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The history of psychedelic substance use, modern research efforts, and their potential clinical applications addressing current treatment resistant mental health disorders evolved through an intriguing and complexly interwoven story linking ancient cultures, modern discovery, pop cultural movements, national and international politics, and well-intentioned laws with unintended consequences. In the context of this history, this commentary discusses the 21st century resurgence of psychedelic drug assisted psychotherapeutic research, the challenges imposed by the United States Controlled Substance Act (US CSA), and the potential for development of medicinal products for the treatment of persisting mental health disorders.

The unrelenting persistence of behavioral disorders, for which those who are afflicted and refractory to current evidenced based therapies, reveal a powerful incentivizing force for advancing new medicinally assisted psychotherapeutic treatments. On the other hand, we enter the 21st century humbled by the daunting challenge of developing medicines for central nervous system (CNS) disorders in response to the failure of so many seemingly promising medicines that emerged from years of clinical trials, billions of US dollars invested, with benefit to risk profiles which at the time, were acceptable to regulatory agencies in the US and globally (Hyman, 2012; Pangalos et al., 2007; Pankevich et al., 2014). With these considerations in mind, the present commentary is not postured as advocacy for a simple or certain solution to the challenges posed by mental health disorders or “brain diseases.” Nonetheless, it suggests that pressing public health challenges involving behavioral disorders may be addressed in part by recent advances in neuropharmacology, on the effects, mechanisms of action, and potential clinical applications of psychedelic drugs discussed in this special issue of Neuropharmacology. Together, these advances support our conclusion that increased scientific investigation of psychedelic substances for potential clinical application merits serious consideration among the many other efforts that are vigorously being pursued to address mental health illnesses that continue to be so pervasive in the United States and globally.

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