Drug-induced mitochondrial toxicity has been described over the last several years for many different drug classes and the Fluoroquinolones are at the top of the list.   Unfortunately, most patients are unaware of the risks and most doctors are woefully ignorant about the long-term damage these drugs can inflict.

An overwhelming amount of anecdotal data in addition to several research articles point to an assault on the mitochondria as the underlying problem.  The fluoroquinolones assault both the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) resulting in heavy epigenetic pressure and poorly understood mechanism that cause acquired pathogenic processes.  I wrote a previous article titled, “Pulling The Trigger: How the Fluoroquinolones Can Cause Mutations and Disease” which explained one mechanism how Fluoroquinolones can cause mitochondrial disease without having genetic predispositions.

This assault impacts the machinery that governs all facets of DNA maintenance and biogenesis. I have, in the past, alluded as to how the Fluoroquinolones are an epigenetic monster in the way they put pressure on areas of the genome that have yet to be understood by medical science and can subsequently ‘pull the trigger’ on disease processes, which makes them very dangerous indeed.  

This article discussess how a Mayo researcher discovered a Fluoroquinolone induced mitochondrial pathology in myself and one other person.    

I am a firm believer that no one gets out unscathed. Even in those individuals who appear to ‘handle’ a single course of Fluoroquinolones or multiple courses, there is always a certain amount of damage that takes place, and it is be cumulative.    There are, however, classes of people who manifest chronic long-lasting damage more often than others, and although there are solid exceptions to any rules, my collected data over the last decade, has highlighted that a larger cohort of people who become very chronically impacted by the Fluoroquinolones tend to be middle-aged or older.

We can ‘split hairs’ on what age group defines middle aged, but for me, I was 47 when Levaquin permanently altered the course of my life, and I have seen this bandwidth run from middle to late 30’s up to late 50’s.  One other person, who is referenced in this article, was in their 50’s when they became chronically impacted.

Before you point your finger at me and tell me that there are younger people that are permanently damaged, I will fully concede that fact. The point I am making is that, according to my data, there are more middle-aged and older people who become chronically disabled as opposed to younger.

I believe the reason for this has to do with the bioenergetic phenotype of the mitochondria of older individuals versus the young.  This reason probably accounts for the quicker healing we tend to see in many, but not all, of the younger people who suffer from Fluoroquinolone Toxicity.  The young’s ability to heal is not the product of some miraculous ‘cure’ they discovered, but has to do more with the phenotype of the mitochondria.  

Environmental factors, along with the age of the individual, contribute to the decline in the ability of molecular regulation to repair mitochondrial damage. This, in my opinion, is the primary factor that impedes the ability of aging mitochondria to withstand or adapt to being hit by the Fluoroquinolone’s toxic onslaught.  Basically, this is common sense, because it is probably this loss of homeostatic regulation that underlies the sometimes-greater susceptibility of older patients to have drug-induced adverse events in general.

Nevertheless, all age groups need to pay attention to the dangers that Fluoroquinolones pose, as the pathogenic process I am highlighting here poses a risk to all age groups. 

Over the last fourteen years I have taken many ‘deep dives’ into various realms of my metabolism; my gut, brain, nervous system, connective tissues, genetics, and everything in between.  I attended seminars, patronized various doctors (even some of the ‘so-called’ Fluoroquinolone experts), worked with some academic level researchers, and interviewed former pharmaceutical scientists.  There have been many blind alleys and doors slammed shut but along the way I collected data and absorbed everything I could about the Fluoroquinolones.  You’ve heard the old adage, “know your enemy as you know yourself.”

Pardon me when I tell you that despite all this time spent on researching I want to let you in on a little secret, “I hated it.”  I hated having my life diverted from the way it was by a pharmaceutical that was deemed safe.  I had plans that were shelved, dreams that were shattered, and limitations placed on my life in ways that I never would have dreamt.   However, pragmatically speaking, Fluoroquinolone toxicity, or at least the downstream impacts from their assault on my body, wasn’t going away. So, despite many attempts to put it behind me, it stayed with me like a monkey on my back.

