Worldwide, the United Nations Office on Drugs and Crime (UNODC) estimates the global annual prevalence of cocaine use to be between .3 and .4 %, affecting 13–20 million individuals between 15 and 64 years of age. North America remains among the top 3 markets for cocaine with more than 5 million past year users and an estimated 3000 deaths annually due to cocaine use (United Nations Office on Drugs and Crime (UNODC) 2012). The impact of cocaine use disorders on our healthcare system is significant, making it a major public health issue. A recent US National Survey on Drug Use and Health noted that cocaine use disorders accounted for 8 % of all patients who entered substance abuse treatment programs (SAMHSA 2012a, b). Further, of patients 21 years or older, cocaine was found to be the most common illicit drug involved in drug-related emergency department (ED) visits, accounting for almost half of the approximately one million illicit drug-related ED visits annually (NIH-NIDA 2011). These drug-related ED visits cover a wide range of brain and cardiovascular-related disorders (Kosten et al. 2011). Brain disorders include seizures, strokes, movement disorders, more general neuropsychiatric impairment, and psychoses. Movement disorders associated with stimulants include chorea, dystonia, akathisia, and choreoathetosis. While cocaine-induced psychosis is uncommon, users can experience delusions of persecution and hallucinations of virtually any type. Cocaine’s profound effects on the cardiovascular system can result in serious and often lethal complications including myocardial ischemia and infarction, cardiomyopathy, myocarditis, arrhythmias, endocarditis, and aortic dissection. Within the first hour after cocaine intake, the risk of myocardial infarction (MI) is significant and is 23.7 times greater compared to 3 h following intake in individuals who are otherwise at low risk for MI (Mittleman et al. 1991). Chest pain is commonly experienced by cocaine users that present to emergency departments and is associated with acute MI in upward of 6 % of these patients (Mukherjee 2008). Obstructive coronary artery disease has been found in 35–40 % in patients that experience cocaine-induced chest pain that underwent diagnostic angiography (Dressler et al. 1990). Thus, developing a medication that would not only reduce the reinforcing properties of cocaine but also its many medical complications is a critical need. Although research is advancing, there are presently no FDA-approved pharmacotherapies for cocaine dependence (Kosten et al. 2011; Haile et al. 2012).

In terms of optimal pharmacotherapeutic interventions for the treatment of cocaine use disorder, characteristics such as agent duration of action and frequency of administration are primary considerations. Immunotherapies present a relevant and timely intervention, since they can be long-acting agents to prevent relapse as well as blocking a broad range of cocaine’s effects, including those in the central nervous system (e.g., reward, reinforcement, neuropsychiatric sequelae) as well as cardiovascular system. Active vaccines against cocaine have a substantial history of development and can potentially reduce reinforcement and some acute toxicity from cocaine (Kosten and Owens 2005; Orson et al. 2008; Haney and Kosten 2004). These vaccine-induced antibodies are meant to bind to cocaine molecules in the circulation, preventing their ability to traverse the blood–brain barrier, and prevent activation of the brain’s reinforcement pathways (e.g., dopamine activation of the nucleus accumbens) and thus blunt the addictive liability of cocaine. An important component of this capture of cocaine by the antibody is that bound cocaine molecules are metabolized into inactive compounds which minimally bind to the antibody and are subsequently excreted (Fox et al. 1996). The cocaine is broken down by pseudocholinesterase in the circulation or by nonenzymatic hydrolysis into inactive metabolites such as benzoylecgonine, ecgonine methylester, and benzoic acid body (Stewart et al. 1979). In theory, these inactive metabolites do not bind to the antibody. Therefore, free antibody is available to bind more cocaine, rather than remaining attached to metabolites. This detachment from inactive metabolites likely prolongs and potentiates the antibodies’ capacity for blocking more cocaine from entering the brain (Kosten et al. 2012).

This simple “sponge” model of anti-cocaine antibodies probably describes a significant component of their actions (Shen and Kosten 2011). However, these antibodies cannot indefinitely soak up the abused drugs since the total number of antibody binding sites is necessarily limited. Furthermore, not every cocaine molecule of a bolus dose can be tightly bound. The additional actions of the anti-cocaine antibodies act as pharmacokinetic buffers against the rapid transit of cocaine into the brain. The rapid brain accumulation within seconds from a bolus cocaine dose delivered by either smoked or intravenous cocaine administration is prevented by the relatively slower equilibrium developed between free and antibody-bound cocaine in the blood. Smoked cocaine administration is highly reinforcing while cocaine powder for intranasal administration has much less reinforcement for an equivalent dose (Nelson et al. 2006; Cornish and O’Brien 1996; Walsh et al. 2009; Smith et al. 2001; Rush et al. 1999). Furthermore, oral cocaine requires considerably larger doses to be as reinforcing as the intravenous route of administration. This need for an increased dose in part reflects that oral cocaine reaches the brain relatively slowly, and although high blood and brain levels can be attained, much higher levels are needed to produce euphoria or other reinforcing effects. The kinetic effects of a pool of antibodies in circulation may act in a similar way by slowing drug entry into the brain and reducing the reinforcing effects of this drug. Thus, the specificity and ability of antibodies to slow cocaine entry from the blood vessels into the brain, heart, and other key organs can be a more effective blocker of reinforcement and perhaps toxicity than a transporter-based antagonist. However, any antibody strategy will be a competitive antagonism that can be overridden by sufficient doses of cocaine. Overall, these immunotherapies are aids to prevent relapse among patients motivated to become and remain abstinent and are less likely to be successful for inducing abstinence among current heavily cocaine-dependent individuals. Vaccines also will be most successful in conjunction with other behavioral and pharmacological therapies (Kosten et al. 2012).