Colchicine: Our Deal with the Devil

by Meghan Spyres

January 2021

“Colchicine for Early COVID-19? Trial May Support Oral Therapy at Home”
“Health Experts Green-Light Colchicine for Treating Outpatient COVID”
“Colcorona: Colchicine Reduces Complications in Outpatient COVID-19”

I can say with near certainty that upon reading these headlines, the global toxicology community, my colleagues, and I, all gasped a horrified “Oooohhhhh sh*t.” After this dumpster fire of a year and the seemingly endless series of dangerous, largely futile, overhyped cures or preventions for COVID…… colchicine?! You have got to be kidding me. Can’t a toxicologist catch a break?

via GIPHY

To start, here’s what we know from the COLCORONA pre-publication data:

This was a randomized trial looking at colchicine vs placebo for the treatment of non-hospitalized patients with COVID. A composite outcome of death or hospitalization for COVID was defined as the primary outcome. In what appears to be the initial study group (patients with either a PCR confirmed diagnosis of COVID or a clinical diagnosis of COVID), there was no statistically significant difference between those receiving colchicine vs placebo (4.7% vs 5.8% CI 0.61-1.03; p=0.08) in the primary outcome. When they narrowed it down to strictly PCR confirmed COVID cases, colchicine fared slightly better, and the outcome became statistically significant in favor of colchicine (4.6% vs 6.0% CI 0.57-0.99; p=0.04)

My take: I’m not convinced by the non-significant results (or barely significant results when a modified population was analyzed) reported in a paper that has yet to be peer reviewed. Not to mention the negative results for colchicine in the RECOVERY trial leading to its early termination. But I hope there is something there. I really do. Reducing severe illness, hospitalizations, and death would certainly be welcomed with open arms by our overtaxed, faltering healthcare system and our wearied healthcare workers.

But for perspective, as a toxicologist, I have a lot of inherent hesitancy (dread) with the hype surrounding the COLCORONA study because it involves colchicine. Toxicologists rarely agree on anything, but I promise you we all feel ill at the thought of a colchicine overdose.

To understand our apprehension you need to know a little about our frenemy, colchicine.

We’ve been here before

Colchicine has been in use medicinally since the 1st century AD.^​1​ In truth, it’s quite the miracle drug for many inflammatory ailments. It works wonders for gout, is approved for use in familial Mediterranean fever, and has been shown to be beneficial in other off label indications such as pericarditis.^​2​ For the botanists, anthophiles, and general lovers-of-plants (I discourage you from looking up ‘plantophile’ in the urban dictionary. . .) the alkaloid colchicine is derived from beautiful plants.

For the science minded among you, its mechanism of action is both elegant and evil. Colchicine, along with podophyllotoxin and the vinca alkaloids, exerts both its therapeutic and toxic effects by binding tubulin units on microtubules, thereby interfering with microtubule formation and function.

Down The Tubes

Microtubules are found broadly in cells throughout the body, and are essential for diverse and vital cellular functions including mitosis, cellular transport, and cell structure.^​3​

Think of them as millions of tiny hands guiding the internal functioning of the cell. Structurally, microtubules exist as hollow tubes composed of tubulin proteins (alpha, beta, gamma) joined as heterodimers. But these tubulin units aren’t static, they are in a state of constant flux and instability. Additional heterodimers are continuously being added or removed from the ends of microtubules. This dynamic process of growth and retraction allows microtubules to transport elements within the cell, or even to move cells themselves as tubulin is added or removed. Microtubules function as the mitotic spindle to separate chromosomes in metaphase, as the railroad for axonal transport in neurons, and as the engine for cilia and flagella.

Colchicine acts by irreversibly binding to the interface of alpha and beta tubulin subunits, altering the protein’s secondary structure. Once that happens, this new colchicine-tubulin Frankenstein’s monster can still bind to the ends of the microtubule, but that’s the last one. Microtubule dynamics are halted, and additional dimers can no longer bind. At low concentrations, that’s where colchicine’s action stops, as a polymerization inhibitor. In particular, this impact on microtubules in neutrophils is critical for its therapeutic effect. Resultant inhibition of neutrophil adhesion, chemotaxis, and degranulation enables it to serve as an excellent medication for inflammatory conditions like gout.

At high concentration however, this monster goes beyond inhibition of polymerization and overtly destroys already formed microtubules by inducing depolymerization.^​4​

Instead of pausing or halting growth, the microtubules in the body effectively unravel. Understanding the omnipresent and essential nature of microtubules, it is not surprising that colchicine toxicity is characterized by multisystem organ failure. No microtubules, no functioning cells. No functioning cells, no functioning human.

