PT  - JOURNAL ARTICLE
AU  - Václav Havel
AU  - Andrew C. Kruegel
AU  - Benjamin Bechand
AU  - Scot McIntosh
AU  - Leia Stallings
AU  - Alana Hodges
AU  - Madalee G. Wulf
AU  - Melissa Nelson
AU  - Amanda Hunkele
AU  - Mike Ansonoff
AU  - John E. Pintar
AU  - Christopher Hwu
AU  - Najah Abi-Gerges
AU  - Saheem A. Zaidi
AU  - Vsevolod Katritch
AU  - Mu Yang
AU  - Jonathan A. Javitch
AU  - Susruta Majumdar
AU  - Scott E. Hemby
AU  - Dalibor Sames
TI  - Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Addiction States
AID  - 10.1101/2021.07.22.453441
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.07.22.453441
4099  - http://biorxiv.org/content/early/2021/07/23/2021.07.22.453441.short
4100  - http://biorxiv.org/content/early/2021/07/23/2021.07.22.453441.full
AB  - Substance 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.Competing Interest StatementV.H., A.C.K, B.B., M.G.W, J.A.J., S.E.H and D.S. are named inventors on a patent(s) related to oxa-iboga compounds. A.C.K and D.S. are co-founders of Gilgamesh Pharmaceuticals. All other authors declare no competing interests.