From African Plant Medicine to Potential Medicinal Breakthrough: Ibogaine-Inspired Drugs Outperform Popular Antidepressants in Addiction and Depression

In a significant breakthrough, scientists have successfully developed two new drug candidates with the potential to treat addiction and depression. Inspired by the traditional African psychedelic plant medicine ibogaine, these compounds have demonstrated the ability to alleviate symptoms of both conditions in mice when administered at extremely low doses.

Published on May 2 in the prestigious journal Cell, the groundbreaking study drew inspiration from ibogaine’s influence on the serotonin transporter (SERT) — a key target for widely used SSRI antidepressants such as fluoxetine (Prozac). Collaborating across leading institutions including UCSF, Yale, and Duke universities, the research team employed virtual screening techniques to sift through a staggering 200 million molecular structures, ultimately identifying compounds that mimicked ibogaine’s SERT-blocking mechanism.

“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 U.S.,” remarks senior author Brian Shoichet. “Our compounds mimic just one of ibogaine’s many pharmacological effects, and still replicate its most desirable effects on behavior, at least in mice.”

New Drug Candidates Outperform SSRI Antidepressants while Avoiding Dangerous Side Effects

Researchers from the laboratories of Shoichet, Allan Basbaum, PhD, Aashish Manglik, MD, PhD (UCSF), Gary Rudnick, PhD (Yale), and Bill Wetsel, PhD (Duke) collaborated to showcase the practical potential of these groundbreaking molecules, initially discovered through Shoichet’s computational docking techniques.

The process of docking entails a methodical evaluation of virtual chemical structures to determine their ability to bind with a specific protein. This approach allows scientists to identify potential drug candidates without the need for immediate synthesis in the laboratory.

“This kind of project begins with visualizing what kinds of molecules will fit into a protein, docking the library, optimizing, and then relying on a team to show the molecules work,” explains first co-author Isha Singh. “Now we know there’s a lot of untapped therapeutic potential in targeting SERT.”

For centuries, the iboga plant’s roots, native to central Africa, have been utilized in sacred shamanistic ceremonies, unveiling the powerful properties of ibogaine. In the 19th and 20th centuries, European and American doctors embarked on experiments to harness its potential in treating various conditions. However, despite initial intrigue, ibogaine failed to attain widespread recognition and eventually faced legal restrictions in numerous nations.

According to Shoichet, the intricate nature of human biology presents a significant hurdle for ibogaine’s acceptance. The substance disrupts multiple facets of our biological processes, contributing to its challenges in gaining mainstream adoption.

“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,” Shoichet adds. “Before this experiment, we didn’t even know if the benefits of ibogaine came from its binding to SERT.”

Shoichet, renowned for his use of docking techniques to identify drugs for depression and pain relief, developed a keen interest in SERT (serotonin transporter) and ibogaine following a sabbatical in his lab by SERT expert Rudnick from Yale. In 2018, Singh took charge of the project, aiming to gain a deeper understanding of SERT by leveraging the growing interest in ibogaine.

This marked a significant milestone for the Shoichet lab, as it was their first docking experiment focusing on a transporter protein responsible for facilitating the movement of molecules into and out of cells, rather than a receptor. Through a meticulous round of docking, they narrowed down the initial virtual library of 200 million molecular structures to a mere 49, out of which 36 were viable for synthesis. Rudnick’s lab then rigorously tested these molecules and discovered that 13 effectively inhibited SERT.

To further refine their selection, the team organized virtual-reality-guided “docking parties,” enabling Singh to prioritize five molecules for optimization. The two most potent SERT inhibitors were subsequently shared with Basbaum and Wetsel’s teams, who conducted thorough testing using animal models of addiction, depression, and anxiety.

“All of a sudden, they popped—that’s when these drugs looked a lot more potent than even paroxetine [Paxil],” remarks Shoichet.

Manglik, a cryo-electron microscopy (cryo-EM) expert, has verified that a particular drug, named ‘8090, meticulously aligned with Singh and Shoichet’s computational projections, fitting into SERT at the atomic level. These drugs exhibited a similar inhibitory effect on SERT as ibogaine but without the psychedelic properties. Notably, they demonstrated potent and selective action, with no adverse effects observed on a wide array of other receptors and transporters.

“With this sort of potency, we hope to have a better therapeutic window without side effects,” Basbaum adds. “Dropping the dose almost 200-fold could make a big difference for patients.”

Shoichet has submitted the chemical structures of the two new drug candidates inspired by ibogaine to Sigma Aldrich, a chemical manufacturing company. The aim is to make the molecules available for further testing by other scientists, while Shoichet continues his quest to find more precise molecules.

Millions of patients worldwide continue to suffer from addiction and depression, highlighting the urgent need for new and effective therapies. The submission of the new molecules to Sigma Aldrich represents a significant step towards the development of potential treatments for these conditions.

“This is really the way science should be done,” Basbaum adds. “We took a group with expertise in disparate fields and came up with something that might really make a difference.”

Source: 10.1016/j.cell.2023.04.010

Image Credit:  Juan Arredondo/Getty Images Reportage