During my long quest for answers, I kept drawing one conclusion, no one, and I mean no one, fully understands the mechanisms of these drugs and their ability to cause harm; this would even include the scientists that developed the drugs themselves. I found that a lot researchers are fully honest about their limitations on knowledge, while some clinicians, not so much, probably being driven more by profit. 

The reason I briefly mention this is because I am contacted almost daily from someone seeking help trying to find a practitioner to treat them.  Despite certain clinicians/practitioners claim that they can ‘treat’ Fluoroquinolone toxicity, the overall track record, according to my tally from data shared by others, is actually quite abysmal. Most of these practitioners tend to follow outdated ‘paradigms’ that were never meant to work with synthetic DNA altering pharmaceuticals, or they throw various treatments at the patient hoping one of them will stick,  or, worse yet, they target what I call “low hanging fruit,” which are people whose issues are not so complex and are easier to treat and they have the means to pay the exorbitant treatment costs and fees. 

The truth is, there are some cases of Fluoroquinolone toxicity that are easier to help than others. To the person experiencing these symptoms, their problems may seem quite terrible, but generally, in the scheme of things, they have fairly simple problems that many arm-chair practitioners can successfully help with, plus they were more than likely going to heal on their own either way.

The true hard-core cases of FQAD generally defy treatments and their resolution remains elusive because the mechanisms involved are elusive; these are the hard-core cases. Unfortunately, there are a lot of people impacted in this fashion and they are the ones that pique my interest, mainly because I am one of them.

In my case, traditional and alternative medical practitioners offered me little relief, but then again, I didn’t expect much.   The type of damage that we are talking about in this article is usually far above the heads of most medical practitioners both standard and alternative, and for the most part is in the realm of the research scientists.

Despite my forward journey through Fluoroquinolone toxicity being about as difficult as walking through waist deep snow, tantalizing clues and answers would occasionally reveal themselves along the way.  Even though I would appear ‘normal’ on most standard lab tests, clues would occasionally show up in the ‘rare’ and/or ‘quirky’ health related areas that would point to the next level of investigation. Like the movie National Treasure, one clue would lead to another, each getting deeper and deeper.  Despite distractions, the occasional trip down the rabbit hole, blind alleys, and taking some wrong turns, most of the clues agonizingly kept pointing to one area, the mitochondria.

I know some readers are probably going “duh, we know the mitochondria are involved, tell us something we don’t know.” While it is true that for years research as shown mitochondrial damage as a mechanism of Fluoroquinolone toxicity, I was still driven by the “why?” This question must be answered for successful treatments to be discovered. Despite this, when pressed, people in-the-know could never elucidate a satisfactory mechanism or theory. Bottom line, it wasn’t good enough to just point fingers at the mitochondria, I had to know “why” the Fluoroquinolones were causing permanent long-lasting problems in many people.

It wasn’t until I got connected with an altruistic Mayo researcher that some critical pieces of the Fluoroquinolone puzzle were revealed…at least in a few cases.

Through some friends, I was put in contact with a very curious, and like I said, altruistic PhD researcher at Mayo clinic in 2019, prior to the COVID-19 pandemic. I will call her “Dr. M.” Dr. M’s sole function at Mayo is to research difficult cases from a genetics standpoint. She does not clinically see patients but instead performs exploratory research and occasionally acts at the behest of other doctors working like a private detective looking for answers in puzzling cases. 

After a brief email exchange, she became interested in my case and in early 2020 she obtained permission to retrieve the remaining residual muscle biopsy sample that was previously frozen locally at a tertiary care center.  Talking tech in my interchanges with her, I was amazed at the diagnostic technology Mayo had at their disposal.  This piqued my interest.

