Fluvoxamine: The Little SSRI that Could – Part I

Brief Overview, Tortuous History, and Mechanisms of Action

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Over the past two years, the validation of a viable COVID therapeutic was always based off of the mantra of “safe and effective”. However, we have seen a great disparity in the evocation of the mantra as it relates to both EUA approved therapeutics as well as repurposed drugs.

There’s no doubt that Remdesivir has been greatly misused as it continues to be deployed far too late into the disease, yet it is still considered as part of the standard of care here in the US. Molnupiravir, who hardly meets the criteria for being safe due to the vast number of unknown mutagenic toxicities, and who’s effectiveness should now be brought under greater scrutiny due to the results of the latter half of their Phase III clinical trials, is still under EUA authorization and is likely to hit the market within the next few weeks.

Repurposed drugs have certainly been given a bad name over the course of this pandemic. Meeting a similar criticism as Remdesivir, Hydroxychloroquine’s use as an immunomodulator in hospitalized patients is superseded by the risk of cardiac arrhythmias and prolonged QT intervals that may appear in hospitalized/intubated patients, likely due to a patient’s multiple comorbidities as well as organ and heart damage from severe viral infection and hyper inflammation rather than from Hydroxychloroquine itself. Under both circumstances, Remdesivir and Hydroxychloroquine appear unfit for use in hospitalized patients, and yet one continues to be deployed as a main form of treatment while another has had their EUA revoked.

Ivermectin itself has had a slew of hit pieces against itself, most notably being relegated to a position of “horse dewormer”. It’s an interested name to give Ivermectin, considering that Ivermectin itself is used in many monthly dewormer drugs for dogs, and I hardly doubt that there are far more horse owners in the world than there are dog owners. The castigation doesn’t end there, as the criticisms for Ivermectin’s lack of effectiveness came at a time when there have been no approved at-home, outpatient therapeutics aside from the expensive monoclonal antibodies. Take into consideration that two of the most widely used monoclonals have had their EUAs revoked, and the number of possible outpatient treatments has become nearly nonexistent.

Know that this doesn’t mean that I endorse or approve the use of repurposed drugs, and that this information is intended to be informative rather than prescriptive. However, we can’t dismiss the hypocrisy and lack of nuance that has been on display for any attempt to use a repurposed drug. It’s certainly true that the attempts to deploy cheap therapeutics, and ones that have had decades of clinical data, have been shuttered over more expensive, novel therapeutics with their own questionable safety and efficacy profiles.

But there has been one repurposed drug that appears to have gone under the radar, at least in medical circles that have attempted to dissuade the use of repurposed drugs.

That drug is Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) that, for all intents and purposes, has been left out of the war over repurposed drugs. It’s a drug that many in the FLCCC and even Steve Kirsch himself has advocated for by funding Fluvoxamine clinical trials. Yet the discussion in the mainstream media seems to be relatively lacking. In fact, there really doesn’t appear to be any pushback at all by mainstream medical professionals (aside from a purported lack of evidence- note that the paper cited here also cites the completely debunked Hydroxychloroquine study from The Lancent in an attempt to castigate dissenters), and instead it appears that there haven’t been much noise against the SSRI but rather its advocates.

So how is it that a drug that was initially designed for mental disorders can target SARS-COV2? More importantly, how does this drug appear to be effective in treating symptoms of long COVID?

We’ll discuss all of this here within this series, going over a brief history of Fluvoxamine, its multifaceted mechanisms of action, and the clinical evidence to support its use in treating COVID, including its possible mechanism of action in treating long COVID. Lastly, we’ll examine why this drug has essentially been left out of the overall discourse.

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A Brief History

The story of Fluvoxamine is not one entrenched within decades of medical history as the likes of Hydroxychloroquine, nor is it a naturally derived compound as seen with either Ivermectin or Quercetin.

