Agranulocytosis After Consumption of Cocaine Adulterated With Levamisole

Letters17 February 2009Agranulocytosis After Consumption of Cocaine Adulterated With LevamisoleFREENancy Y. Zhu, MD, Donald F. LeGatt, PhD, and A. Robert Turner, MDNancy Y. Zhu, MDFrom the University of Alberta, Edmonton, Alberta T6G 2B7, Canada., Donald F. LeGatt, PhDFrom the University of Alberta, Edmonton, Alberta T6G 2B7, Canada., and A. Robert Turner, MDFrom the University of Alberta, Edmonton, Alberta T6G 2B7, Canada.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-150-4-200902170-00102 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Background: Levamisole is a veterinary antihelminthic previously used as an immunomodulator in rheumatoid arthritis and as adjuvant therapy in the treatment of colorectal cancer. It is no longer available in North America for human use but is available in the United States and South America for veterinary administration.Since 2004, pharmaceutical agents have been found in cocaine supplies in North America and Europe (1). Levamisole contaminated 30% of cocaine seized by the U.S. Drug Enforcement Agency from July to September 2008 (U.S. Department of Justice, Drug Enforcement Administration. Cocaine Signature Program Report. January–October 2008. Internal document.) and 11% of cocaine samples tested in Alberta, Canada, from April to December 2008 (Office of Research and Surveillance, Health Canada. Personal communication.). Levamisole causes reversible agranulocytosis in up to 20% of cases (2), but the clinical effects of cocaine adulterated with levamisole have not been described.Objective: To describe 5 patients with severe agranulocytosis after exposure to cocaine and levamisole.Case Report: Between July and November 2008, 5 patients with a history of cocaine use were hospitalized for agranulocytosis, fever, and a variety of infectious complications in northern Alberta, Canada (Table). Two patients had iron deficiency anemia, and 1 had chronic stable hepatitis C. Patients had no history of medication use or nutritional deficiencies, malignant conditions, or rheumatologic disorders that can cause agranulocytosis. Serum vitamin B12 and erythrocyte folate levels were normal. Imaging of the chest, abdomen, and pelvis with radiography and ultrasonography or computed tomography did not show any malignant conditions. Bone marrow examination in 2 patients showed reduced granulocytic proliferation and maturation (Figure) consistent with past reports of agranulocytosis from levamisole (3).Table. Clinical Details of Patients With Febrile Agranulocytosis Associated With Use of Cocaine Adulterated With LevamisoleFigure. Photographs of bone marrow aspirate (top) and trephine biopsy (bottom) from a patient with agranulocytosis and levamisole found in the urine.Neutrophils and bands are almost completely absent. The abundance of granulocytic precursors suggests toxin-related impairment of granulopoiesis with reduction of neutrophil maturation. The remainder of the bone marrow shows normal heterogeneity. Top. Bone marrow aspirate (May-Grünwald–Giemsa stain). Bottom. Bone marrow trephine biopsy (hematoxylin–eosin stain). Download figure Download PowerPoint Urine toxicology testing using gas chromatography/mass spectrometry (GC/MS) detected cocaine or its metabolites and levamisole. The presence of the drugs was verified by injecting urine extracts into the GC/MS and then comparing readings with those from pure standards according to 2 parameters: drug fragmentation pattern (total ion mass spectra) and time for the drug to pass through the system (retention time). Because lupus anticoagulant has been associated with levamisole use (4), we tested for it and detected it in all 5 patients with confirmed levamisole exposure.All patients fully recovered with use of filgrastim, intravenous antibiotics, and close monitoring. One patient presented with another episode of fevers and agranulocytosis 3 months later, when cocaine and levamisole were again found on urine testing. We treated 6 additional patients with a history of cocaine use who were hospitalized for agranulocytosis and fever. We suspected levamisole-adulterated cocaine as a cause but could not confirm the presence of the drug by using toxicology testing in these patients.Discussion: It is unknown why pharmaceutically active agents are added to the cocaine supply; it is possible that cocaine producers or suppliers think that the agents enhance the drug's effects or attenuate its side effects. Cocaine achieves its psychoactive effects by increasing dopamine concentrations in