Archives of Toxicology

, Volume 91, Issue 6, pp 2303–2313 | Cite as

Adverse effects of levamisole in cocaine users: a review and risk assessment

  • Tibor Markus Brunt
  • Jorrit van den Berg
  • Ed Pennings
  • Bastiaan Venhuis
Review Article
First Online:
Received:
Accepted:

Abstract

The immunomodulatory adjuvant and antihelminth levamisole is increasingly used as an adulterant in cocaine worldwide. An accumulating body of clinical and toxicological literature has appeared since 2010 describing neutropenia, agranulocytosis, leukoencephalopathy and vasculitis in cases associated with levamisole-adulterated cocaine. Mostly, neutropenia and agranulocytosis were reported, characterized by a decimation of neutrophils. A large proportion of cases also involved vasculopathy, characterized by pronounced black and purple skin purpura with cutaneous necrosis. Females are more susceptible for both agranulocytosis and vasculitis. Another complication reported with levamisole-adulterated cocaine is leukoencephalopathy, a disabling and potentially fatal neurological disorder caused by cerebral demyelination. In this review, all adverse effects associated with therapeutic levamisole and levamisole-adulterated cocaine are described. In addition, this review provides an update of the pharmacology of levamisole, its metabolism, including toxic metabolites and metabolites that are relevant for levamisole’s addition to cocaine. Special emphasis is put on the immunopathology and the dose–effect relationship of chronic levamisole exposure. Finally, a risk assessment is provided based on the current level of levamisole adulteration in street cocaine, the dose range calculated per gram and the pattern of chronic exposure in heavy or dependent users.

Keywords

Levamisole Cocaine Adverse effects Agranulocytosis Vasculitis Neutropenia Risk assessment 
This is a preview of subscription content, log in to check access.

References

  1. Agarwal A, Shukla OP, Ghatak S, Tekwani BL (1990) Biogenic amines, metabolites and monoamine oxidase in the filarial worm Setaria cervi. Int J Parasitol 20:873–881. doi: 10.1016/0020-7519(90)90025-I CrossRefPubMedGoogle Scholar
  2. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders. American Psychiatric Association Publishing, Arlington, VACrossRefGoogle Scholar
  3. Amery WKP, Bruynseels JPJM (1992) Levamisole, the story and the lessons. Int J Immunopharmacol 14:481–486. doi: 10.1016/0192-0561(92)90179-O CrossRefPubMedGoogle Scholar
  4. Amery WK, Butterworth BS (1983) The dosage regimen of levamisole in cancer: is it related to efficacy and safety? Int J Immunopharmacol 5:1–9CrossRefPubMedGoogle Scholar
  5. Ammar AT, Livak M, Witsil JC et al (2015) Old drug new trick: levamisole-adulterated cocaine causing acute kidney injury. Am J Emerg Med 33(309):e3–e4. doi: 10.1016/j.ajem.2014.08.015 Google Scholar
  6. Arora NP (2013) Cutaneous vasculopathy and neutropenia associated with levamisole-adulterated cocaine. Am J Med Sci 345:45–51. doi: 10.1097/MAJ.0b013e31825b2b50 CrossRefPubMedGoogle Scholar
  7. Barker SA (2009) The formation of aminorex in racehorses following levamisole administration. A quantitative and chiral analysis following synthetic aminorex or levamisole administration vs. aminorex-positive samples from the field: a preliminary report. J Vet Pharmacol Ther 32:160–166. doi: 10.1111/j.1365-2885.2008.01015.x CrossRefPubMedGoogle Scholar