Fluvoxamine was first developed and distributed in Switzerland during the early 1980s through the pharmaceutical company Solvay Pharmaceuticals, with its initial purpose focusing on treating obsessive compulsive disorders. It would eventually see usage across the globe for other psychiatric disorders such as major depressive disorder and other disorders usually treated by other SSRI’s (excerpt taken from ChemEurope):

Fluvoxamine was one of the first of the SSRI antidepressants to be launched (1984 - Switzerland) and was developed by Solvay Pharmaceuticals. It has been in use in clinical practice since 1983 and has a clinical trial database comprised of approximately 35,000 patients. It was launched in the US in December 1994 and in Japan in June 1999. As of the end of 1995, more than 10 million patients worldwide have been treated with fluvoxamine.[1]

Fluvoxamine was the first SSRI to be registered for the treatment of Obsessive Compulsive Disorder in children by FDA in 1997.[2]

Fluvoxamine was the first drug approved for the treatment of social anxiety disorder in Japan in 2005.[3]

Fluvoxamine is considered to be one of the earliest SSRI’s still in use today. It’s considered to have a relatively safe profile, and is actually considered to be safer than other SSRIs on the market. In cases of adverse reactions and possible contraindications from other antidepressants, Fluvoxamine has been considered a safer alternative and is usually prescribed for those who have had prior adverse reactions.

Fluvoxamine is mostly found under the brand name of Luvox®, Faverin®, Fevarin®, and Dumyrox®, with the common daily dosage revolving around either 50 mg/day or 100 mg/day. Most generic names may also refer to it as Fluvoxamine Maleate. Because of the amine group, Fluvoxamine tends to be protonated at physiological pH, and thus a counter negative ion is added to neutralize the positive charge which allows Fluvoxamine to be administered in pill form. In general, a typical 50 mg dose costs under 1 dollar. Put into perspective, a 15 day course of 100 mg/day would be expected to cost under $40 USD.

Additional information is provided by Marčec, R. & Likić, R.(emphasis mine):

Fluvoxamine was first registered in Switzerland in 1983 and is one of the oldest SSRIs still in clinical use. Many post-marketing studies have so far demonstrated its good safety profile. Data from the first 17 years of global post-marketing surveillance, during which 28 million patients were exposed to fluvoxamine, prove that it is a safe and well-tolerated drug in all age groups (30). Even when compared with other SSRIs, fluvoxamine retains a more favorable safety profile as it has a low risk of QT prolongation (31). Unlike other SSRIs, fluvoxamine is also a weak CYP2D6 and a potent CYP1A2 inhibitor (32), but the reported incidence of its drug-associated interactions remains low (33).

Fluvoxamine’s important characteristics considering the SARS-CoV-2 pandemic are its wide availability and affordability. Having at least 15 trade names worldwide, it is highly available (34). The price of one 100 mg oral tablet is US $0.74 (35), which makes the cost of a 15-day treatment as used by Lenze et al only US $33.3.

Fluvoxamine’s role in COVID likely first appeared in a clinical trial by Lenze et. al. from 2020 in which researchers looked into Fluvoxamine’s potential therapeutic role due to its agonistic activity with sigma-1 receptors (more on the sigma receptor and the clinical trial later). The idea to use Fluvoxamine was spurred on by a recent study at the time which highlighted that Fluvoxamine’s sigma-1 agonist activity produced a robust anti-inflammatory response. Following that logic, the use of Fluvoxamine within a hospital setting was done with the intent to reduce the hyper inflammatory state, and here Fluvoxamine was seen to be effective at preventing deterioration in hospitalized patients to a greater extent than the control group.

The results of this study later influenced outpatient usage by Seftel, D. & Boulware, D. in 2021, who quickly deployed Fluvoxamine after a COVID outbreak had occurred at the Golden Gate horse track in California. Here, the results proved phenomenal, as no one given Fluvoxamine required hospitalization. This provided the first real-world, outpatient evidence about the effectiveness of Fluvoxamine against COVID.

Taken together, the results of these two studies would eventually lead to further investigation in regards to the use of Fluvoxamine, and clinical trials are still underway as of now.

