Smoking Cessation, Tobacco Use Disorder
Conditions
Brief summary
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.
Detailed description
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.
Interventions
Lorcasering 10mg Oral Tablet (BID)
DRUGPlacebo oral tablet
Placebo Oral Tablet (BID)
Sponsors
The Mind Research Network
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. age 18-65 2. smoking 5+ cigarettes per day (average) over the past year, with no period of abstinence \> 90 days 3. biochemical verification of smoking status 4. at least low to moderate nicotine dependence 5. reporting long-term motivation to quit smoking 6. willingness to take study pills and complete study procedures 7. willingness to complete lab sessions involving cigarette smoking
Exclusion criteria
1. meeting DSM-5 criteria for substance use disorder aside from tobacco use disorder and mild cannabis use disorder 2. recent (30 day) illicit drug use (except marijuana), based on self-report and urine drug screen 3. past 30-day use of tobacco cessation aids or nicotine/tobacco products other than cigarettes 4. past 30-day use of SSRIs, other psychiatric medications, or weight control medications 5. lifetime diagnosis of severe mental illness (e.g., psychotic or bipolar I disorder) 6. significant medical or neurological illness, including severe hepatic impairment or cirrhosis, or insulin dependent diabetes 7. actively engaged in smoking cessation treatments or a smoking cessation attempt (or intent to start an attempt in the next 90 days) 8. interested in quitting smoking immediately (i.e., in the next two months) 9. Medications contraindicated for use with lorcaserin or which have a significant interaction with lorcaserin 10. body mass index (BMI) under normal range (BMI \< 18 kg/m2) 11. history of significant cardiovascular conditions including history of arrhythmias or heart block, heart failure, valvular heart disease, heart attack, stroke, unstable angina 12. abnormal electrocardiogram (ECG) results 13. nursing, pregnant, or anticipating pregnancy 14. history of suicide attempt or recent suicidal thoughts (intent or plan) in the last month 15. Plans to travel outside of the local area during the study period, or inability to commit to entire duration of study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Smoking Lapse | Laboratory session following 7 days of medication or placebo pills | Duration (in minutes) until lapsing to smoking during a 50-minute period |
| Laboratory Cigarette Smoking | Laboratory session following 7 days of medication or placebo pills | Number of cigarettes consumed during a 60-minute period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Impulsivity | Laboratory session following 7 days of medication or placebo pills. | 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. |
| Reward Sensitivity | Laboratory session following 7 days of medication or placebo pills. | 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). |
| Daily Cigarette Smoking | During 7 days of medication or during 7 days of placebo pills (difference score between weeks). | Cigarettes smoked per day |
Countries
United States
Participant flow
Pre-assignment details
Three participants provided informed consent. Due to the study being canceled, only two participants were assigned to condition.
Participants by arm
| Arm | Count |
|---|---|
| Lorcaserin First, Then Placebo Lorcaserin (10mg BID) for 7 days, then placebo pill (BID) for 7 days | 1 |
| Placebo First, Then Lorcaserin Placebo pill (BID) for 7 days, then lorcaserin (10mg BID) for 7 days | 1 |
| Total | 2 |
Baseline characteristics
| Characteristic | Lorcaserin First, Then Placebo | Placebo First, Then Lorcaserin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment United States | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 1 / 2 | 0 / 2 |
| serious Total, serious adverse events | 0 / 2 | 0 / 2 |
Outcome results
Primary
Laboratory Cigarette Smoking
Number of cigarettes consumed during a 60-minute period
Time frame: Laboratory session following 7 days of medication or placebo pills
Population: The trial was halted after randomizing the first two participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lorcaserin | Laboratory Cigarette Smoking | 4 number of cigarettes | Standard Deviation 1.41 |
| Placebo | Laboratory Cigarette Smoking | 3 number of cigarettes | Standard Deviation 1.41 |
Primary
Smoking Lapse
Duration (in minutes) until lapsing to smoking during a 50-minute period
Time frame: Laboratory session following 7 days of medication or placebo pills
Population: The trial was halted after randomizing the first two participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lorcaserin | Smoking Lapse | 16.5 minutes | Standard Deviation 4.9 |
| Placebo | Smoking Lapse | 30.5 minutes | Standard Deviation 0.71 |
Secondary
Daily Cigarette Smoking
Cigarettes smoked per day
Time frame: During 7 days of medication or during 7 days of placebo pills (difference score between weeks).
Population: The trial was halted after randomizing the first two participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lorcaserin | Daily Cigarette Smoking | 8.79 cigarettes per day | Standard Deviation 0.3 |
| Placebo | Daily Cigarette Smoking | 8.79 cigarettes per day | Standard Deviation 0.3 |
Secondary
Impulsivity
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.
Time frame: Laboratory session following 7 days of medication or placebo pills.
Population: The trial was halted after randomizing the first two participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lorcaserin | Impulsivity | 280.2 milliseconds | Standard Deviation 11.6 |
| Placebo | Impulsivity | 255.4 milliseconds | Standard Deviation 34.5 |
Secondary
Reward Sensitivity
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).
Time frame: Laboratory session following 7 days of medication or placebo pills.
Population: The trial was halted after randomizing the first two participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lorcaserin | Reward Sensitivity | .89 log(ratio) | Standard Deviation 0.51 |
| Placebo | Reward Sensitivity | .80 log(ratio) | Standard Deviation 0.41 |