Recent advances in psychedelic and entactogen research spotlight a reinvigorated pursuit of enhanced treatments for psychiatric, neurological, and various peripheral disorders. Psychedelics and entactogens, interacting with 5-HT2A among other serotonergic receptors and/or monoamine reuptake transporters, offer innovative therapeutic avenues. Yet, alongside their potential, these substances carry known safety and toxicity risks, necessitating comprehensive non-clinical testing to forecast clinical efficacy and address safety concerns during development and post-approval.Heal et al. delineate challenges in developing novel serotonergic psychedelics and entactogens, proposing a multi-tiered screening approach to predict clinical efficacy and mitigate safety/toxicity risks. This includes early-stage non-clinical screening cascades to pharmacologically characterize novel drug candidates, detection of hallucinogenic activity, differentiation between hallucinogens and entactogens, and the application of Preclinical Lead Optimisation Technology (PLOT) screening. Moreover, optimized animal models are recommended for assessing the abuse/dependence potential of these substances, underscoring the importance of a balanced benefit-risk assessment in delivering safer, more effective clinical psychedelics.This structured approach to developing next-generation psychedelics emphasizes the need for vigilant monitoring of potential abuse and physical dependence, addressing both neurological and cardiotoxicity concerns. The authors stress that while classical psychedelics and entactogens offer promising therapeutic benefits, their comprehensive pharmacological characterization, coupled with a rigorous assessment of abuse and dependence risks, is imperative to ensure patient safety and public health.This article contributes significantly to our understanding of psychedelic and entactogen development, highlighting the critical intersection between groundbreaking therapeutic potential and the imperative for stringent safety evaluations. Its insights into screening strategies, safety concerns, and regulatory considerations provide a valuable framework for advancing psychedelic and entactogen research with an emphasis on harm reduction and public safety.