  8. Bertol E, Mari F, Milia MG Di et al (2011) Determination of aminorex in human urine samples by GC–MS after use of levamisole. J Pharm Biomed Anal 55:1186–1189. doi: 10.1016/j.jpba.2011.03.039 CrossRefPubMedGoogle Scholar
  9. Bharadwaj M, Illing P, Theodossis A et al (2012) Drug hypersensitivity and human leukocyte antigens of the major histocompatibility complex. Annu Rev Pharmacol Toxicol 52:401–431. doi: 10.1146/annurevpharmtox-010611-134701 CrossRefPubMedGoogle Scholar
  10. Brabant W, Mazure D, Vantilborgh A et al (2012) Agranulocytosis after cocaine use: a case of suspected levamisole contamination in Belgium. Clin Neurol Neurosurg 114:1159–1160. doi: 10.1016/j.clineuro.2011.12.012 CrossRefPubMedGoogle Scholar
  11. Bradford M, Rosenberg B, Moreno J, Dumyati G (2010) Bilateral necrosis of earlobes and cheeks: another complication of cocaine contaminated with levamisole. Ann Intern Med 152:758–759. doi: 10.7326/0003-4819-152-11-201006010-00026 CrossRefPubMedGoogle Scholar
  12. Brunt TM, Rigter S, Hoek J et al (2009) An analysis of cocaine powder in the Netherlands: content and health hazards due to adulterants. Addiction 104:798–805. doi: 10.1111/j.1360-0443.2009.02532.x CrossRefPubMedGoogle Scholar
  13. Buchanan JA, Oyer RJ, Patel NR et al (2010) A confirmed case of agranulocytosis after use of cocaine contaminated with levamisole. J Med Toxicol 6:160–164. doi: 10.1007/s13181-010-0060-3 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Buchanan JA, Heard K, Burbach C et al (2011) Prevalence of levamisole in urine toxicology screens positive for cocaine in an inner-city hospital. JAMA 305:1657–1658. doi: 10.1001/jama.2011.531 CrossRefPubMedGoogle Scholar
  15. Casale JF, Boudreau DK, Jones LM (2008) Tropane ethyl esters in illicit cocaine: isolation, detection, and determination of new manufacturing by-products from the clandestine purification of crude cocaine base with ethanol. J Forensic Sci 53:661–667. doi: 10.1111/j.1556-4029.2008.00698.x CrossRefPubMedGoogle Scholar
  16. Casale JF, Colley VL, Legatt DF (2012) Determination of phenyltetrahydroimidazothiazole enantiomers (Levamisole/Dexamisole) in illicit cocaine seizures and in the urine of cocaine abusers via chiral capillary gas chromatography-flame-ionization detection: clinical and forensic perspectives. J Anal Toxicol 36:130–135. doi: 10.1093/jat/bkr025 CrossRefPubMedGoogle Scholar
  17. Chang A, Osterloh J, Thomas J (2010) Levamisole: a dangerous new cocaine adulterant. Clin Pharmacol Ther 88:408–411. doi: 10.1038/clpt.2010.156 CrossRefPubMedGoogle Scholar
  18. Chastel C, Mabin D (1996) Encephalopathies after levamisole therapy. Neurology 46:288CrossRefPubMedGoogle Scholar
  19. Ching JA, Smith DJ Levamisole-induced necrosis of skin, soft tissue, and bone: case report and review of literature. J Burn Care Res 33:e1–5. doi: 10.1097/BCR.0b013e318233fc64
  20. Chrisp P, McTavish D (1991) Levamisole/fluorouracil. Drugs Aging 1:317–337. doi: 10.2165/00002512-199101040-00007 CrossRefPubMedGoogle Scholar
  21. Chung C, Tumeh PC, Birnbaum R et al (2011) Characteristic purpura of the ears, vasculitis, and neutropenia—a potential public health epidemic associated with levamisole-adulterated cocaine. J Am Acad Dermatol 65(722–725):e2. doi: 10.1016/j.jaad.2010.08.024 Google Scholar
