What is the lowest lethal dose of colchicine?

Abstract Colchicine is known for its narrow therapeutic index, unclear boundaries between non-toxic, toxic and lethal doses and limited use due to its toxicity. In the scientific literature the opinion has prevailed that ‘The lowest reported lethal doses of oral colchicine have ranged from 7 to 26 mg’. In conjunction with our results of a life-saving effect of higher loading doses of colchicine up to 5 mg for the Coronavirus disease 2019 (COVID-19) treatment, we analyze the deaths reported in the literature with colchicine doses of 7–7.5 mg and show that they are due to drug interactions. To a large extent, this also applies to the described lethal doses of colchicine of 15–18 mg. We consider that doses of colchicine below 0.1 mg/kg are completely safe, and those between 0.1 and 0.2 mg/kg may lead to intoxication in some cases, but not to death. Hence, we suggest that the classic statement quoted above needs to be reworded as follows: ‘The lowest reported lethal doses of oral colchicine have ranged from 15 to 26 mg’. Our analysis indicates that colchicine can be used safely to treat COVID-19 in the mentioned doses, provided that liver and kidney damage are not present and adverse drug interactions are avoided.


Introduction
Colchicine has a history of more than 3500 years.It is approved for the treatment mainly of gout and familial Mediterranean fever (FMF) as well as many other diseases of the heart, liver, kidneys and over 30 nosological units in dermatology [1].
Given the multiple anti-inflammatory, antifibrotic, immunosuppressive actions and effects on microtubules, macrophages and neutrophils, several case reports, over 50 observational studies and randomized clinical trials, small randomized non-controlled trials and retrospective cohort studies were initiated to test its treatment effect on Coronavirus disease 2019 (COVID- 19), leading to conflicting, rather disappointing results [2,3].
All these studies were carried out within the so-called standard doses of colchicine between 0.015 and 0.03 mg/kg.For FMF and acute gout, the Food and Drug Administration recommends maximum oral doses of colchicine of 2.4 mg/day and 1.8 mg/day, respectively [4].It is obvious that no matter how many clinical trials are carried out for COVID-19 treatment with these doses of colchicine, different results will not be obtained.
The purpose of this review is to critically analyze the data from 1947 to the present on the determination of the lowest lethal doses of colchicine.Increasing the therapeutic doses of colchicine within reasonable limits can be key to save the lives of COVID-19 patients predisposed to hyperactivation of the NLRP3 inflammasome, cytokine storm, multiorgan damage and death.

Why can colchicine prevent COVID-19 cytokine storm and in what doses?
The key to colchicine's effect is its remarkable ability to accumulate in myeloid cells, where the cytokine storm is generated [5].Increasing doses of colchicine can lead to such an accumulation in macrophages, neutrophils and monocytes that is sufficient to inhibit the NLRP3 inflammasome and, accordingly, the cytokine storm.On the one hand, an effective inhibition of the NLRP3 inflammasome is needed, and on the other hand, it has to be achieved without intoxicating the patient.We have demonstrated that higher doses of colchicine can prevent the COVID-19 cytokine storm, decreasing the mortality of inpatients about 5 times in 452 patients from two hospital centres [Combined Odds and Risks from both centres RR (0.23, 95%CI 0.136-0.387);OR (0.23, 95%CI = 0.1296-0.4068)p < 0.0001] [5].We administered colchicine in a loading dose of 0.04-0.045mg/kg, but not more than 5 mg/ day [6,7].

Are these doses dangerous?
Wu and Liu [8], state that colchicine poisoning with a high mortality rate is a rare but life-threatening event.
There is no clear-cut line between nontoxic, toxic and lethal doses of colchicine in human subjects [4].
As previously reviewed [8], oral ingestion exceeding the maximum oral dose of 2.4 mg/day is commonly considered to be a colchicine overdose.Colchicine overdose can lead to multiple organ dysfunction by inhibiting cell mitosis progression, particularly in the liver, kidneys and intestines.The colchicine dose-related risk is estimated as follows: <0.5 mg/kg -Gastrointestinal symptoms; 0.5-0.8mg/kg -Systemic toxicity (10% mortality); and >0.8 mg/kg -Cardiovascular collapse, coagulopathy, acute renal failure (close to 100% mortality) [9].The high risk of toxicity caused intravenous formulations to be withdrawn from the market [10].
The range of colchicine tolerance can reach up to massive colchicine overdoses such as 60 mg (0.96 mg/ kg) [11], 90 mg (1.125 mg/kg) [12] or 90 mg (1.38 mg/ kg) [13] and even as high as 350 mg [14].What is more important for medical practice, however, is to establish the minimum lethal doses of colchicine.
Finkelstein et al. [4] conducted a large-scale study spanning 44 years in search of the minimal lethal dose of colchicine.Their conclusion that 'the lowest reported lethal doses of oral colchicine have ranged from 7 to 26 mg' is accepted as dogma and is often quoted [4].Reported cases are for 7 mg colchicine [15], 7.5 mg [16], 15 mg [17], 18 mg [18] and 26.5 mg [19].However, careful analysis of these scarce publications shows drug interactions or insufficiently detailed description of the cases.

