Laboratory Screening of Lorcaserin for Alcohol Use Disorder

Study Overview
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Brief Summary
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Heavy-drinking smokers, including those with alcohol use disorder (AUD), are at increased risk for numerous negative health outcomes relative to those who use alcohol or cigarettes only. Although heavy-drinking smokers are recognized as an important subgroup for clinical and public health interventions, there are presently no approved medications for the joint indication of alcohol reduction and smoking cessation. Based on evidence that the serotonin system plays a role in alcohol and nicotine consumption and relapse, this study aims to examine whether a serotonin medication alters alcohol and nicotine responses in smokers with AUD, informing its potential utility as a candidate therapy for this clinical subgroup.

Detailed Description
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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 objective. 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. 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. 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 Phase II human laboratory screening trial will evaluate lorcaserin as a novel candidate therapy for smokers with AUD. Effects of lorcaserin vs. placebo will be evaluated in a double-blind, within-subjects, crossover study with human laboratory endpoints. This study will provide early 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.

Official Title
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Human Laboratory Screening of Lorcaserin in Smokers With Alcohol Use Disorder

Conditions
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Alcohol Use Disorder, Tobacco Smoking

Intervention / Treatment
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* Drug: Lorcaserin Oral Tablet
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 21-65 Meeting DSM-5 criteria for current (past year) AUD, as well as current at-risk drinking (i.e., ≥14/21 drinks per week for women/men, on average), with at least four episodes of 4+/5+ drinks in the past 30 days Daily smoker, defined as reporting smoking 1+ cigarettes per day, on average, over the past 12 months Willingness to take study pills and complete study procedures Willingness to complete lab sessions involving alcohol administration Exclusion Criteria: Recent (30 day) illicit drug use (with the exception of cannabis) based on self-report or toxicology screen Meeting DSM-5 criteria for a past-year substance use disorder other than alcohol use disorder, tobacco use disorder, or mild cannabis use disorder Significant alcohol withdrawal, based on a Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-Ar) score of 8+ at baseline medical visit, or any reported history of severe withdrawal symptoms (e.g., seizures) Past 30-day use of nicotine replacement 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 based on medical staff (i.e., physician or nurse practitioner) evaluation including severe hepatic impairment or cirrhosis, insulin dependent diabetes Current alcohol or smoking cessation treatment or efforts to cut down on drinking/smoking Medications contraindicated for use with lorcaserin or which have a significant interaction with lorcaserin Body mass index (BMI) under normal range (<18kg/m2) History of significant cardiovascular conditions including history of arrhythmias or heart block, heart failure, valvular heart disease, heat attack, stroke, unstable angina Abnormal electrocardiogram (ECG) results Currently nursing, pregnant, or anticipating pregnancy history of suicide attempt or recent suicidal ideation (i.e., 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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lorcaserin first, then placebo<br>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. | Drug: Lorcaserin Oral Tablet<br>* Lorcasering 10mg Oral Tablet (BID)<br>* Other names: Belviq;|
| Placebo Comparator: Placebo first, then lorcaserin<br>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. | Drug: Placebo oral tablet<br>* Placebo Oral Tablet (BID)<br>* Other names: Placebo pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Laboratory Alcohol Consumption | Number of drinks consumed during a 2-hour alcohol self-administration session | Laboratory session following 7 days of medication or laboratory session following 7 days of placebo pills. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjective Responses to Alcohol | Maximum self-reported stimulation during alcohol self-administration, as measured by the Brief Biphasic Alcohol Effects Scale. The final reported score is the sum of each item in the stimulation scale divided by the total number of items (3). The range of scores is 0-10, with higher numbers indicating higher subjective stimulation from alcohol. | Laboratory session following 7 days of medication or laboratory session following 7 days of placebo pills | 
| Motivation to Consume Alcohol | Self-reported alcohol demand, as measured by elasticity in the Alcohol Purchase Task. Elasticity was computed according to Jacobs & Bickel (1999), using the estimated parameters a and b from the equation ln C = ln L + b(ln P) - aP, where C is number of drinks that would be consumed at price P, and L is a constant that represents the number of drinks consumed at P = 1. Overall elasticity is determined by computing elasticity (a-b(P)) for each price/consumption pair and taking the mean. Greater values of elasticity (i.e., less negative in this case) indicate increased willingness to consume the same number of drinks even as the price increases. | Laboratory session following 7 days of medication or laboratory session following 7 days of placebo pills. | 
| Motivation to Smoke Cigarettes | Self-reported cigarette demand, as measured by elasticity in the Cigarette Purchase Task. Elasticity was computed according to Jacobs & Bickel (1999), using the estimated parameters a and b from the equation ln C = ln L + b(ln P) - aP, where C is number of cigarettes that would be purchased at price P, and L is a constant that represents the number of cigarettes purchased at P = 1. Overall elasticity is determined by computing elasticity (a-b(P)) for each price/consumption pair and taking the mean. Greater values of elasticity (i.e., less negative in this case) indicate increased willingness to purchase the same number of cigarettes even as the price increases. | Laboratory session following 7 days of medication or laboratory session following 7 days of placebo pills. | 
| Daily Alcohol Consumption | Self-reported drinks per drinking day | During 7 days of medication or during 7 days of placebo pills. | 
| Cigarette Consumption | Number of cigarettes smoked per day | During 7 days of medication or during 7 days of placebo pills. |