Quality & Science

Cocaine Vaccine: Research Review

by Diana Martinez, MD, and Pierre Trifilieff, PhD | October 14, 2014

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There are still no FDA-approved medications for cocaine use despite many clinical trials that have tested potential treatments. Recent research has instead focused on developing an anti-cocaine vaccine – while a review of the literature shows a vaccine could help in treatment, vaccines do not appear to directly address the underlying neurobiological mechanism behind addiction.

When cocaine is ingested, it passes into the bloodstream and then into the brain, where it greatly increases dopamine levels and produces subjective effects. The idea behind the vaccine is to get the body’s immune system to make antibodies against cocaine. Then, when cocaine is ingested, the antibodies will bind to the cocaine and trap it in the bloodstream. By binding to the cocaine molecule, the antibodies keep cocaine from crossing into the brain and effectively inhibit its pleasurable effects.

To create a vaccine, the body has to be convinced to generate antibodies against cocaine when it circulates through the bloodstream. Because cocaine is a small molecule, humans do not naturally generate these antibodies. Researchers have had success in generating an antibody response by conjugating a minor metabolite of cocaine (nor-cocaine) to a non-toxic subunit of cholera toxin (subunit B) - which is the protein secreted from the cholera bacteria. Once in the body, this compound is able to generate a very powerful immune response that causes the body to create antibodies quickly and in high levels. Vaccination therefore results in the production of IgG antibodies against cocaine that can rapidly neutralize cocaine as it enters the bloodstream.

Studies using this type of vaccine have been previously performed in human volunteers. The initial studies were very promising and showed that subjects who had a good antibody response to the vaccine (called TA-CD) significantly decreased their cocaine use (Martell et al, 2009 Arch.Gen.Psychiatry 66,1116–1123). These early results led to a larger study that was recently published and unfortunately did not show the same success (Kosten et al, 2014 Drug and Alcohol Dependence 140,42–47).

In Kosten’s recent study, three hundred actively using cocaine-dependent subjects with the willingness to quit or decrease cocaine use were enrolled, and were given either placebo or active vaccination. The subjects were then divided into three groups based on the levels of IgG they produced following vaccination: those who had high levels of IgG antibody, those who had low IgG levels and those who received placebo. The results showed that the cocaine-positive urine rates were not significantly different between the three groups at 16 weeks, even though the high IgG group was less likely to drop out of the study. Furthermore, at some points of the study, the high antibody group had more cocaine-positive urines than those with low IgG levels, which is the opposite of the expected outcome.

Why would some of the subjects who had the best response to the vaccine actually have more cocaine use? It’s likely that they were overcoming the effect of the vaccine (i.e. decrease pleasurable effect of cocaine) by taking more cocaine. This was shown in a previous study where cocaine-dependent subjects administered the vaccine were able to override the antibody response by taking more cocaine (Haney et al 2010, Biol Psychiatry.Jan 1;67(1):59-65). This can occur because the IgG antibody levels generated by the vaccine are finite. Taking higher doses of cocaine saturates the antibodies, so that free cocaine is then available to enter the brain.

A similar vaccine was made for nicotine dependence (nicVAX), which used a pseudomonas protein instead of cholera toxin, to generate an immune response. However, experiments using this vaccine showed a similar trajectory: promising early studies but larger Phase 3 studies were not able to confirm that the vaccine was effective in stopping smoking (Hoogsteder Addiction. 2014 Aug;109(8):1252-9).

These results raise an important issue. Patients who are greatly motivated to overcome their addiction may still benefit from these types of vaccines, particularly if it is combined with additional treatment. However, these vaccines themselves do not address the underlying neurobiology of addiction, which is a substantial shortcoming and likely explains the limited efficacy of this treatment.

Nonetheless, there is a significant population of patients who may be able to respond to treatment with the assistance of a vaccine that would help prevent relapses. To this end, there is work currently being done to develop enzymes that would rapidly metabolize the cocaine to inactive metabolites (Gao et al 2004 J. Pharmacol. Exp. Ther. 310, 1046–1052) and to develop vaccines that may be more effective than the TA-CD (Koob et al, 2011 CNS Neurol Disord Drug Targets. Dec;10(8):899-904).

Diana Martinez, MD

Dr. Martinez is an Associate Professor at Columbia University/New York State Psychiatric Institute. She is a psychiatrist and imaging researcher whose work has focused on using Positron Emission Tomography (PET) imaging in drug addiction. PET imaging allows the measurement of dopamine receptors and dopamine release in the human brain, and her work focuses on using this imaging technique, based on animal models of addiction, to better understand the neurochemistry of substance use disorders. Through these types of studies, her work is geared toward developing innovative treatments for addiction.

Pierre Trifilieff, PhD

Dr. Trifilieff is an Assistant Professor at INRA in the University of Bordeaux. His research focuses on the role of the mesolimbic dopaminergic transmission in physiologic and pathological conditions. Since the activity of the dopaminergic D2 receptor is altered in various psychiatric disorders that involve a dysregulation of the reward system, his work aims at unraveling the role of D2 receptor-dependent signaling in the modulation of reward processing and motivation. This includes studying the impact of D2 receptor manipulations on goal-directed behaviors as well as identifying environmental factors that impact D2-dependent signaling and related behaviors.