Ibogaine’s unconventional “matrix pharmacology” may underlie both its therapeutic promise and unpredictable cardiac risks. Unraveling this mechanism could help drug developers hoping to bring ibogaine analogs to market.
Though ibogaine has been around a long time, the way the hallucinogen works is still shrouded in mystery. But Columbia University’s Dalibor Sames has a theory.
Ibogaine acts across different molecules in cells, impacting serotonin signaling via a broader transporter network rather than acting on a single target, the professor hypothesized with colleagues in a January 2026 study where they coined this phenomenon “matrix pharmacology.” This could explain both why the plant-derived drug has shown promise in treating serious mental health conditions and why it has been linked to more than two dozen deaths.
It could also be valuable information for companies such as DemeRx and Gilgamesh Pharmaceuticals who are looking to bring ibogaine analogs to market. DemeRx recently received the FDA greenlight for the first ever U.S. trial of an ibogaine-derived drug.
“What we found over and over is that ibogaine doesn’t fit into the standard pharmacological scientific paradigms,” said Sames, who helped form Gilgamesh, which recently executed a major deal with AbbVie. “Ibogaine is defining a new category, and we need a new term, and that’s where the matrix pharmacology comes in.”
Traditional drug development is built around the concept of single targets, Sames told BioSpace: small doses of a drug bind to a molecule receptor, prompting cascades of effects that lead to strong outcomes.
“Ibogaine has not been following this rule, and now—over the years—we see that it’s almost the opposite,” Sames said. “The interactions are weak, and there are many.” It’s an extreme type of polypharmacology, he continued, calling it “a new logic.”
Because ibogaine is much less potent than other drugs, it’s more difficult to separate the safety risks from the therapeutic effects, Sames said. In normal drug development, the gap between doses that achieve health benefits and those that lead to adverse events is wide so there’s a large area of safe space to operate in, Sames explained. In ibogaine, the window between the desired therapeutic effect and adverse event “is very narrow.”
The biggest safety concern is cardiotoxicity—with potentially fatal outcomes. In a 2021 analysis of 24 datasets, two ibogaine deaths were recorded among 705 individuals who received the classic drug or its primary active metabolite noribogaine. No noribogaine deaths were reported. An earlier 2016 paper examined 27 deaths that occurred following ibogaine use.
Forensic toxicology studies have found ibogaine and its metabolites throughout the body after overdose or fatal exposure. The higher systemic exposure means there’s also a higher chance of hitting unintended targets. Notably, noribogaine is known to stay in the system much longer than ibogaine.
Pre-existing cardiovascular conditions likely contributed to many of the deaths in which post-mortem data were available, according to the 2016 analysis published in Clinical Toxicology. However, eight patients who experienced ibogaine-induced cardiac effects didn’t have a pre-existing cardiovascular condition or family history.
In another study published in Molecules this February, researchers noted arrhythmic events after both modest and extremely high doses of ibogaine, underscoring significant “variability in cardiac susceptibility” across individuals.
While Sames and other scientists are examining how small changes made to molecules impact ibogaine’s matrix pharmacology, there’s still a long way to go before cracking the toxicity code. “We’re not there yet. We need better tools, but we’re developing those tools to understand: this changes this effect.”
Despite the uncertainty around ibogaine’s mechanism of action, DemeRx and Gilgamesh are forging ahead with efforts to create safer versions of the compound. Both companies are working to develop drugs that maintain ibogaine’s therapeutic effects but minimize the dangerous side effects.
Clarification (June 16): This story has been updated to clarify that the two deaths found in the 2021 analysis were in patients who took ibogaine, not an ibogaine derivative.
