Propranolol + Memory Reactivation for PTSD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: Massachusetts General Hospital

Must be taking: Propranolol

Must not be taking: Antihypertensives, Antiarrhythmics, Benzodiazepines

Disqualifiers: Low blood pressure, Heart conditions, Asthma, Pregnancy, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The proposed R21 project will attempt to further develop a novel intervention for posttraumatic stress symptoms inspired by the science of memory reconsolidation. Work in normal humans has shown that when a stable, consolidated memory is reactivated (i.e., retrieved) under appropriate conditions, it reverts to an unstable state, a process referred to herein as deconsolidation. In such a state, the memory is susceptible to the action of various "amnestic" agents that may inhibit its reconsolidation, thereby weakening it. The β-adrenergic blocker propranolol (PPNL) possesses such amnestic properties. More recent research has found that in order to initiate deconsolidation, there must be a prediction error, or mismatch, between what is expected and what occurs when the memory is reactivated. Prior placebo-controlled, randomized clinical trials (PBO-RCT) from our laboratory have found that when propranolol is administered concomitant with the reactivation of a psychologically traumatic memory, the memory is weakened, as revealed by subsequent lower physiological (heart rate, skin conductance, facial electromyogram) responding during script-driven mental imagery. Clinical applicability was evaluated in a PBO-RCT, in which PTSD participants receiving propranolol underwent six weekly sessions of 10-20 min of "standard" (STD) traumatic memory reactivation stimulated by reading a narrative. At post-treatment, these participants showed a greater reduction of PTSD symptoms compared to participants who had taken PBO. The goal of the proposed study is to test whether intentionally incorporating innovative mismatch (MM) into traumatic memory reactivation can improve upon physiological responding during script-driven mental imagery. Participants will be randomized to one of 2 treatment arms: STD/PPNL and MM/PPNL. A baseline assessment will measure psychophysiological responsivity to script-driven mental imagery (target measure). PPNL will be administered 90-min prior to each of six weekly 10-20 min. traumatic memory reactivation sessions. In the MM condition, a different, unexpected mismatch (e.g., singing the narrative) will be incorporated into the reactivation. In the STD condition, the participant will read the narrative the same way each time. The focus of the R21 proposal will be to assess whether the MM/PPNL group shows lower subsequent physiological responses than the STD/PPNL group

Will I have to stop taking my current medications?

If you are taking medications like anti-hypertensives, antiarrhythmics, or benzodiazepines, you may need to stop them due to potential interactions with propranolol. If you are on stable doses of other medications, you should not change them during the study unless it's urgent.

What data supports the effectiveness of the drug propranolol combined with memory reactivation for treating PTSD?

Research shows that propranolol, when combined with memory reactivation, can reduce PTSD symptoms by blocking memory reconsolidation. In some studies, patients with severe PTSD symptoms experienced continued improvement after treatment with propranolol, compared to those who received a placebo. ^{1 2 3 4 5}

Is propranolol safe for use in humans?

Propranolol, a medication often used to treat high blood pressure and anxiety, has been studied for its effects on memory and fear responses in both humans and animals. It is generally considered safe for use in humans, with studies showing it can reduce physiological responses to stress and fear without significant adverse effects. ^{2 3 4 5 6}

How does the drug propranolol combined with memory reactivation differ from other PTSD treatments?

This treatment is unique because it combines propranolol, a drug that blocks certain stress-related receptors, with memory reactivation sessions to potentially disrupt the reconsolidation of traumatic memories, which may help reduce PTSD symptoms. ^{1 3 4 5 6}

Eligibility Criteria

This trial is for men and women aged 18-65 who have experienced a traumatic event and show significant stress symptoms, with a PCL-5 score over 33. They must react strongly during baseline imagery testing to qualify. Exclusions include certain medical conditions like heart failure or asthma, low blood pressure or heart rate, drug abuse, pregnancy, other psychiatric disorders, current psychotherapy (except supportive), inability to understand English or give informed consent.

Inclusion Criteria

I am between 18-65, experienced a traumatic event, and have a high stress score.

We are looking for participants who have experienced a traumatic event, which may include those with PTSD.

During a specific test, participants need to meet certain mental and physical criteria to be randomly selected for the study.

Exclusion Criteria

Current participation in any psychotherapy other than supportive. Participants will be asked not to initiate new psychotherapy during the proposed two-month study period (excluding the one-month follow-up) except in clinically urgent circumstances. If this becomes necessary, a decision will be made on a case-by-case basis about retaining the participant or terminating participation

I haven't started or changed any mental health medication in the last two months.

