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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.

RATIONALE: Selective serotonin reuptake inhibitors (SSRIs) are considered first-line medication for anxiety-like disorders such as panic disorder, generalized anxiety disorder, and post-traumatic stress disorder. Fear learning plays an important role in the development and treatment of these disorders. Yet, the effect of SSRIs on fear learning are not well known.OBJECTIVE: We aimed to systematically review the effect of six clinically effective SSRIs on acquisition, expression, and extinction of cued and contextual conditioned fear.METHODS: We searched the Medline and Embase databases, which yielded 128 articles that met the inclusion criteria and reported on 9 human and 275 animal experiments.RESULTS: Meta-analysis showed that SSRIs significantly reduced contextual fear expression and facilitated extinction learning to cue. Bayesian-regularized meta-regression further suggested that chronic treatment exerts a stronger anxiolytic effect on cued fear expression than acute treatment. Type of SSRI, species, disease-induction model, and type of anxiety test used did not seem to moderate the effect of SSRIs. The number of studies was relatively small, the level of heterogeneity was high, and publication bias has likely occurred which may have resulted in an overestimation of the overall effect sizes.CONCLUSIONS: This review suggests that the efficacy of SSRIs may be related to their effects on contextual fear expression and extinction to cue, rather than fear acquisition. However, these effects of SSRIs may be due to a more general inhibition of fear-related emotions. Therefore, additional meta-analyses on the effects of SSRIs on unconditioned fear responses may provide further insight into the actions of SSRIs.

Introduction: Preclinical research suggests that cannabidiol (CBD) may have therapeutic potential in pathological anxiety. Guidelines to inform the study design of future human studies are however lacking. Aims: We aimed to determine the boundary conditions for anxiolytic effects of CBD in humans by integrating, both qualitatively and quantitatively, pharmacokinetic (PK) and pharmacodynamic (PD) (and subsidiary safety) data from preclinical and clinical studies. Methods: We conducted two systematic reviews in Pubmed and Embase up to August 2021, into PK and PD data of systemic CBD exposure in both humans and animals, which includes anxiolytic and potential side effects. Risk of bias was assessed for effects on anxiety outcomes (SYRCLE’s RoB tool [1] and Cochrane RoB 2.0 [2]), PK outcomes, and harm-related outcomes. A control group was an inclusion criterion in outcome studies across species. In human outcome studies, randomisation was required. We excluded studies that co-administered other substances. We used the IB-de-risk tool [3] for a translational integration of PK and PD data. Further, a meta-analysis, stratified by type of anxiety and using three-level random effects models, was conducted to investigate sources of heterogeneity of CBD effects on anxiety outcomes. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach [4] was used to rate the quality of the evidence. Results: We synthesized data from 87 articles with the IB-derisk tool. Most studies (70.3%) reported null effects of CBD on anxiety outcomes. There was no identifiable relation between anxiety outcomes and drug levels across species. In all species (humans, mice, rats), anxiolytic effects of CBD seemed to be clustered in certain differential concentration ranges, which differed between species. Data from 61 articles were included in the meta-analysis. The overall pooled effects of CBD on anxiety differed significantly from zero, p≤.02. T

Selective serotonin reuptake inhibitors (SSRIs) are the first choice of treatment for anxiety-like disorders such as panic disorder, generalized anxiety disorder and post-traumatic stress disorder. Fear learning plays an important role in the etiopathology of these disorders. However, it is unclear if and which fear learning processes are affected by SSRIs. This systematic review investigated the effect of six clinically effective SSRIs on the fear learning processes acquisition, expression and extinction. Since SSRIs have been shown to effectively treat anxiety-like disorders, the results of this systematic review could provide insight into which fear learning processes are important to include in future research regarding the development and treatment of anxiety-like disorders. A systematic search in the Medline and Embase databases yielded 128 articles that met the inclusion criteria. Of these articles 120 were eligible for the meta-analysis. Data regarding the study subjects, intervention, experimental design and size and direction of the effects were extracted. Meta-analysis was conducted in R, the R-package metafor [1] was used to estimate the overall effect size, using a random-effects model. Five categorical predefined moderators were coded to account for between-studies heterogeneity (type of SSRI, duration of treatment, disease induction, species, type of test). The effect of these moderators was analysed with a Bayesian penalized meta-regression (BRMA) which is a new method. This analysis was carried out with the pema R-package [2]. The meta-analysis showed that SSRIs significantly reduced contextual fear expression and facilitated extinction learning to cue. Bayesian penalized meta-regression further suggested that chronic treatment with SSRIs is associated with stronger anxiolytics effects on cued fear expression than acute treatment. Other variables, including type of SSRI, species, disease induction and type of test, did not seem to