Agonist Medications for the Treatment of Cocaine Use Disorder

Agonist Medications for the Treatment of Cocaine Use Disorder (Link to full-length article)

Author(s): S. Stevens Negus and Jack Henningfield


Cocaine addiction is a persistent and insidious public health problem. Despite evidence for sustained prevalence, clinical harm, and demand for treatment, the Food and Drug Administration (FDA) has yet to approve any pharmacotherapy. “Agonist” medications such as amphetamine maintenance have emerged as one intriguing but controversial class of candidates, and this Circumspectives Article presents pros and cons of agonist medications for treatment of cocaine use disorder from the perspectives of the empirical evidence and the regulatory challenges. Specifically, a substantial and growing body of evidence has been collected in laboratory animals, human laboratory studies, and clinical trials to support the potential therapeutic effectiveness of amphetamine and pharmacologically related “agonist” medications for treatment of cocaine use disorder. However, the use of these medications for this purpose would require FDA review and approval, and the path to FDA approval is impeded by significant obstacles. Drs. Negus and Henningfield discuss these issues and suggest future directions to (a) advance a candidate agonist medication toward FDA approval, and (b) clarify the mechanisms of action by which agonist medications reliably reduce cocaine consumption.



We recently reported that sub-chronic lisdexamfetamine treatment reduced cocaine choice in rhesus monkeys (Banks et al., Int J Neuropsychopharm doi: 10.1093/ijnp/pyv009). These results add to the growing evidence for effectiveness of maintenance on amphetamine or pharmacologically similar monoamine releasers to reduce cocaine self-administration. Lisdexamfetamine is intriguing as a candidate agonist medication because, as a prodrug for amphetamine, it displays a slower onset of action and potentially reduced abuse liability in comparison to amphetamine despite its status as a Schedule II drug by FDA.
Steve Negus
Posted: Mar 06, 2015 1:53 PM
It would certainly be of interest from a scientific perspective to evaluate effectiveness of RTI-336 in clinical trials. Prevailing evidence suggests that monoamine releasers are more effective monoamine uptake inhibitors to reduce metrics of cocaine use, and some citations on this point are provided in the manuscript. However, studies with a selective DA uptake inhibitor like RTI-336 would provide a strong test of this hypothesis.
Steve Negus
Posted: Mar 06, 2015 1:43 PM
Agonist medications seem to have a major role in treatment, at least at this time. Putting aside the problems with agonists, additional agonist medications are needed. The paper by Negus and Henningfield provides an excellent discussion of the issues in advancing an agonist medication for psychostimulant users. This comment focuses on an agonist medication that has been on the table for some time now. It is RTI-336 (Carroll FI, Howard JL, Howell LL, Fox BS, Kuhar MJ. Development of the Dopamine Transporter Selective RTI-336 as a Pharmacotherapy for Cocaine Abuse. AAPS Journal. 2006; 8(1): E196-E203. DOI: 10.1208/aapsj080124). A good agonist will be more specific than cocaine in that it should only target the “addicting” site of cocaine, the dopamine transporter; this will result in fewer “side effects”. It should enter the brain more slowly than cocaine, have a longer duration of action, and substitute for cocaine in behavioral experiments. RTI336 has these qualities (see paper referred to above). It has also passed phase I clinical trials and appears safe in humans. Funding and support is needed to move forward to phase II clinical trials. Overall, RTI-336 should be a serious consideration as an agonist medication for cocaine.
Mike Kuhar
Posted: Dec 22, 2014 2:06 PM

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