Presence of a contraindicating psychiatric condition, e.g., psychotic, bipolar, melancholic, or active substance use disorder; or suicidality (see below)

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Baseline Assessment

Baseline assessment to measure psychophysiological responsivity to script-driven mental imagery

1 day

1 visit (in-person)

Treatment

Participants undergo six weekly sessions of traumatic memory reactivation with propranolol administration

6 weeks

6 visits (in-person)

Post-Treatment Assessment

Post-treatment psychophysiological testing to assess the effect of the intervention

1 week

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Memory Reactivation Procedures (Behavioral Intervention)
• Propranolol (Beta Blocker)

Trial Overview The study tests if adding an unexpected element ('mismatch') when recalling traumatic memories with propranolol can better reduce physiological stress responses than standard memory reactivation alone. Participants will be randomly assigned to either the mismatch/propranolol group or the standard/propranolol group and undergo six weekly sessions of memory reactivation.

Participant Groups

Group I: Mismatch reactivation condition Experimental Treatment 2 Interventions

The participant will recite their trauma narrative to the psychologist for 10-20 minutes. However, during each recitation, a "mismatch" condition, different for each session, will be added to the reactivation procedure by having the participant do the following (in order of sessions.

Group II: Standard reactivation condition Active Control 2 Interventions

The intervention will be the same for each of the six intervention sessions. The participant will recite to the psychologist the narrative they previously composed for 10-20 min. The psychologist will congratulate the participant for having succeeded in this task and advise them they are finished for the day.

Memory Reactivation Procedures is already approved in India for the following indications:

Approved in India as Ciplar for:

• Angina
• Hypertension
• Atrial fibrillation
• Migraine prevention
• Tremors

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Findings from Research

In a study of 66 adults with longstanding PTSD, both propranolol and placebo led to significant reductions in PTSD and depression symptoms during treatment, but there was no significant difference between the two groups.

However, for patients with severe PTSD symptoms, those treated with propranolol showed continued improvement in symptoms three months after treatment, while those on placebo experienced a worsening, suggesting that propranolol may have long-term benefits for certain individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Traumatic memory reactivation with or without propranolol for PTSD and comorbid MD symptoms: a randomised clinical trial. Roullet, P., Vaiva, G., Véry, E., et al.[2021]

In a study involving 19 subjects with chronic post-traumatic stress disorder (PTSD), propranolol administered after recalling traumatic memories significantly reduced physiological responses during later mental imagery of those events.

This suggests that propranolol can effectively dampen the body's stress reactions to traumatic memories, similar to its effects when given shortly after a traumatic event.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. Brunet, A., Orr, SP., Tremblay, J., et al.[2022]

In a 6-week open-label trial with 33 patients suffering from longstanding PTSD, the combination of propranolol and trauma recall sessions significantly improved quality of life and reduced depressive symptoms and negative emotions.

The study suggests that memory reconsolidation may be effectively blocked by propranolol, leading to better treatment outcomes, although further validation through randomized-controlled trials is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trauma reactivation under the influence of propranolol: an examination of clinical predictors. Poundja, J., Sanche, S., Tremblay, J., et al.[2021]

In a 6-week clinical trial involving 60 adults with long-standing PTSD, propranolol significantly reduced PTSD symptoms compared to a placebo, with a notable effect size of 1.76 for the Clinician-Administered PTSD Scale (CAPS).

The study suggests that administering propranolol before trauma memory reactivation sessions is an effective treatment strategy for PTSD, indicating its potential as a novel therapeutic approach based on reconsolidation theory.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduction of PTSD Symptoms With Pre-Reactivation Propranolol Therapy: A Randomized Controlled Trial. Brunet, A., Saumier, D., Liu, A., et al.[2019]

Propranolol, a non-selective β-adrenergic antagonist, has been shown to effectively reduce exaggerated fear responses by decreasing memory trace reactivation in specific brain regions, particularly the dorsal dentate gyrus, in both humans and animal models.

The study found that propranolol also significantly reduced activity in the hilus of the dentate gyrus, particularly affecting parvalbumin-expressing cells, suggesting that it may alter the balance of excitatory and inhibitory signals involved in fear memory processing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Propranolol Administration Modulates Neural Activity in the Hippocampal Hilus During Fear Retrieval. Leal Santos, S., Chen, BK., Pereira, GR., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Traumatic memory reactivation with or without propranolol for PTSD and comorbid MD symptoms: a randomised clinical trial. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Disruption of reconsolidation but not consolidation of auditory fear conditioning by noradrenergic blockade in the amygdala. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Trauma reactivation under the influence of propranolol: an examination of clinical predictors. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Reduction of PTSD Symptoms With Pre-Reactivation Propranolol Therapy: A Randomized Controlled Trial. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Propranolol Administration Modulates Neural Activity in the Hippocampal Hilus During Fear Retrieval. [2022]