  22. Cooper KM, Whelan M, Danaher M, Kennedy DG (2011) Stability during cooking of anthelmintic veterinary drug residues in beef. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 28:155–165. doi: 10.1080/19440049.2010.542775 CrossRefPubMedGoogle Scholar
  23. Cossaart N, SantaCruz KS, Preston D et al (2003) Fatal chemotherapy-induced encephalopathy following high-dose therapy for metastatic breast cancer: a case report and review of the literature. Bone Marrow Transpl 31:57–60. doi: 10.1038/sj.bmt.1703768 CrossRefGoogle Scholar
  24. Crossley R (1995) Chirality and the biological activity of drugs. Taylor & Francis Group, Abingdon, UKGoogle Scholar
  25. Fassas AB, Gattani AM, Morgello S (1994) Cerebral demyelination with 5-fluorouracil and levamisole. Cancer Invest 12:379–383CrossRefPubMedGoogle Scholar
  26. Figueredo AT, Fawcet SE, Molloy DW et al (1995) Disabling encephalopathy during 5-fluorouracil and levamisole adjuvant therapy for resected colorectal cancer: a report of two cases. Cancer Invest 13:608–611CrossRefPubMedGoogle Scholar
  27. Freyer CW, Peters M (2012) Palpable purpura complicated by streptococcal toxic shock syndrome resulting in limb necrosis and amputation: a case of levamisole and cocaine coingestion. Pharmacother J Hum Pharmacol Drug Ther 32:e17–e23. doi: 10.1002/PHAR.1012 CrossRefGoogle Scholar
  28. Fucci N, Anonymous, Valentino AM et al (2007) Unusual adulterants in cocaine seized on Italian clandestine market. Forensic Sci Int 172:e1. doi: 10.1016/j.forsciint.2007.05.021 CrossRefPubMedGoogle Scholar
  29. Gaertner EM, Switlyk SA (2014) Dermatologic complications from levamisole-contaminated cocaine: a case report and review of the literature. Cutis 93:102–106PubMedGoogle Scholar
  30. Gertner E, Hamlar D (2002) Necrotizing granulomatous vasculitis associated with cocaine use. J Rheumatol 29:1795–1797PubMedGoogle Scholar
  31. González-Duarte A, Williams R (2013) Cocaine-induced recurrent leukoencephalopathy. Neuroradiol J 26:511–513CrossRefPubMedPubMedCentralGoogle Scholar
  32. Graf J, Lynch K, Yeh C-L et al (2011) Purpura, cutaneous necrosis, and antineutrophil cytoplasmic antibodies associated with levamisole-adulterated cocaine. Arthritis Rheum 63:3998–4001. doi: 10.1002/art.30590 CrossRefPubMedGoogle Scholar
  33. Gulati S, Donato AA (2012) Lupus anticoagulant and ANCA associated thrombotic vasculopathy due to cocaine contaminated with levamisole: a case report and review of the literature. J Thromb Thrombolysis 34:7–10. doi: 10.1007/s11239-012-0711-0 CrossRefPubMedGoogle Scholar
  34. Hantson P, Di Fazio V, Del Mar Ramirez Fernandez M et al (2015) Susac-like syndrome in a chronic cocaine abuser: could levamisole play a role? J Med Toxicol 11:124–128. doi: 10.1007/s13181-014-0422-3 CrossRefPubMedGoogle Scholar
  35. Hernando G, Berge I, Rayes D, Bouzat C (2012) Contribution of subunits to caenorhabditis elegans levamisole-sensitive nicotinic receptor function. Mol Pharmacol 82:550–560. doi: 10.1124/mol.112.079962 CrossRefPubMedGoogle Scholar
  36. Hess C, Ritke N, Broecker S et al (2013) Metabolism of levamisole and kinetics of levamisole and aminorex in urine by means of LC-QTOF-HRMS and LC-QqQ-MS. Anal Bioanal Chem 405:4077–4088. doi: 10.1007/s00216-013-6829-x CrossRefPubMedGoogle Scholar
