A Novel Drug Combination for Alcohol-Use Disorders: A Human Laboratory Study

Alcohol-use disorder (AUD) is an unrelenting public-health concern. AUD is characterized by perturbations of central monoamine (i.e., dopamine [DA], serotonin [5HT], and norepinephrine [NE]) systems making them a logical target for medications development. Individual monoamine-uptake inhibitors are moderately effective in a majority of the trials in which they were tested for managing AUD. Continuing to target monoamine-uptake inhibition for AUD is warranted, but novel strategies are needed to identify a highly efficacious pharmacotherapy. We propose to demonstrate the initial efficacy of an innovative pharmacological strategy for managing AUD: Triple Monoamine-Uptake Inhibition. Triple monoamine-uptake inhibitors are under development, but are not yet available commercially for human use. Combining available medications; however, makes it possible to achieve triple monoamine-uptake inhibition. Duloxetine (DUL), an antidepressant, has high affinity for the 5HT (ki = 0.8 nM) and NE (ki = 7.5 nM) transporters, but lower affinity for the DA transporter (ki = 240 nM). Methylphenidate (MTH) has high affinity for the DA transporter (ki = 34 nM), but lower affinity for the 5HT (ki = >10,000 nM) and NE (ki = 339 nM) transporters. We will combine DUL and MTH to functionally produce a triple monoamine-uptake inhibitor. A mixed-model study will be conducted in which separate cohorts of non-treatment-seeking AUD participants will be randomized to different maintenance doses of delayed-release DUL (i.e., DUL dose is a between-subject factor). Participants (N=16) in each DUL cohort will be maintained concurrently on varying doses of long-acting MTH (i.e., MTH dose is a within-subject factor). The reinforcing effects of alcohol (ALC) will be determined after participants in each DUL cohort are maintained for 6 days on each MTH dose. A reverse-engineered ALC self-administration (ALC SA) procedure with good predictive validity for clinical efficacy will be used to demonstrate the initial efficacy of DUL-MTH combinations. ALC craving will also be assessed. We hypothesize DUL-MTH combinations will produce an additive or supra-additive reduction in ALC SA relative to the constituent drugs alone. Innovations include: 1) testing a novel pharmacological strategy, triple monoamine-uptake inhibition, for AUD; 2) testing a combination of marketed drugs as opposed to waiting for compounds under development to be available for testing in humans, thereby impacting clinical research and practice more quickly; 3) the use of once-daily dosing formulations of the constituent compounds which will improve compliance when advanced to clinical trials or practice; 4) the use of a sophisticated ALC SA procedure; 5) testing multiple doses of DUL and MTH alone and in combination to identify the most effective and tolerable dose combination which will enhance the probability of success when advanced to a clinical trial or practice; and 6) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of DUL-MTH combinations for AUD.