In January 2021, several media reports put a spotlight on colchicine, an alkaloid from the autumn crocus (Colchicum autumnale, Colchicaceae), after a randomized, double-blind clinical study with 4,488 patients with COVID-19¹ showed a reduction in hospitalization and death rates in the colchicine group, according to the preprint conclusion.^2,3 While the authors of the study reported this as a major breakthrough, many scientists pointed to the lack of statistical significance between the colchicine and placebo groups in the primary endpoints of the study and emphasized the need for more data.^4-6 Nevertheless, the results seem promising and reinforce that plant constituents can be important sources of medications.

Historical Uses

The autumn crocus has been known for centuries, but many older medical texts mainly mention its toxicity. In his De Materia Medica, Greek physician, pharmacologist, and botanist Pedanius Dioscorides (ca. 40–90) describes a plant named ephemeron, also referred to as colchicon, which flowers in fall and has flowers like a crocus (Crocus spp., Iridaceae). He wrote, “when eaten, it has a fatal effect by choking, as is with mushrooms.” Ingestion of small amounts (less than five grams) of autumn crocus, all parts of which contain colchicine,⁷ can cause gastrointestinal symptoms with diarrhea and loss of fluids, followed by life-threatening complications (e.g., heart failure, arrhythmias, renal failure, hepatic injury, respiratory distress, impaired blood clotting) and possibly death.⁸

However, the Greek physician Alexander of Tralles (ca. 525–605) also noted the benefits of a plant known to him as hermodactyl for the treatment of gout, an inflammatory condition caused by the crystallization of monosodium urate in and around joints. Since he did not provide any botanical descriptions, the identity of hermodactyl is debatable, but many scholars believe that it was a Colchicum species.^9,10 This is supported by the writings of Arab physicians such as Serapion the Younger (ca. 12th century) and Ibn al-Baitar (1197–1248), who treated the name hermodactyl as a synonym for the Arab name surugen, which al-Baitar described as “similar to the saffron, has leaves like the onion, a stem one span long, and a white root with a red cover, the root being soft, sweet, and toxic as mushrooms.”⁹

The plant was almost absent in early European medical writings until Anton Freiherr von Störck (1731–1803), a physician in Vienna, Austria, wrote a book about the usefulness of autumn crocus for the treatment of edema. But it was not until 1780, when Nicolas Husson, an officer in the French army, introduced a medicinal water that contained an infusion of C. autumnale as the main ingredient and successfully used it to treat patients with gout, that the potential medicinal virtues of the plant started to spark the interest of the European medical community.⁹

The main active alkaloid in autumn crocus was isolated in 1820 by French pharmacists Pierre-Joseph Pelletier (1788–1842) and Joseph-Bienaimé Caventou (1795–1877).^11,12 They gave it the name veratrine due to its similarity with a constituent from the roots of white hellebore (Veratrum album, Melanthiaceae) and sabadilla (Schoenocaulon officinale, syn. V. sabadilla, Melanthiaceae). After further inspection, German pharmacist and chemist Philipp Lorenz Geiger (1785–1836) noticed that veratrine was different from the constituents obtained from white hellebore and named it “colchicine.”^9,12 However, the structure of colchicine was not fully confirmed until 1952.¹³

Colchicine and Inflammatory Conditions

Prescription drugs containing colchicine started to be used in the 1950s for the treatment of gout, but use declined due to the narrow therapeutic index (the difference between effective and toxic doses). In 2010, the US Food and Drug Administration (FDA) banned the manufacture, distribution, and marketing of unapproved oral colchicine (i.e., medications that had been grandfathered due to longstanding use without going through the FDA drug approval process). One company, URL Pharma (Philadelphia, PA), successfully took colchicine through the FDA approval process, and eventually received three years of market exclusivity for Colcrys® for the treatment of gout, as well as a seven-year exclusivity period for its use to treat familial Mediterranean fever (FMF), an autoinflammatory disorder that causes recurrent fevers and painful inflammation of the abdomen, lungs, and joints.¹⁴

