Psychedelics: A review of their effects on recalled aversive memories and fear/anxiety expression in rodents

Threatening events can create maladaptive memories that existing treatments often fail to address. This review of nearly 400 studies since 1957 examined how various psychedelics—including psilocybin, LSD, DMT, mescaline, 5-MeO-DMT, DOI, and MDMA—affect aversive memory extinction, reconsolidation, learned fear, anxiety, and locomotion in rodents. Psychedelics frequently show biphasic effects on locomotion at doses that enhance extinction learning, impair memory reconsolidation, or reduce learned fear and anxiety. Emerging evidence suggests a dissociation between prospective benefits and locomotor effects. Under-explored aspects include sex differences, memory age and generalization, repeated treatments, and timing of changes. Validating findings in traumatic-like memory models is essential for improving therapeutic approaches.

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Abstract

Threatening events and stressful experiences can lead to maladaptive memories and related behaviors. Existing treatments often fail to address these issues linked to anxiety/stress-related disorders effectively. This review identifies dose ranges associated with specific actions across various psychedelics. We examined psilocybin/psilocin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), mescaline, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), serotonin 2 A/2 C agonists (e.g., DOI) and 3,4-methylenedioxymethamphetamine (MDMA) on aversive memory extinction and reconsolidation, learned fear, anxiety, and locomotion in rodents. Nearly 400 studies published since 1957 were reviewed. Psychedelics often show biphasic effects on locomotion at doses that enhance extinction learning/retention, impair memory reconsolidation, or reduce learned fear and anxiety. Emerging evidence suggests a dissociation between their prospective benefits and locomotor effects. Under-explored aspects include sex differences, susceptibility to interference as memories age and generalize, repeated treatments, and immediate vs. delayed changes. Validating findings in traumatic-like memory and maladaptive fear/anxiety models is essential. Understanding how psychedelics modulate threat responses and post-retrieval memory processes in rodents may inform drug development and human studies, improving therapeutic approaches for related psychiatric conditions.