A Tortuous Past

Now, what’s interesting to note is that many anti-depressants have come under heavy scrutiny over the past few years due to their association with perpetrators of mass tragedies. Atrocious incidences of school shootings and mass murders have tended to implicate antidepressants as possible causative agents, as many of these suspects are later found to have had a history of being prescribed antidepressants.

Now, it should be noted that the evidence is not quite clear in favor of blaming antidepressants alone. In fact, I would argue that the evidence so far is sparse aside from evidence of possible correlations. There are many factors at play when considering why someone may decide to commit such atrocities, and even the concept of the “chicken vs egg” phenomenon should not be discredited when examining these scenarios.

All this to say, unfortunately, that Fluvoxamine is not without such a tried history, as Fluvoxamine was found to have been prescribed to one of the perpetrators of the Columbine Massacre of 1999 (excerpt taken again from ChemEurope):

In 1999, fluvoxamine came under great public scrutiny after it was discovered that Eric Harris, one of the two teenaged shooters involved in the Columbine High School massacre, had been taking the drug as treatment for depression. Many immediately pointed fingers at fluvoxamine and its manufacturer Solvay Pharmaceuticals (which sells fluvoxamine under the widely known brandname Luvox), since Solvay's own clinical trials indicated the drug had the propensity to induce mania in 4% of the youth who took it. What was not made public however was that Solvay concealed from the public the fact that a homicide occurred during the clinical trials involving adults. Solvay, while acknowledging the risks inherent in taking an SSRI medication like fluvoxamine, downplayed any role the drug may have had in the killings. The American Psychiatric Association (A.P.A.) took a similar stance; Rodrigo Munoz, M.D., President of the A.P.A., said: "Despite a decade of research, there is little valid evidence to prove a causal relationship between the use of anti-depressant medications and destructive behavior. On the other hand, there is ample evidence that undiagnosed and untreated mental illness exacts a heavy toll on those who suffer from these disorders as well as those around them." It was also pointed out by many that Luvox was often safer than the other SSRI medications available--for example, fluoxetine (Prozac) caused mania in 6% of youth tested on the drug (versus fluvoxamine's 4%). Nonetheless, the reputation of Luvox was irreparably damaged. Sales fell, and Solvay withdrew the medication from the U.S. market in 2002 while several generic versions continue to be available; the company maintains, however, that this move had nothing to do with the safety profile of fluvoxamine, which they still sell in many countries around the world. In the United States, fluvoxamine can only be purchased generically.

The FDA currently issues the following warning with Luvox: Taking antidepressants may increase suicidal thoughts and actions in about 1 out of 50 people 18 years or younger.[1] The UK and Health Canada have taken similar actions.

Whether Fluvoxamine can be considered a causative agent in this tragedy, the damage was already done and the perception of the drug has been somewhat tainted. Now, whether or not this can be considered a contributing factor to the Fluvoxamine/COVID discourse is up for debate, and from what I can tell this sordid past has not come up in the pieces I have seen.

For now, this should not be taken into heavy consideration when examining Fluvoxamine within the context of COVID, but it does indicate a history that is not so easy to disabuse. Know that the history is there but should not be used to immediately discredit the other information here, and we will take this information into account when providing some perspective further on.

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Mechanisms of Action

To begin our examination of Fluvoxamine’s MOA, let’s examine a general overview. This post will go into more detail over several of the MOAs outlined below (taken from LiverTox):

Fluvoxamine (floo vox' a meen) is a selective serotonin reuptake inhibitor (SSRI) that was developed largely for use in obsessive-compulsive disorder. Fluvoxamine acts by blocking the reuptake of serotonin in CNS synaptic clefts, thus increasing serotonin levels in the brain which is associated with its psychiatric effects...

Fluvoxamine is also a potent sigma-1 receptor (S1R) agonist, which results in an inhibition of proflammatory cytokine production. Because the proinflammatory cytokines such as IL-6 play a role in the hyperinflammatory response in severe COVID-19 pneumonia, fluvoxamine has been proposed as a therapy for COVID-19. Several small case series and clinical trials have suggested that fluvoxamine may prevent clinical deterioration in patients with SARS-CoV-2 infection, particularly if used before the onset of respiratory failure and the full scale hyperinflammatory state. Clinical trials of the efficacy or safety of fluvoxamine are currently underway.