While generally known as an agent that inhibits cell division, colchicine’s anti-inflammatory properties have been the subject of much interest in recent years as a first line treatment for gout. Colchicine is able to prevent the formation of pro-inflammatory signal molecules and restricts the movement of cells of the innate immune system that can exacerbate inflammatory processes.^15,16 This has led to a number of new uses, such as the treatment of FMF, pericarditis (inflammation of the pericardium fibrous membrane surrounding the heart), and Behçet’s disease, a rare disorder that causes blood vessel inflammation.¹⁷ In addition, a 2020 study of 5,522 patients with coronary heart disease found a significant reduction in the risk of death in patients taking 0.5 mg oral colchicine per day compared to placebo.¹⁸

Colchicine and COVID-19

Based on the promising results of clinical studies in these inflammatory conditions, researchers started to investigate if colchicine could help prevent or limit complications resulting from the inflammatory effects known as cytokine storm in patients with COVID-19.¹⁹ In July 2020, Schlesinger et al¹⁶ listed 10 registered clinical studies that were investigating the usefulness of colchicine for patients with COVID-19, including two large clinical trials with a targeted enrollment of 2,500 (COLCOVID trial) and 6,000 (COLCORONA trial) patients. By November 2020, the total number of trials had grown to 22.¹⁷ The initial results of two studies suggest that patients treated with 0.5–1 mg oral colchicine per day had a longer survival time²⁰ and a lower risk of death.²¹

The COLCORONA trial

A preprint of the results of the COLCORONA clinical study was published in January 2021.¹ This randomized, double-blind, placebo-controlled trial compared 0.5 mg oral colchicine (twice daily for the first three days and then once daily for 27 days thereafter) to placebo in 4,488 patients who had been diagnosed with COVID-19, either by polymerase chain reaction (PCR) testing or using clinical criteria. While the study initially planned to enroll 6,000 patients, the investigators terminated the study once 75% of the planned patients were recruited due to logistical issues and the need to provide results in a timely fashion given the urgent need for therapeutic options for patients with COVID-19. The study assessed hospitalization and death rates as the primary endpoints and the need for mechanical ventilation as the secondary endpoint.

Of the 2,235 patients in the colchicine group, 101 patients were hospitalized and five patients ultimately died, compared to 128 hospitalizations and nine deaths in the placebo group (n = 2,253). Mechanical ventilation was necessary for 11 patients in the colchicine group and 21 in the placebo group. Among the 4,159 patients with PCR-confirmed COVID-19, death or hospitalization occurred in 4.6% and 6.0% of patients in the colchicine and placebo groups, respectively (odds ratio, 0.75; 95% CI, 0.57-0.99; P = 0.04).¹

Serious adverse events were reported in 4.9% of the colchicine group and 6.3% in the placebo group (P = 0.05). Pneumonia occurred in 2.9% and 4.1% of patients, respectively (P = 0.02). Diarrhea was reported in 13.7% and 7.3% of patients, respectively (P < 0.0001). Among patients with diabetes, hospitalization or death occurred in 6.1% of those in the colchicine group and 9.6% in the placebo group (odds ratio, 0.61; 95% CI, 0.37-1.01), possibly because the primary endpoints are more likely to occur in high-risk patients.

The initial results of the COLCORONA trial suggest that colchicine may be able to reduce hospitalization and death rates.¹ As the paper has not yet been peer reviewed, the results should be interpreted with caution. Additional findings from other studies of colchicine in patients with COVID-19 are expected to be published later this year.

Conclusion

The medicinal value of the autumn crocus and colchicine is closely linked to their toxicity. Ingestion of any parts of this plant can be fatal. Due to the small difference between the effective and toxic dosages, the medicinal use of colchicine has been limited to patients with gout and pericarditis. However, new clinical research on colchicine’s anti-inflammatory effects using lower doses has brought a renewed interest in the drug. Its potential benefits for life-threatening diseases such as COVID-19 may lead to wider professional use of this fascinating plant constituent. More research to confirm colchicine’s benefits to treat symptoms of inflammation in patients with COVID-19 is needed to establish its suitability as a valuable therapeutic agent.

References

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