On a side note, many people have relayed their bad experiences with Mayo clinic regarding their quest to seek help for Fluoroquinolone toxicity, and I can relate.  The clinical side is completely separate from the research side.  I have found the clinical side very good with certain, very specific, medical problems but still the clinical side suffers from the same disconnect as other health systems. Although I have had some very good doctors at Mayo, especially dealing with intracranial hypotension, there were exceptions. I have encountered two doctors that were less than stellar.  There was a clinical mitochondrial doctor that was totally incompetent, dismissive, and not worthy of the Mayo mantle, and this is saying something because in my travels I have seen some pretty incompetent doctors, but I digress. 

Fast forward to March 2021. After a major delay caused by the COVID pandemic, I received an excited email from the Mayo researcher informing me that they completed mitochondrial studies on my muscle biopsy, and there were abnormal findings.

In an in-depth mitochondrial analysis, they had captured abnormalities that other experts had missed. Mayo uncovered an mtDNA depletion syndrome, much like a patient with an actual hereditary mtDNA depletion syndrome but fully acquired. 

Understanding mitochondrial disease fairly good, I was very puzzled.  I knew that I did not harbor any pathogenic variants in either the nuclear or mitochondrial genome as those would have been discovered by now.  Despite this and thanks to Mayo’s diagnosis, I was able to obtain yet ‘another’ specific clinical sequencing performed by Prevention Genetics that just focused on looking for known pathogenic variants, or combinations, of variants that could cause mitochondrial depletion syndrome.  Nothing was found.  

In my genetic testing repertoire, I have genotyping (23andme), whole exome clinical sequencing performed twice (GeneDX), rare gene screening (Sequencing.com), entire genome (nDNA and mtDNA) sequencing (Dante Genomics), and an two genetic panels specifically looking for pathogenic mitochondrial genes (GeneDX).  If there was a known pathogenic variant, statistically it should have been discovered.  I even had a comparison exome sequencing done on my two siblings to look for any comparative clues (GeneDX).

On a side note, there are several genes involved in Mitochondrial Maintenance and Replication. Medical science knows of only ten genes that can present as depletion syndrome with the symptoms I possess.  Of those ten only two can occur in adults and there are probably less than 100 cases in the entire world with even much less than that in the United States. The other eight genes are always fatal in infancy.  Additionally, my life experience would rule out this rare form of depletion based on the fact that prior to being floxed I was higher functioning both physically and mentally. No, I am not self-aggrandizing here, just point out that depletion syndrome usually results in certain physical and cognitive deficits or ‘clues’ that would be present throughout life.

So, if I did not have the pathogenic genes, what else could have caused the depletion syndrome?

In her email, Dr. M. went on to say, “We also had one other patient from whom we were able to get a residual muscle biopsy from the time they were acutely symptomatic from their fluoroquinolone exposure and, lo and behold, their mtDNA was abnormal, too.” 

Additionally Dr. M. said, “And, like you, that patient (also seen at Mayo) had whole exome sequencing done which essentially rules out a genetic cause for this finding. “

Dr. M was convinced that I and the other floxed person did not harbor any hereditary predispositions to mtDNA depletion syndromes.  Because of this, Mayo’s sent me the information on my results to share with my local doctors that my case of mtDNA depletion syndrome was a considered fully acquired.

Looking at my entire medical history, including drug exposure history, and genetic testing, Dr. M. was confident that the Fluoroquinolones were the culprit so much so that they intend to publish the results.

There are some pretty interesting theories as to how the Fluoroquinolones could interact with mitochondrial thymidine kinase or other ‘maintenance genes’ to initiate a self-sustaining depletion syndrome. 

One case doesn’t necessarily signal an epidemic, however a second case lends confidence that there were probably others, maybe many others, who suffer from the chronic forms of Fluoroquinolone Toxicity.  Again, Dr. M was going to publish a case study on these two cases to get the documentation in writing.  I also do not want to give the impression that, at the time this discovery was made, Mayo had tested a lot of people, they didn’t.  Actually it was very few, which makes this finding more provocative. 

