The Effects of Sedatives on Tobacco Use Disorder Version 2

Study Overview
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Brief Summary
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Double-blind, placebo-controlled, randomized mechanistic clinical trial to test an intravenous dose of either ketamine, midazolam, dexmedetomidine, or a placebo (saline) on cigarette smoking behavior, craving, and neural effects.

Detailed Description
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This double-blind, placebo-controlled, randomized mechanistic clinical trial will test non-treatment seeking smokers with an intravenous infusion of ketamine (0.71 mg/kg), midazolam (0.025 mg/kg), dexmedetomidine (0.025 mg/kg), or placebo, at least 2 weeks apart. Participants will complete 7-day ecological momentary assessment (EMA) of daily craving, withdrawal, and smoking behavior before and after each infusion. They will be asked to abstain from tobacco/nicotine for twenty-four hours post-infusion to induce withdrawal symptoms and return to the lab the following day to complete measures of craving, withdrawal, an MRI scan, and smoking latency. After this study visit, participants will be allowed to smoke as usual for the rest of the EMA diary period. Physical and subjective effects and adverse effects will be closely monitored throughout.

Official Title
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The Effects of Sedatives on Tobacco Use Disorder Version 2

Conditions
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Tobacco Smoking

Intervention / Treatment
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* Drug: Ketamine
* Drug: Midazolam
* Drug: Dexmedetomidine
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Smokes cigarettes daily for at least 2 years Afternoon expired breath carbon monoxide at least 5 ppm or morning urinary cotinine at least 100 ng/ml Negative urine drug screen for psychoactive drugs and negative breath alcohol Exclusion Criteria: Have an unstable medical condition or stable medical condition that would interact with study drug or participation, including chronic pulmonary disease, coronary artery disease, current brain tumor, current increased intracranial pressure or impaired consciousness History of serious head trauma or neurological disorder (e.g., seizure disorder) Have any of the following: hypertension (i.e., systolic >140 mm Hg and/or diastolic >90 mm Hg on three separate measures; systolic >170 or diastolic > 110 on any occasion), pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). Use of drugs that would interact with study drug or increase risk of adverse events Among women, pregnancy or lactation

