In recent years, psychedelics have generated considerable excitement and interest as potential novel therapeutics for an array of conditions, with the most advanced evidence base in the treatment of certain severe and/or treatment-resistant psychiatric disorders. An array of clinical and pre-clinical evidence has informed our current understanding of how psychedelics produce profound alterations in consciousness. Mechanisms of psychedelic action include receptor binding and downstream cellular and transcriptional pathways, with long-term impacts on brain structure and function-from the level of single neurons to large-scale circuits. In this perspective, we first briefly review and synthesize separate lines of research on potential mechanistic processes underlying the acute and long-term effects of psychedelic compounds, with a particular emphasis on highlighting current theoretical models of psychedelic drug action and their relationships to therapeutic benefits for psychiatric and brain-based disorders. We then highlight an existing area of ongoing controversy we argue is directly informed by theoretical models originating from disparate levels of inquiry, and we ultimately converge on the notion that bridging the current chasm in explanatory models of psychedelic drug action across levels of inquiry (molecular, cellular, circuit, and psychological/behavioral) through innovative methods and collaborative efforts will ultimately yield the comprehensive understanding needed to fully capitalize on the potential therapeutic properties of these compounds., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Charles Nemeroff reports financial support was provided by National Institutes of Health. Charles Nemeroff reports financial support was provided by National Institute of Mental Health. Gregory Fonzo reports financial support was provided by National Institute of Health. Gregory Fonzo reports financial support was provided by Baszucki Brain Research Fund. Manoj K Doss reports a relationship with VCENNA, Inc that includes: consulting or advisory. Gregory Fonzo reports a relationship with Alto Neuroscience, Inc. that includes: equity or stocks. Gregory Fonzo reports a relationship with SynapseBio AI that includes: consulting or advisory. Charles Nemeroff has patent #US 6,375,990B1 licensed to Charles Nemeroff. Charles Nemeroff has patent #US 7,148,027B2 licensed to Charles Nemeroff. Gregory Fonzo has patent #16/981,822 pending to A. Etkin. Charles B Nemeroff is a compensated board member for Gratitude America, Anxiety and Depression Association of America, and Lucy Scientific Discovery; a consultant for Abbive, AneuroTech (division of Anima BV), Signant Health, Magstim, Inc, Intra-Cellular Therapies, Inc., EMA Wellness, Sage, Silo Pharma, Engrail Therapeutics, Pasithea Therapeutics Corp., GoodCap Pharmaceuticals, Inc., Senseye, Clexio, Ninnion Therapeutics, EmbarkNeuro, SynapseBio, BioXcel Therapeutics, Relmada Therapeutics, Galen Mental Health, LLC, and AutoBahn Therapeutics, Inc; a scientific advisory board member for ANeuoTech (division of Anima BV), Brain and Behavior Research Foundation (BBRF), Anxiety and Depression Assocation of America (ADAA), Skyland Trail, Signant Health, Laureate Institute for Brain Research (LIRB), Inc., Heading Health, Pasithea Therapeutic Corp., and Sage; and owns stock in Seattle Genetics, Antares Inc., Corcept Therapeutics Pharmaceuticals Company, EMA Wellness, Naki Health, and Relmada Therapeutics. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)