remarkable correlation with its severity and tissue damage related to COVID-19. Mounting
(van Kempen, 2021). It has been proposed that mag- evidence suggests that SARS-CoV-2 infection leads to
nesium supplementation might help protect against multiple instances of endothelial dysfunction, includ-
SARS-CoV-2 infection, reduce the severity of COVID-19 ing reduced nitric oxide (NO) bioavailability, oxidative
symptoms, and facilitate recovery after the acute phase stress, and endothelial injury which are thought to be
(Trapani, 2022). underlying mechanisms in the pathophysiology of
COVID-19. Endothelial integrity is critical for micro- and
Coenzyme Q10 (CoQ10): 100 mg, 3x per day macro-vascular health. ALA has been shown to improve
endothelial function by restoring the endothelial nitric
Coenzyme Q10 is a fat-soluble substance ubiquitously
oxide synthase activity and reducing oxidative stress.
expressed throughout the body that is important for the
By improving mitochondrial function, ALA can help
generation of ATP and mediation of inflammatory disease.
sustain the tissues’ homeostasis and by enhancing
CoQ10 has an integral anti-inflammatory role in the body
glutathione it could indirectly strengthen the immune
as a free radical scavenger and has been utilized in the
system (Rochette and Ghibu, 2021). A small prospective
treatment of a variety of inflammatory-mediated diseases
randomized controlled clinical trial evaluated the use
(Polymeropoulus, 2020). CoQ10 supplementation has
of ALA in critically ill COVID-19 patients. The mortality
also been used in several inflammatory disease models
in the ALA group was much lower (37.5%) than in the
of platelet aggregation, fibrosis, and chronic inflamma-
control group (77.8%). However, because the number of
tory disease (Mantle et al., 2020). CoQo10 has been found
patients was small (n=17) it did not reach statistical sig-
to successfully reduce fatigue and improve performance
nificance (Zhong, 2019).
in both healthy people (Mizuno, 2007) and patients with
chronic fatigue (Nicolson, 2004). Furthermore, a pro- Acetyl-L-Carnitine (ALC): 1000 mg, 4x per day
spective, randomized, double-blind, placebo-controlled
trial of 12-week duration in 207 patients with myalgic L-Carnitine (3-hydroxy-4-N-trimethyl-aminobutyrate) is
encephalomyelitis/chronic fatigue syndrome, the sup- a nutrient composed of the essential amino acids lysine
plemented group (n=104) using 200 mg of CoQ10 and and methionine. L-Carnitine is a trimethylated amino
20 mg of reduced nicotinamide adenine dinucleotide acid and functions as a cofactor to convert long-chain
(NADH) had a significant reduction in cognitive fatigue free fatty acids to acylcarnitine and transfer them to the
and an overall improvement in health related quality mitochondrial matrix. Therefore, ALC plays a central role
of life compared to the placebo group (n=103) (Castro- in the metabolism of fatty acids and its inadequacy will
Moreno, 2021). CoQ10 performs several cellular functions induce feelings of tiredness, lethargy, general fatigue.
of potential relevance to the immune system. CoQ10 has Many clinical trials have shown the effectiveness of
a key role in cellular energy supply, via its role in oxidative L-carnitine in relieving fatigue caused by the intense
phosphorylation within the mitochondria. The immune treatment of cancer and multiple sclerosis (MS), amon-
response has intensive energy requirements and an gother conditions (Vaziri-harami and Delkash, 2022).
adequate supply of CoQ10 is required to enable the var- Evidence from clinical trials has shown that providing
ious immune cell types to optimally function. . There are mitochondrial metabolic cofactors CoQ10, lipoic acid,
two forms of CoQ10: ubiquinone (oxidized form) and and carnitine through supplementation can lower the

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An Orthomolecular Protocol for Long COVID