  37. Hess C, Ritke N, Sydow K et al (2014) Determination of levamisole, aminorex, and pemoline in plasma by means of liquid chromatography-mass spectrometry and application to a pharmacokinetic study of levamisole. Drug Test Anal 6:1049–1054. doi: 10.1002/dta0.1619 CrossRefPubMedGoogle Scholar
  38. Hodinka L, Géher P, Merétey K et al (1981) Levamisole-induced neutropenia and agranulocytosis: association with HLA B27 leukocyte agglutinating and lymphocytotoxic antibodies. Int Arch Allergy Appl Immunol 65:460–464CrossRefPubMedGoogle Scholar
  39. Hofmaier T, Luf A, Seddik A et al (2014) Aminorex, a metabolite of the cocaine adulterant levamisole, exerts amphetamine like actions at monoamine transporters. Neurochem Int 73:32–41. doi: 10.1016/j.neuint.2013.11.010 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Hook CC, Kimmel DW, Kvols LK et al (1992) Multifocal inflammatory leukoencephalopathy with 5-fluorouracil and levamisole. Ann Neurol 31:262–267. doi: 10.1002/ana.410310306 CrossRefPubMedGoogle Scholar
  41. Indorato F, Romano G, Barbera N et al (2016) Levamisole-adulterated cocaine: two fatal case reports and evaluation of possible cocaine toxicity potentiation. Forensic Sci Int 265:103–106. doi: 10.1016/j.forsciint.2016.01.005 CrossRefPubMedGoogle Scholar
  42. Karch SB, Defraia B, Messerini L et al (2014) Aminorex associated with possible idiopathic pulmonary hypertension in a cocaine user. Forensic Sci Int 240:e7–e10. doi: 10.1016/j.forsciint.2014.03.028 CrossRefPubMedGoogle Scholar
  43. Kimmel DW, Wijdicks EF, Rodriguez M (1995) Multifocal inflammatory leukoencephalopathy associated with levamisole therapy. Neurology 45:374–376CrossRefPubMedGoogle Scholar
  44. Knowles L, Buxton JA, Skuridina N et al (2009) Levamisole tainted cocaine causing severe neutropenia in Alberta and British Columbia. Harm Reduct J 6:30. doi: 10.1186/1477-7517-6-30 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Kouassi E, Caillé G, Léry L et al (1986) Novel assay and pharmacokinetics of levamisole andp-hydroxylevamisole in human plasma and urine. Biopharm Drug Dispos 7:71–89. doi: 10.1002/bdd.2510070110 CrossRefPubMedGoogle Scholar
  46. Larocque A, Hoffman RS (2012) Levamisole in cocaine: unexpected news from an old acquaintance. Clin Toxicol (Phila) 50:231–241. doi: 10.3109/15563650.2012.665455 CrossRefGoogle Scholar
  47. Liu HM, Hsieh WJ, Yang CC et al (2006) Leukoencephalopathy induced by levamisole alone for the treatment of recurrent aphthous ulcers. Neurology 67:1065–1067. doi: 10.1212/01.wnl.0000237344.06122.79 CrossRefPubMedGoogle Scholar
  48. Long L, Song Y, Xu L, Xiao B (2015) Levamisole-induced leukoencephalopathy mimicking Baló disease. Neurology 84:328. doi: 10.1212/WNL.0000000000001150 CrossRefPubMedGoogle Scholar
  49. Luppi G, Zoboli A, Barbieri F et al (1996) Multifocal leukoencephalopathy associated with 5-fluorouracil and levamisole adjuvant therapy for colon cancer. A report of two cases and review of the literature. Ann Oncol 7:412–415. doi: 10.1093/oxfordjournals.annonc.a010610 CrossRefPubMedGoogle Scholar
  50. Luyckx M, Rousseau F, Cazin M et al (1982) Pharmacokinetics of Levamisole in healthy subjects and cancer patients. Eur J Drug Metab Pharmacokinet 7:247–254. doi: 10.1007/BF03189626 CrossRefPubMedGoogle Scholar
  51. Marinelli MA, McGhee J (2012) Clinical pathologic conference: a 51-year-old man with rash and joint pain. Acad Emerg Med 19:e41–e44. doi: 10.1111/j.1553-2712.2012.01398.x CrossRefPubMedGoogle Scholar
