Targeting the Endocannabinoid System in the Treatment of Posttraumatic Stress Disorder: A Promising Case of Preclinical-Clinical Translation?

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.

Keywords: 2-AG; Anandamide; Clinical trials; Endocannabinoid; FAAH; PTSD; THC.

Figure 1.

Overview of therapeutic targets to enhance cannabinoid signaling. Currently, there are three distinct ways to modulate cannabinoid signaling via the CB₁R in humans. The primary psychoactive ingredient of cannabis, THC, can activate CB₁Rs and has been used in humans extensively for medical and nonmedical purposes. More recently, enzyme inhibition approaches have been used to modulate endogenous cannabinoid function. Inhibition of FAAH can increase AEA availability, while inhibition of MAGL can similarly promote 2-AG. All three methods appear to influence stress and fear learning, although dose and route of administration may be critical. Currently, THC and FAAH inhibition are each being used together with prolonged exposure therapy to treat posttraumatic stress disorder in separate clinical trials. MAGL inhibition is currently being evaluated on neuroimaging biomarkers in posttraumatic stress disorder population, as well. Future work will hopefully highlight the shared and unique features of each pharmacological target in this patient population. Figure created with BioRender.com. 2-AG, 2-arachidonoyl glycerol; AEA, anandamide; CB₁R, CB₁ receptor; FAAH, fatty acid amide hydrolase; MAGL, monoacylglycerol lipase; THC, Δ⁹-tetrahydrocannabinol.