And for those like me who prefer to learn visually, here’s a schematic diagram outlining several of these MOAs as well. Note that there are a multitude of mechanisms of action, and therefore for the sake of some brevity we will discuss the most important MOAs. In particular, we will go into more detail in regards to MOAs 1, 3 and 5.

Taken from Sukhatme et. al.

General Antidepressant Overview

Fluvoxamine is considered to be a selective serotonin reuptake inhibitor (SSRI), although it has also been described as a serotonin/norepinepherine reuptake inhibitor (SNRI) as well. However, it should be noted that Fluvoxamine does not appear to inhibit the reuptake of norepinepherine to the same extent as serotonin, so its role as an SNRI is still yet to be fully determined.

Although the abbreviation SSRI has been adopted into common daily language, it doesn’t describe the actual direct mechanisms of actions of the drugs that fall into this categorization.

In short, serotonin is a neurotransmitter responsible for a multitude of signaling pathways, with end results usually involving increased mood, cognitive function, and memory.

Unlike acetylcholine, a neurotransmitter responsible primarily for neuromuscular signaling which is also metabolized within the synaptic cleft (the gap between the presynaptic axon terminal of one neuron and the postsynaptic dendrites of the next neuron), serotonin is not metabolized after fulfilling its signaling duties.

Instead, high levels of serotonin within the synaptic cleft leads to feedback signaling for serotonin to be taken back up by cells where they await another signaling cascade to once again be released.

For many typical SSRIs, the blocking of serotonin reuptake is usually caused by the inhibition of serotonin transporters (taken from StatPearls):

SSRIs inhibit the serotonin transporter (SERT) at the presynaptic axon terminal. By inhibiting SERT, an increased amount of serotonin (5-hydroxytryptamine or 5HT) remains in the synaptic cleft and can stimulate postsynaptic receptors for a more extended period.[4][5][6]

The hypothesis here is that reduced levels of serotonin may play a causative role in reduced brain signaling that may lead to depression and other psychiatric disorders. By inhibiting serotonin transporters, serotonin will begin to accumulate within the synaptic cleft to higher levels than would normally be available, and thus this greater signaling effect is assumed to help alleviate depressive mood as well as other disorders. In short, SSRI’s block the reuptake of serotonin, increasing their concentration which leads to increased signaling, all done in the hopes that this will eventually alleviate the disorder.

Fluvoxamine does not serve to just hinder serotonin transporters, and its difference in structure compared to other antidepressants and SSRIs provides it a multitude of other MOAs.

For instance, Fluvoxamine is considered one of the only monocyclic SSRIs and its structure relegates it more to the category of 2-aminoethyloximethers of arylketones. The important functional groups for Fluvoxamine that place it into this category are circled below.

2D structure of Fluvoxamine. The circled functional groups place Fluvoxamine into the “aminoethyloximether” class of drugs.

1) Inhibition of Serotonin Transporters/ Platelet Aggregation

As an antidepressant, Fluvoxamine has been indicated to prevent the reuptake of serotonin through inhibition of the serotonin transporters. Platelets are apparently known to have a high level of serotonin transporters and are responsible for leading to platelet aggregation. By administering an SSRI/SNRI, platelet aggregation is halted and thus the uptake of serotonin is halted as well. Interesting enough, the act of inhibiting platelet aggregation appears to play a role in alleviating the hyper inflammation seen in severe COVID.

