Saladin ME, Gray KM, McRae-Clark AL, Larowe SD, Yeatts SD, Baker NL et al. A double blind, placebo-controlled study of the effects of post-retrieval propranolol on reconsolidation of memory for craving and cue reactivity in cocaine dependent humans. Psychopharmacology (Berl) 226: 721-737

Department of Health Sciences and Research, Medical University of South Carolina (MUSC), Charleston, SC, USA, .
Psychopharmacology (Impact Factor: 3.88). 04/2013; 226(4):721. DOI: 10.1007/s00213-013-3039-3
Source: PubMed


This study examined the effects of propranolol vs. placebo, administered immediately after a "retrieval" session of cocaine cue exposure (CCE), on craving and physiological responses occurring 24 h later during a subsequent "test" session of CCE. It was hypothesized that compared to placebo-treated cocaine-dependent (CD) individuals, propranolol-treated CD individuals would evidence attenuated craving and physiological reactivity during the test session. Secondarily, it was expected that group differences identified in the test session would be evident at a 1-week follow-up CCE session. Exploratory analyses of treatment effects on cocaine use were also performed at follow-up.

CD participants received either 40 mg propranolol or placebo immediately following a "retrieval" CCE session. The next day, participants received a "test" session of CCE that was identical to the "retrieval" session except no medication was administered. Participants underwent a "follow-up" CCE session 1 week later. Craving and other reactivity measures were obtained at multiple time points during the CCE sessions.

Propranolol- vs. placebo-treated participants evidenced significantly greater attenuation of craving and cardiovascular reactivity during the test session. Analysis of the follow-up CCE session data did not reveal any group differences. Although there was no evidence of treatment effects on cocaine use during follow-up, this study was insufficiently powered to rigorously evaluate differential cocaine use.

This double-blind, placebo-controlled laboratory study provides the first evidence that propranolol administration following CCE may modulate memories for learning processes that subserve cocaine craving/cue reactivity in CD humans. Alternative interpretations of the findings were considered, and implications of the results for treatment were noted.

