Impairing memory reconsolidation with propranolol in healthy and clinical samples: a meta-analysis

Sereena Pigeon; Michelle Lonergan; Olivia Rotondo; Roger K. Pitman; Alain Brunet

doi:10.1503/jpn.210057

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Figure 1
Study selection flow chart. *Thomas and colleagues45 and Deng and colleagues51 each had 2 studies in healthy samples. Roullet and colleagues58 had 2 separate clinical samples. Brunet and colleagues30 had 3 clinical studies.
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Figure 2
Reconsolidation interference in healthy samples. CI = confidence interval; LL = lower limit; UL = upper limit; SE = standard error.
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Figure 3
Reconsolidation interference in clinical samples. CI = confidence interval; LL = lower limit; UL = upper limit; SE = standard error.

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Table 1

Characteristics of studies included in the qualitative review but excluded from the meta-analysis

Study	Population or clinical diagnosis	Propranolol/placebo		Male/ female, %	Age, yr, mean ± SD	Study protocol	Outcome measures of interest	Primary results of interest

		No. enrolled	No. on test day or post-treatment
Brunet et al.30 (2011; study 1)	Chronic PTSD	28/0	28/0	32/68	37.9 ± 9.5	Week 1: pre-treatment assessment Week 2: 0.67 mg/kg (short-acting) followed by 1 mg/kg (long-acting), script preparation 90 min later Weeks 3–7: propranolol (short-and long-acting, same dose) 90 min before reactivation Week 8: post-treatment assessment Follow-up: 6 mo after pre-treatment	CAPS and PCL pre-treatment, post-treatment and follow-up	Scores pre-treatment, post-treatment and follow-up (mean ± SD) PCL:60.4 ± 11.4, 37.9 ± 14.9 and 36.0 ± 15.1 CAPS:71.8 ± 18.6, 45.8 ± 21.9 and 42.7 ± 24.6
Brunet et al.30 (2011; study 2)	Chronic PTSD	7/0	7/0	29/71	40.1 ± 11.8	Week 1: pre-treatment assessment Week 2: 40 mg (short-acting) followed by 80 mg (long-acting) and oral script preparation 90 min later Weeks 3–7: propranolol (short-and long-acting, same dose) 90 min before reactivation Week 8: post-treatment assessment Follow-up: 6 mo after pre-treatment	CAPS pre-treatment, post-treatment and follow-up	Scores pre-treatment, post-treatment and follow-up (mean ± SD) CAPS:68.4 ± 15.8, 35.6 ± 31.2 and 34.1 ± 33.2
Brunet et al.30 (2011; study 3)	Chronic PTSD	7/0	7/0	29/71	47.9 ± 15.7	Week 1: pre-treatment assessment Week 2: 40 mg (short-acting) followed by 80 mg (long-acting) and script preparation 90 min later Weeks 3–7: 80 mg (long-acting) 90 min before reactivation Week 8: post-treatment assessment Follow-up: 6 mo after pre-treatment	PCL 6 mo post-disaster, pre-treatment, post-treatment and follow-up	Score 6 mo post-disaster, pre-treatment, post-treatment and follow-up (mean ± SD) PCL: 60.9 ± 5.3, 60.7 ± 4.1, 41.0 ± 4.3 and 38.4 ± 3.6
