It was a medical mystery. In the summer of 2008, a man and woman, both in their 20s and both cocaine users, were separately admitted to a Canadian hospital with unremitting fevers, flulike symptoms and dangerously low white blood cell counts. Their symptoms were consistent with a life-threatening immune-system disorder called agranulocytosis, which kills 7% to 10% of patients and is rare except in chemotherapy patients and those taking certain antipsychotic medications.Neither of the Canadian patients fit that bill, but they did have one thing in common: illegal drug use, says Dr. Nancy Zhu, who treated the patients during her hematology fellowship at the University of Alberta Hospital in Edmonton. "We were theorizing that maybe it was something in the cocaine," she says. The medical literature didn't contain any studies linking agranulocytosis with cocaine. However, earlier that same year, in April, a New Mexico lab had identified a small number of unexplained cases of the disorder, also in people who had snorted, injected or smoked cocaine. Later, in 2009, a few cocaine addicts in San Francisco — crack smokers, mostly — began displaying even stranger symptoms, like dead, darkened skin. "It looked like people were getting burns all over their body," says Dr. Jonathan Graf, a rheumatologist at the University of California, San Francisco. "[Their skin was] black, as if you had taken a cigarette butt to it. In some people, it was all over, on their legs and bellies."By this time, back in Canada, a toxicologist at Alberta Hospital had noticed an unusual chemical in the urine of the two cocaine-using patients: levamisole. Zhu contacted him and they put the puzzle together. Further research revealed that levamisole, a drug that was once used to treat colon cancer but is now reserved for veterinary use as a medication to get rid of worms, can cause agranulocytosis in humans. The "burns" seen in Californian patients, who were also suffering from agranulocytosis, were the result of skin infections related to patients' compromised immunity. There have now been several dozen cases of cocaine-related agranulocytosis reported in North America — and one known death. "For some reason, this drug called levamisole keeps popping up," Zhu says. Where is it coming from? According to the U.S. Drug Enforcement Agency, levamisole has become increasingly popular as a "cut" or diluting agent in cocaine and possibly some heroin. It is now found in 70% of all cocaine seized in the United States, up from 30% in 2008. Unlike most cuts — usually inert or relatively harmless substances like the B-vitamin inositol, which are added by lower-level dealers looking to stretch supplies — levamisole appears to be added to cocaine from the outset, in the countries of origin. The substance has been found in various concentrations in cocaine analyzed in various countries around the world, from Switzerland to Australia. And urine tests of cocaine users attending a drug clinic in San Francisco General Hospital in 2009 — one floor above Graf's office — found that 90% of samples were positive for levamisole; similar tests in Seattle revealed that 80% of cocaine users there had levamisole in their systems too."If it's showing up in all those different places, that's a prima facie indicator that it's happening at the highest levels of production," says Craig Reinarman, a sociologist at the University of California, Santa Cruz who has long studied cocaine. But since cocaine is illegal, there's no easy way to remove levamisole from the supply chain. Law enforcement could instead target large purchasers, possibly putting pressure on dealers to switch to other cuts.

Levamisole is cheap, widely available and seems to have the right look, taste and melting point to go unnoticed by cocaine users, which may alone account for the popularity of the cut.

"Ease of availability seems likely to be important," says Reinarman. "Let's remember that producer countries are widely agrarian." Levamisole is used on farms and its cost per gram is minimal.An understanding of how levamisole affects the body, however, may better explain its explosive popularity. A 1998 paper found that levamisole relieved symptoms of heroin withdrawal in rats and also raised levels of various brain chemicals related to drug highs. "It may increase dopamine and by so doing may enhance cocaine effects," speculates Dr. Nora Volkow, director of the National Institute on Drug Abuse. Research conducted by Eldo Kuzhikandathil, assistant professor of pharmacology at University of Medicine and Dentistry of New Jersey, suggests that levamisole may indirectly increase the number of D1 dopamine receptors in the brain by affecting gene expression there. "Cocaine increases D1 expression," he says, "And this would probably accentuate that," which could enhance both highs and craving.Levamisole also affects acetylcholine receptors throughout the body, which can boost heart rate — and studies of cocaine users show that they associate jumps in heart rate with getting high, spurring good feelings even before the drug hits the brain. A cut that accelerates heart rate might make them think that they're getting the real thing. In the brain, levamisole may affect the same acetylcholine receptors activated by nicotine, another addictive drug that raises dopamine levels — and another possible clue to levamisole's lure.
But despite the wide use of levamisole, cases of agranulocytosis are relatively uncommon. According to government surveys, nearly two million Americans have taken cocaine at least once in the last month. "Why aren't 90% of cocaine users [in San Francisco] getting sick?" says Graf, who says he sees about one case every few weeks, mostly in women. He suspects that men are less likely to be affected because they are less vulnerable to autoimmune disorders than women, but says that the truth is, no one really knows why certain users become ill. Zhu and Graf urge users who are suffering from fever or unexplained infections to seek medical help immediately — the sooner agranulocytosis is treated, the greater the odds of survival.



To both physicians, the biggest mystery may be the power of cocaine addiction itself. Some of Graf's patients waited months before seeking help, as patches of painful, blackened skin continued to grow — and some continued to use cocaine despite learning that it caused their immune problems and that they could require plastic surgery to avoid permanent disfigurement. Zhu has treated several patients with life-threatening infections, some needing breathing tubes and intensive care. "It's quite sad, every time they use [cocaine], it happens. They wind up in the hospital for several weeks and almost die. But as soon as they go home and back into that environment, the cycle begins again."