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. The effect was moderate to large for conditioned anxiety in animals, Hedge’s G=0.68, 95%CI[0.11, 1.26], moderate for unconditioned anxiety in animals, Hedge’s G=0.50, 95%CI[0.29, 0.70], and large for human experimental anxiety, Hedge’s G=0.79, 95%CI[0.28, 1.31]. In all cases, compared to placebo/vehicle, CBD exerted beneficial effects on anxiety outcomes. No severe adverse effects were reported. There was substantial heterogeneity between average effect sizes within studies, σ2w Conclusions: A straightforward recommendation for optimal dosing was not possible, because there was no consistent linear effect of CBD on anxiety reduction, and concentration-effect relations were variable across species. Acute and (sub)chronic dosing studies with integrated PK and PD outcomes are required for substantiated dose recommendations. The low quality meta-analytic evidence confirmed the often discussed potential of CBD for treating anxiety symptoms. The compound induced anxiolytic effects, regardless of the type of anxiety studied. Moderator analyses will be conducted to determine other sources of heterogeneity of CBD effects, such as type of anxiety test and anxiety outcome
