A Novel Anti-Obesity Drug Combination as a Pharmacotherapy for Cocaine Dependence

Cocaine (COC) dependence is a significant public health concern. A widely effective
pharmacotherapy has not yet been identified for COC dependence. Innovative strategies are
needed to identify an effective pharmacotherapy for COC dependence. Testing medications
effective for disorders that share neurobiological substrates with drug dependence, for
example, could yield treatments for managing COC dependence.

Obesity is also a significant public health concern. Although obesity and COC dependence are
typically considered distinct clinical entities, both diseases involve perturbations of
central biogenic amine and/or hypothalamic-melanocortin systems. The obesity epidemic has
spurred development of medications to promote weight loss. A combination of bupropion (BUP)
and naltrexone (NTX) is effective for obesity. The overarching goal of this application is to
demonstrate the initial efficacy, safety, and tolerability of BUP-NTX combinations for COC
dependence. A mixed-model experiment will be conducted in which separate cohorts of
non-treatment-seeking, COC-dependent participants will be randomized to different maintenance
doses of NTX (i.e., NTX is a between-subject factor). Participants (N=12) in each NTX cohort
will be maintained concurrently on BUP (i.e., BUP is a within-subject factor). The
reinforcing effects of intranasal COC will be determined after participants in each NTX
cohort are maintained for 4-7 days on each of the BUP doses (i.e., COC is a within-subject
factor). COC (0, 40 and 80 mg) will be tested with multiple dose combinations of BUP (0, 100,
200, 400 mg/day) and NTX (0, 25, 50 mg/day). The proposed study will also identify the
optimal dose combination of BUP and NTX that most effectively attenuates the reinforcing
effects of COC.

This research will provide critical information regarding the initial efficacy and optimal
doses of a novel drug combination, BUP and NTX, for COC dependence, which will enhance the
probability of success when advanced to a clinical trial. Innovations of the proposed
research include: 1) testing a combination of marketed drugs that demonstrated modest
efficacy when tested as mono-therapies; 2) the use of a sophisticated drug
self-administration procedure; 3) providing the impetus for the conduct of a Phase II
clinical trial to further demonstrate the efficacy of BUP-NTX combinations for COC
dependence; and 4) demonstrating the initial efficacy and optimal doses of a combination of
commercially available drugs, as opposed to waiting for novel molecules to be available for
testing in humans, thereby impacting clinical research and practice more quickly. In these
ways, the proposed project will shift the current clinical research paradigm in
pharmacotherapy development and have a significant impact on the treatment of COC dependence.

Inclusion Criteria:

- Recent cocaine use

Exclusion Criteria:

- Abnormal screening outcome (e.g., ECG, blood chemistry result) that study physicians
deem clinically significant.

- Current or past histories of substance abuse or dependence that are deemed by the
study physicians to interfere with study completion.

- History of serious physical disease, current physical disease, impaired cardiovascular
functioning, chronic obstructive pulmonary disease, history of seizure or current or
past histories of serious psychiatric disorder that in the opinion of the study
physician would interfere with study participation will be excluded from
participation.

- Females not currently using effective birth control.

- Contraindications to cocaine, bupropion or naltrexone,