A new class of iboga alkaloids, called oxa-iboga, was created by modifying the iboga molecular structure to replace a key component with a benzofuran ring. These compounds lack the heart rhythm risks (proarrhythmic effects) of ibogaine and noribogaine when tested on human heart cells. In male rats, oxa-iboga compounds were more effective than ibogaine at reducing opioid use. They act as potent kappa opioid receptor agonists but produce different behavioral effects than typical kappa agonists. A single dose or short treatment with oxa-noribogaine led to long-lasting reductions in morphine, heroin, and fentanyl intake, reversed persistent opioid-induced pain sensitivity, and suppressed drug-seeking behavior in relapse models. These compounds offer a mechanistically distinct approach to treating opioid use disorder.
A new class of iboga alkaloids, called oxa-iboga, was created by modifying the iboga skeleton to include a benzofuran group. These compounds act as potent kappa opioid receptor agonists but show atypical behavioral effects compared to standard kappa psychedelics. Oxa-noribogaine, a key oxa-iboga compound, demonstrated greater therapeutic efficacy in rat models of opioid use than noribogaine, with no cardiac pro-arrhythmic potential. A single dose produced long-lasting suppression of morphine and fentanyl intake, and a short treatment regimen persistently reduced morphine intake and reinforcing efficacy. It also suppressed drug seeking in relapse models and elevated neurotrophin proteins in brain regions linked to addiction, suggesting targeted neuroplasticity. Oxa-iboga compounds are candidates for a novel pharmacotherapy for opioid use disorder.