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Heifets BD, Malenka RC. 
“Disruptive Psychopharmacology”. 
JAMA Psychiatry. 2019 Jun 26.
The paucity of medications with novel mechanisms for the treatment of mental illnesses combined with the delayed response to currently available medications has led to great excitement about the potential therapeutic utility of previously demonized drugs, which offer the hope of generating rapid symptom reductions in some of the sickest patients. Within the past 2 years, the US Food and Drug Administration approved esketamine for treatment-resistant depression and 2 compounds that are still on the US Drug Enforcement Administrationís most restrictive schedule, 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin, have received breakthrough therapy designation. If these latter drugs are approved, they will require a new mental health care infrastructure that is capable of administering powerful psychoactive substances while simultaneously incorporating appropriate psychotherapeutic support. The sheer prevalence of the conditions these drugs are meant to treat (depression and posttraumatic stress disorder among other emerging indications) will mean that clinicians will have to deal with safety issues, including appropriate patient selection, substance abuse potential, and emergent psychiatric and medical crises. These considerations justify investment in elucidating the detailed neural mechanisms by which these drugs work so that we might better control their safety and efficacy while simultaneously developing better treatments with fewer adverse effects.
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