Autumn Crocus

Scientific Name(s): Colchicum autumnale L. Other species used medicinally have included Colchicum speciosum Steven and Bulbocodium vernum L. Ker-Gawl. Family: Liliaceae (lilies)

Common Name(s): Crocus , autumn crocus , fall crocus , meadow saffron , mysteria , naked lady , vellorita , wonder bulb

Uses

The plant and its extracts are used to treat gout and related inflammatory disorders. Autumn crocus may ameliorate hepatitis and cirrhosis, and may have potential in chemotherapeutic regimens. However, no clinical trials are available to support the use of autumn crocus for any indication.

Dosing

Colchicine 1 to 2 mg is a typical oral dose for gout, corresponding to crocus seed 200 mg or corm 250 mg. Colchicine also has been studied for osteoarthritis of the knee, refractory constipation, and postpericardiotomy syndrome at similar doses. Its narrow therapeutic index requires medical supervision. However, autumn crocus has not been studied at these doses for verification.

Contraindications

Contraindications have not yet been identified.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is contradictory. Avoid use.

Interactions

Avoid use in patients taking colchicine. Caution is warranted in patients on cyclosporine, gemfibrozil, macrolide antibiotics, and St. John's wort.

Adverse Reactions

GI disturbances (eg, diarrhea, steatorrhea, reversible malabsorption syndrome) are common following acute therapeutic use of colchicine.

Toxicology

All parts are highly toxic. It may produce severe gastric distress, shock, and inhibit normal cell growth.

Botany

Crocus plants are members of the lily family and often are cultivated for their long, ornamental flowers. This perennial herb grows to approximately 0.3 m in height and has pale purple flowers and a fleshy conical root (corm). The corm has a bitter, acrid taste and radish-like odor. 1 , 2 Low-lying leaves are arranged around the base of the plant, growing from the bulb. In the springtime, the plant has leaves but no blossoms. 3 The plant is native to grassy meadows, woods, and riverbanks in Ireland, England, and portions of Europe and has been cultivated throughout much of the world.

History

The name Colchicum is derived from the district of Colchis, located on the ancient eastern shore of the Black Sea. 4 The plant and its extracts have been used for centuries in the treatment of gout, rheumatism, dropsy, prostate enlargement, and gonorrhea. 1 Extracts have been used to treat cancers. The first official Pharmacopeia of the United States (1820) listed Colchicum preparation. 4 Today the plant is a primary source of colchicine, which is used therapeutically to treat gout and experimentally in cellular chromosomal studies. In addition to its FDA-approved use (gout), colchicine has been used in the following conditions: neurologic disability caused by chronic progressive multiple sclerosis, familial Mediterranean fever, hepatic cirrhosis, primary biliary cirrhosis, and as adjunctive treatment of primary amyloidosis, 5 Behçet disease, 6 pseudo-gout, skin manifestations of scleroderma, psoriasis, palmo-plantar pustulosis, and dermatitis herpetiformis. 7

Chemistry

Colchicine is the main active principle found in autumn crocus and is present in a concentration of approximately 0.6% of corm; concentrations may exceed 1% in the seeds. 1 , 8 Dried leaves and flowers contain the same concentration of colchicine as fresh parts; however, dried flowers and seeds contain 15 times as much colchicine as leaves. 8 A variety of other related alkaloids have been isolated from the plant, including colchicerine, colchamine, colchicoside, demethyl-3-colchicine, cornigerine, and 2-demethylcolchifoline. 8 , 9 Colchicine is not destroyed by heat or boiling and is highly soluble in water. 1 Colchysat is a hydro-ethanolic extract of fresh Colchicum autumnale blossoms. 10

Uses and Pharmacology

Colchicine inhibits normal cell division, specifically by interfering with microtubule growth and mitosis during cell division. It also may interfere with the normal function of cyclic adenosine monophosphate (cAMP) or the cellular membrane. 7 , 11

Gout

The plant and its extracts are used to treat gout and related inflammatory disorders.

