Reconsolidation-based treatment for fear of public speaking: a systematic pilot study using propranolol

Abstract

Pharmacological manipulation of memory reconsolidation opens up promising new avenues for anxiety disorder treatment. However, few studies have directly investigated reconsolidation-based approaches in subclinical or clinical populations, leaving optimal means of fear memory reactivation unknown. We conducted a systematic pilot study to assess whether a reconsolidation-based treatment could tackle public speaking anxiety in a subclinical sample (N = 60). As lab studies indicate that the duration of reactivation may be important for inducing reconsolidation, we investigated several speech lengths to help inform further translational efforts. Participants underwent a stressinducing speech task composed of 3-min preparation, and from 0 to 9 min of public speaking, in 1-min increments. They then received either 40 mg of propranolol (n = 40) or placebo (n = 20), double-blind, allocated 4:2 for each speech duration. Participants performed a second speech 1 week post treatment, and were followed up with questionnaires 1-and 3 months later. Both self-reported speech distress and questionnaire measures of public speaking anxiety showed clear reductions following treatment. However, propranolol did not reliably outperform placebo, regardless of speech duration at treatment. Physiological responses (heart rate and salivary cortisol) to the public speaking task remained stable from treatment to test. These findings highlight the challenges facing the translation of laboratory research on memory reconsolidation into clinical interventions. Lack of explicit controls for factors beyond duration, such as 'prediction error', could explain these null findings, but positive results in clinical interventions are needed to demonstrate that taking such factors into account can deliver the promises of reconsolidation-based therapy.

Placebo and Non-specific Effects in Reconsolidation-Based Treatment for Arachnophobia

“…Notably, the presence of placebo/non-specific effects among arachnophobic patients here, and amongst participants undergoing a reconsolidation-based intervention for fear of public speaking in another recent study (20), does not point to non-specific effects as an explanation for previously observed effects of propranolol in reconsolidation-based studies. Soeter and Kindt (21) included controls for both non-specific effects of propranolol, and a placebo + reactivation control.…”

“…Attempts have been made to translate such an approach to the treatment of post-traumatic stress disorder, with both promising and disappointing results (17)(18)(19). A more recent study also aimed to tackle a naturalistic fear of public speaking using a reconsolidation-based approach, but found that propranolol + reactivation did not outperform placebo + reactivation [ (20); throughout, we use the term "reconsolidationbased" to refer to the ideas underpinning such treatments, but not as a conclusive statement that reconsolidation necessarily underpins any observed effects]. Perhaps the most convincing demonstration of the prospect of harnessing reconsolidation to tackle naturalistic fears was a placebo-controlled study of participants with a subclinical fear of spiders (21).…”

Perioperative Propranolol Against Dental Anxiety: A Randomized Controlled Trial

“…Moreover, the findings suggest that propranolol in our study may have actually inhibited traumatic memory extinction, rather than disrupting its reconsolidation, in absence of a prediction error. To date it remains uncertain how promising findings of propranolol's putative reconsolidation blocking effects in Pavlovian fear conditioning laboratory trials can be best translated into clinically meaningful interventions, as this study and other recent trials ( 30 , 31 ) suggest that this may be substantially more difficult than previously expected ( 9 , 30 ).…”

“…Most compelling evidence for propranolol's effects on human fear memory reconsolidation originates from laboratory trials by Kindt et al ( 3 – 8 ). They showed that, dependent on minor environmental changes that are difficult to control in clinical practice, fear memory reactivation may initiate three transitory phases: the first being labilization and reconsolidation; the second being stability; and the third being the generation of a new memory trace and extinction ( 6 , 9 – 11 ). In 2018, Brunet et al ( 12 ) showed propranolol to block fear memory reconsolidation in a clinical population.…”

Interfering with contextual fear memories by post-reactivation administration of propranolol in mice: a series of null findings

“…Translation of these findings to real-life anxiety disorders and posttraumatic stress disorder remains a great challenge (Kindt, 2014). At present, both promising (Brunet et al, 2008(Brunet et al, , 2011(Brunet et al, , 2018Soeter and Kindt, 2015a;Kindt and van Emmerik, 2016) as well as disappointing (Wood et al, 2015;Elsey et al, 2020;Roullet et al, 2021) results have been reported to treat real-life fears that have been acquired outside the laboratory. These relatively mixed observations have often been attributed to the subtle conditions under which amnestic agents interfere with fear memories (Elsey et al, 2018(Elsey et al, , 2020.…”