New Synthesis Method Makes Ibogaine More Accessible for Research

Ibogaine, a psychoactive compound derived from plants, has gained attention for its potential anti-addictive and antidepressant properties. However, its availability is limited, as it is extracted primarily from African plants such as the iboga shrub (Tabernanthe iboga) and the small-fruited voacanga tree (Voacanga africana). Additionally, its use raises safety concerns, particularly due to the risk of irregular heartbeats, underscoring the need for a deeper understanding of its molecular effects.

A recent study published in Nature Chemistry by researchers from the University of California, Davis Institute for Psychedelics and Neurotherapeutics (IPN) reports a significant breakthrough: the successful total synthesis of ibogaine, its analogs, and related compounds using pyridine, a widely available and cost-effective chemical.

The research team’s approach enabled the synthesis of four naturally occurring ibogaine-related alkaloids and several non-natural analogs. Their method achieved yields ranging from 6% to 29% in just six or seven steps, marking a substantial improvement in efficiency compared to previous synthetic techniques.

“Ibogaine’s complex chemical structure makes large-scale production challenging, historically limiting medicinal chemistry efforts to develop improved analogs. Total synthesis addresses both issues—we can produce ibogaine without harvesting vast amounts of plant material, and we can create analogs, some of which are showing promising properties,” said David E. Olson, corresponding author of the study and director and professor at the University of California.

Despite the cardiac risks associated with ibogaine, its use continues to grow in the treatment of substance use disorders, traumatic brain injury, and other conditions.

“Some researchers aim to make ibogaine safer through careful cardiac monitoring and magnesium supplementation. But perhaps the better approach is to develop ‘Ibogaine 2.0’—a version that retains its profound anti-addictive and antidepressant effects without the associated cardiac risks,” Olson noted.

Analog Compounds of Interest

Olson highlighted two ibogaine analogs of particular significance from the study.

The first analog was a mirror image of ibogaine, a property known in chemistry as chirality. Similar to how left and right hands are mirror images but not identical, chiral molecules cannot be superimposed on one another.

“Nature only produces one version of ibogaine. If its therapeutic effects stem from interactions with another chiral entity—such as an enzyme or receptor—only the natural version should be active. If the effects are non-specific, then both versions should work,” Olson explained.

When tested on neurons, only the natural version of ibogaine promoted neuronal growth.

“This allowed us to demonstrate, for the first time, that ibogaine’s effects are likely tied to binding a specific receptor. While we don’t yet know exactly which receptor that is, this unnatural compound serves as a valuable tool for investigating the biology behind it,” Olson said.

The second analog of interest, (-)-10-fluoroibogamine, showed remarkable effects on neuronal structure and function, promoting growth and reconnection. It also displayed strong activity on serotonin transporters, proteins that regulate serotonin levels at synapses.

“The serotonin transporter is a target for many antidepressants and is believed to contribute to ibogaine’s therapeutic effects,” Olson noted. These findings suggest (-)-10-fluoroibogamine warrants further study as a potential treatment for substance use disorders, depression, and related neuropsychiatric conditions.

Toward Safer and More Effective Medicines

According to Olson, the research spanned a decade, with the team exploring multiple synthetic routes, each with varying degrees of success.

“Many iboga alkaloids and ibogaine analogs are not derived from inexpensive, readily available materials. Our approach differs because we rely on abundant, low-cost chemicals, assembling the molecular structure in just a few steps. Ultimately, our goal was to create a more efficient synthesis process,” Olson said.

This research opens the door to developing safer and more accessible alternatives to ibogaine, potentially transforming the landscape of addiction and mental health treatments. Further investigation into these analogs may pave the way for new therapeutic options with fewer safety concerns.