Researchers have successfully created ibogaine and its analogs entirely through chemical synthesis from pyridine, a chemical that is both inexpensive and readily accessible. This advancement simplifies the investigation into ibogaine’s potential therapeutic benefits.
Ibogaine, a psychoactive substance derived from plants, has gained attention for its potential in treating addiction and depression. However, ibogaine is sourced from limited resources, specifically plants found in Africa such as the iboga shrub (Tabernanthe iboga) and the voacanga tree (Voacanga africana). Additionally, its usage can lead to heart rhythm issues, underscoring the importance of understanding its molecular structure and its effects on the body.
A study published in Nature Chemistry by researchers at the University of California, Davis Institute for Psychedelics and Neurotherapeutics (IPN) details the complete synthesis of ibogaine, its analogs, and related compounds using pyridine.
The researchers were able to synthesize four naturally occurring ibogaine-related alkaloids along with several synthetic analogs. The overall efficiency of this process was significantly improved, with yields ranging from 6% to 29% after just six or seven synthesis steps, compared to previous methods.
“The complexity of ibogaine’s chemical structure has historically made it difficult to produce in substantial amounts, which has hindered medicinal chemistry from advancing better analogs,” noted David E. Olson, the study’s lead author and director of the IPN, as well as a chemistry and biochemistry professor at UC Davis. “By accomplishing total synthesis, we can produce ibogaine without depleting natural plant resources and create analogs that exhibit intriguing properties.”
Despite the potential heart risks of ibogaine, Olson pointed out that it is becoming more accepted as a treatment for issues such as substance abuse and traumatic brain injuries.
“Some individuals seek safer methods to administer ibogaine, and risks might be diminished through careful heart monitoring and the addition of magnesium,” he explained. “Alternatively, we may need to create an improved version of ibogaine that retains its powerful anti-addictive and anti-depressive effects while minimizing cardiac risks.”
Promising Analogues
Olson highlighted two particular ibogaine analogues from their research that are of special interest.
The first is an analogue that acts as the mirror image of ibogaine, a property referred to in chemistry as chirality. These molecular forms cannot be superimposed, much like left and right hands.
“Nature produces just one type, and if ibogaine’s therapeutic effects depend on interactions with specific chiral entities like receptors, then only the natural version would be effective,” Olson stated. “However, if the interactions are not specific, then both versions may have an effect.”
Upon testing both ibogaine and its mirror image on neurons, researchers found that only the natural version encouraged neuronal growth.
“This discovery suggests that ibogaine’s effects are likely linked to its binding with a particular receptor,” Olson remarked. “While we don’t yet know the exact receptor, the unnatural analogue serves as a valuable tool for studying this biology.”
The second intriguing analogue is (-)-10-fluoroibogamine. During experiments, this compound demonstrated remarkable properties regarding neuronal architecture and functionality, fostering growth and reconnections. Furthermore, it exhibited strong effects on serotonin transporters, which regulate serotonin levels at synapses.
“Serotonin transporters are targeted by many antidepressants and are thought to play a role in ibogaine’s therapeutic effectiveness,” noted Olson.
The researchers believe that their findings warrant further exploration of (-)-10-fluoroibogamine as a potential treatment for substance use disorders, depression, and related neuropsychiatric conditions.
Aiming for Safer Medicines
Olson shared that this research has taken 10 years to complete, during which the team evaluated multiple synthesis pathways with varying levels of success.
“Many of these iboga alkaloids and analogues originate from expensive and rare starting materials,” Olson explained. “Our approach differs by using abundant and low-cost chemicals, allowing us to construct these compounds in just a few steps. We aimed for a more efficient process overall.”
The team aspires that their total synthesis approach will provide other researchers with a framework for accessing ibogaine analogues more readily, ultimately paving the way for safer and more effective medicines.
This research was funded by the National Institute of General Medical Sciences and the National Institute on Drug Abuse, part of the National Institutes of Health, under award numbers R35GM14182 and R01DA056365. The views expressed here are solely those of the authors and do not necessarily reflect those of the National Institutes of Health. The project also received support from the Camille Dreyfus Teacher-Scholar Award.