Download full-text


Available from: Michael Saladin
  • Source
    • "In this report, we examined the clinical feasibility and preliminary efficacy of impairing drug-related memory reconsolidation using propranolol as an adjunct to treat substance dependence. This study extends previous findings to the realm of clinical populations and demonstrates an impairing effect of propranolol on tonic craving in addition to the previously-found phasic (cue-elicited ) craving (see Saladin et al., 2013). Our results highlight the feasibility of, and demand for, larger randomized controlled trials Fig. 1. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: The reconsolidation blocker propranolol abolishes alcohol and drug-seeking behavior in rodents and attenuates conditioned emotional responses to drug-cues in humans in experimental settings. This suggests a role for its use in the treatment of substance dependence. In this translational pilot study, we explored the feasibility and efficacy of this procedure as an adjunct treatment for addiction. We hypothesized that guided addiction-related memory reactivation under propranolol would significantly attenuate tonic craving, a central element in relapse following addiction treatment. Methods: Seventeen treatment-seeking adults diagnosed with substance dependence were randomized to receive double-blind propranolol (n = 9) or placebo (n = 8) on six occasions prior to reading a personalized script detailing a drug-using experience. The primary outcome measure was self-reported craving intensity. Results: After controlling for baseline craving scores, intent-to-treat analysis revealed a time by group interaction, F(1, 14) = 5.68, p = .03, η(2) = 0.29; craving was reduced in the propranolol-treated group (Cohen's d = 1.40, p < .05) but not in the placebo group (d = 0.06, n.s.). Limitations: The usual limitations related to small sample size and the lack of a follow-up apply here. Conclusion: Drug-related memory reactivation under propranolol can subsequently reduce craving among substance-dependent individuals. Considering the relapse rate among individuals treated for substance dependence, our study highlights the feasibility of, and need for, more comprehensive trials of this treatment approach.
    Full-text · Article · Oct 2015 · Journal of Behavior Therapy and Experimental Psychiatry
  • Source
    • "We recently demonstrated that of two classes of drugs that show translational promise for blocking MMM reconsolidation, NMDAR antagonists and β-blockers, NMDAR antagonists display much more robust effects than β-adrenergic antagonists (Das et al. 2013). Only one study (Saladin et al. 2013) has attempted to translate these preclinical findings into humans. This attempt to use propranolol to disrupt reconsolidation in cocaine-dependent individuals found the relatively modest effects predicted from the metaanalytic findings. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Preclinical reconsolidation research offers the first realistic opportunity to pharmacologically weaken the maladaptive memory structures that support relapse in drug addicts. N-methyl D-aspartate receptor (NMDAR) antagonism is a highly effective means of blocking drug memory reconsolidation. However, no research using this approach exists in human addicts. The objective of this study was to assess the potential and clinical outcomes of blocking the reconsolidation of cue-smoking memories with memantine in quitting smokers. Fifty-nine dependent and motivated to quit smokers were randomised to one of three groups receiving the following: (1) memantine with or (2) without reactivation of associative cue-smoking memories or (3) reactivation with placebo on their target quit day in a double-blind manner. Participants aimed to abstain from smoking for as long as possible. Levels of smoking and FTND score were assessed prior to intervention and up to a year later. Primary outcome was latency to relapse. Subjective craving measures and attentional bias to smoking cues were assessed in-lab. All study groups successfully reduced their smoking up to 3 months. Memantine in combination with smoking memory reactivation did not affect any measure of smoking outcome, reactivity or attention capture to smoking cues. Brief exposure to smoking cues with memantine did not appear to weaken these memory traces. These findings could be due to insufficient reconsolidation blockade by memantine or failure of exposure to smoking stimuli to destabilise smoking memories. Research assessing the treatment potential of reconsolidation blockade in human addicts should focus on identification of tolerable drugs that reliably block reward memory reconsolidation and retrieval procedures that reliably destabilise strongly trained memories.
    Full-text · Article · Jun 2015 · Psychopharmacology
  • Source
    • "The present study is the first to propose that the DCS/PROP administration in combination with memory retrieval can be a potential treatment for interference on fear memory reconsolidation . Related to this, it should be noted that both DCS and PROP drugs are accepted for human use, and that the disruptive effect of PROP on the reconsolidation of fear and drug-related memories has been previously demonstrated in pre-clinical and clinical studies (Debiec and LeDoux, 2004; Kindt et al. 2009; Wouda et al., 2010; Saladin et al., 2013). The mechanism by which DCS promotes retrieval-induced memory destabilization is still unknown. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Withdrawal from chronic ethanol facilitates the formation of contextual fear memory and delays the onset to extinction, with its retrieval promoting an increase in ethanol consumption. Consequently, manipulations aimed to reduce these aversive memories, may be beneficial in the treatment of alcohol discontinuation symptoms. Related to this, pharmacological memory reconsolidation blockade has received greater attention due to its therapeutic potential. Here, we examined the effect of post-reactivation amnestic treatments such as Midazolam (MDZ, 3 mg/kg i.p) and Propranolol (PROP, 5 mg/kg i.p) on contextual fear memory reconsolidation in ethanol- withdrawn (ETOH) rats. Next, we examined whether the activation of N-methyl-D-aspartate (NMDA) receptors induced by d-cycloserine (DCS, 5 mg/kg i.p., a NMDA partial agonist) before memory reactivation can facilitate the disruptive effect of PROP and MDZ on fear memory in ETOH rats. We observed a resistance to the disruptive effect of both MDZ and PROP following memory reactivation. Although intra-basolateral amygdala (BLA; 1.25 ug/side) and systemic PROP administration attenuated fear memory in DCS pre-treated ETOH rats, DCS/MDZ treatment did not affect memory in these animals. Finally, a decrease of both total and surface protein expression of the α1 GABAA receptor (GABAA-R) subunit in BLA was found in the ETOH rats. Ethanol withdrawal facilitated the formation of fear memory resistant to labilization post-reactivation. DCS administration promoted the disruptive effect of PROP on memory reconsolidation in ETOH rats. The resistance to MDZ's disruptive effect on fear memory reconsolidation may be, at least in part, associated with changes in the GABAA-R composition induced by chronic ethanol administration/withdrawal. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    Full-text · Article · Jan 2015 · The International Journal of Neuropsychopharmacology
Show more