It's a mystery worthy of Sherlock Holmes: Who put the veterinary worm medicine in cocaine? (And who would know more about cocaine than that connoisseur of the seven-per-cent solution?) The story started in April 2008 when the New Mexico Department of Health began investigating a cluster of cases of agranulocytosis in which no known cause was identified. The only feature these cases had in common was use of cocaine (powder and crack). But no association between cocaine use and agranulocytosis had ever been described. Eventually, the department identified 11 cases, including one patient who died of Serratia marcescens sepsis, and had an absolute neutrophil count of zero.

Meanwhile, in Canada, health officials reported detecting levamisole in clinical samples and drug paraphernalia of cocaine users diagnosed with agranulocytosis. Levamisole, a veterinary antihelminthic drug, is used mostly in animals as a dewormer. It also is used as adjunctive therapy for certain human malignancies, rheumatoid conditions, and skin diseases, but most significantly, it is known to cause agranulocytosis in a small percentage of patients exposed to it.

While these investigations were proceeding in New Mexico and Canada, 10 cases of agranulocytosis were identified in Washington state. Again, the only common thread was that all patients reported use of cocaine. So at that point, 21 otherwise unexplained cases of agranulocytosis were reported in the United States. But was levamisole the essential link that connected all these cases? It is important to understand that in clinical situations, the presence of levamisole is difficult to determine. Because the half-life of the drug is about five hours, it might not be detected unless specimens are obtained promptly. Nevertheless, tests were carried out in five of the 21 patients, and four tested positive for levamisole.

Although identified cases of agraunlocytosis associated with cocaine use are still relatively rare, the presence of levamisole in illicit samples is not at all unusual. In July 2009, the Drug Enforcement Administration announced that 69 percent of cocaine samples intercepted coming into the United States were adulterated with levamisole, at an average concentration of 10%.

Although it is not immediately obvious why drug traffickers would cut cocaine with a veterinary worm medicine, there have been some interesting hypotheses. One case report suggested that it might enhance cocaine-induced euphoria because levamisole increases dopamine levels in the brain's pleasure centers. (Ann Intern Med 2009;150[4]: 287.) A more detailed theory was posited by Raymon and Isenschmid in the Journal of Analytical Toxicology (2009;33[9]:620).

They pointed out the levamisole, like many antihelminthics, acts as an agonist at nicotinic receptors. This nicotinic effect, in fact, is responsible for levamisole's success as a dewormer. Just as the nicotinic actions of organophosphate insecticides or nerve agents cause uncontrollable muscle contractions, levamisole produces spastic paralysis in the worm, which releases its grip on the gastrointestinal tract, and is then expelled. The authors speculate that the nicotine-like effect at ganglia also may release norepinephrine and dopamine, enhancing sympathomimetic activity and elevating mood. Other neurotransmitters such as GABA, epinephrine, and glutamate may also be involved.

The take-home lesson for clinicians: If a patient comes in with otherwise unexplained neutropenia or agranulocytosis, take a careful history of possible illicit drug use.

Anthrax in Heroin

And as if it weren't enough to have to ask why a dewormer is in cocaine, recent events also force us to ask: How did anthrax show up in heroin?

Last December, health officials in Scotland reported that two, possible three, heroin users had died in the hospital of disseminated anthrax infection. By January, six anthrax deaths had been reported, with additional patients ill from the infection.

This had happened before. In 2000, a team from Oslo, Norway, published a case report describing a 49-year-old heroin skin-popper who was seen in the clinic for an infection in his right buttock. (Lancet 2000;356[9241]:1574.) He was afebrile, and had no detectable pus on incision. He was started on outpatient treatment with dicloxacillin.

Four days later he was brought to the emergency department, comatose and in shock. A spinal tap revealed hemorrhagic meningitis. He was started on treatment with high-dose penicillin, chloramphenicol, and dexamethasone. Surgical exploration found massive edema of the right buttock area but no pus or necrosis. CSF and wound cultures grew Bacillus anthracis. Despite therapy, the patient died on about the third hospital day. The authors hypothesized that he might have contracted anthrax from contaminated heroin, and pointed out that most of Europe's heroin supply originated in Pakistan, Afghanistan, and Iran, where anthrax spores are commonly found.

Was the contamination of heroin with B. anthracis inadvertent? It's possible, but with this recent cluster of cases, some health officials have suggested another explanation. Heroin is commonly cut with a variety of substances, either to increase bulk or to enhance the pharmacokinetics or effects of the drug. (See table.) Some have speculated that the heroin could have been adulterated with bone meal, an animal product that very well could contain anthrax spores.

In any event, it is important for clinicians to remember that it is never safe to assume that a skin infection in a drug user is just cellulitis or an uncomplicated abscess. Aside from the possibility that a drug user's immune system might be compromised, cases of wound botulism among black tar heroin users (Washington, 2003) and tetanus among injecting drug users (California, 1997) have been well documented. Gangrene is always a possibility, too. Now we can add injectional anthrax to the list of complications to consider in these patients.

Substances Used to Adulterate Heroin

Acetaminophen

Amphetamines

Caffeine

Cocaine

Fentanyl

Lead

Methaqualone

Noscapine

Phenobarbital

Procaine

Quinine

Scopolamine

Strychnine

Thallium

Sources: Goldfrank's Toxicologic Emergencies. New York: McGraw-Hill Professional; 2006; Forensic Sci Int 1994;64(2-3):171.