Here’s additional information from Hashimoto et. al.:

The primary action of all antidepressants, such as SSRIs and SNRIs, is serotonin transporter inhibition in the brain, resulting in increasing levels of serotonin in the synaptic cleft. The human platelets have a high density of serotonin transporter [34–36]. Through serotonin transporter inhibition in the platelets by SSRIs or SNRIs, these antidepressants could reduce platelet aggregation, contributing to their effects [37]. Preclinical and clinical studies show that SSRIs or SNRIs have anti-inflammatory effects in rodents and depressed patients [38–42]. Therefore, antidepressants can possibly have anti-inflammatory effects through serotonin transporter inhibition (Fig. 2). It is also reported that fluvoxamine attenuates inflammation on injured striatal neurons by increasing anti-inflammatory cytokines while decreasing pro-inflammatory cytokines in the brain of Parkinson’s disease model [43]. Furthermore, fluvoxamine inhibits carrageenan-induced inflammation in rat paw edema [44] and fluvoxamine attenuated experimental autoimmune encephalomyelitis severity in a rat model of multiple sclerosis [45]. Collectively, it seems that fluvoxamine has potent anti-inflammatory effects in vitro and in vivo models.

3) Lysosomotropism

I have included this analysis in my post from last week, but I’ll reiterate the same comments here.

As can be seen by Fluvoxamine’s structure, Fluvoxamine contains an amine group which confers a slightly basic nature to the drug, meaning that it can pick up free hydrogen ions from the environment. The ability to shift between a protonated/deprotonated form provides Fluvoxamine a similar MOA as Hydroxychloroquine by targeting the endosomal pathway through the targeting of lysosomes.

When a neutral Fluvoxamine molecule is taken up by host cell lysosomes, the acidic lysosomal environment causes Fluvoxamine to become protonated, causing the pH of the lysosomes to increase. By increasing the pH, the regular functions of endosomal organelles are halted.

SARS-COV2 appears to traffic itself through the endosomal pathway by utilizing lysosomes. The increase in pH of lysosomes containing viral particles may halt the distribution of viral particles to neighboring host cells, as these lysosomes will be rendered ineffective and unable to interact with host cell membranes and release viral particles that can then infect nearby host cells.

This increase in pH is also irreversible, as the cationic (positively charged molecule) Fluvoxamine molecule cannot re-cross lysosomal membranes due to the positive charge and becomes trapped within these lysosomes.

I’ll add this excerpt from Sukhatme et. al. for additional information:

S1R agonists like FLV and fluoxetine are lysosomotropic (Hallifax and Houston, 2007; Kazmi et al., 2013). Fluvoxamine has a predicted pKa of 8.86 (DrugBank, 2005; Wishart et al., 2018) and is susceptible to protonation in the physiological pH range. Less polar, unionized form of basic drugs can easily cross membranes. Basic drugs like FLV can get protonated in the lysosome, which hinders the now-charged moieties from crossing membranes. β-coronaviruses, like SARS-CoV-2 and mouse hepatitis virus (MHV), use lysosomal trafficking to escape from infected cells (Ghosh et al., 2020) (Figure 1). GRP78/BIP, a chaperone that facilitates coronavirus infectivity (Chu et al., 2018; Ha et al., 2020), is co-released with β-coronaviruses through this pathway (Ghosh et al., 2020). The SARS-CoV open reading frame protein 3A (ORF3a) (Gordon et al., 2020) is a viroporin that localizes to lysosomes (Ghosh et al., 2020), disrupts their acidification (Yue et al., 2018), and contributes to viral egress (Lu et al., 2006; Castano-Rodriguez et al., 2018; Yue et al., 2018). Given the lysosomal egress of β-coronaviruses from infected cells, lysosomotropic drugs like FLV could have antiviral effects in the virus laden lysosomes (Homolak and Kodvanj, 2020) (Figure 1).

This MOA is extremely important for Omicron because of Omicron’s greater dependency upon the endosomal pathway. It must be said that a drug should properly target a virus based on how it infects and spreads within a host. As Omicron relies more on the endosomal pathway, evaluations of Fluvoxamine’s use should be taken with greater consideration. We will have to wait and see on that front, but hopefully this will lead to further research into Fluvoxamine.

5) Sigma-1 Receptor Agonism and Severe COVID

There’s a lot to discuss here, so most of this information will be truncated and saved for another post which will go into further detail.

Serotonin receptors are not the only receptors to be targeted by Fluvoxamine. More important to COVID infections are Sigma 1-receptors, which are likely to play a potentially pivotal role in the course of an infection.