levels of several inflammatory biomarkers (Ambrosi, damages caused by ROS-mediated apoptosis. Therefore,
2016; Donnino, 2011; Soltani, 2020; Savica 2005). ALC astaxanthin looks promising to prevent the progres-
may help alleviate fatigue by supporting the production sion of multi-organ damage. (Fakhri, Yosifova, Aneva, et
of mitochondrial energy, interfering with acetylcholine al., 2019).
synthesis in the brain, and via anti-inflammatory and
antioxidant mechanisms. Vitamin E (Tocopherols and Tocotrienols): 400 IU,
4x per day
Mixed Phospholipids: 1000 mg, 3x per day
Vitamin E has the potential be utilized to prevent oxi-
Evidence indicates that diminished mitochondrial func- dative damages associated with the SARS-CoV-2
tion through loss of efficiency in the electron transport pathogenesis due to its free radical scavenging effects
chain caused by oxidation occurs during fatiguing ill- (Samad et al., 2021). In addition, some studies suggest
nesses. Lipid Replacement Therapy (LRT) administered that vitamin E has antiplatelet and antithrombotic effects
as a nutritional supplement of phospholipids (phospha- (González-Correa, 2005; Dowd, 1995), which might be
tidylcholine, phosphatidylserine, phosphatidylinositol, useful considering that coagulopathies are a common
phosphatidyletanolamine) with antioxidants can pre- complication in severe COVID-19 cases. In addition, a
vent oxidative membrane damage, and LRT can be used literature evaluation of 12 randomized controlled tri-
to restore mitochondrial and other cellular membrane als (246 participants in the intervention arms and 249
functions via delivery of undamaged replacement lipids participants in control arms), found that serum levels
to cellular organelles. Recent clinical trials using patients of C-reactive protein (CRP), an inflammatory biomarker,
with chronic fatigue have shown the benefit of LRT plus were significantly lower in patients taking vitamin E
antioxidants in restoring mitochondrial electron trans- (α-tocopherol or γ-tocopherol); thus supporting the
port function and reducing moderate to severe chronic notion that vitamin E may have anti-inflammatory prop-
fatigue. The LRT seems to work by protecting mito- erties (Saboori, 2014).
chondrial and other cellular membranes from oxidative
damage as well as removing and replacing damaged N-Acetyl Cysteine (NAC): 600 mg, 2x per day
lipids (Nicolson and Ellithorpe, 2004). N-Acetyl Cysteine (NAC), a precursor of the potent anti-
oxidant glutathione has been used in clinical practice
Astaxanthin (ASX): 12 mg, 4X per day
to treat critically ill septic patients and more recently for
Astaxanthin is a red pigment related to the carotenes COVID-19 patients. In a 36-week open-label clinical trial
present in some algae with powerful antioxidant and conducted in eight older adults and eight young adults,
immune-modulating properties. Specifically, ASX sup- a combination of NAC with glycine was supplemented.
ports the regulation of cyclooxygenase-2 (COX-2) Supplementation in older adults help corrected red
pathways and the suppression of cytokines (Ahmadi, blood cell glutathione, glutathione deficiency, oxida-
2021). It has been shown to exert a protective effect by tive stress, and mitochondrial dysfunction (Kumar et
regulating the expression of pro-inflammatory cyto- al., 2021). Based on the results of multiple comprehen-
kines interleukin beta (IL-1β) interleukin 6 and 8 (IL-6, sive measurements, NAC supplementation also helped
IL-8), and tumour necrosis factor alpha (TNF-α). ASX has improve inflammation, endothelial dysfunction, insulin
been shown to prevent oxidative damage and attenuate resistance, genomic-damage, cognition, strength, gait
exacerbation of the inflammatory responses by regu- speed, and exercise capacity (Kumar et al., 2021). Given
lating signaling proteins and pathways such as nuclear the antioxidant, anti-inflammatory, and immune-mod-
factor kappa B (NF-ĸB), nucleotide-binding domain, ulating properties of NAC, it may be a potentially
leucine-rich–containing family, pyrin domain–contain- beneficial, safe, and feasible adjunctive treatment or
ing-3 (NLRP3), and the Janus kinase/signal transducers prevention option for SARS-Cov-2 infection (Shi and
and activators of transcription (JAK/STAT).This evidence Puyo, 2020).
provides a rationale for considering natural astaxan-
thin as a therapeutic agent in COVID-19 infection to Glutathione (GSH): 1000mg liposomal, 4x daily
reduce inflammation propagated by the cytokine storm Glutathione is an endogenous compound made from
(Talukdar et al.2020). Growing evidence suggests a the amino acids glycine, cysteine, and glutamic acid. It
specific association between the therapeutic effects is produced by the liver and involved in many processes,
of astaxanthin and its antiapoptotic properties which including protein manufacturing, tissue repair, meta-
are of particular interest in COVID-19 given the known bolic detoxification, and also acts as potent intracellular