None of this should really be that surprising since drug-induced mitochondrial toxicity has been recognized to cause permanent damage to the skeletal muscle, liver, kidney, heart and the central nervous system. There have been several drugs identified that can cause mitochondrial toxicity to varying degrees and in my opinion certain anti-cancer drugs and Fluoroquinolones are at the top of the list _(source).  

It is important to note that most studies about drug induced mitochondrial toxicity have been conducted using isolated mitochondria and cell systems and often these systems are not of human nature.  However, over the last fourteen years, I have amassed enough anecdotal data to convict the fluoroquinolones of being lethal to the mitochondria, even though most drug safety researchers refuse to look at them seriously.   These drugs have truly fallen through the cracks of the pharmacovigilance system.  

Most doctors  dismiss drug toxicities by referring to the fact that safety margin for a particular drug will depend on a whole host of environmental variables as well as other contributing mechanistic toxicities.  If they do acknowledge that the Fluoroquinolones caused something they usually refer to it as ‘rare’ and dismiss it.

In my case I was decidedly different.  Prior to floxing I was very athletic and healthy.  I had very few, if any, external environmental factors that could confound the fact that the Fluoroquinolones were to blame.

Despite the dismissive and gas lighting atmosphere that surrounds most adverse events to Fluoroquinolones in our healthcare system, I always knew that Levaquin was the “terminus ad quo,” or the instigator.  It was the finger that pulled the trigger on disease processes in my body by damaging my mitochondria.

However, mitochondrial disease that is fully drug induced or acquired, one that does not involve a known pathogenic variant(s), is not well understood.  Clinicians who normally deal with the standard mitochondrial diseases, like most of the rest of doctors, put people in ‘neat little boxes.’  You either have the mutation or you don’t.  If you don’t have the mutation, you can’t possibly have the disease. Bottom line, they will dismiss or ignore you.

However, I believe I am living proof that the Fluoroquinolones initiated a mitochondrial disease process through mechanisms that are not well understood by medical science.

First, let me dispel any misunderstandings for those thinking that I can just initiate research on a dime or put you in contact with a researcher that can assist you, it is not that easy although I wish it was. Also, not to sound like a martyr, but I have had to fight every step of the way to get to this point in my journey and most of the personal discoveries were chiseled out on my own.  Don’t get me wrong, I have been helped by some very incredibly talented people, many whom are much smarter than I, but nonetheless I am not rich, nor do I have a medical degree.  

Having higher education has helped me understand the whole research and scientific publication game, which was very helpful given the biased nature of most of the academic research today, but  it still took me a very long time just to get to this point in my understanding; too long, much longer than it should. 

On a side note, I do have a very good primary care physician who has helped along the way, but I have had to educate him in certain aspects and like I mentioned earlier, this journey it is like walking in waste deep snow and doing it while you’re sick, tired, and broken; even working with Mayo clinic with this most recent diagnosis was no exception.

I will concede that COVID-19 hit Mayo Clinic hard.  The research genetics lab that was working on my case lost over 50% of their staff, funding, and basic supplies that were all rechanneled to focus on COVID-19.  This has hampered my forward progression, yet once again.  I am pretty sure that Mayo has now directed the Dr. L to focus on more pressing issues that pursuing my case any further has fallen to the backburner. I will continue to pester them from time to time. Despite this, I am grateful for their discovery.

Since Mayo found this unique depletion in myself and another person suffering from FQAD, I can’t help thinking that it is occurring in other cases of FQAD.  No, I am not a person who sees Fluoroquinolones hiding under every rock, but they do represent an underrecognized health crisis and over the years I have encountered a lot of people with long-term chronic cases, so I do strongly believe that there is probably a good-sized subset of individuals in the Fluoroquinolone community who are impacted similarly.   

