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Memory Reconsolidation Blockade as a Novel Intervention for Nicotine Dependence

Information source: Massachusetts General Hospital
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Smoking Cessation

Intervention: Propranolol (Drug); Placebo (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Massachusetts General Hospital

Official(s) and/or principal investigator(s):
A. Eden Evins, MD, MPH, Principal Investigator, Affiliation: Massachusetts General Hospital


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.

Clinical Details

Official title: Memory Reconsolidation Blockade as a Novel Intervention for Nicotine Dependence

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Primary outcome:

Change in the Skin Conductance Level, Caused by Smoking Cues, Measured Using Script Driven Imagery

Change in Heart Rate (Beats Per Minute), Caused by Smoking Cues, Measured Using Script Driven Imagery

Change in the Corrugator Muscle (EMG) Level, Caused by Smoking Cues, Measured Using Script Driven Imagery

Secondary outcome: Change in Craving Level to Smoking Cues Caused by Smoking Cues, Measured Using Script Driven Imagery

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


Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.



- 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


- 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

Locations and Contacts

Massachusetts General Hospital - Center For Addiction Medicine, Boston, Massachusetts 02114, United States
Additional Information

Related publications:

Lee JL, Everitt BJ, Thomas KL. Independent cellular processes for hippocampal memory consolidation and reconsolidation. Science. 2004 May 7;304(5672):839-43. Epub 2004 Apr 8.

Alberini CM. Mechanisms of memory stabilization: are consolidation and reconsolidation similar or distinct processes? Trends Neurosci. 2005 Jan;28(1):51-6. Review.

Suzuki A, Josselyn SA, Frankland PW, Masushige S, Silva AJ, Kida S. Memory reconsolidation and extinction have distinct temporal and biochemical signatures. J Neurosci. 2004 May 19;24(20):4787-95.

McGaugh JL. The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annu Rev Neurosci. 2004;27:1-28. Review.

Pitman RK, Sanders KM, Zusman RM, Healy AR, Cheema F, Lasko NB, Cahill L, Orr SP. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol Psychiatry. 2002 Jan 15;51(2):189-92.

Vaiva G, Ducrocq F, Jezequel K, Averland B, Lestavel P, Brunet A, Marmar CR. Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biol Psychiatry. 2003 Nov 1;54(9):947-9. Erratum in: Biol Psychiatry. 2003 Dec 15;54(12):1471.

Przybyslawski J, Roullet P, Sara SJ. Attenuation of emotional and nonemotional memories after their reactivation: role of beta adrenergic receptors. J Neurosci. 1999 Aug 1;19(15):6623-8.

Debiec J, Ledoux JE. Disruption of reconsolidation but not consolidation of auditory fear conditioning by noradrenergic blockade in the amygdala. Neuroscience. 2004;129(2):267-72.

Orr SP, Metzger LJ, Pitman RK. Psychophysiology of post-traumatic stress disorder. Psychiatr Clin North Am. 2002 Jun;25(2):271-93. Review.

Diergaarde L, Schoffelmeer AN, De Vries TJ. Beta-adrenoceptor mediated inhibition of long-term reward-related memory reconsolidation. Behav Brain Res. 2006 Jun 30;170(2):333-6. Epub 2006 Apr 5.

Bernardi RE, Lattal KM, Berger SP. Postretrieval propranolol disrupts a cocaine conditioned place preference. Neuroreport. 2006 Sep 18;17(13):1443-7.

Robinson MJ, Franklin KB. Central but not peripheral beta-adrenergic antagonism blocks reconsolidation for a morphine place preference. Behav Brain Res. 2007 Aug 22;182(1):129-34. Epub 2007 May 24.

Starting date: April 2008
Last updated: September 16, 2014

Page last updated: August 23, 2015

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