Deng et al.51 (2020; experiment 1)	Differential fear conditioning	15/16	15/16	% female Propranolol: 53.3 Placebo: 50	Propranolol: 23.71 ± 0.19 Placebo: 23.47 ± 0.46	Day 1: learning Day 2: 40 mg 60 min before reactivation Day 3: long-term memory test	SCR to unconditioned stimulus on day 3 at reinstatement	Propranolol < placebo on SCR to unconditioned stimulus on day 3 at reinstatement
Deng et al.51 (2020; experiment 2)	Differential fear conditioning	18/17	18/17	% female Propranolol: 42.9 Placebo: 52.9	Propranolol: 23.67 ± 0.48 Placebo: 23.24 ± 0.50	Day 1: learning 2 wk later: 40 mg propranolol before reactivation 24 h later: long-term memory test	SCR to unconditioned stimulus stimulus at visit 3	Unconditioned stimulus retrieval + propranolol blocked the return of fear (SCR) at reinstatement
Kroes et al.49 (2016)	Differential fear conditioning	23/24	22/24	41/59	21.72 ± 2.2	Day 1: learning Day 2: 40 mg 60 min before reactivation Day 3: long-term memory task	SCR, explicit memory and subjective experience of fear on day 3	Propranolol < placebo on SCR and explicit memory, but not subjective experience of fear at day 3
Lin et al.59 (2021)	Nicotine dependence	27/25	27/25	100/0	Propranolol: 27.8 ± 6.69 Placebo: 28.24 ± 7.94	Day 1: baseline and cue-induced craving Day 2: 40 mg 60 min before reactivation (smoking-related pictures) Day 3: baseline and cue-induced craving	Baseline craving measured with FNDT; cue-induced craving measured with brain imaging on day 3	Significant reduction in craving in propranolol group only; propranolol < placebo on FNDT and cue-induced reactivity on day 3
Mahabir et al.55 (2015)	Chronic PTSD	9/0	7/0	29/71	33.1 ± 7.0	Week 1: pre-treatment assessments and script preparation Week 2: fMRI session Weeks 3–8: 1 mg/kg 75 min before reactivation with script Week 9: fMRI session Week 10: diagnostic assessment	CAPS and IES-R pre-treatment and post-treatment	Score pre-treatment and post-treatment (mean ± SD) CAPS: 80.4 ± 17.6 and 41.0 ± 27.2 IES-R: 62.8 ± 12.9 and 24.4 ± 23.4
Saladin et al.25 (2013)	Cocaine dependence	35/32	26/24	66/34	Propranolol: 39.1 ± 8.2 Placebo: 40.8 ± 9.8	Day 1: 40 mg immediately after CCE sequence Day 2: CCE session with no medication Follow-up: 1 wk	CDMS, heart rate and SCR to CCE on day 2 and at follow-up	Propranolol < placebo on CDMS and heart rate but not SCR
Wood et al.57 (2015)	Chronic PTSD	12/0	10/0 (n = 8 no reactivation + propranolol)	100/0	38.7 ± 14.9	Day 2: 0.67 mg/kg (short-acting) 90 min before reactivation and 1 mg/kg (long-acting) immediately before reactivation (script preparation) Day 8: script-driven imagery	Heart rate, SCR and IES-R to script on day 8	Propranolol = placebo on heart rate, SCR and IES-R on day 8