the euphoric centers of the brain, and animal studies have found that levamisole also increases dopamine levels in these regions (5). We speculate that levamisole may potentiate the euphoric effects of cocaine by further increasing brain dopamine levels.We did not test cocaine samples in the patients' possession for levamisole, so we cannot directly attribute the agranulocytosis to levamisole or prove that the cocaine was adulterated with levamisole. To directly connect levamisole to agranulocytosis, we would have to examine its effects on in vitro stem cell growth (by granulocyte-macrophage colony-forming unit clonogenic assay) (6).Other nonprescribed medications consumed and not detected on toxicology testing, or other adulterants, might also explain the agranulocytosis. Nevertheless, we advise clinicians to consider the possibility of cocaine use and, specifically, the use of levamisole-adulterated cocaine, in patients with otherwise unexplained fever and agranulocytosis. Prompt urine toxicology testing is essential because levamisole has a short-elimination half-life of 5.6 hours (7) and little of the parent drug (2% to 5%) is detected in urine (8). In addition, cocaine metabolites are detected up to 3.4 days on average after last use (9). Because levamisole is not detected by routine immunoassay toxicology screening tests, other techniques, such as GC/MS, are required.Conclusion: Cocaine adulterated with levamisole may be a cause of febrile agranulocytosis in cocaine users. Clinicians should consider the possibility of exposure to levamisole-adulterated cocaine in patients with otherwise unexplained fever and agranulocytosis.Nancy Y. Zhu, MDDonald F. LeGatt, PhDA. Robert Turner, MDUniversity of AlbertaEdmonton, Alberta T6G 2B7, CanadaReferences1. Fucci N. Unusual adulterants in cocaine seized on Italian clandestine market [Letter]. Forensic Sci Int. 2007;172:1. [PMID: 17681688] CrossrefMedlineGoogle Scholar2. Levamisole. In: DRUGDEX system. Greenwood Village, CO: Thomson Healthcare. Accessed at www.thomsonhc.com/hcs/librarian on 13 January 2009. Google Scholar3. Symoens J, Veys E, Mielants M, Pinals R. Adverse reactions to levamisole. Cancer Treat Rep. 1978;62:1721-30. [PMID: 365327] MedlineGoogle Scholar4. Rongioletti F, Ghio L, Ginevri F, Bleidl D, Rinaldi S, Edefonti A, et al. Purpura of the ears: a distinctive vasculopathy with circulating autoantibodies complicating long-term treatment with levamisole in children. Br J Dermatol. 1999;140:948-51. [PMID: 10354040] CrossrefMedlineGoogle Scholar5. Spector S, Munjal I, Schmidt DE. Effects of the immunostimulant, levamisole, on opiate withdrawal and levels of endogenous opiate alkaloids and monoamine neurotransmitters in rat brain. Neuropsychopharmacology. 1998;19:417-27. [PMID: 9778663] CrossrefMedlineGoogle Scholar6. Negro GD, Bonato M, Gribaldo L. In vitro bone marrow granulocyte-macrophage progenitor cultures in the assessment of hematotoxic potential of the new drugs. Cell Biol Toxicol. 2001;17:95-105. [PMID: 11499700] CrossrefMedlineGoogle Scholar7. Kouassi E, Caillé G, Léry L, Larivière L, Vézina M. Novel assay and pharmacokinetics of levamisole and p-hydroxylevamisole in human plasma and urine. Biopharm Drug Dispos. 1986;7:71-89. [PMID: 3754161] CrossrefMedlineGoogle Scholar8. Reid JM, Kovach JS, O'Connell MJ, Bagniewski PG, Moertel CG. Clinical and pharmacokinetic studies of high-dose levamisole in combination with 5-fluorouracil in patients with advanced cancer. Cancer Chemother Pharmacol. 1998;41:477-84. [PMID: 9554592] CrossrefMedlineGoogle Scholar9. Preston KL, Epstein DH, Cone EJ, Wtsadik AT, Huestis MA, Moolchan ET. Urinary elimination of cocaine metabolites in chronic cocaine users during cessation. J Anal Toxicol. 2002;26:393-400. [PMID: 12422991] CrossrefMedlineGoogle Scholar Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: From the University of Alberta, Edmonton, Alberta T6G 2B7, Canada.Acknowledgment: The authors acknowledge colleagues from the University of Alberta Division of Hematology, University of Alberta, and DynaLIFEDX Toxicology laboratories; the Royal Canadian Mounted Police; and the Canadian and U.S. governments for helpful assistance.Disclosures: None disclosed. 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2009Volume 150, Issue 4Page: 287-289KeywordsBone marrowCocaineDopamineDrug administrationDrugsFeversMetabolitesNeutrophilsToxicologyUrine ePublished: 17 February 2009 Issue Published: 17 February 2009 Copyright & PermissionsCopyright © 2009 by American College of Physicians. 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