Medical Research

The ECS & Fear Extinction

The ECS & Fear Extinction
Written by Loren Devito, PhD

Insights into how endocannabinoids may affect PTSD

Fear is a natural emotion that is expressed by all healthy individuals. Excessive fear, however, is maladaptive and can result from chronic or severe events–a common example being post-traumatic stress experienced by veterans as they return from war and assimilate back into non-combat life. However, post-traumatic stress disorder (PTSD) affects many people, not just veterans. Survivors of childhood trauma, domestic violence, and rape, among others, may also experience PTSD, the symptoms of which may range from flashback memories, sleep disturbances, and irritable or aggressive behavior that significantly impacts daily life.

Treatments, including psychotherapy, are available and can be effective. Medications like antidepressants can also help manage symptoms. But, for many of the estimate
7-8% of the population that will experience PTSD in their lifetime, these treatments and medications are not sufficient. Therefore, developing new therapies to address PTSD is a very important topic of research, reflected by the number of clinical trials underway (currently over 1,300).

At the core of PTSD is an inability to extinguish fear memories. Fortunately, it is quite easy to replicate this type of memory in pre-clinical models to evaluate novel compounds, as these circuits are hard-wired into the brain [1]. In this way, researchers have made progress into understanding how endocannabinoids affect fear and stress.

Studies have found that inhibition of fatty acid amide hydrolase (FAAH), the enzyme that breaks down the endocannabinoid anandamide, can reverse the effects of stress in pre-clinical models (FAAH inhibition blocks anadamide break down to increase its levels) [2-3]. While these results are encouraging, studies in humans using medical cannabis have been a bit mixed [4]. These lines of evidence indicate that a more targeted approach may be most beneficial and one recent study showed just that.

Forty-five healthy individuals received an oral FAAH inhibitor called
PF-04457845 or an inactive substance (placebo) across 10 days [5]. On the last two days of treatment, they performed fear learning and other tasks to evaluate their response to stress. The researchers found that PF-04457845 treatment improved their fear extinction and improved stress response. In addition, treatment increased levels of anandamide without affecting hormones that are linked to fear and stress. While evaluated in a small sample, these results suggest that targeting FAAH could be an effective strategy for PTSD.

“Our study shows that this class of medications, called FAAH inhibitors, may offer a new way to treat PTSD and perhaps also other stress-related psychiatric conditions,” said study lead investigator Leah Mayo in a press release.

“The next important step will be to see if this type of medication works in patients, particularly those with PTSD.”



  1. Kida, S., “Reconsolidation/destabilization, Extinction and Forgetting of Fear Memory as Therapeutic Targets for PTSD.” Psychopharmacology. vol.236, no.1, 2019, pp. 49-57.
  2. Bluett, R.J., et al., “Central Anandamide Deficiency Predicts Stress-induced Anxiety: Behavioral Reversal through Endocannabinoid Augmentation.” Transl Psychiatry. vol.4, 2014, pp. e408.
  3. Bortolato, M., et al. “Antidepressant-like Activity of the Fatty Acid Amide Hydrolase Inhibitor URB597 in a Rat Model of Chronic Mild Stress.” Biol Psychiatry. vol.62, no.10, 2007, pp. 1103-1110.
  4. Shishko, I. “A Review of Medical Marijuana for the Treatment of Posttraumatic Stress Disorder: Real Symptom Re-leaf or Just High Hopes?” Ment Health Clin. vol.8, no.2, 2018, pp. 86-94.
  5. Mayo, L.M., “Elevated Anandamide, Enhanced Recall of Fear Extinction, and Attenuated Stress Responses Following Inhibition of Fatty Acid Amide Hydrolase:
    A Randomized, Controlled Experimental Medicine Trial.” Biol Psychiatry. 2019, epub.


About the author

Loren Devito, PhD

Loren DeVito, PhD is a neuroscientist and science writer with expertise in cannabis science and medicine. She is committed to communicating evidence-based information about cannabis and its healing properties. Learn more about her work at