What does a colchicine overdose look like clinically?

Due to rapid cell turnover in the gut, GI symptoms herald the onset. In fact, diarrhea or vomiting is the most common side effect of therapeutic colchicine use. In overdose, GI losses start within several hours and can lead to severe volume depletion over the first 12-24 hours.

This is followed by multisystem organ failure. Bone marrow failure is prominent and classic. Pancytopenia typically emerges over the next several days. Interestingly, an initial leukocytosis (WBC counts of up to 30K) occurs first, followed closely by profound leukopenia (WBC counts <1K can be seen) and pancytopenia over the subsequent 48 to 72 hours.

Along the unhappy road of colchicine poisoning, cardiac dysrhythmias (thought to be secondary to a reduced effective refractory period that triggers ventricular fibrillation) and cardiovascular collapse can occur. Although volume depletion can cause, or contribute to, cardiovascular collapse, it is likely compounded by the direct effects of colchicine on myocardium and skeletal muscles. Rhabdomyolysis can be seen. ARDS, AKI, and electrolyte derangements may also come along for the ride. Seizures have been reported, but when you think of direct CNS effects from a microtubule inhibitor, think podophyllotoxin (I’m looking at you tox fellows). For survivors, myopathy and neuropathy may develop, as well as a reversible alopecia 2-3 weeks after the initial overdose.

Not only is colchicine one of our most deadly toxins in intentional overdose , it also has a very narrow therapeutic index. A therapeutic sweet spot that can easily tip into toxic territory with dosing errors, or in the setting of liver or kidney impairment. Plus, it has significant drug-drug interactions. I know to many, the topic of drug interactions feels painful (unless you are a toxicologist), but the ultimate disposition of colchicine in the body depends on heavy hitters like CYP3A4 and p-glycoprotein (P-gp). Many drugs alter these pathways, compounding the risk of unintentional toxicity. With regards to CYP3A4, inhibitors such as erythromycin, clarithromycin, or even foods like grapefruit juice, will increase levels of colchicine in the body. P-gp is a cell membrane protein that pumps foreign substances like colchicine out of the cell. Unfortunately, multiple drugs inhibit this protein including ketoconazole (this one also gets CYP3A4!), cyclosporine, ritonavir, proton pump inhibitors, SSRIs, and some statins, leading to increased absorption and higher concentrations.

And here’s the real kicker: there’s no antidote. You can’t dialyze it, and supportive treatments often fail. Management focuses on supportive care (i.e., fluid resuscitation, vasopressors, etc.). Granulocyte colony stimulating factor (G-CSF) can be given for leukopenia. GI decon should be considered, but I’ll leave that topic here.

And so, we have a trifecta of badness:

1. We have a highly toxic medication
2. The therapeutic index is narrow
3. There is really no good way to treat it

And now, due to enthusiasm from a non-peer reviewed trial, we may see a lot more of this medication in homes during a time when our collective mental health is, shall we say, depolymerizing?

On that note, back to COVID. . .

Does colchicine even make sense mechanistically? Is there a possibility that it could get us out of this hellscape?

Despite my hesitancy, I’ll admit colchicine does make plausible mechanistic sense as a tool against COVID, although several other failed therapies arose for the same reason. Remember hydroxychloroquine? The working theory is that an overblown inflammatory response is crucial to the pathogenesis of COVID morbidity and mortality. Colchicine is one of the oldest and most effective anti-inflammatory drugs we have. By halting polymerization of microtubules in therapeutic doses, colchicine is a potent inhibitor of neutrophils as discussed above. Reduced number of neutrophils running around wreaking havoc, reduced inflammatory sequelae. This could be key in preventing COVID complications. Steroids work, so why not this?

But is it our panacea? I don’t think so. Nor is it presented as such in the available scientific literature. Perhaps it can reduce severe illness. Time and science will tell. Unfortunately, if it mirrors any of the other trending cures, I suspect we will be disappointed.^​5​

We all dream of silver linings

As I said, there is no antidote to colchicine, but that’s not entirely accurate. The French created a Fab fragment that was shown in animal models to bind colchicine and to serve as an effective antidote. There is even a compelling NEJM case report describing a severely ill colchicine poisoned patient who survived after getting the antidote.^​6​ Unfortunately, however, this antidote was never mass produced, nor is it available for clinical use (sacré bleu!) We know how to treat colchicine toxicity, we just can’t. Perhaps now is the moment to revamp that Fab fragment antidote. I for one could use a little silver lining.