Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Addiction States

Abstract

AbstractSubstance use and related mental health epidemics are causing increasing suffering and death in diverse communities.1,2 Despite extensive efforts focused on developing pharmacotherapies for treating substance use disorders, currently approved medications do not reverse the persistent neurocircuitry and psychological changes that underlie addiction states, highlighting an urgent need for radically different therapeutic approaches.3,4 Ibogaine provides an important drug prototype in this direction, as a psychoactive iboga alkaloid suggested to have the ability to interrupt maladaptive habits including opioid use in drug-dependent humans.5 However, ibogaine and its major metabolite noribogaine present considerable safety risk associated with cardiac arrhythmias.6 We introduce a new class of iboga alkaloids - “oxa-iboga” - defined as benzofuran-containing iboga analogs and created via structural editing of the iboga skeleton. The oxa-iboga compounds act as potent kappa opioid receptor agonists in vitro and in vivo but exhibit atypical behavioral features compared to standard kappa psychedelics. We show that oxa-noribogaine has greater therapeutic efficacy in addiction models and no cardiac pro-arrhythmic potential, compared to noribogaine. Oxa-noribogaine induces long-lasting suppression of morphine intake after a single dose in rat models of addiction and persistent reduction of morphine intake after a short treatment regimen. Oxa-noribogaine maintains and enhances the ability of iboga compounds to effect lasting alteration of addiction-like states while addressing iboga’s cardiac liability. As such, oxa-iboga compounds represent candidates for a new kind of anti-addiction pharmacotherapeutics.