It has been established that the endogenous cannabinoid (endocannabinoid) system plays key modulatory roles in a wide variety of pathological conditions. The endocannabinoid system comprises both cannabinoid receptors, their endogenous ligands including 2-arachidonoylglycerol (2-AG), N-arachidonylethanolamine (anandamide, AEA), and enzymes that regulate the synthesis and degradation of endogenous ligands which include diacylglycerol lipase alpha (DAGL-α), diacylglycerol lipase beta (DAGL-β), fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), α/β hydrolase domain 6 (ABHD6). As the endocannabinoid system exerts considerable involvement in the regulation of homeostasis and disease, much effort has been made towards understanding endocannabinoid-related mechanisms of action at cellular, physiological, and pathological levels as well as harnessing the various components of the endocannabinoid system to produce novel therapeutics. However, drug discovery efforts within the cannabinoid field have been slower than anticipated to reach satisfactory clinical endpoints and raises an important question into the validity of developing novel ligands that therapeutically target the endocannabinoid system. To answer this, we will first examine evidence that supports the existence of an endocannabinoid system role within inflammatory diseases, neurodegeneration, pain, substance use disorders, mood disorders, as well as metabolic diseases. Next, this review will discuss recent clinical studies, within the last 5 years, of cannabinoid compounds in context to these diseases. We will also address some of the challenges and considerations within the cannabinoid field that may be important in the advancement of therapeutics into the clinic.

已经确定内源性大麻素（内源性大麻素）系统在多种病理状况中起着关键的调节作用。内源性大麻素系统包括大麻素受体、它们的内源性配体，包括 2-花生四烯酰甘油 (2-AG)、N-花生四烯基乙醇胺（anandamide，AEA），以及调节内源性配体合成和降解的酶，包括二酰基甘油脂肪酶 α (DAGL-α) ）、二酰基甘油脂肪酶β（DAGL-β）、脂肪酸酰胺水解酶（FAAH）、单酰基甘油脂肪酶（MAGL）、α/β水解酶结构域6（ABHD6）。由于内源性大麻素系统在体内平衡和疾病的调节中发挥了相当大的作用，因此在了解内源性大麻素相关的细胞、生理、和病理水平，以及利用内源性大麻素系统的各种成分来生产新的疗法。然而，大麻素领域的药物发现工作在达到令人满意的临床终点方面比预期的要慢，并且对开发治疗靶向内源性大麻素系统的新型配体的有效性提出了一个重要问题。为了回答这个问题，我们将首先检查支持内源性大麻素系统在炎症性疾病、神经变性、疼痛、物质使用障碍、情绪障碍以及代谢疾病中存在作用的证据。接下来，本综述将讨论最近 5 年内大麻素化合物与这些疾病相关的临床研究。