Memory Reconsolidation Blockade as a Novel Intervention for Nicotine Dependence (SCP)

Smoking is the leading cause of preventable morbidity and mortality in the US. While approximately 70% of smokers attempt to quit each year, only 5-15% maintain abstinence for 12 months, even with effective pharmacological and psychological interventions. Novel therapies are needed for smoking cessation and relapse prevention. Previous studies show that early post-cessation craving or urge to smoke is a powerful predictor of relapse. A current model of the pathogenesis of addiction maintains that a substance of abuse causes a marked increase release in phasic dopamine release, which in turn strengthens or increases the salience of the memory of the drug experience, leading to a powerful and persistent memory that is easily activated, leading to drug craving and often to drug use. This highly salient memory is also implicated in the physiological arousal associated with craving responses to smoking cues. This process is thought to be implicated in relapse to drug use after even long periods of abstinence. Recent animal research indicates that retrieval returns a consolidated memory such as those associated with drug craving, to a labile state from which it must be restabilized to persist in a process termed reconsolidation. If memories of drug-related experiences are labile when reactivated, this could represent a window of opportunity in which the memory of drug use that underlies drug craving can be influenced pharmacologically. Our hypothesis is that post-reactivation administration of the B-adrenergic blocker, propranolol, following retrieval of drug-associated memories will reduce the strength or salience of the memory by influencing reconsolidation, a process called memory reconsolidation blockade. In this study we will test the hypothesis that a single dose of propranolol given one hour prior to smoking-related cue exposure (post-reactivation treatment) will decrease psychophysiological responses to smoking cues one week later and will predict clinical response to an ensuing series of 6 post-reactivation treatments with script-driven imagery and propranolol. In order to do so, we propose to conduct a randomized, double-blind, placebo-controlled trial of post-reactivation treatment with propranolol in 50 adult smokers. Outcome measures will include in physiological responses to smoking-related cues after one and six post-reactivation treatments and smoking behavior during the treatment and during a 3-month follow-up period.

SPECIFIC AIMS

1. To evaluate, in current smokers, the efficacy of a single dose of study medication given an hour prior to smoking-related cue exposure (post-reactivation treatment) on psychophysiological response to smoking cues one week later.
2. To evaluate, during the smoking cessation process, the clinical effect of study medication in an ensuing series of 6 post-reactivation treatments on psychophysiologic response to smoking cues measured one week after the last post-reactivation treatment.
3. To evaluate whether medication effect on psychophysiologic response during a single memory reactivation session with script-driven imagery will predict clinical response to an ensuing series of 6 post-reactivation treatments with script-driven imagery and study medication.
4. . To assess whether a single post-reactivation treatment or series of six post-reactivation treatments is associated with reduction in self-reported craving for cigarettes as assessed with the Tiffany QSU.
5. To assess whether a series of six post-reactivation treatments is associated with reduction in smoking as assessed with self-report of cigarettes smoked per day and expired air CO.

To achieve these aims, we will conduct a double-blind, randomized, placebo-controlled trial in a convenience sample of 50 smokers.

• Drug: Propranolol
  Visit 2 (first smoking-related memory reactivation session) the subject will be given 0.67 mg/kg (minimum 40 mg; maximum 80 mg) of short-acting propranolol (or placebo) rounded to the nearest 10 mg. Ninety minutes after this dose, if subject has tolerated the short-acting dose well, and if systolic blood pressure has not fallen by 10 mmHg or more to below 100 mmHg, the subject will be given oral long-acting propranolol 1 mg/kg (minimum 60 mg; maximum 120 mg) or placebo rounded to the nearest 20 mg. . If the subject tolerates the combination dose well, during treatment phase (from visit 7 to 12), both the short- and long-acting doses will be given together immediately prior to memory reactivation.
  Other Name: Inderal
• Drug: Placebo
  Visit 2 (first smoking-related memory reactivation session) the subject will be given 0.67 mg/kg (minimum 40 mg; maximum 80 mg) of short-acting propranolol (or placebo) rounded to the nearest 10 mg. Ninety minutes after this dose, if subject has tolerated the short-acting dose well, and if systolic blood pressure has not fallen by 10 mmHg or more to below 100 mmHg, the subject will be given oral long-acting propranolol 1 mg/kg (minimum 60 mg; maximum 120 mg) or placebo rounded to the nearest 20 mg. . If the subject tolerates the combination dose well, during treatment phase (from visit 7 to 12), both the short- and long-acting doses will be given together immediately prior to memory reactivation.
  Other Name: placebo

• Active Comparator: Propranolol
  Intervention: Drug: Propranolol
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

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Inclusion:

• Healthy smokers aged 18-65 who have smoked at least 10 cigarettes/day for the past 3 months

Exclusion:

• Age <18 or >65
• Systolic blood pressure <100 mm Hg;
• Medical condition that contraindicates the administration of propranolol, e.g., history of congestive heart failure, heart block, insulin-dependent diabetes, chronic bronchitis, emphysema, or asthma. With regard to asthma, because many persons who say they have had an asthma attack, especially as a child, may only have had hay fever, another allergy, or another non-asthmatic episode, a blanket exclusion criterion may be overly restrictive. Therefore, asthma attacks will only be exclusionary if they a.) occurred within the past ten years, b.) occurred at any time in life if induced by a B-blocker, or c.) are currently being treated, regardless of the date of last occurrence. Cardiological consultation will be obtained as necessary;
• Previous adverse reaction to, or non-compliance with, a B-blocker;
• Current use of medication that may involve potentially dangerous interactions with propranolol, including, other B-blockers, antiarrhythmics, or calcium channel blockers.
• Use of drugs of abuse other than nicotine or caffeine, such as opiates, marijuana, cocaine, or amphetamines, as determined by saliva or urine testing;
• Pregnancy (in women of child-bearing potential, a pregnancy test will be performed) or breast-feeding;
• Current PTSD, or psychotic, melancholic, or bipolar disorder
• Diagnosis of major depressive disorder in the past 6 months or HAM-D score >15 at screening
• Current participation in any additional nicotine dependence treatment.
• An urgent need to stop smoking: subjects who receive placebo may not achieve optimal smoking cessation results.
• Inability to understand the study's procedures, risks, and side effects, or to otherwise give informed consent for participation;
• Subject candidate does not understand English