Can 7-7.5 mg of colchicine be lethal?
The minimal lethal dose of oral colchicine is repeatedly said to be 7 mg [18].An article, with a dose of colchicine of 7 mg, from the distant year of 1947 [15] is cited in the literature as 'the garden scarecrow' in support of this statement [4,16,[18][19][20][21][22][23].However, a subtle detail appears to have stayed away from the spotlight: in this case [15] colchicine was taken simultaneously with mercury pills (B.P.C.) thrice daily.In addition, so far there has been no confirmation [16] of the authors' opinion that some patients have increased sensitivity to colchicine [15].We consider it is more proper to refer this case to colchicine-drug interactions.
Similarly, the 7.5 mg (0.125 mg/kg) colchicine case reported in 1979 concerns a woman with a weight of 60 kg after taking an unknown quantity of the veterinary drug phenylbutazone (prohibited for any human use in the United States since 2003) together with 'five or six glasses of vodka' [16].Early signs of phenylbutazone toxicity include loss of appetite, and depression [24].This 41-year-old woman clearly showed signs of phenylbutazone intoxication, because she felt 'worthless' for 1 month [16].Furthermore, it is well known that colchicine poisoning has been reported in patients with kidney or liver failure [18,25] that phenylbutazone can cause.
In this case, there are signs of phenylbutazone intoxication, a large amount of alcohol, probably taken daily, combined with a single high dose of colchicine.In our experience, in the absence of drug interactions and liver and kidney damage, colchicine cannot be lethal at these doses [7].

Can 15-18 mg of colchicine be lethal?
The case of a '37-year-old female presented after deliberately overdosing on 15 mg of colchicine' is described rather briefly [17].There is insufficient information on whether she had taken any other medications in this suicide attempt or consumed alcohol, whether she had liver or kidney problems, and what her weight was.
In another case, 18 mg of colchicine (0.2 mg/kg) caused the death of a 48-year-old man with a history of gout and alcoholism [18].As noted by the authors, the 'history of alcohol abuse may have compromised his liver function and worsened his prognosis' , because liver disease may predispose to intoxication [18].The patient was also treated with i.v.vancomycin and cefipime [18].However, cefepime may decrease the excretion rate of colchicine resulting in a higher serum level [26].On the other hand, colchicine may decrease the excretion rate of vancomycin, which could result in a higher serum level.Colchicine-probenecid oral increases the level or effect of cefepime i.v. by acidic drugs competing for the same pathway through the kidney [27].
Thus, in the fatal cases with 15 and 18 mg of colchicine, it can be concluded that it is more likely for drug interactions to have occurred on the background of a damaged liver.
In the absence of drug interactions and damaged liver and kidneys, a dose of 15-18 mg of colchicine is more likely to cause intoxication rather than death.For example, cases of severe poisoning of patients who took 15 mg (0.2 mg/kg) or 18 mg (~0.4 mg/kg) colchicine were described with abdominal cramps, vomiting, pancytopenia, hypocholesterolemia, severe hypertriglyceridemia rhabdomyolysis, multiple organ failure, and recovery [28,29].In the first case, the patient suffered from fibromyalgia, in addition to intestinal Behçet's disease and was taking Neurotropin®, pregabalin, butylscopolamine bromide, Lactomin, together with colchicine [28].The second case was a suicide attempt and it is not clear if the patient was taking other medications and alcohol [29].
In a retrospective study of clinical data of 43 patients for a period of 10 years, the lowest lethal dose was 0.63 mg/kg [20].We described a case of a single mistaken administration of 15 mg of colchicine to a COVID-19 inpatient with bilateral pneumonia and pericardial effusion.All treatment was stopped and the patient was discharged in good health on day 9 [30].We have also reported a number of other cases of accidental colchicine overdose (12.5-15mg) in the treatment of COVID-19 inpatients and outpatients without serious consequences and complete recovery [31].
A fatal case of a 16-year-old girl of unknown body weight, who took 12.5 mg of colchicine in combination with 5 drugs, including erythromycin and ampicillin, was described by Harris and Gillet [21].Both erythromycin and ampicillin may increase the blood levels of colchicine to dangerous levels, increasing the risk of serious side effects [26,32].In another fatal case, a 15-year-old boy took 18 mg of colchicine (approximately 0.4 mg/kg) and 4 g of quinine in a suicide attempt [33].
Jayaprakash et al. [22] describe 8 colchicine overdose deaths over 15 years in New Zealand.The doses of colchicine range from 18 to 40 mg for five of the patients, and for the other three the doses are unknown; four patients are cases of attempted suicide; two others are with chronic renal impairment.The cases are presented extremely succinctly and it is not clear whether other medications were taken during the suicide attempts.The authors emphasize that due to the reported case of 1947 [15], the maximum recommended doses have been reduced to 6 mg (in New Zealand) and 10 mg (in the United Kingdom), respectively [34].
Analysis of these articles suggests that doses of 15-18 mg of colchicine may cause serious side effects or not, rather than death.Probably the statement that colchicine is toxic in doses greater than 0.1 mg/kg is closest to reality [35].Colchicine in a dose of 0.2 mg/ kg can lead to serious complications but is not lethal [28].
Hence, we suggest that the classic quote needs to be reworded as follows: 'The lowest reported lethal doses of oral colchicine have ranged from 15 to 26 mg' .Our maximum loading dose of 5 mg (0.045 mg/kg) is significantly lower than those listed above.

