Mechanisms of Lorcaserin for Smoking Cessation

Identifying new medication options is critical for curbing the health burdens of cigarette smoking. Currently approved smoking cessation medications act on nicotinic receptors, and additional work is needed to identify medications with alternate pharmacological targets. Based on evidence that the serotonin system plays a role in nicotine consumption and relapse, this study will examine whether a selective serotonin medication alters smoking-related behaviors and responses to cigarette smoking under controlled conditions, informing its potential utility for smoking cessation.

Tobacco use remains the foremost cause of preventable deaths in the U.S. and worldwide. Advancing new smoking cessation therapies, including those with novel pharmacological targets, is a critical public health priority. The serotonin (5-hydroxtytryptamine; 5-HT) system is broadly implicated in the regulation of reward- related behavior, including drug seeking, in part reflecting its modulatory role in dopamine (DA) function. Recent studies show that targeted manipulation of the serotonin 5-HT2C receptor alters drug-related behavior; in particular, 5-HT2C receptor agonists are shown to reduce nicotine intake and reinstatement. Of the selective 5-HT2C receptor agonists, lorcaserin has the best near-term potential for repurposing as a smoking cessation therapy, having been approved by the U.S. Food and Drug Administration for weight management. Preclinical findings implicate several potential behavioral mechanisms by which 5-HT2C receptor agonists might reduce drug intake, including drug-specific processes (e.g., incentive salience of drug cues, self-administration, reinstatement) and drug-nonspecific behaviors (e.g., reductions in impulsivity). To date, potential mechanisms of 5-HT2C receptor agonists have not been characterized in human studies. Given emerging interest in lorcaserin as a novel smoking cessation therapy, further studies are needed to evaluate its efficacy profile, including studies to evaluate candidate treatment mechanisms. This human laboratory investigation will examine the effects of lorcaserin vs. placebo on relapse-related outcomes using a double-blind, within-subjects, crossover design. Impulsivity subdomains will also be examined as candidate mechanisms for medication effects. By evaluating an approved 5-HT2C agonist with emergent efficacy for smoking cessation, this project has near-term potential to inform clinical applications of 5-HT2C agonists for addiction.

Participants first receive lorcaserin (10 mg BID) for 7 days. After a washout period of 7 days, they then receive placebo tablets (BID) for 7 days.

Participants first receive placebo (BID) for 7 days. After a washout period of 7 days, they then receive lorcaserin (10 mg BID) for 7 days.

Performance on a behavioral measure of impulsivity, the stop signal task. Reported is the stop signal reaction time, the number of milliseconds required to activate the "stop" process in the stop signal task.

Performance on a behavioral measure of reward sensitivity (response bias measure on a signal detection task). Response bias is computed by the following equation: 1/2 * log((# correct stim 1 * # incorrect stim 2)/(# incorrect stim 1 * # correct stim 2)) Stimulus 1 is associated with a higher proportion of correct feedback than Stimulus 2, and by computing the ratio above, we are able to determine the response bias of the participant. The response bias measure provides an objective measure of reward sensitivity (i.e., the degree to which participants are biased towards choosing the more frequently rewarded response).

Inclusion Criteria: age 18-65 smoking 5+ cigarettes per day (average) over the past year, with no period of abstinence > 90 days biochemical verification of smoking status at least low to moderate nicotine dependence reporting long-term motivation to quit smoking willingness to take study pills and complete study procedures willingness to complete lab sessions involving cigarette smoking Exclusion Criteria: meeting DSM-5 criteria for substance use disorder aside from tobacco use disorder and mild cannabis use disorder recent (30 day) illicit drug use (except marijuana), based on self-report and urine drug screen past 30-day use of tobacco cessation aids or nicotine/tobacco products other than cigarettes past 30-day use of SSRIs, other psychiatric medications, or weight control medications lifetime diagnosis of severe mental illness (e.g., psychotic or bipolar I disorder) significant medical or neurological illness, including severe hepatic impairment or cirrhosis, or insulin dependent diabetes actively engaged in smoking cessation treatments or a smoking cessation attempt (or intent to start an attempt in the next 90 days) interested in quitting smoking immediately (i.e., in the next two months) Medications contraindicated for use with lorcaserin or which have a significant interaction with lorcaserin body mass index (BMI) under normal range (BMI < 18 kg/m2) history of significant cardiovascular conditions including history of arrhythmias or heart block, heart failure, valvular heart disease, heart attack, stroke, unstable angina abnormal electrocardiogram (ECG) results nursing, pregnant, or anticipating pregnancy history of suicide attempt or recent suicidal thoughts (intent or plan) in the last month Plans to travel outside of the local area during the study period, or inability to commit to entire duration of study