Serotonergic Psychedelics as a Potential Therapeutic Strategy for Anxiety, A Systematic Review

Background and objective: Anxiety disorders are among the most prevalent psychiatric disorders worldwide and affect all age groups. Current pharmacological treatments, such as selective serotonergic reuptake inhibitors (SSRI’s) and benzodiazepines, have limitations in terms of adverse effects and efficacy, which highlights the need for alternative therapies. Serotonergic psychedelics have demonstrated promising anxiolytic-like behaviors in preclinical studies, primarily thought to be mediated through agonism of the 5-HT2A receptor. This systematic review aimed to investigate the preclinical evidence of anxiolytic-like potential of serotonergic psychedelics in animal models, and to evaluate the validity and limitations of the included behavioral tests. Methods: This systematic review was conducted in accordance with the PRISMA 2020 guidelines. A systematic search was conducted in PubMed and Embase. Inclusion and exclusion criteria were defined prior to screening to ensure a transparent inclusion of studies and minimize bias. The title, abstract and full-text screening were conducted independently by two reviewers, with conflicts being resolved through discussion. In total, 18 studies were included after the final screening. Results: Overall, the results demonstrate that serotonergic psychedelics, such as psilocybin and DOI, exerted anxiolytic-like effects across several behavioral tests. However, anxiogenic and null effects were also reported. This suggests that the effects are context-dependent, influenced by dosage, administration pattern, biological variables, as well as the experimental conditions. The predictive and face validity of the included behavioral models was generally acceptable. However, the construct validity had some limitations, and inconsistencies in the experimental conditions create a need for more standardization to ensure more transparent and reproducible data, and further the research field. Conclusions: The preclinical studies included in this review indicate that the serotonergic psychedelics have therapeutic potential in the treatment of anxiety, especially psilocybin elicited consistent anxiolytic-like effects, possibly due to 5-HT2A receptor agonism. However, future studies should focus on understanding mechanisms, sex-specific effects, and further the combinations of behavioral tests to ensure better interpretation of behavioral outcomes.