Traditional, small-molecule approaches have only been marginally successful in developing innovative therapies for substance use disorders (SUDs). For example, there are no FDA-approved medications to treat stimulant (e.g., cocaine and methamphetamine) use disorders, and based on an analysis of trials listed on www.​clinicaltrials.​gov, no approvals are anticipated during the next 5–7 years. Even when multiple pharmacotherapies are available (e.g., anti-smoking medications), efficacy over the long term is disappointing. Thus, 1-year abstinence rates are less than 20 % for individuals treated with approved products (e.g., nicotine patches and gum, bupropion, and varenicline). There are multiple factors contributing to this dearth of pharmacotherapies, including a high regulatory “bar” for approval (a period of end-of-trial abstinence is currently the only acceptable endpoint measure) (McCann and Li 2012; Winchell et al. 2012; Donovan et al. 2012), low medication compliance during the conduct of clinical trials (Czobor and Skolnick 2011; Anderson et al. 2012, 2014; Somoza et al. 2013), and, with few exceptions, the perception by pharma that developing medications to treat SUDs will not provide a favorable return on investment in real-world practice (Acri and Skolnick 2013). Biological approaches offer an alternative that may resolve some of the drawbacks associated with conventional pharmacotherapies.

Biological approaches are all grounded on a common mechanism: either exclude or retard the entry of an abused substance from the central nervous system. There are currently three means of achieving this objective: (1) vaccines that stimulate the immune system to produce antibodies directed against a specific drug of abuse, (2) passive immunization by administering monoclonal antibodies directed against a specific drug of abuse, (3) genetically engineered esterases that catalyze the hydrolysis of cocaine at a rate >3 orders of magnitude higher than the wild-type enzyme.

Positive signals have been reported in proof of principle clinical trials with both a cocaine (TA-CD) and a nicotine vaccine (NicVax®) (Martell et al. 2009; reviewed in Shen and Kosten 2011; Kosten et al. 2014; Hatsukami et al. 2011) in subjects who developed relatively high titers of antidrug antibodies. Perhaps the principal challenge to developing effective vaccines to drugs of abuse is the inability of the immune system to recognize these low molecular weight molecules (e.g., nicotine, cocaine, heroin). These molecules are rendered antigenic through chemical modification, enabling covalent linkage to a protein (e.g., cholera toxin B in the case of the TA-CD cocaine vaccine) (Shen and Kosten 2011; Shen et al. 2012). Nonetheless, despite multiple immunizations, none of the vaccines developed to date resulted in high titers of high affinity antidrug antibodies in a majority of patients. This problem is exemplified in the Martell et al. (2009) report using the TA-CD cocaine vaccine. Robust antibody titers to cholera toxin B were noted in every patient, but far fewer than half of the patients achieved serum antibody levels high enough to affect cocaine use (Martell et al. 2009; Shen and Kosten 2011). Potential strategies to overcome this challenge include the use of more effective adjuvants, alternative vaccine platforms (adenovirus-based vaccines, nanoparticle-based vaccines, DNA scaffolded vaccines), and the design of more effective haptens, topics that will be reviewed in this volume.

In contrast to the vaccines described here that require multiple immunizations to raise therapeutically relevant levels of antibodies (Hatsukami et al. 2011; Martell et al. 2009), monoclonal antibodies provide passive immunization and are thus immediately effective upon administration. Clinical studies have been initiated with a monoclonal antibody directed against methamphetamine (Owens et al. 2011), with first-in-man studies completed in 2013 (Stevens et al. 2014). The limitations of monoclonal antibodies include the potential cost of a commercial product and a limited biological half-life, which could necessitate weekly to monthly administration. Novel technologies that may lower manufacturing costs and the ability to genetically engineer mABs with significantly longer biological half-lives may contribute to the development of a commercially viable treatment for stimulant use disorders. These approaches are also described in this volume.

Also described in this volume is the genetic modification of wild-type enzymes derived from both bacteria and humans that results in an extraordinarily rapid hydrolysis of cocaine. Point mutations in these enzymes can increase the catalytic rate by more than 1000-fold compared to the wild-type enzyme. For example, administration of a mutated butyrylcholinesterase linked to serum albumin dramatically reduces both the toxicological and behavioral effects of cocaine in rodents and nonhuman primates. These effects are attributable to a rapid degradation of cocaine in plasma (and a corresponding rise in a hydrolysis product of cocaine, ecgonine methyl ester) (reviewed in Brimijoin 2011; Schindler et al. 2013). A Phase II facilitation of abstinence study of this product (TV 1380) in cocaine-dependent subjects has recently been completed (www.clinicaltrials.gov). In this study, the enzyme was administered weekly because of its proteolytic degradation. However, recent studies in rodents (Zlebnik et al. 2014) have demonstrated that gene transfer of this enzyme using an adenovirus vector results in a sustained (lasting for the duration of the study, >2 months) reduction in the reinforcing effects of intravenously administered cocaine. Reckitt Benckiser Pharmaceuticals recently reported (Nasser et al. 2014) that a mutated form of bacterial cocaine esterase reduced cocaine plasma exposures by >90 % in response to an intravenous cocaine challenge (50 mg infused over 10 min) in non-treatment seeking volunteers. The sponsor is developing this bacterially derived enzyme as a pharmacotherapy for cocaine intoxication (Nasser et al. 2014).