[Acknowledgment—the authors acknowledge The American Academy of Addiction Psychiatry (AAAP) for helping to bring this article to fruition. The AAAP is a professional membership organization for learning and sharing about the science of Addiction Psychiatry translating the research into clinical practice. As relentless advocates for those suffering from the devastation of substance use disorders and mental health disorders, AAAP is driven to transform lives through a commitment to using evidenced-based research to continually improve clinical approaches and outcomes for patients.]
Illicit drug use is on the rise in the US. According to the National Survey on Drug Use and Health, 27 million people aged 12 years or older were illicit drug users in 2014—an increase from the 2002 to 2013 numbers. Results also indicate that 1.5 million people aged 12 years or older who were current users of cocaine (in all forms) included about 354,000 users of crack cocaine.1
According to the National Institute on Drug Abuse, the national cost of illicit drug use is $11 billion in health care and $193 billion overall (including costs related to crime and lost productivity).2 Improving treatments for illicit drug use may have a widespread effect on the affected individual, on his or her family, and on society as a whole.
There are no FDA-approved pharmacotherapies for cocaine use disorder. In this article we review the off-label use of promising medications for cocaine use disorder (Table). These treatments can be divided into 3 categories: dopaminergic agents, noradrenergic agents, and those with mixed mechanisms of action. Among these treatment targets are proteins with relatively frequent genetic variants that appear to mediate enhanced responses to specific pharmacotherapies. These proteins include metabolic enzymes, receptors, and receptor transducers that mediate the coupling of receptors to second messenger systems such as cyclic adenosine monophosphate.
We will focus specifically on dopamine β-hydroxylase (DβH), dopamine receptor, ankyrin repeat and kinase domain-containing 1 (ANKK1), and α1A-adrenoceptor(ADRA1A).
Dopaminergic agents include levodopa-carbidopa, dextroamphetamine, and lisdexamfetamine. Levodopa-carbidopa has been studied for the treatment of cocaine use disorder because of its ability to increase brain dopamine levels and subsequently correct cocaine-induced hypodopaminergia. Levodopa is able to cross the blood-brain barrier but is administered with carbidopa (a peripheral decarboxylase inhibitor) to slow the breakdown of levodopa and allow a greater portion of it to enter the brain rather than being metabolized to inactive compounds.3
The DβH gene polymorphism rs1611115 has been studied for pharmacogenetics matching with levodopa.4 This functional, regulatory polymorphism leads to a substantial 10- to 100-fold reduction in the amount of the DβH enzyme. With substantially lower DβH levels, the conversion of dopamine to norepinephrine is much slower and lower than normal. For patients with the low DβH activity genotypes (CT/TT) who were treated with levodopa, the odds of having cocaine-positive urine samples decreased significantly, compared with placebo. Individuals with the normal DβH activity genotype (CC) showed no differential levodopa response between active agent and placebo.
Dextroamphetamine, an amphetamine derivative, has also been studied for its ability to correct hypodopaminergia and decrease D2 receptor binding observed with chronic cocaine use.3 However, dextroamphetamine does this via reversal of the dopamine transporter, which results in indirect enhancement of dopaminergic function.
Lisdexamfetamine dimesylate is a prodrug consisting of dextroamphetamine covalently bonded to the amino acid lysine. Following oral administration, red blood cells convert lisdexamfetamine into dextroamphetamine (the active drug) by enzymatic rate-limited hydrolysis of lysine from amphetamine. The kinetics of the rate limiting is such that the medication has long-lasting effectiveness but a slow onset, similar to a sustained-release amphetamine preparation.5 Study participants who received lisdexamfetamine reported less need for cocaine than those given placebo.6 Although cocaine use did not differ between the lisdexamfetamine and placebo groups, lisdexamfetamine recipients reported significantly less craving than those given placebo.
Dr Andry is Addiction Psychiatry Fellow, Dr Shorter is Assistant Professor, and Dr Kosten is JH Waggoner Chair and Professor of Psychiatry, Neuroscience, Pharmacology, Immunology & Pathology and Co-Director, Dan Duncan Institute for Clinical and Translational Research at the The Menninger Department of Psychiatry & Behavioral Sciences, Baylor College of Medicine in Houston, TX. Dr Kosten is also Editor of the American Journal on Addictions, the official journal of the American Academy of Addiction Psychiatry. The authors report no conflicts of interest concerning the subject matter of this article.
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