Neuropharmacology of levamisole and its phase I metabolites: lack of evidence for levamisole-cocaine interactions

The anthelmintic agent, levamisole, is a cocaine adulterant that causes serious adverse effects in humans. A number of hypotheses have been proposed to explain why levamisole is used as an adulterant. Here, we examined whether levamisole might enhance acute pharmacological effects of cocaine.

Levamisole and its phase I metabolites were tested for in vitro activity at monoamine receptors and transporters. The effect of levamisole (0.1-10 µM) on cocaine-induced inhibition of [³H]dopamine uptake was examined in rat brain synaptosomes. In vivo microdialysis in nucleus accumbens of male rats was employed to determine neurochemical effects of cocaine (1-3 mg/kg, intravenous), in the absence or presence of levamisole (1:1 ratio with cocaine).

Levamisole displayed no measurable activity at monoamine receptors or transporters. The metabolite aminorex acted as a potent substrate at transporters for dopamine, norepinephrine and serotonin, whereas rexamino had affinity for adrenoreceptors and weak substrate activity at norepinephrine transporters. Levamisole did not alter cocaine-induced inhibition of dopamine uptake in vitro. Administration of cocaine, or cocaine plus levamisole, produced similar increases in extracellular dopamine and locomotor stimulation in vivo.

We found no evidence that levamisole alters the acute pharmacological effects of cocaine in male rats. The metabolite aminorex is a potent monoamine transporter substrate which could contribute to effects of levamisole under certain conditions (e.g., repeated, high-dose exposure), but most studies in human users of levamisole-adulterated cocaine have failed to detect measurable quantities of aminorex.