Memory Reconsolidation Blockade as a Novel Intervention for Nicotine Dependence
Condition: Smoking Cessation
MeSH terms: Tobacco Use Disorder
Intervention: Propranolol; Placebo
Intervention description: 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.; 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.
Intervention MeSH terms: Propranolol
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 113.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Smoking cessation; propranolol; memory reconsolidation blockade; craving

Summary:

      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.
    

Eligibility criteria:

        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