Summary: In a randomized, double-blind experimental trial, a drug that raises levels of the body’s own cannabis-like chemicals—endocannabinoids—by inhibiting the enzyme FAAH (fatty acid amide hydrolase) enhanced recall of fear extinction and reduced stress responses in healthy volunteers. These findings suggest FAAH inhibitors may help improve therapies for post-traumatic stress disorder (PTSD) and other stress-related psychiatric conditions.
Source: Linköping University
A medication that increases the brain’s natural cannabis-like substances—endocannabinoids—shows potential for helping the brain unlearn fear memories when those memories are no longer relevant. Results from an early-stage experimental study in healthy volunteers at Linköping University in Sweden indicate that FAAH inhibitors, which block the enzyme that breaks down the endocannabinoid anandamide, can strengthen the retention of fear extinction learning. The study is reported in the journal Biological Psychiatry.
Researchers administered a FAAH inhibitor to volunteers to raise levels of anandamide, an important endocannabinoid involved in regulating fear and stress responses. By blocking FAAH, the medication slows the breakdown of anandamide and thereby increases its availability in brain regions that control fear and anxiety. The compound tested was originally developed as a potential pain reliever and was repurposed here to test its effects on fear extinction and stress reactivity.
The trial was randomized, placebo-controlled and double-blind. Healthy adult volunteers received either the FAAH inhibitor (PF-04457845, 4 mg once daily; n=16) or placebo (n=29) for ten days. On days nine and ten, participants completed tests measuring fear learning, extinction recall, physiological stress reactivity and affective responses to stress.
One core task modeled the principle behind prolonged exposure therapy (PE) for PTSD. Participants learned to associate an aversive sound—fingernails on a blackboard—with a visual cue (a red or blue lamp). After conditioning, they were repeatedly re-exposed to the lamp without the unpleasant sound, a process that allows extinction learning: forming the new memory that the cue no longer predicts danger. The following day participants were tested on how well they recalled that extinction learning—whether they remembered the lamp no longer signaled threat.
“Participants who received the FAAH inhibitor showed substantially better recall of the extinction memory,” says Leah Mayo, senior postdoctoral fellow and lead investigator. “This finding is very encouraging.”
In addition to improved extinction recall, FAAH inhibition produced a roughly ten-fold increase in baseline anandamide levels. The treatment also reduced physiological stress responses: autonomic reactivity measured via skin conductance was attenuated, and measures of negative affect assessed with facial electromyography were protected against stress-induced increases. Together, these effects suggest FAAH inhibition both strengthens the retention of safety learning and blunts the immediate emotional and bodily reactions to stress.
PTSD can develop after life-threatening or severely traumatic events and is characterized by persistent, distressing fear memories and heightened stress responses. Patients with PTSD often avoid reminders of the trauma and may experience chronic hyperarousal, withdrawal and sleep disturbances. Current psychological treatments, particularly prolonged exposure therapy, aim to extinguish pathological fear memories, but many patients fail to achieve lasting benefit and relapse is common.
The current human results are notable because they translate findings from animal studies showing that raising anandamide via FAAH inhibition facilitates fear extinction and protects against stress-induced anxiety. “Many promising treatments from preclinical research have not translated successfully to humans,” notes Professor Markus Heilig. “This is one of the first mechanisms where preclinical and early human experimental results align. The next important step is to evaluate whether FAAH inhibitors improve outcomes in patients with PTSD.”
Funding: The study received financial support from several sources, including the Swedish Research Council and the Canadian Institutes of Health Research. Pfizer AB provided the FAAH inhibitor and matching placebo for the trial at no charge and did not influence the study’s design, conduct, analysis or reporting.
Source:
Linköping University
Media contacts:
Leah Mayo – Linköping University
Image source:
Anna Nilsen / Linköping University.
Original research: Open access. Title: “Elevated anandamide, enhanced recall of fear extinction, and attenuated stress responses following inhibition of fatty acid amide hydrolase (FAAH): a randomized, controlled experimental medicine trial”. Authors include Leah M. Mayo, Anna Asratian, Johan Lindé, Maria Morena, Roosa Haataja, Valter Hammar, Gaëlle Augier, Matthew N. Hill and Markus Heilig. Published in Biological Psychiatry (2019).
Abstract summary
Background: PTSD involves persistent fear memories and maladaptive stress responses. In animal models, increasing anandamide levels through FAAH inhibition facilitates fear extinction and reduces stress-induced anxiety. Human genetic data have suggested similar associations when FAAH function is reduced.
Methods: In this double-blind, placebo-controlled experimental medicine trial, healthy adults received a FAAH inhibitor or placebo for ten days. On days nine and ten a battery of tasks assessed fear learning and extinction, autonomic stress reactivity, and stress-induced affective responses.
Results: FAAH inhibition elevated anandamide by an order of magnitude and improved recall of fear extinction tested 24 hours after extinction training. The drug also attenuated autonomic markers of stress and reduced stress-induced negative affect.
Conclusions: These preliminary human data indicate that FAAH inhibition can enhance retention of extinction learning and reduce anxiogenic effects of stress, supporting further development of FAAH inhibitors as potential treatments to augment exposure-based therapy and address unmet needs in PTSD care.