Pharmacotherapy development remains a critical objective for reducing health and societal burdens associated with alcohol use disorder (AUD). Developing targeted treatments for specific AUD subgroups is a key aim under the NIAAA medication development strategy. Among those with AUD, cigarette smokers comprise a sizable and critical subgroup with disproportionally high long-term health risks, making it a key priority to advance therapies for concurrent AUD and cigarette smoking. The serotonin (5-hydroxtytryptamine; 5-HT) system is broadly implicated in addictive behaviors, in part reflecting the role of 5-HT in modulating dopamine function. Preclinical studies of 5-HT receptor drugs have shown that targeted modulation of the 5-HT2C receptor (implicated in 5-HT-related inhibition of DA function) alters the consumption and reinstatement of addictive drugs, including alcohol and nicotine. Additionally, preclinical evidence shows that 5-HT2C receptor agonists attenuate behavioral indices of impulsivity. Of the selective 5-HT2C receptor agonists, lorcaserin has superior near-term potential for repurposing as an AUD therapy, having been approved by the Food and Drug Administration for weight management. A recent Phase II clinical trial supported efficacy of lorcaserin for smoking cessation; however, no human trials have examined lorcaserin's effects on alcohol-related outcomes or measures of impulsivity. Human laboratory medication trials offer a time- and cost-effective option for validating preclinical findings prior to larger randomized controlled trials, and for testing candidate treatment mechanisms. This application proposes a human laboratory screening trial to evaluate lorcaserin as a novel candidate therapy for smokers with AUD. The effects of lorcaserin vs. placebo will be evaluated in a double- blind, within-subjects, crossover study with human laboratory endpoints. This study will provide initial human data on the effects of a 5-HT2C receptor agonist in relation to alcohol-related outcomes, informing its potential for further evaluation as a candidate treatment for AUD.
Among those with alcohol use disorder (AUD), smokers are recognized as an important and high-risk clinical subgroup. Heavy drinkers who also smoke cigarettes face significantly increased risk for cancers and other negative health outcomes, relative to those who use alcohol or cigarettes only. Presently, there are no approved medications for the joint purpose of reducing drinking and smoking. Based on evidence that the serotonin system plays a role in both alcohol and nicotine consumption and relapse, this study aims to examine whether a recently approved serotonin medication alters alcohol and nicotine responses in smokers with AUD. This study will provide initial data on whether lorcaserin could be helpful those AUD, and whether the medication might prove useful as a joint treatment for alcohol and nicotine addiction.
