To the Editor:
Levamisole has been identified as an adulterant of illicit cocaine for several years. Levamisole is an imidazothiazole with anthelmintic and immunostimulating properties. It is the levo-isomer of tetramisole. Initially marketed as an antiparasitic, it is increasingly used in cancer management. Recently, the U.S. Drug Enforcement Administration reported that 30% of all seizures of cocaine bricks contained the anti-parasitic drug (1). In this Letter, we theorize about the possible pharmacological roles of levamisole and cocaine, pending the availability of experimental data to validate these assertions. Many anthelmintics have nicotine-like properties and mimic the effects of acetylcholine at the neuronal nicotinic receptors of autonomic ganglia and adrenal medulla. Levamisole is also a research ligand used in studying the variety of nicotinic acetylcholine receptors. As an antiparasitic, levamisole acts as a ganglionic nicotinic acetylcholine agonist. It causes muscular contraction of the worm and eventual spastic paralysis of the parasite, which can then be expelled. The nicotinic receptor bound by levamisole also stimulates the parasympathetic and sympathetic ganglia of susceptible worms and mammals given
the drug. Studies in the 1970s demonstrated increased sympathetic activity in dogs receiving levamisole (2), as well as mood elevation (3).
The autonomic nervous system (ANS) has three subdivisions: sympathetic, parasympathetic, and enteric nervous systems. Sensory inputs from the viscera modulate autonomic activity and participate in many important autonomic reflexes. These ascending neurons synapse in the intermediate gray matter of the spinal cord or in the brainstem nucleus of the solitary tract (through cranial nerves VII, IX, and X). Central control involves hypothalamic nuclei. The efferent pathway of the autonomic nervous system consists primarily of two neurons in series, pre- and postganglionic. Acetylcholine is the neurotransmitter released at the ganglionic synapse. Its effect is mediated by stimulation of a ganglionic or neuronal type of nicotinic receptor. Levamisole could stimulate this receptor, increasing the firing of postganglionic neurons and increasing the release of norepinephrine at sympathetic innervated synapses with peripheral tissue (Figure 1A), as suggested in animal studies (2). Cocaine increases sympathetic activity by blocking reuptake of norepinephrine at the postganglionic synapse. Additive, if not synergistic effects could be expected when the drugs are combined. Concerns of increased toxicity with exaggerated pressure response or development of arrhythmia could then arise when cocaine is combined with levamisole.
Reward or pleasurable effects of drugs have long been associated with increased dopamine in the meso-limbic system (4,5). In this system, dopamine containing neurons arise from the ventral tegmental area (VTA) and project to limbic structures such as nucleus accumbens (NAcc) (implicated in predicting reward and expressing adaptive behaviors), the ventral pallidum (with access to basal ganglia and motor control), the prefrontal cortex (behavioral control), and basolateral amygdala (stress responses). These structures in turn communicate back with the VTA primarily through glutamatergic or GABAergic neurons. Behavioral reinforcement is associated with increased dopamine in NAcc. Dopaminergic neurons in the VTA are under modulation by glutamate, an excitatory transmitter that causes an increased dopamine, and GABA, an inhibitory neurotransmitter that causes a decreased dopamine release (6). For example, cannabinoids and opiates are postulated to inhibit GABA release, indirectly stimulating dopaminergic transmission through disinhibition, resulting in euphoria. Interestingly, levamisole was used in the 1990s to alleviate opiate withdrawal in rats (7).
On the other hand, nicotine, and possibly ethanol, would cause a stimulation of glutamate release and increase dopamine in the same brain areas. Stimulation of cholinergic neurons is known to cause release of various neurotransmitters including dopamine, GABA, epinephrine, and glutamate. One possible explanation could be that levamisole potentiates the pleasurable or behavior-reinforcing effects associated with cocaine use through its nicotinic agonist pharmacology (Figure 1B). Whereas cocaine increases dopamine at the synaptic level through its blockade of reuptake, levamisole as a nicotinic agonist may work on glutamate containing neurons at the level of the cell body of the dopaminergic neuron, indirectly stimulating it through the release of excitatory glutamate. Thus, interactions of levamisole at central neuronal nicotinic acetylcholine receptors may explain the linkage with cocaine. The central effect of the combination could likely result in a greater chance of developing seizures (8). Although it was recently shown that levamisole is only a weak agonist of nicotinic receptors (9), the study was aimed at skeletal muscle type of nicotinic receptors. Other research has shown the complex modulatory effects of levamisole on human type neuronal populations of nicotinic receptors. Non-competitive binding of levamisole to central nicotinic receptors
resulted in potentiation or inhibition of acetylcholine responses and other nicotinic agonists, depending on the concentrations used in the in vitro assay (10).
The recent report of agranulocytosis after consumption of cocaine with levamisole suggests another possible toxic effect of levamisole (11). Although an immunostimulant drug, levamisole is also a thioazole. Drugs with reactive thiol groups can behave as haptens and trigger immune or cytotoxic responses, generally by opsonization of white blood cells and subsequent destruction resulting in agranulocytosis. For instance, thioazoles such as the antithyroid drug methimazole have been known for decades to be associated with such an immune response. Methimazole and other sulfur-containing drugs such as carbimazole, clozapine, dapsone, dipyrone, penicillins, procainamide, propylthiouracil, rituximab, sulfasalazine, and ticlopidine account for most clinical cases of non-chemotherapy-induced agranulocytosis. In 2008, at the Wayne County Medical Examiner’s Office in Detroit, Michigan, there were 372 postmortem cases in which
cocaine and/or its metabolites were detected in at least 1 specimen (out of 2412 tested). Of these, 136 (36.6%) also had levamisole present. Interestingly, 89 of these 136 cases (65.4%) had parent cocaine detected in blood, suggesting that levamisole is more likely to be detected after recent cocaine use. These findings are not surprising given the short half-lives of both drugs [cocaine, 0.7–1.5 h (12); levamisole, 5.6 ± 2.5 h (13)]. There were no cases in which levamisole was detected but cocaine and/or metabolites were not.
Although considered an adulterant, levamisole possesses its own pharmacology and potentially augments the euphoria and cocaine-associated toxicities through increased peripheral sympathetic activity and increased central neurotransmission. To validate and empirically prove this hypothesis, we encourage the publication of toxicity reports and new research involving the combination of levamisole and cocaine. Identifying such cases may be complicated by the many combinations of drugs often ingested with cocaine. Of the 372 cocaine-related postmortem cases described, 111 cases also contained detectable concentrations of 6-acetylmorphine in either blood (N = 56), vitreous humor (N = 44), or excretion fluids (N = 11). In addition, ethanol was detected in 99 (26.6%) of cocaine-positive cases. Other common findings included other opiates, antidepressants (cyclic and serotonin reuptake inhibitors), benzodiazepines, and atypical antipsychotics. Many of these drugs may themselves induce seizures.
Lionel P. Raymon
Daniel S. Isenschmid