CAPS = Clinician-Administered PTSD Scale; CCE = cocaine cue exposure; CDMS = Craving/Distress/Mood States scale; fMRI = functional MRI; FNDT = Fagerstrom Nicotine Dependence Test; IES-R = Impact of Event Scale–Revised; PCL = PTSD Checklist; PTSD = posttraumatic stress disorder; SCR = skin conductance response; SD = standard deviation.

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Table 2

Characteristics of included reconsolidation interference studies — healthy samples

Study	Materials	Propranolol/placebo		Male/ female, %	Age, yr, mean ± SD or SEM	Study protocol	Outcome measures of interest	Primary results of interest	Quality

		No. randomized	No. analyzed on test day
Bos et al.38 (2012)	Differential fear conditioning	15/15	15/15	33/67	21 ± 2.6	Day 1: learning Day 2: 40 mg 80 min before reactivation Day 3: long-term memory test	SCR and fear-potentiated startle to conditioned stimulus during extinction/ reinstatement on day 3	Propranolol = placebo on SCR and fear-potentiated startle to conditioned stimulus on day 3	4.5
Chalkia et al.37 (2019)	Differential fear conditioning	15/15	15/15	27/73	Propranolol: 22.3 ± 4.33 Placebo: 21.5 ± 2.45	Day 1: learning Day 2: 40 mg post-reactivation Day 3: long-term memory test	Fear-potentiated startle and unconditioned stimulus expectancy ratings to conditioned stimulus during extinction on day 3	Propranolol = placebo on fear-potentiated startle and unconditioned stimulus to conditioned stimulus on day 3	4.5
de Quervain et al.39 (2007)	Emotionally valenced word list	14/14	14/14	50/50	23.9 ± 2.9	Day 1: learning Day 2: 40 mg 60 min before long-term memory test 2 wk later: second long-term memory test	Free recall no. of words during second long-term memory test	Propranolol = placebo on free recall of words during second long-term memory test	3
Kindt et al.40 (2009)	Differential fear conditioning	20/20	20/20	28/72	20.70 ± 2.4	Day 1: learning Day 2: 40 mg 90 min before reactivation Day 3: long-term memory test	Fear-potentiated startle to conditioned stimulus during extinction/ reinstatement on day 3	Propranolol < placebo on fear-conditioned startle on day 3	3
Kroes et al.41 (2010)	Emotionally valenced word list	12/12	11/12	58/42	24.4	Day 1: learning Day 2: 40 mg 90 min before reactivation Day 3: long-term memory test	% free recall on day 3	Propranolol < placebo on % free recall on day 3	3
Schwabe et al.42 (2012)	Emotionally valenced images	13/13	13/13	50/50	18–30	Day 1: learning Day 2: 40 mg 90 min before reactivation Day 3: long-term memory test	% recognition of images on day 3	Propranolol < placebo on % recognition of images on day 3	2
Sevenster et al.50 (2012)	Differential fear conditioning	20/20	18/18	68/32	21.1 ± 2.6	Day 1: learning Day 2: 40 mg 90 min before reactivation Day 3: long-term memory test	SCR, fear-potentiated startle and unconditioned stimulus expectancy ratings to conditioned stimulus during extinction on day 3	Propranolol < placebo on fear-potentiated startle, but not SCR or unconditioned stimulus expectancy ratings to conditioned stimulus on day 3	3
Soeter et al.43 (2010)	Differential fear conditioning	20/20	20/20	25/75	20.4 ± 3.8	Day 1: learning Day 2: 40 mg 90 min before reactivation Day 3: long-term memory test	Fear-potentiated startle to conditioned stimulus during extinction/ reinstatement on day 3	Propranolol < placebo on fear-potentiated startle to conditioned stimulus on day 3	4.5
Soeter et al.44 (2012)	Differential fear conditioning	12/12	12/12	12/88	20.9 ± 3.5	Day 1: learning Day 2: 40 mg 90 min before reactivation Day 3: long-term memory test	Fear-potentiated startle to conditioned stimulus during extinction/ reinstatement on day 3	Propranolol < placebo on fear-potentiated startle to conditioned stimulus on day 3	4.5
Thomas et al.45 (2017, experiment 1)	Emotional story paradigm	14/14	14/12	59/41	32.6 ± 11.7	Week 1: learning Week 2: 0.67 mg/ kg, immediately after reactivation Week 3: long-term memory test	% recognition of content of slides at week 3	Propranolol = placebo on % recognition content of slides at week 3	4.5
Thomas et al.45 (2017, experiment 2)	Emotional story paradigm	18/16	17/16	31/69	25.4 ± 7.8	Week 1: learning Week 2: 0.67 mg/kg, 60–75 min before reactivation Week 3: long-term memory test	% recognition of content of slides at week 3	Propranolol < placebo on % recognition content of slides at week 3	4.5
Thome et al.46 (2016)	Differential fear conditioning	20/20	20/19	0/100	Propranolol: 25.5 ± 3.71 Placebo: 23.9 ± 3.1	Day 1: learning Day 2: 40 mg 5 min post-reactivation Day 3: long-term memory test	Fear-potentiated startle to conditioned stimulus during extinction on day 3	Propranolol = placebo on fear-potentiated startle to conditioned stimulus on day 3	3.5
Tollenaar et al.47 (2009)	Emotionally valenced word list	26/27	26/27	100/0	Propranolol: 20.6 ± 2.1 Placebo: 19.5 ± 1.4	Week 1: learning Week 2: 80 mg 75 min before reactivation Week 3: long-term memory test	% recognition of words in week 3	Propranolol = placebo on % recognition of words at week 3	4.5
Tollenaar et al.48 (2009)	Script-driven imagery	27/26	27/26	100/0	Propranolol: 20.7 ± 2.2 Placebo: 19.5 ± 1.4	Week 1: script preparation Week 2: 80 mg 90 min before reactivation Week 3: heart rate and SCR to script	Heart rate and SCR at week 3	Propranolol = placebo on % recognition of words at week 3	4

SCR = skin conductance response; SD = standard deviation; SEM = standard error of the mean.