Also, keep in mind that mitochondrial depletions can be organ and system specific, meaning they can impact several organs of the body, just a few, or maybe just one, each causing a myriad of puzzling symptoms and manifesting with a wide spectrum of severity.  In other words, all the symptoms do not need to ‘line up’ with everyone else’s.  Also, depleted levels of mitochondria can vary greatly, impacting people differently.  For instance, one person experiencing 25% depletion could have minimal symptoms, whereas someone else could be bedridden. 

Although not heavily researched, it has been basically shown that Fluoroquinolones can impact mitochondrial thymidine kinase, which phosphorylates the pyrimidine nucleosides thymidine and deoxycytidine.  If these nucleosides are impacted the results could be either depletions or deletions.

How can the Fluoroquinolones put in place a mechanism without having a pathogenic variant that causes the nucleosides to be diminished?  I don’t know.  I don’t have that answer, yet.  However, this is something we have seen in the Fluoroquinolones in other areas.  For example, Fluoroquinolones can cause a person to have upregulated metalloproteinases for years, without having pathogenic variants that would predispose, so this behavior is not outside the realm of possibilities.  

In my case I am looking at trying to check the levels of thymidine and deoxycytidine. Dysfunction in circulating pools of these nucleosides would indicate a fault in mitochondrial biogenesis.  I am trying to get connected with a doctor who is considered the world expert in depletion syndromes at Columbia in New York to consult about this, however New York has some of the most ridiculous medical regulations regarding out-of-state clinician video visits.   If anyone lives in New York and has an “in” to Columbia, let me know.

At this juncture in my long journey, I have come to the conclusion, for now, that the gold standard for testing that is needed to the get to bottom of the Fluoroquinolone problem is whole methylome analysis.  This analysis will identify novel, rare, and potentially de novo epigenetic alterations made by the Fluoroquinolones that are causative of, or at least highly contributory to, the pathogenesis of FQAD. 

I am convinced that the Fluoroquinolones cause epigenetic modifications impacting DNA methylation. They do so by initiating changes at the genomic loci and often these changes do not alter the underlying nucleic acid sequence but none the less, have profound effects on gene expression and functional regulation.

The equipment needed to do this ‘epigenomic profiling’ is an Illumina Infinium MethylationEPIC 850K array. This equipment allows the researchers to interrogate over 850,000 methylation sites quantitatively across the genome. If needed array scanning and next generation sequencing can be a follow-up using an Illumina NextSeq 550 system.

If I, we, had access to this level of analysis I believe we could finally unravel the Fluoroquinolone mystery once and for all by shining light on the areas of the genome that are being impacted by the Fluoroquinolones and how these changes are being sustained in the human body.  This equipment would allow each person to be analyzed comprehensively.  It would both case and wide net and conversely be very specific at the same time.

But alas, since I do not have millions of dollars at my disposal getting access to such equipment is currently out of my reach.  If any of my readers has one of these machines lying around or has access to one, let me know.  In the meantime, if my health allows, I will push on to the next clue!

This section is for those nerdy types of individuals who are interested in how to detect mitochondrial depletions.

While the ability to noninvasively diagnose disease or conditions involving the mitochondria has vastly improved, too many doctors are overly utilizing genetic testing just from blood or saliva. Until there are much greater improvements, tissue must still be analyzed and preferably muscle tissue.

Nonetheless, I do recommend that everyone who is getting into this level of detective work get their own genetic sequencing performed.  If you can get it through insurance great, but many patients have to resort to paying for their own.  In some ways this is better, because you are the master of the data and can have access to your own genome in the future.

The good news is that the prices over the last several years has come down drastically, and it is now possible to get complete genome (nDNA & mtDNA) sequencing for under $400 dollars.   Once you have sequencing accomplished you can find several reputable aftermarket companies that will screen your genome for rare mutations.

For the biopsy it is very important that clinically affected tissue, such as skeletal muscle, is the tissue that is biopsied. Myopathy or myopathic changes are a common symptom with mitochondrial involvement, but it is possible to have other organs/tissue involved. 