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 55 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Saline first injection; ketamine second injection<br>Subjects in this arm will receive a single intravenous infusion of placebo at the first injection visit and a single intravenous infusion ketamine at the second injection visit. | Drug: Ketamine<br>* A single dose of IV ketamine will be administered.<br>* Other names: a dissociative anesthetic used medically for induction and maintenance of anesthesia;Drug: Saline<br>* A single dose of IV saline will be administered<br>|
| Experimental: Saline first injection; midazolam second injection<br>Subjects in this arm will receive a single intravenous infusion of placebo at the first injection visit and a single intravenous infusion midazolam at the second injection visit | Drug: Midazolam<br>* A single dose of IV midazolam will be administered<br>* Other names: benzodiazepine medication;Drug: Saline<br>* A single dose of IV saline will be administered<br>|
| Experimental: Saline first injection; dexmedetomidine second injection<br>Subjects in this arm will receive a single intravenous infusion of placebo at the first injection visit and a single intravenous infusion dexmedetomidine at the second injection visit. | Drug: Dexmedetomidine<br>* A single dose of IV dexmedetomidine will be administered<br>* Other names: benzodiazepine medication;Drug: Saline<br>* A single dose of IV saline will be administered<br>|
| Experimental: Ketamine first injection; Saline second injection<br>Subjects in this arm will receive a single intravenous infusion of ketamine at the first injection visit and a single intravenous infusion placebo at the second injection visit. | Drug: Ketamine<br>* A single dose of IV ketamine will be administered.<br>* Other names: a dissociative anesthetic used medically for induction and maintenance of anesthesia;Drug: Saline<br>* A single dose of IV saline will be administered<br>|
| Experimental: Ketamine first injection; midazolam second injection<br>Subjects in this arm will receive a single intravenous infusion of ketamine at the first injection visit and a single intravenous infusion midazolam at the second injection visit. | Drug: Ketamine<br>* A single dose of IV ketamine will be administered.<br>* Other names: a dissociative anesthetic used medically for induction and maintenance of anesthesia;Drug: Midazolam<br>* A single dose of IV midazolam will be administered<br>* Other names: benzodiazepine medication;|
| Experimental: Ketamine first injection; dexmedetomidine second injection<br>Subjects in this arm will receive a single intravenous infusion of ketamine at the first injection visit and a single intravenous infusion dexmedetomidine at the second injection visit. | Drug: Ketamine<br>* A single dose of IV ketamine will be administered.<br>* Other names: a dissociative anesthetic used medically for induction and maintenance of anesthesia;Drug: Dexmedetomidine<br>* A single dose of IV dexmedetomidine will be administered<br>* Other names: benzodiazepine medication;|
| Experimental: Midazolam first injection; Saline second injection<br>Subjects in this arm will receive a single intravenous infusion of midazolam at the first injection visit and a single intravenous infusion placebo at the second injection visit. | Drug: Midazolam<br>* A single dose of IV midazolam will be administered<br>* Other names: benzodiazepine medication;Drug: Saline<br>* A single dose of IV saline will be administered<br>|
| Experimental: Midazolam first injection; ketamine second injection<br>Subjects in this arm will receive a single intravenous infusion of midazolam at the first injection visit and a single intravenous infusion ketamine at the second injection visit. | Drug: Ketamine<br>* A single dose of IV ketamine will be administered.<br>* Other names: a dissociative anesthetic used medically for induction and maintenance of anesthesia;Drug: Midazolam<br>* A single dose of IV midazolam will be administered<br>* Other names: benzodiazepine medication;|
| Experimental: Midazolam first injection; dexmedetomidine second injection<br>Subjects in this arm will receive a single intravenous infusion of midazolam at the first injection visit and a single intravenous infusion dexmedetomidine at the second injection visit. | Drug: Midazolam<br>* A single dose of IV midazolam will be administered<br>* Other names: benzodiazepine medication;Drug: Dexmedetomidine<br>* A single dose of IV dexmedetomidine will be administered<br>* Other names: benzodiazepine medication;|
| Experimental: Dexmedetomidine first injection; Saline second injection<br>Subjects in this arm will receive a single intravenous infusion of dexmedetomidine at the first injection visit and a single intravenous infusion placebo at the second injection visit. | Drug: Dexmedetomidine<br>* A single dose of IV dexmedetomidine will be administered<br>* Other names: benzodiazepine medication;Drug: Saline<br>* A single dose of IV saline will be administered<br>|
| Experimental: Dexmedetomidine first injection; ketamine second injection<br>Subjects in this arm will receive a single intravenous infusion of dexmedetomidine at the first injection visit and a single intravenous infusion ketamine at the second injection visit. | Drug: Ketamine<br>* A single dose of IV ketamine will be administered.<br>* Other names: a dissociative anesthetic used medically for induction and maintenance of anesthesia;Drug: Dexmedetomidine<br>* A single dose of IV dexmedetomidine will be administered<br>* Other names: benzodiazepine medication;|
| Experimental: Dexmedetomidine first injection; midazolam second injection<br>Subjects in this arm will receive a single intravenous infusion of dexmedetomidine at the first injection visit and a single intravenous infusion midazolam at the second injection visit. | Drug: Midazolam<br>* A single dose of IV midazolam will be administered<br>* Other names: benzodiazepine medication;Drug: Dexmedetomidine<br>* A single dose of IV dexmedetomidine will be administered<br>* Other names: benzodiazepine medication;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in craving between drug and placebo | difference in self-reported craving for cigarettes after infusions | 24-hours post infusion | 
| Difference in tobacco withdrawal symptoms | difference in self-reported withdrawal symptoms after infusions | 24-hours post infusion | 
| Difference in cigarette demand | difference in self-reported cigarette demand after infusions | 24-hours post infusion | 
| Number of cigarettes smoked ad lib |  | 24-hours post infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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nicotine addiction, smoking, placebo, sedatives