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.

内源性大麻素 (eCB) 系统是大脑中最普遍的信号系统之一，提供丰富的药理学，包括多个可药物靶点。临床前研究表明，eCB 活动影响前额皮质和杏仁核之间的功能连接，从而影响生物体应对威胁和压力经历的能力。动物研究表明，杏仁核内 CB ₁受体的激活对于消除恐惧记忆至关重要。无法消除创伤记忆是创伤后应激障碍的核心症状，这表明增强 eCB 信号传导可能在这种情况下具有治疗潜力。然而，尚不清楚该领域的动物发现是否适用于人类。为这一关键问题提供信息的数据现已出现，也是本次审查的重点。

我们首先简要总结了 eCB 系统的生物学以及支持其在恐惧消退和压力反应中作用的动物研究。然后我们讨论可用于治疗目的的药理学 eCB 靶向策略：使用 Δ ⁹ -四氢大麻酚或其合成类似物直接激活 CB ₁受体；或间接增强，通过抑制 eCB 降解酶，anandamide 降解酶脂肪酸酰胺水解酶；或 2-AG（2-花生四烯酰甘油）- 降解酶单酰甘油脂肪酶。然后，我们回顾了最近通过 Δ ⁹ -四氢大麻酚直接激活 CB ₁受体的人体数据，以及通过脂肪酸酰胺水解酶阻断增强 anandamide 的作用。现有的人类数据一致支持动物研究结果对恐惧记忆和应激反应的转化，并表明其对人类具有潜在的治疗效用。