A traditional African psychedelic plant medicine has inspired two new drugs to treat addiction and depression. Ibogaine has been used for thousands of years during shamanistic rituals as a hallucinogen, to suppress hunger and tiredness, and even as an aphrodisiac.
But ibogaine, the main active ingredient of Tabernanthe iboga - a West African shrub that grows in the Congo and Angola, can be fatal. Now scientists have developed two new drug candidates for potentially treating addiction and depression, modelled on the pharmacology of ibogaine.
They say, at very low doses, the new compounds were able to "blunt" symptoms of both conditions in mice. The findings, published in the journal Cell, took inspiration from ibogaine’s impact on the serotonin transporter (SERT), which is also the target of antidepressants such as Prozac.
A team of American scientists virtually screened 200 million molecular structures to find ones that blocked SERT in the same way as ibogaine. Co-senior author Professor Brian Shoichet, of University of California, San Francisco (UCSF), said: "Some people swear by ibogaine for treating addiction, but it isn’t a very good drug.
"It has bad side effects, and it’s not approved for use in the United States. Our compounds mimic just one of ibogaine’s many pharmacological effects, and still replicate its most desirable effects on behaviour, at least in mice.”
Dozens of scientists helped demonstrate the real-world promise of the novel molecules, which were initially identified using Prof Shoichet’s computational docking methods. Docking involves systematically testing virtual chemical structures for binding with a protein, enabling researchers to identify new drug leads without having to synthesise them in the lab.
Co-first author Dr Isha Singh said: “This kind of project begins with visualising what kinds of molecules will fit into a protein, docking the library, optimising, and then relying on a team to show the molecules work. Now we know there’s a lot of untapped therapeutic potential in targeting SERT.”
In the 19th and 20th Centuries, doctors in Europe and America experimented with ibogaine's use in treating a variety of ailments, but the drug never gained widespread acceptance and was ultimately made illegal in many countries. Prof Shoichet explained that part of the problem is that ibogaine interferes with many aspects of human biology.
Subscribe here for the latest news where you live
He said: “Ibogaine binds to hERG, which can cause heart arrhythmias, and from a scientific standpoint, it’s a ‘dirty’ drug, binding to lots of targets beyond SERT. Before this experiment, we didn’t even know if the benefits of ibogaine came from its binding to SERT.”
Co-author Professor Allan Basbaum said: “With this sort of potency, we hope to have a better therapeutic window without side effects. Dropping the dose almost 200-fold could make a big difference for patients."
Prof Shoichet has submitted the structures of both new molecules to Sigma Aldrich, the chemical manufacturing company, aiming to make the them available for further testing by other scientists, while he continues to hunt for more precise molecules Prof Basbaum, also of UCSF, added: “This is really the way science should be done. We took a group with expertise in disparate fields and came up with something that might really make a difference.”
