Dose-dependent effect of acute THC on extinction memory recall and fear renewal: a randomized, double-blind, placebo-controlled study

Background and Objective

Posttraumatic stress disorder (PTSD) is characterized by persistent fear-related memories and impaired regulation of fear responses. Exposure-based therapies aim to reduce these responses through extinction learning, a process in which individuals learn new associations that inhibit conditioned fear. However, fear responses often re-emerge over time, limiting treatment effectiveness. Preclinical and clinical evidence suggests that the endocannabinoid system may play an important role in fear extinction and emotional regulation.

This study investigated whether acute administration of different doses of THC would influence fear extinction memory and fear renewal in adults with PTSD, and whether these effects would vary over time.

Methods

In this randomized, double-blind, placebo-controlled trial, 36 adults with PTSD participated in a multi-day fear-conditioning protocol combined with functional magnetic resonance imaging (fMRI).

Participants underwent fear conditioning on Day 1 and extinction learning on Day 2. Prior to extinction learning, they were randomized to receive either placebo (n=11), 5 mg THC (n=11), or 10 mg THC (n=14). Extinction recall and fear renewal were assessed 24 hours later and again one week after treatment. Brain activation patterns were measured using fMRI.

Key Findings

THC produced dose- and time-dependent effects on neural circuits involved in fear regulation, extinction memory, and emotional processing.

At the 24-hour assessment, participants who received 5 mg THC showed greater activation in the anterior cingulate cortex and prefrontal cortex during early fear renewal compared with those receiving placebo. These brain regions are known to play important roles in emotional regulation and fear processing.

At the one-week follow-up, participants who received 10 mg THC demonstrated greater activation in the hippocampus during extinction recall and increased prefrontal cortex activation during fear renewal. The hippocampus is critically involved in contextual learning and memory processes.

Different THC doses were therefore associated with distinct patterns of brain activation at different time points following administration.

Conclusion

This study suggests that acute oral THC may modulate neural circuits involved in fear extinction and fear regulation in adults with PTSD. The observed effects were dependent on both dose and timing, with distinct neurobiological responses emerging at 24 hours and one week after administration.

While the findings provide preliminary evidence supporting the role of the endocannabinoid system in fear-memory processing, the study did not assess long-term clinical outcomes or demonstrate direct improvement in PTSD symptoms. Further large-scale clinical studies are needed to determine whether these neurobiological changes translate into meaningful therapeutic benefits and improved treatment outcomes for individuals with PTSD.