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Table 3

Characteristics of included reconsolidation interference studies — clinical samples

Study	Clinical diagnosis	Propranolol/placebo		Male/ female, %	Age, yr, mean ± SD	Study protocol	Outcome measures of interest	Primary results of interest	Quality

		No. randomized	No. analyzed on test day
Brunet et al.52 (2008)	Chronic PTSD	9/10	9/10	47/53	Propranolol: 34.8 ± 10.1 Placebo: 35.1 ± 10.5	Week 1: script preparation, 40 mg (short-acting) immediately after reactivation and 60 mg (long-acting) after 2 h Week 2: script-driven imagery	Heart rate SCR to personal script at week 2	Propranolol < placebo on heart rate and SCR to personal script	4
Brunet et al.56 (2014)	Chronic PTSD	28/10	22/10^*	32/68	37.9 ± 9.5	Week 1: 0.67 mg/kg (short-acting) followed by 1 mg/kg (long-acting), script preparation 90 min later Weeks 2–6: 0.67 mg/kg (short-acting) and 1 mg/kg (long-acting) 90 min before reactivation Week 7: script-driven imagery 4 mo follow-up: script-driven imagery	Heart rate and SCR to personal script at 1 wk post-treatment	Propranolol < placebo on heart rate and SCR to personal script at 1 wk post-treatment	N/A
Brunet et al.23 (2018)	Chronic PTSD	30/30	21/23	42/58	Propranolol: 37.0 ± 11.3 Placebo: 41.8 ± 11.1	Week 1: 0.67 mg/kg (short-acting) then 1.0 mg/kg (long-acting) 60 min before script preparation Weeks 2–6: 0.67 mg/kg (short-acting) plus 1.0 mg/kg (long-acting) 90 min before reactivation Week 7: Post-treatment assessment	PCL-S and CAPS at post-treatment	Propranolol < placebo on PCL-S and CAPS at post-treatment	5
Elsey et al.54 (2020)	Fear of public speaking	40/20	40/20	17/83	Propranolol: 21.65 ± 2.78 Placebo: 22.10 ± 1.92	Week 1: Baseline measures, speech preparation; 40 mg of propranolol administered < 5 min post-speech (reactivation) Week 2: stress-inducing speech task (0 to 9 min) as reactivation 1 mo follow-up: symptom evaluation 3 mo follow-up: symptom evaluation	GPSP, SUDS and PRPSA at week 2	Propranolol = placebo on GPSP, SUDS and PRPSA at week 2	4
Jobes et al.27 (2015)	Cocaine abuse in poly-drug dependence	19/16	18/15	48/52	Propranolol: 41.6 Placebo: 42.1	Week 1: personalized cocaine script, tactile drug-related paraphernalia Week 2: 40 mg 120 min before reactivation Week 3: re-exposure test session Week 7: re-exposure test session	CCQ and VAS at 1 wk post-intervention	Propranolol > placebo on CCQ and VAS at 1 wk post-intervention	3.5
Lonergan et al.24 (2016)	Substance dependence	9/8	6/4	71/29	Propranolol: 44.78 ± 18.66 Placebo: 35.63 ± 16.09	Week 0: assessment and craving script preparation Week 1–3: 6 biweekly sessions (separated by 48 h) of 1 mg/kg of propranolol 60 min before craving-memory reactivation Week 4: post-treatment assessment	Self-report craving questionnaires post-treatment	Propranolol < placebo on self-reported craving at post-treatment (in intention-to-treat analysis)	4.5
Pachas et al.28 (2015)	Nicotine dependence	35/39	23/31	73/27	Propranolol: 41.6 ± 10.9 Placebo: 42.5 ± 9.8	Week 1: screening and evaluation; 0.67 mg/kg (short-acting), 1 mg/kg (long-acting) 90 min later, followed by reactivation (personal script) Week 2: script-driven imagery	Heart rate, SCR and self-reported craving at week 2	Propranolol = placebo on heart rate, SCR and self-reported craving at week 2	3.5