Sigma-1 receptors are receptors found on the endoplasmic reticulum of eukaryotic cells, and its name is likely to have stemmed from confusion over its relationship to sigma/opioid receptors. Sigma receptors are broken into two categories (Sigma-1 and Sigma-2), but we will focus solely on Sigma-1 receptors here.

With respect to the endoplasmic reticulum, the endoplasmic reticulum is an organelle responsible for a plethora of cellular activities, including protein synthesis, folding, and export as well as lipid formation and calcium storage.

The folding of proteins is an area that tends to be overlooked, yet misfolded proteins have been extensively detailed in immune dysfunction and in inflammatory responses.

Many cellular functions operate under a precarious nature where even the slightest dysfunction will lead to a cascade of events in order to ameliorate the problem.

It is here where viruses are likely to cause severe cellular damage and lead to a hyper inflammatory immune response.

In short, the endoplasmic reticulum undergoes regulation for proper protein folding. However, when the threshold of misfolded proteins becomes too elevated, the endoplasmic reticulum and the host cell undergoes a corrective response to alleviate the issue. However, when the rate of misfolded proteins are far too high to address, an immune response occurs, leading to what’s called the unfolded protein response (UPR) where pro-inflammatory markers are released. Under extensive UPR, cell death and rampant cytokine production is likely to occur (taken from Xue, M. & Feng, L.):

Endoplasmic reticulum with normal function is essential for protein synthesis, folding, modification, and transport (Ron and Walter, 2007; Fung et al., 2014a; Hetz and Papa, 2017). Disturbances in the structure and function of the ER with the accumulation of unfolded/misfolded proteins lead to ER stress. The three major ER stress sensors [protein kinase R-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6)] are activated by accumulated unfolded/misfolded proteins in the ER and initiated the unfolded protein response (UPR) (Credle et al., 2005; Ron and Walter, 2007; Hetz and Papa, 2017). The initiation marker of UPR is the expression of ER chaperone molecules, such as immunoglobulin heavy chain binding protein (BiP/GRP78) and glucose regulatory protein 94 (GRP94). UPR maintains ER homeostasis by turning off the translation of ER proteins and increasing their folding ability. However, UPR can induce apoptosis and cytokine production under sustained ER stress (Ron and Walter, 2007).

Many factors can contribute to ER stress, but in the context of this post we can see how viral infection can induce excessive ER stress through the hijacking of host cell functions in order to produce viral proteins:

Coronavirus genome replication occurs in the cytoplasm, and the synthesis and translation of viral proteins are closely related to ER and its transducers. It is well documented that coronavirus replication causes ER stress and induces UPR in the infected cells. Coronaviruses, such as SARS-CoV-2, SARS-CoV, mouse hepatitis virus (MHV), IBV, TGEV, and PEDV, can all induce significant ER stress following infection (Versteeg et al., 2007; Krahling et al., 2009; DeDiego et al., 2011; Liao et al., 2013; Xue et al., 2018; Echavarria-Consuegra et al., 2021). GRP78 and GRP94 are overexpressed in SARS-CoV infected cells. Some SARS-CoV proteins have been shown to induce ER stress responses, such as spike protein, ORF3a, ORF6, ORF7a, ORF8ab, or ORF8b proteins (Chan et al., 2006; Ye et al., 2008; Minakshi et al., 2009; Sung et al., 2009; Shi et al., 2019). It is recognized that protein processing after synthesis is an important step in gene expression, and protein misfolding plays an important role in coronavirus infection. 

The role of sigma-1 receptors are yet to be fully elucidated, but the evidence so far suggests a multitude of pathways (taken from Shi et. al.):

To date, Sig-1R involvement has been reported in multiple pathophysiological processes, including calcium homeostasis, ER stress, autophagy, excitotoxicity, mitochondrial dysfunction, and reactive oxygen species (ROS) scavenging.

Sigma-1 Receptors play an important role in how a cell maintains proper functions, and whether a drug supports or hinders signaling alters the direction a cell takes. More specifically, sigma-1 agonists (compounds that increase the signaling of sigma-1 receptors) promote cell survivability while sigma-1 antagonists (compounds that block signaling) promote cell death.