Animal/Clinical data

Research reveals no animal or clinical data regarding the use of autumn crocus for gout. A review of gout mentions use in 1936 of colchicine to reduce acute gouty attacks and a 1961 report of efficacy and safety of daily colchicine prophylaxis. 11

Anticancer agent

Because colchicine arrests mitosis during metaphase, it was thought to be useful as an anticancer agent. Although it demonstrated antineoplastic activity in vitro and in some in vivo models, the toxicity of the drug has limited use in humans. 1 Immunochemotherapy of multidrug resistant renal cell carcinoma using a combination of vinblastine, tamoxifen, colchicine, and 5-flourouracil demonstrated an overall response rate of 23.5% with limited toxicity. 12 Incorporating a lower dose colchicine into chemotherapeutic regimens may decrease overall toxicities. 12

Chronic hepatitis/cirrhosis

Colchicine has been investigated for its effectiveness in limiting the progression of chronic hepatitis and cirrhosis; however, a double-blind, randomized, placebo-controlled trial of 55 patients with alcoholic cirrhosis did not demonstrate any evidence of a beneficial effect of colchicine in survival or incidence of complications. It appears to decrease inflammation, inhibit collagen synthesis, and increase collagen degradation, thereby slowing disease progression and fibrosis and perhaps extending survival time. 13 , 14 , 15 , 16 , 17 , 18 A prospective, double-blind trial comparing colchicine and methotrexate in treatment of primary biliary cirrhosis demonstrated equal efficacy in treating pruritus; however, only methotrexate improved liver histology. 19 Combined use of colchicine with methotrexate and ursodeoxycholic acid may be beneficial. 19

Idiopathic pulmonary fibrosis

A controlled, randomized, prospective trial of 26 patients treated with colchicine or prednisone showed no improvement with either agent. 20 A prospective, nonrandomized study using colchicine and/or D-penicillamine with prednisone did not halt progression of idiopathic pulmonary fibrosis. 21 One retrospective study comparing colchicine, oxygen, and prednisone with no therapy demonstrated no differences in survival. 22

Dosage

Colchicine 1 to 2 mg is a typical oral dose for gout, corresponding to crocus seed 200 mg or corm 250 mg. Colchicine also has been studied for osteoarthritis of the knee, 23 , 24 refractory constipation, 25 , 26 recurrent pericarditis, 27 Henoch-Schönlein purpura cutaneous manifestations, 28 refractory chronic thrombocytopenic purpura, 29 Behçet syndrome, 6 and postpericardiotomy syndrome 30 at similar doses. Its narrow therapeutic index requires medical supervision.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is contradictory.

A medical botany text lists autumn crocus as a mutagen and teratogen. 31 Although no mutagenic effects were reported in a small number of colchicine-exposed human fetuses, sperm abnormalities have been reported in men treated with colchicine. Effects seen were azoospermia and abnormal numbers of chromosomes including trisomy 21, which causes Down syndrome. 32

Colchicine is excreted in human breast milk. 32 , 33 The American Academy of Pediatrics designates colchicine as compatible with breast-feeding. 34

Women and their male partners planning pregnancy should avoid use of autumn crocus because of potential complications and limited data available for use in humans. 32

Interactions

Autumn crocus should be avoided in patients on colchicine because of the potential for additive adverse and therapeutic effects.

Colchicine is listed as a substrate of CYP3A4 (cytochrome P450) hepatic metabolism enzyme. 35 , 36 Monitor therapy when patients are on CYP3A4 substrates/inhibitors (especially if renal and/or hepatic dysfunction is demonstrated) and ingesting autumn crocus, as colchicine metabolism can be inhibited. 35 , 36 , 37

The following medications/herbs have demonstrated interactions that warrant close observation or discontinuation of autumn crocus (colchicine).

Cyclosporine

Up to 50% of renal transplant recipients on concurrent cyclosporine and colchicine therapy experience myopathies, rhabdomyolysis, and neuromyopathy. 38 , 39 Dose-dependent, cyclosporine-induced muscular toxicity has been observed after addition of colchicine to treat a gout attack. Symptoms abated in 7 days after colchicine withdrawal. 40 One case of multiple organ failure in a renal transplant patient receiving colchicine and cyclosporine has been documented. 41 Concomitant use may potentiate adverse and toxic effects of cyclosporine and colchicine. 42 Avoid use of autumn crocus with cyclosporine therapy.

Gemfibrozil

A case of rhabdomyolysis potentially caused by concurrent gemfibrozil and colchicine therapy was reported. 37

Macrolide antibiotics

Colchicine toxicity was reported with coadministration of erythromycin or clarithromycin. 43 , 44

St. John's wort

Colchicine is a substrate of CYP3A4, which St. John's wort induces. Coadministration increases drug metabolism. 35

Monitor the following levels because of potential decreased absorption and/or increased excretion

Cyanocobalamin (vitamin B 12 ) absorption may be decreased resulting in anemia. 45 , 46 Betacarotene levels have been shown to decrease from abnormal absorption. 45 , 46 Sodium and potassium levels may decrease because of increased fecal excretion. 45

