Targeting the Endocannabinoid System in the Treatment of Posttraumatic Stress Disorder: A Promising Case of Preclinical-Clinical Translation?
L. Mayo, Christine A Rabinak, M. Hill, M. Heilig
Biological Psychiatry July 1, 2021 DOI: 10.1016/j.biopsych.2021.07.019 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Intervention | Δ9-tetrahydrocannabinol |
| Topics | PTSD |
| Key findings | The authors argue that animal evidence linking endocannabinoid signaling, especially CB1 receptor activation in the amygdala, to fear extinction and stress responding appears to translate to humans. They contend that available human data on Δ9-tetrahydrocannabinol and fatty acid amide hydrolase blockade consistently support this translation and suggest potential therapeutic utility, including for posttraumatic stress disorder. |
Abstract
The endocannabinoid (eCB) system is one the most ubiquitous signaling systems of the brain and offers a rich pharmacology including multiple druggable targets. Preclinical research shows that eCB activity influences functional connectivity between the prefrontal cortex and amygdala and thereby influences an organism’s ability to cope with threats and stressful experiences. Animal studies show that CB1 receptor activation within the amygdala is essential for extinction of fear memories. Failure to extinguish traumatic memories is a core symptom of posttraumatic stress disorder, suggesting that potentiating eCB signaling may have a therapeutic potential in this condition. However, it has been unknown whether animal findings in this domain translate to humans. Data to inform this critical question are now emerging and are the focus of this review. We first briefly summarize the biology of the eCB system and the animal studies that support its role in fear extinction and stress responding. We then discuss the pharmacological eCB-targeting strategies that may be exploited for therapeutic purposes: direct CB1 receptor activation, using Δ9-tetrahydrocannabinol or its synthetic analogs; or indirect potentiation, through inhibition of eCB-degrading enzymes, the anandamide-degrading enzyme fatty acid amide hydrolase; or the 2-AG (2-arachidonoyl glycerol)–degrading enzyme monoacylglycerol lipase. We then review recent human data on direct CB1 receptor activation via Δ9-tetrahydrocannabinol and anandamide potentiation through fatty acid amide hydrolase blockade. The available human data consistently support a translation of animal findings on fear memories and stress reactivity and suggest a potential therapeutic utility in humans.
Comparable studies
Other narrative reviews on PTSD, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelic Psychiatry's Brave New World. | 2020 | Review | |
| Reviewing the Potential of Psychedelics for the Treatment of PTSD | 2020 | Review | |
| Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA. | 2016 | Review | |
| MDMA-assisted psychotherapy for PTSD: Are memory reconsolidation and fear extinction underlying mechanisms? | 2018 | Review | |
| Clinical applications of hallucinogens: A review. | 2016 | Review |
Citations in the library
Cited by 11
- Alleviating anxiety and taming trauma: Novel pharmacotherapeutics for anxiety disorders and posttraumatic stress disorder Neuropharmacology January 6, 2023
- First few seconds for flow: A comprehensive proposal of the neurobiology and neurodynamics of state onset. Neuroscience & Biobehavioral Reviews December 1, 2022
- Novel Pharmacologic and Other Somatic Treatment Approaches for Posttraumatic Stress Disorder in Adults: State of the Evidence. American Journal of Psychiatry December 1, 2024
- Challenges and considerations for treating PTSD with medicinal cannabis: the Australian clinician's perspective. Expert Review of Clinical Pharmacology 2023
- Investigational drugs in PTSD. Neuropsychopharmacology June 1, 2026
and 6 more in the library
Cites 4
- The short-term impact of 3 smoked cannabis preparations versus placebo on PTSD symptoms: A randomized cross-over clinical trial PLoS One March 17, 2021
- Cannabinoid modulation of corticolimbic activation to threat in trauma-exposed adults: a preliminary study. Psychopharmacology June 2020
- Dose-related effects of delta-9-THC on emotional responses to acute psychosocial stress. Drug and Alcohol Dependence August 1, 2017
- Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans. Neurobiology of Learning and Memory September 2014