As a Sigma-1 agonist, Fluvoxamine has the capabilities of promoting the signaling pathways of the Sigma-1 receptors and calm down the inflammatory response and cytokine production caused by the unfolded protein response.

This MOA explains Fluvoxamine’s possible anti-inflammatory effects, and it also explains why hospitalized patients may fare better on Fluvoxamine. Extrapolating the evidence further, this may also suggest that Fluvoxamine may have a therapeutic effect in those who suffer from long COVID, and there is some evidence of Fluvoxamine being investigated as a possible therapeutic for long COVID.

If all of this seems confusing, I’ll lay out the sequence of events:

1. A person becomes infected by SARS-COV2 and viral particles begin to invade the host’s body.

2. SARS-COV2 invades certain cells, including lung epithelials and possibly cells of the CNS.

3. SARS-COV2 hijacks the protein production processes of the cell including the endoplasmic reticulum in order to produce viral proteins.

4. Rampant viral protein production leads to a higher degree of host cell misfolded proteins, leading to a feedback corrective pathway of the cell that attempts to alleviate the errors.

5. Extensive, prolonged ER stress leads to the unfolded protein response (UPR) which produces pro-inflammatory biomarkers including cytokines and interleukins. Widespread UPR’s in cells are likely to play a role in the cytokine storm and hyper inflammation found in severe COVID patients.

6. Sigma-1 receptors, which are found on the endoplasmic reticulum, are responsible for maintaining homeostasis and regulating cellular pathways of both the ER and the cell.

7. Administering drugs that serve as Sigma-1 agonists, such as Fluvoxamine, increase the response by Sigma-1 receptors and are likely to reduce ER stress by limiting the UPR, and thus reduce the rampant production of pro-inflammatory biomarkers. The benefits here are likely to alleviate the cytokine storm in severe COVID, and may actually alleviate some of the symptoms of long COVID.

I’ve dedicated a lot of time to illustrating the role of Sigma-1 receptors and their relationships to Fluvoxamine because this is an area where many parallels can be drawn.

Fluvoxamine elicits both antiviral and anti-inflammatory properties, and may even benefit those afflicted with long COVID. Not only that, but if the hijacking of the ER to produce massive amounts of protein is likely to play a contributing factor in the disease pathology of COVID, we may hypothesize and extrapolate this point even further to draw parallels in other scenarios.

One has to wonder if another product, who’s intent is to cause rampant protein production to produce an antigen and elicit a protective immune response, may also hijack the protein synthesis and folding pathways of cells and lead to the unintended consequence of producing rampant UPR’s among a diverse array of host cells. The consequences of such an event may highlight the possible adverse reactions seen in said products, and are likely to play a causative role in the symptoms of long COVID that have also been described among those who have experienced said adverse reactions.

There’s a lot more to discuss in regards to this hypothesis, and so I’ll save this for a later post in this series where I can hypothesize and postulate on this idea even further.

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Another Repurposed, Multifaceted Drug

Overall, we can see how a drug known for one pharmacological effect may be responsible for a multitude of other events. The structure and function of a therapeutic illustrates the relationship that drugs have on many facets of our bodies. Sometimes these effects greatly benefit us by alleviating symptoms and diseases, but the unintended consequences of drugs should also not be overlooked or understated.

Fluvoxamine, a drug commonly known for treating psychiatric disorders, can serve to treat many other diseases, including to serve as an antiviral against SARS-COV2 infection and the cascade of events that occur from an infection. Greater emphasis must be put into understand pharmacological pathways, and how these pathways lead to the treatment or worsening of a disease. Knowing what effects a drug has on our cells, what these drugs bind to, and the sequence of events that follow from taking a drug are important to understanding the clinical presentation from taking these drugs.

With respect to Fluvoxamine, we will dive more into the nonclinical studies and see if there are some studies that examine Fluvoxamine’s direct role in SARS-COV2 infection in Part II (and possibly Part III).

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