Adverse Reactions

GI disturbances (eg, diarrhea, steatorrhea, reversible malabsorption syndrome) are common after acute therapeutic use of colchicine. 45 , 46

Toxicology

Animal poisonings

Veterinary poisonings have been associated with autumn crocus; these often are observed in grazing animals. There have been reports of calves becoming intoxicated by drinking milk from cows that have ingested the plant. 47

Accidental poisoning

There have been reports of children becoming intoxicated by drinking milk from cows that have ingested the plant. 47 Human intoxications have occurred after corms were mistaken for onions, wild garlic ( Allium ursinum ), Japanese domestic allium ( Allium victorialis platyphyllum ), and leeks, while others have suffered overdosages from seed- or corm-derived natural medicinals. 1 , 3 , 39 , 49 , 50 , 51 , 52 Consider differential diagnosis of C. autumnale poisoning in unexplained extensive GI symptoms after ingestion of wild plants used as spices or in salads. 49 , 51 Toxicity has been observed when colchicine was accidentally taken by nasal insufflation in place of methamphetamine. 53

Intentional poisoning

Two cases of attempted suicide by self-poisoning with C. autumnale L. flowers have been reported. A 16-year-old girl who ingested more than a dozen flowers (calculated at about colchicine 270 mg) experienced convulsions and subsequently died. 2 A 44-year-old man ingested 40 flowers (calculated at up to colchicine 102 mg [1.5 mg/kg]) but survived after gastric lavage and aggressive treatment. 2 , 9

Signs and symptoms of colchicine poisoning follows 3 phases

Phase 1 (0 to 24 hours) includes gastrointestinal symptoms, volume depletion, and peripheral leukocytosis; phase 2 (day 2 through 7): respiratory distress, cardiovascular shock, thrombocytopenia, metabolic acidosis, rhabdomyolysis, and renal failure; phase 3 (beyond day 7): rebound leukocytosis and alopecia. Death may follow in the first 24 to 48 hours but may be delayed up to 14 days. 2 , 50 , 54

GI symptoms

The entire plant is toxic, primarily because of the colchicine content. After ingestion, immediate burning of the mouth and throat is followed by intense thirst, nausea, and vomiting. Abdominal pain and persistent diarrhea attributed to disturbance of water and electrolyte balance develop because of small and large intestine mucosal lining damage. 55 An experimental study in cattle reported that autumn crocus not only arrests mitosis in gastrointestinal tract tissue but also causes apoptosis. 56 One study found a species difference; orally administered toxic amounts of autumn crocus caused guinea pigs to develop diarrhea while mice did not. 57

Toxicities with extended use/other toxic effects/lethal dose

Prolonged therapeutic use of colchicine may cause agranulocytosis, aplastic anemia, thrombocytopenia, peripheral neuritis, and epithelial atypia. 54 , 58 Colchicine-induced myopathy and neuropathy have been diagnosed in patients taking usual doses for gout; however, patients also had renal dysfunction, causing increased colchicine plasma levels. 59 , 60 One case of colchicine-induced neuromyopathy has been reported in a patient with normal renal function. 61 If myopathy is suspected, monitor muscle strength and creatine phosphokinase levels. 61 The volatile oils emitted during commercial slicing of the fresh corm may irritate the nostrils and throat, and the fingertips holding the corm may become numb. 1 The lowest reported human lethal dose is 186 mcg in 4 days. 53 Although ingestion of colchicine 7 mg has been reported to be lethal to humans, the more typical lethal dose is 65 mg. 1 , 51 , 54

Symptom management/antidote

Fluid loss may lead to hypovolemic shock and renal impairment with oliguria has been reported. 54 , 62 Because of the slow elimination of colchicine from the body, intoxication follows a long course. Fluid replacement and supportive therapy are recommended. 62 Because no specific antidote is available for colchicine poisoning, emesis followed by gastric lavage, with or without oral activated charcoal, also has been of value along with supportive therapy for shock. 9 , 53 Patients with cardiac disease, hepatic disease, and/or renal insufficiency have a worse prognosis because they may have a more severe clinical presentation. 48 , 58 Fab fragment antibodies produced in rabbits or goats have been effective in treating colchicine poisoning when tested in mice and rabbits. Colchicine-specific fab fragments have been successfully used to treat a life-threatening, intentional overdose of colchicine tablets in a 25-year-old woman. 63 However, fab fragments of anticolchicine antibody are not commercially available. 64 Pancytopenia in patients surviving the initial stages of autumn crocus poisoning has been successfully treated with granulocyte colony-stimulating factor, which may help prevent life-threatening sepsis. 65 , 66

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