Are the doses of colchicine we used unusual?
Today they are, but in the recent past they were common.Colchicine has repeatedly been administered in the so-called overdoses.For example, in FMF, colchicine can be used up to a daily dose of 2 mg in children and 3 mg in adults, or 'the maximum tolerated dose' if necessary [36].In a number of cases, high loading doses of colchicine have been used, such as 4.8 mg [37] and 6.7 mg [38].In France, up to 2006, the prescription was of 3 mg on the first day of treatment of gout flare [39].Kevorkian et al. [40] use loading doses of 3.5 mg/26h in their COVID-19 treatment regimen.Pascart et al. [39] reported that 3 mg was the most common initial dose prescribed by 80.6% of physicians for treatment of gout flare; however, 4.3% of them prescribed higher loading doses between 4 and 6 mg.
Pediatric daily doses that range from 0.03 to 0.07 mg/kg [41] are 2 times higher than the so-called standard doses between 0.015 and 0.03 mg/kg [4].In 2010, the only study of the effect of colchicine for treatment of gout flare with two doses (low of 1.8 mg and a high of 4.8 mg) showed a lack of differential effect.This makes it pointless to use a high dose of colchicine in this case, in which patients with diarrhea reach 76.9% [37].Perhaps this is why all of the dozens of COVID-19 clinical trials and research used only low doses of colchicine.Colchicine administered according to our scheme (max dose of 5 mg) successfully inhibits the NLRP3 inflammasome/cytokine storm because it has a remarkable effect of accumulating in white blood cells [6,7].

Colchicine toxicity in drug-drug interactions
Certain drugs increase the potential for colchicine toxicity via modulation of P-glycoprotein 1 (P-gp1) and cytochrome P450 3A4 (CyP3A4) activity, because colchicine is their substrate.Colchicine can also cause myotoxicity, and cases of myopathy and/or rhabdomyolysis have been reported in patients receiving colchicine with concomitant use of statins, fenofibrate/ gemfibrozil, cyclosporine or digoxin [10].Other exclusion criteria should also be considered [42].A typical case of toxicity due to drug-drug interaction is that of colchicine and clarithromycin [43].Other dangerous interactions of colchicine are with telithromycin, ketoconazole, itraconazole, HIV protease inhibitors, nefazodone, calcium channel blockers (e.g.diltiazem, verapamil), macrolide antibiotics (e.g.erythromycin), antifungals (e.g.fluconazole), etc.For a full list, see New Zealand Formulary (NZF) [44].
There are 257 known interactions of colchicine with other drugs, along with 7 disease interactions and 1 alcohol/food interaction.Of the total drug interactions, 107 are major, 145 are moderate and 5 are minor [45].
For example, all generic drug interactions for colchicine-probenecid oral include: 5 contraindicated drug interactions; 42 serious drug interactions; 386 significant drug interactions and 51 minor drug interactions [46].Adverse colchicine drug interactions can almost always be prevented through proper management and patient education [47].
Detailed descriptions of dangerous life-threatening drug-drug interactions, such as pancytopenia, multiorgan failure and cardiac arrhythmias are reviewed in Hansten et al. [47].The risk of colchicine toxicity is detailed in [48].

Recommendations
The doses we used (maximum dose of 5 mg) are safe and have already been administered for COVID-19 treatment without severe side effects or life-threatening conditions.The attending physician must be familiar with the side effects of colchicine and unwanted interactions with other drugs.As colchicine is primarily eliminated by hepatobiliary and renal (10-20%) excretion, the patient should be questioned about diseases of the liver and kidneys.The patient should be well informed about possible risk conditions during treatment with colchicine.All this will reduce the risk of colchicine intoxication to practically zero.

Conclusions
Here we demonstrated that the doses of colchicine of up to 5 mg we use for the treatment of COVID-19 are completely safe.Although there has been skepticism about the safe dosage of colchicine and its potential effectiveness in COVID-19 treatment, we believe a large part of the reported negative results can be attributed to unaccounted drug interactions and/or concomitant liver/kidney conditions, or to inadequate doses.For the time being, we believe that our approach to treating COVID-19 is highly effective, and also the cheapest.In COVID-19 patients with a high risk of lethal outcome, the discomfort caused by side effects (such as diarrhea) is a small price to pay for a life saved.