Not all neurologists are well versed in mitochondrial pathology and if they are not they often overlook many issues, basically they will screw it up and not even suspect they are screwing it up.  I have firsthand experience with this.  Make sure your neurologist knows what your goals are, and that he is up to the task, as it is unfortunately, up to you to determine quarterback the process.   Do not hesitate to interrogate the doctor, surgeon, and pathologist, several times if you have to, to make sure they are competent.  Reach out to organizations that are familiar with muscle biopsies such as the UMDF to educate yourself. You only get one chance.  If the tissue is not handled correctly, it is easy to miss a diagnosis.  In my case, I had a deep muscle biopsy of the vastus lateralis, but other tissues may result in better outcomes.

Mayo found abnormalities when looking at the ratio of mitochondrial DNA. More specifically copies of the RNR1 gene in mtDNA compared to nuclear DNA, specifically copies of the RPP30 gene, which is exclusively in the nucleus of the cell.  They compare to the nuclear DNA because they want to control for the fact that different samples from different patients might have different total numbers of cells present. 

For example, a sample that happened to have only 5 cells present is obviously going to have fewer numbers of mitochondria present than a sample with 500 cells.  By dividing the quantity of mtDNA by nuclear DNA, you arrive at the quantity of mtDNA per cell rather than per sample.  Effectively taking care of the issue of different numbers of cells potentially being present. 

On a side note, mitochondrial depletion is not something that is ‘on the radar’ of most specialists. I was asked “why don’t doctors test for this?”  The answer is simple, if you have sequencing completed and no clinical variants show up, they have no reason to pursue specialized testing such as this.  Additionally, most neurologist won’t even submit muscle biopsies for mitochondrial depletion testing.  It is off their radar, so to speak.

Over the last decade, I have become more and more convinced that the Fluoroquinolones cause epigenetic modifications that impact DNA methylation. An abundance of anecdotal evidence, along with peripheral scientific research, is proving this hypothesis correct.   This important research finding from Mayo further bolsters this theory.

I believe the Fluoroquinolones are accomplishing these long-term devastating impacts by initiating changes at the genomic loci that is responsible for mitochondrial maintenance.  These changes do not seem to alter the underlying nucleic acid sequence but somehow have profound effects on gene expression and functional regulation.

This is really not unusual behavior for the Fluoroquinolones.  Like I mentioned earlier, anecdotally, we have often seen ‘unusual’ things in floxed individuals such as long-term upregulation of metalloproteinases, long term increased oxidative stress and other pathophysiology without genetic predispositions.  This is what makes these drugs so very dangerous.

Again, I am confident that these mysteries can be fully explained with access to funding and the proper equipment, but for now I will have to be satisfied with the current results.

There is still much more to be done before I, we, rest. However, living in the days of COVID-19 and its impact on medicine makes everything harder, not easier, especially getting answers to complex metabolic mysteries.   Everything is now clouded by COVID, post-COVID syndrome, vaccine injuries and even supply issues.

The vast majority of Fluoroquinolone adverse events, if they are considered at all, are still considered rare outcomes by clinicians. Don’t expect to walk into your PCP’s office, or even your neurologist for that matter, and talk shop about depletion syndrome.  If you do, most will ‘glaze over’ within a minute since this stuff is generally way over their head and more than likely they will think you have been reading too much ‘Dr. Google’ or you have some sort of psychological conversion disorder.  However, if for some rare chance they believe you, 90% will go right to a genetic origin to put you in a neat little box.

Today, our medical system lacks curiosity leaving it up to the patients to purse answers. As for me, I will slowly push on, until I finally get to the very bottom of the problem or it finally gets me, whatever comes first. 

In the words of Dr. Chris Martenson….” It didn’t have to be this way.”

I have been slowly implementing changes to the website to keep it more secure, comply with regulations, ease accessibility and incorporate some unobtrusive ads to help generate revenue for Fluoroquinolone research.  I recently made changes to the registration process and now info on this site is freely available to everyone.

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Thank you.