  52. Martinez-Cabriales S, Ocampo-Garza J, Barbosa-Moreno L, et al (2015) Purpura fulminans 10 years after contaminated cocaine use. Lancet (London, England) 386:e21. doi: 10.1016/S0140-6736(15)60069-1 CrossRefGoogle Scholar
  53. McGrath MM, Isakova T, Rennke HG et al (2011) Contaminated cocaine and antineutrophil cytoplasmic antibody-associated disease. Clin J Am Soc Nephrol 6:2799–2805. doi: 10.2215/CJN.03440411 CrossRefPubMedPubMedCentralGoogle Scholar
  54. Metwally O, Hamidi M, Townsend L et al (2013) The cocaine trail: levamisole-induced leukocytoclastic vasculitis in a cocaine user. Subst Abus 34:75–77. doi: 10.1080/08897077.2012.718318 CrossRefPubMedGoogle Scholar
  55. Moertel CG, Fleming TR, Macdonald JS et al (1990) Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322:352–358. doi: 10.1056/NEJM199002083220602 CrossRefPubMedGoogle Scholar
  56. Muirhead TT, Eide MJ (2011) Images in clinical medicine. Toxic effects of levamisole in a cocaine user. N Engl J Med 364:e52. doi: 10.1056/NEJMicm1008722 CrossRefPubMedGoogle Scholar
  57. Orriols R, Muñoz X, Ferrer J et al (1996) Cocaine-induced Churg-Strauss vasculitis. Eur Respir J 9:175–177CrossRefPubMedGoogle Scholar
  58. Pawlik E, Mahler H, Hartung B et al (2015) Drug-related death: adulterants from cocaine preparations in lung tissue and blood. Forensic Sci Int 249:294–303. doi: 10.1016/j.forsciint.2015.02.006 CrossRefPubMedGoogle Scholar
  59. Pearson T, Bremmer M, Cohen J, Driscoll M (2012) Vasculopathy related to cocaine adulterated with levamisole: a review of the literature. Dermatol Online J 18:1PubMedGoogle Scholar
  60. Pellegrini D, Young P, Grosso V et al (2013) [Agranulocytosis induced by levamisole in association to cocaine]. Medicina (B Aires) 73:464–466.Google Scholar
  61. Reid JM, Kovach JS, O’Connell MJ et al (1998) Clinical and pharmacokinetic studies of high-dose levamisole in combination with 5-fluorouracil in patients with advanced cancer. Cancer Chemother Pharmacol 41:477–484. doi: 10.1007/s002800050770 CrossRefPubMedGoogle Scholar
  62. Rongioletti F, Ghio L, Ginevri F et al (1999) Purpura of the ears: a distinctive vasculopathy with circulating autoantibodies complicating long-term treatment with levamisole in children. Br J Dermatol 140:948–951. doi: 10.1046/j.1365-2133.1999.02833.x CrossRefPubMedGoogle Scholar
  63. Scheinfeld N, Rosenberg JD, Weinberg JM (2004) Levamisole in dermatology. Am J Clin Dermatol 5:97–104. doi: 10.2165/00128071-200405020-00004 CrossRefPubMedGoogle Scholar
  64. Shu YZ, Kingston DG, Van Tassell RL, Wilkins TD (1991) Metabolism of levamisole, an anti-colon cancer drug, by human intestinal bacteria. Xenobiotica 21:737–750. doi: 10.3109/00498259109039513 CrossRefPubMedGoogle Scholar
  65. Silvestri E, Emmi G, D’Elios MM et al (2011) Pulmonary hemorrhage: not only vasculitis. Intern Emerg Med 6:577–580. doi: 10.1007/s11739-011-0655-y CrossRefPubMedGoogle Scholar
  66. Spector S, Munjal I, Schmidt DE (1998) Effects of the immunostimulant, levamisole, on opiate withdrawal and levels of endogenous opiate alkaloids and monoamine neurotransmitters in rat brain. Neuropsychopharmacology 19:417–427. doi: 10.1016/S0893-133X(98)00034-7 CrossRefPubMedGoogle Scholar
  67. Symoens J, Veys E, Mielants M, Pinals R (1978) Adverse reactions to levamisole. Cancer Treat Rep 62:1721–1730PubMedGoogle Scholar
