Department of Experimental Psychology and Helmholtz Institute, Utrecht University, Utrecht, the Netherlands; Altrecht Academic Anxiety Center, Utrecht, the Netherlands.
Department of Experimental Psychology and Helmholtz Institute, Utrecht University, Utrecht, the Netherlands; Brain Research & Innovation Center, Ministry of Defence, Utrecht, the Netherlands; Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands.
Eur Neuropsychopharmacol. 2023 Jul;72:79-94. doi: 10.1016/j.euroneuro.2023.04.001. Epub 2023 Apr 23.
The endocannabinoid system is a promising candidate for anxiolytic therapy, but translation to the clinic has been lagging. We meta-analyzed the evidence for anxiety-reduction by compounds that facilitate endocannabinoid signaling in humans and animals. To identify areas of specific potential, effects of moderators were assessed. Literature was searched in Pubmed and Embase up to May 2021. A placebo/vehicle-control group was required and in human studies, randomization. We excluded studies that co-administered other substances. Risk of bias was assessed with SYRCLE's RoB tool and Cochrane RoB 2.0. We conducted three-level random effects meta-analyses and explored sources of heterogeneity using Bayesian regularized meta-regression (BRMA). The systematic review yielded 134 studies. We analyzed 120 studies (114 animal, 6 human) that investigated cannabidiol (CBD, 61), URB597 (39), PF-3845 (6) and AM404 (14). Pooled effects on conditioned and unconditioned anxiety in animals (with the exception of URB597 on unconditioned anxiety) and on experimentally induced anxiety in humans favored the investigational drugs over placebo/vehicle. Publication year was negatively associated with effects of CBD on unconditioned anxiety. Compared to approach avoidance tests, tests of repetitive-compulsive behavior were associated with larger effects of CBD and URB597, and the social interaction test with smaller effects of URB597. Larger effects of CBD on unconditioned anxiety were observed when anxiety pre-existed. Studies reported few side effects at therapeutic doses. The evidence quality was low with indications of publication bias. More clinical trials are needed to translate the overall positive results to clinical applications.
内源性大麻素系统是一种有前途的抗焦虑治疗候选物，但向临床的转化一直滞后。我们对促进人类和动物内源性大麻素信号的化合物的抗焦虑作用进行了荟萃分析。为了评估特定潜在领域的效果，评估了调节剂的作用。文献检索范围是 Pubmed 和 Embase 截至 2021 年 5 月的内容。需要有安慰剂/载体对照组，并且在人类研究中需要进行随机分组。我们排除了同时给予其他物质的研究。偏倚风险使用 SYRCLE 的 RoB 工具和 Cochrane RoB 2.0 进行评估。我们进行了三级随机效应荟萃分析，并使用贝叶斯正则化荟萃回归（BRMA）探索异质性的来源。系统综述产生了 134 项研究。我们分析了 120 项研究（114 项动物研究，6 项人体研究），这些研究调查了大麻二酚（CBD，61 项）、URB597（39 项）、PF-3845（6 项）和 AM404（14 项）。动物条件性和非条件性焦虑（URB597 对非条件性焦虑除外）以及人体实验性诱导焦虑的荟萃分析结果表明，与安慰剂/载体相比，受试药物更有效。发表年份与 CBD 对非条件性焦虑的影响呈负相关。与接近回避测试相比，重复强迫行为测试与 CBD 和 URB597 的效果更大相关，而社交互动测试与 URB597 的效果更小相关。在存在焦虑的情况下，CBD 对非条件性焦虑的效果更大。研究报告在治疗剂量下很少有副作用。证据质量低，存在发表偏倚的迹象。需要更多的临床试验将总体积极的结果转化为临床应用。