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An Orthomolecular Protocol for Long COVID

antioxidant. Some researchers have indicated that GSH tigators compared routine care versus QCB (quercetin,
is poorly absorbed when administered orally, primarily vitamin C, bromelain) supplementation. Quercetin is a
due to the action of the intestinal enzyme, γ-glutamyl bioflavenoid that activates or inhibits the activities of a
transpeptidase (GGT) which actively degrades GSH number of proteins in vitro. The supplementation group
(Zhang, 2005). However, intravenous administration, had significantly greater decreases in C-reactive protein
liposome encapsulated GSH, and other formulations (CRP) and ferritin, as well asand increases in platelet and
have increased bioavailability (Buonocore, 2016). Some lymphocyte counts (Önal et al., 2021). Another review
observational and research analyses have suggested of 10 studies found that the use of bromelain was effec-
that glutathione deficiency is a plausible explanation tive in reducing pain, inflammation, and stiffness in
for some of the morbidity and mortality associated with patients with osteoarthritis (Brien, 2004). Another study
COVID-19 (Polonikov, 2020; Silvagno 2020). Given this in a group of 116 children with sinusitis showed that
information, it has been proposed that GSH supplemen- those who used bromelain alone had symptom relief
tation may be beneficial in COVID-19. GHS can mitigate in a shorter period than with the other therapies used
the inflammatory response, specific for SARS-CoV-2, (Braun, 2005). Taken together, these studies suggest
and dependent on its binding to its receptor ACE2, that both quercetin, with SPE properties, and bromelain
increased GSH levels may prevent and subdue the dis- may help reduce inflammation and symptoms associ-
ease (Guloyan et al. 2020). ated with COVID-19.
Omega 3: 1000 mg, 3x per day Palmitoylethanolamide (PEA): 600 mg, 2x per day
Omega-3s are polyunsaturated fatty acids (PUFAs). PEA is an amide of endogenous fatty acid of the
Dietary sources include fish oils, algae, and phyto- N-acylethanolamine family with immunomodulatory,
plankton and it’s also present in some plants. Omega-3 anti-inflammatory, neuroprotective, and pain-reliev-
fatty acids, especially eicosapentaenoic acid and ing effects (Noce et al., 2021). PEA is a cannabimimetic
docosahexaenoic acid, are known to be incorporated compound that performs a wide variety of biological
throughout the body into the bi-phospholipid layer of functions to counteract chronic pain and inflammation
the cell membranes leading to the production of fewer (Gatti et al., 2012). An antiphospholipid syndrome sec-
pro-inflammatory mediators. Omega-3 upregulates the ondary to SARS-CoV-2 infection can occur from cytokine
activation of immune cells specifically macrophages, storm resulting in phospholipids consumption. In a case
neutrophils, T-cells, B-cells, dendritic cells, natural killer study, PEA was used successfully in a 45-year-old COVID-
cells, mast cells, basophils, and eosinophils. Omega-3 19 female with antiphospholipid syndrome (Roncati et
fatty acids regulate membrane fluidity and membrane al., 2021).
lipid assembly (Hathaway et al., 2020). Supplemental
forms should be molecularly distilled. Specialized Pro-Resolving Mediators (SPM): 500 mg,
3x per day
Systemic Proteolytic Enzymes (SPE): 3x per day,
Specialized pro-resolving mediators are a group of
on empty stomach
endogenously produced lipid substances that promote
Enzymes break the chain-like molecules of proteins resolution of inflammation. They consist of lipoxins,
(polypeptides) into shorter fragments (peptides) and resolvins, maresins, and protectins and represent a novel
eventually into their smaller basic components known class of bioactive lipids that are generated by enzymatic
as amino acids. Enzymes such as lysozyme, catalase, oxygenation of n-3 and n-6 polyunsaturated fatty acids
bromelain, and papain are known to function as immu- (PUFAs) after the initial stages of the inflammatory
nomodulators and work to combat oxidative stress cascade. SPM may enforce the pro-resolutive axis of
(Rathi et al., 2021). SPE may be capable of breaking inflammatory processes. This might also help improve
down the spike protein. SPE may induce the unfolding chronic courses associated with inflammation of heart
of recombinant spike and envelope proteins by reduc- and lung tissue (Regidor et al., 2021). They can also reg-
ing disulfide stabilizer bridges (Akhter et al., 2021). In ulate macrophage infiltration, cytokine production, and
a prospective randomized controlled cohort study of stimualte pro-resolving macrophage phenotypes (Balta
429 COVID-19 patients with at least one chronic disease et al. 2021).
and moderate-to-severe respiratory symptoms, inves-