  68. Szeto C-C, Gillespie KM, Mathieson PW (2000) Levamisole induces interleukin-18 and shifts type 1/type 2 cytokine balance. Immunology 100:217–224. doi: 10.1046/j.1365-2567.2000.00042.x CrossRefPubMedPubMedCentralGoogle Scholar
  69. Tallarida CS, Egan E, Alejo GD et al (2014) Levamisole and cocaine synergism: a prevalent adulterant enhances cocaine’s action in vivo. Neuropharmacology 79:590–595. doi: 10.1016/j.neuropharm.2014.01.002 CrossRefPubMedPubMedCentralGoogle Scholar
  70. Thompson JS, Herbick JM, Klassen LW et al (1980) Studies on levamisole-induced agranulocytosis. Blood 56:388–396PubMedGoogle Scholar
  71. Tran H, Tan D, Marnejon TP (2013) Cutaneous vasculopathy associated with levamisole-adulterated cocaine. Clin Med Res 11:26–30. doi: 10.3121/cmr.2012.1085 CrossRefPubMedPubMedCentralGoogle Scholar
  72. Trautmann F, Kilmer B, Turnbull P (2013) Further insights into aspects of the EU illicit drugs market. Publications Office of the European Union, Luxemburg. doi: 10.2838/92919 Google Scholar
  73. Tsai M-H, Yang J-H, Kung S-L, Hsiao Y-P (2013) Levamisole-induced myopathy and leukocytoclastic vasculitis: a case report and literature review. Dermatol Ther 26:476–480. doi: 10.1111/dth.12018 CrossRefPubMedGoogle Scholar
  74. Tseng W, Sutter ME, Albertson TE (2014) Stimulants and the lung. Clin Rev Allergy Immunol 46:82–100. doi: 10.1007/s12016-013-8376-9 CrossRefPubMedGoogle Scholar
  75. UNODC (2015) World Drug Report 2015. United Nations, United Nations Office on Drugs and Crime, Vienna, AustriaCrossRefGoogle Scholar
  76. Van Laar M, Cruts G, Van Ooyen-Houben M et al (2015) The netherlands drug situation 2014. Trimbos institute, Utrecht, The NetherlandsGoogle Scholar
  77. Van Der Veer T, Pennings E, Tervaert JW, Korswagen LA. (2015) Levamisole-contaminated cocaine: a hairy affair. BMJ Case Rep. doi: 10.1136/bcr-2015-210970 PubMedGoogle Scholar
  78. Vogel CL, Silverman MA, Mansell PW et al (1980) Mechanisms of levamisole-induced granulocytopenia in breast cancer patients. Am J Hematol 9:171–183CrossRefPubMedGoogle Scholar
  79. Woestenborghs R, Michielsen L, Heykants J (1981) Determination of levamisole in plasma and animal tissues by gas chromatography with thermionic specific detection. J Chromatogr 224:25–32CrossRefPubMedGoogle Scholar
  80. Wolford A, McDonald TS, Eng H et al (2012) Immune-mediated agranulocytosis caused by the cocaine adulterant levamisole: a case for reactive metabolite(s) involvement. Drug Metab Dispos 40:1067–1075. doi: 10.1124/dmd.112.045021 CrossRefPubMedGoogle Scholar
  81. Woolverton WL, Massey BW, Winger G et al (1994) Evaluation of the abuse liability of aminorex. Drug Alcohol Depend 36:187–192CrossRefPubMedGoogle Scholar
  82. Xu N, Zhou W, Li S et al (2009) Clinical and MRI characteristics of levamisole-induced leukoencephalopathy in 16 patients. J Neuroimag 19:326–331. doi: 10.1111/j.1552-6569.2008.00344.x CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Tibor Markus Brunt
    • 1
  • Jorrit van den Berg
    • 2
  • Ed Pennings
    • 3
  • Bastiaan Venhuis
    • 4
  1. 1.Netherlands Institute of Mental Health and AddictionUtrechtThe Netherlands
  2. 2.Netherlands Forensic InstituteThe HagueThe Netherlands
  3. 3.The Maastricht Forensic InstituteMaastrichtThe Netherlands
  4. 4.Laboratory for Health Protection ResearchNational Institute for Public Health and the Environment (RIVM)BilthovenThe Netherlands

Personalised recommendations