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

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.

Detection of Cutting Agents in Drug‐Positive Seized Exhibits within the United States

“…The first cases of toxicity due to the use of levamisole-tainted cocaine were reported in 2009 (39), and some studies already reported deaths as a result of complications secondary to this factor (32,33,(39)(40)(41). Multiple reports link the use of levamisoletainted cocaine to neutropenia, agranulocytosis, methemoglobinemia, and retiform purpura of the face and extremities (27,38,39,(41)(42)(43)(44)(45)(46)(47)(48)(49)(50).…”

Cocaine adulteration with the anthelminthic tetramisole (levamisole/dexamisole): Long‐term monitoring of its intake by chiral LC–MS/MS analysis of cocaine‐positive hair samples

“…21 Further, the pharmacological profile of dexamisole resembles in some respects that of tricyclic antidepressants. 22 In most countries, levamisole and tetramisole have been withdrawn from the market for medical treatment of humans due to serious adverse neurological, immunological, and inflammatory effects. In the past, it was also used as an immunostimulant in humans in the treatment of rheumatoid arthritis, AIDS, colorectal cancer, and nephrotic syndrome, for example.…”

“…21 Nowadays, levamisole is predominantly used as anthelminthic in veterinary medicine. 10,22,23 In spite of the potential harmful effects, biological specimens, such as blood or urine, are rarely tested for levamisole/tetramisole in forensic and clinical toxicology. 22 In most countries, levamisole and tetramisole have been withdrawn from the market for medical treatment of humans due to serious adverse neurological, immunological, and inflammatory effects.…”

Erythema elevatum diutinum-like vasculitis secondary to cocaine adulterated with levamisole

“…Cutaneous vasculitis with retiform purpura secondary to cocaine contaminated with levamisole has been well described in the literature . We report the first case of erythema elevatum diutinum (EED)‐like vasculitis secondary to levamisole exposure.…”

“…Levamisole is a synthetic imidazothiazole used as a cocaine‐bulking agent, which has been found in 66% of the cocaine supply in the US . Originally introduced as an anti‐helminthic drug and later found to have immunomodulatory properties, levamisole was eventually removed from the US market because of severe side effects, including agranulocytosis . LIV has been well described.…”