Roullet et al.58 (2021; severe symptom group, PCL-S score > 65)	PTSD	18/15	Not reported	Unknown^†	Unknown^†	Week 1: 0.67 mg/kg (short-acting) then 1.0 mg/kg (long-acting) 60 min before script preparation Weeks 2–6: 0.67 mg/kg (short-acting) plus 1.0 mg/kg (long-acting) 90 min before reactivation Week 7: post-treatment assessment	PCL-S 3 mo post-treatment	Propranolol < placebo on the PCL-S 3 mo post-treatment	5
Roullet et al.58 (2021; moderate symptom group (PCL-S score > 45 < 65)	PTSD	11/14	Not reported	Unknown^†	Unknown^†	Week 1: 0.67 mg/kg (short-acting) then 1.0 mg/kg (long-acting) 60 min before script preparation Weeks 2–6: 0.67 mg/kg (short-acting) plus 1.0 mg/kg (long-acting) 90 min before reactivation Week 7: post-treatment assessment	PCL-S 3 mo post-treatment	Propranolol = placebo on the PCL-S 3 mo post-treatment	5
Soeter et al.7 (2015)	Spider phobia	15/15	15/15	9/91	21.6 ± 3.2	Day 1: pre-treatment assessments and BAT with baby tarantula Day 5: 40 mg post-reactivation exposure to tarantula Day 16: post-treatment assessment Follow-up: 3 mo and 1 yr	BAT to tarantula and SPQ at post-treatment day 16	Propranolol showed > approach BAT to tarantula than placebo, but = SPQ scores at day 16	4
Xue et al.53 (2017)	Nicotine dependence	96 randomized; 27 excluded Of 69 included: 24 placebo + reactivation, 23 propranolol + reactivation, 22 non-placebo control	23/24	100/0	Propranolol: 24.96 ± 5.9 Placebo: 23.00 ± 4.0	Day 1: screening and baseline tests of preference and craving for pre-existing nicotine conditioned stimulus Days 2–4: conditioning Day 5: post-conditioning test of preference and craving for the conditioned stimulus Day 6: 40 mg 60 min before unconditioned stimulus memory reactivation Day 7: post-treatment test	Subjective ratings of nicotine craving VAS on day 7	Propranolol < placebo on subjective ratings of nicotine craving VAS on day 7	4.5
Zhao et al.26 (2011)	Heroin dependence	18/18	18/18	100/0	Propranolol: 38.11 ± 1.25 Placebo: 38.00 ± 1.30	Day 1: Learning drug-related words Day 2: 40 mg 60 min before reactivation Day 3: long-term memory task	Free recall no. of drug-related words on day 3	Propranolol < placebo on free recall of drug-related words on day 3	3.5

BAT = Behavioural Approach Test; CAPS = Clinician-Administered PTSD Scale; CCQ = Cocaine Craving Questionnaire; GPSP = Global Perception of Speech Performance; PCL-S = PTSD Checklist–Specific; PRPSA = Personal Report of Public Speaking Anxiety; PTSD = posttraumatic stress disorder; SCR = skin conductance response; SD = standard deviation; SPQ = Spider Phobia Questionnaire; SUDS = Subjective Units of Distress; VAS = visual analogue scale.
↵* Data from 10 placebo participants from Brunet and colleagues52 (2008) were included in the between-group analysis in Brunet and colleagues56 (2014). These data were included in the meta-analysis; analyses were conducted with and without these data.
↵† Full sample demographics: propranolol n = 33 randomized, n = 29 treatment completers, n = 20 women, age (mean ± SD) = 35.6 ± 12.8 yr, n = 26 at 3 mo follow-up; placebo n = 33 randomized, n = 29 treatment completers, n = 21 women, age (mean ± SD) = 42.2 ± 12.7 yr, n = 25 at 3 mo follow-up. Analyses were carried out and presented on the intention-to-treat sample.