Scripps Research Institute scientists develop antidote for cocaine overdose

Scientists at The Scripps Research Institute have shown that an injectable solution can protect mice from an otherwise lethal overdose of cocaine. The findings could lead to human clinical trials of a treatment designed to reverse the effects of cocaine in case of emergency. Cocaine is involved in more than 400,000 emergency-room visits and about 5,000 overdose deaths each year in the United States.

The findings, reported recently in the journal Molecular Pharmaceutics, demonstrate the therapeutic potential of a human antibody against cocaine.

"This would be the first specific antidote for cocaine toxicity," said Kim Janda, PhD, senior author of the report. A pioneer in the field of vaccines against drugs of abuse, Janda is the Ely R. Callaway, Jr. Chair in Chemistry, a professor in the Department of Immunology and Microbial Science, and director of The Worm Institute for Research and Medicine, all at Scripps Research. "It's a human antibody so it should be relatively safe, it has a superior affinity for cocaine, and we examined it in a cocaine overdose model that mirrors a real-life scenario," he said.

Janda and his laboratory colleagues have been developing candidate vaccines against cocaine, heroin, nicotine, and even Rohypnol, the "date-rape" drug. But most of these have been active vaccines - solutions of drug-mimicking molecules that provoke a long-term antibody response against a drug, greatly reducing its ability to reach the brain. These are potentially useful against addiction and relapse, but take weeks to stimulate an effective antibody response and thus are of limited value in drug overdose emergencies, which require a fast-acting antidote. Cocaine is a leading cause of illegal-drug overdoses in developed countries; it can cause hyperthermia, irregular heartbeats, seizures and death.

One possibility for an antidote is a "passive" cocaine vaccine, a ready-made solution of antibodies much like those used to treat snakebite. As Janda and his colleagues have shown in previous research, injected drug-specific antibodies can swiftly remove drug molecules from the bloodstream. This immediately reduces a drug's direct effects on the heart and nearby organs, but it also pulls the drug from the organ where it does the most damage-the brain. If the drug molecules are small enough to cross the blood-brain barrier, the sudden lowering of their bloodstream concentration causes them to diffuse rapidly out of brain tissue.

Cocaine molecules are small enough to diffuse this way, and in 2005 Janda and his lab reported that injections of a mouse-derived anti-cocaine antibody, GNC92H2, could keep mice alive despite cocaine doses that killed unprotected mice. Mouse antibodies are not ideal for use in humans, though; they are "foreign" enough that human immune systems eventually develop a reaction against them.

This discovery holds promise for future human clinical trials to treat cocaine overdoses. According to the Scripps Institute, cocaine is responsible for more than 400,000 emergency department visits each year. The Centers for Disease Control and Prevention (CDC) cited and about 5,100 deaths from cocaine overdose in the United States in 2008. Cocaine overdose may present as acute psychosis or paranoia, anxiety, agitation, aggressive behavior, sleeplessness, seizures, delirium, rapid heart rate, tremors or hallucinations. It can also cause deadly heart attacks or arrhythmia.