6 | Journal of Orthomolecular Medicine, Volume 38, Number 1, 2023

An Orthomolecular Protocol for Long COVID

summary of safety and other considerations give important insight into the patterns of metabolites
related to the biochemical dysfunctions of concern.
The list of biological response modifiers that have
been discussed within this protocol (micronutrients, There are other interventions that may improve out-
cofactors, peptides, fatty acids and botanicals) is not comes but that require more specialized medical
exhaustive. Rather, this protocol serves to provide a supervision. Some of these include, Hyperbaric Oxygen
practical overview of several biological response modi- Therapy (HBOT), Photobiomodulation (PBM), Low-Level
fiers and suggest their role in the practical management Laser Therapy (LLLT), Exosomes and mesenchymal stem
of COVID-19. There are many other factors that might cells (MSC).
contribute to recovery (i.e., probiotics). High-dose intra-
venous vitamin C followed by oral supplementation conclusion
is very safe and well tolerated. Some people have lim- The post-acute recovery phase of COVID-19 is assumed
ited tolerance to oral supplements, usually related to a to be accompanied by oxidative stress, inflammation,
weakened gastric or intestinal mucosa. Therefore, sup- and mitochondrial dysfunction which causes physical
plementation should be adjusted based on individual and mental fatigue. Chronic fatigue syndrome and fibro-
tolerance. As some people may not tolerate supple- myalgia-like clinical manifestations following COVID can
mentation with all 14 supplements mentioned within be very challenging to treat; nevertheless, they can be
this protocol, is important to plan a strategy that fits effectively treated when applying a proper therapeutic
the specific needs of each individual patient. First, oral protocol. This protocol should consist of a combination
supplements are better tolerated when consumed with- of synergistic nutrients and co-factors that are known to
meals and it always better to start with fewer products have actions that mitigate the oxidative, inflammatory,
to ensure tolerance before adding other oral products. and energy issues that are common in COVID-19 infec-
Although the first five supplements (vitamin C, Mg, tion. The proposed protocol should have positive effect
CoQ10, ALC, ALA, and phospholipids) have different on diminishing chronic fatigue and other persistent
physiological functions and mechanisms of action, they long COVID symptoms.
all work to support cell energy production. The next four
supplements (ASX, vitamin E, NAC and GSH) also have a
variety of distinct physiological actions and share anti- references
oxidant properties. The last group (omega-3, proteolytic Ahmadi AR, Ayazi-Nasrabadi R. Astaxanthin protective barrier and its
enzymes, PEA and SPM) share anti-inflammatory effects. ability to improve the health in patients with COVID-19. Iran J Microbiol.
2021 Aug;13(4):434-441. DOI: 10.18502/ijm.v13i4.6965. PMID: 34557270;
Some patients with recent trauma, post viral infection PMCID: PMC8421583.
with SARS-Cov-2 or post-COVID-vaccine adverse effects Ambrosi N, Arrosagaray V, Guerrieri D, Uva PD, Petroni J, Herrera MB,
may have elevated levels of D-dimer, coagulation fac- Iovanna JL, León L, Incardona C, Chuluyan HE, Casadei DH. α-Lipoic acid
protects against ischemia-reperfusion injury in simultaneous kidney—
tors, and inflammatory markers. Patients that are on pancreas transplantation. Transplantation. 2016;100:908–15. https://doi.
anticoagulants and/orhave history of coagulation disor- org/10.1097/TP.0000000000000981.
ders should be cautious with medications which have Akhter J, Quéromès G, Pillai K, Kepenekian V, Badar S, Mekkawy AH,
antiplatelet effects like aspirin. Also note that alpha-to- Frobert E, Valle SJ, Morris DL. The Combination of Bromelain and Ace-
copherol (vitamin E) and acetylsalicylic acid have been tylcysteine (BromAc) Synergistically Inactivates SARS-CoV-2. Viruses.
shown to increase gingival bleeding (Liede, 1998). 2021; Mar 6;13(3):425. doi: 10.3390/v13030425. PMID: 33800932; PMCID:
PMC7999995.
However, mixed tocopherols have not shown this
effect. Omega-3 possesses inhibitory effects in platelet Balta MG, Papathanasiou E and Christopoulos PF. Specialized Pro-Re-
solving Mediators as Potential Regulators of Inflammatory Macrophage
function and some clinicians are concerned about pos- Responses in COVID-19. Front. Immunol. 2021;12:632238. doi: 10.3389/
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11 | Journal of Orthomolecular Medicine, Volume 38, Number 1, 2023