The way ibogaine, a plant-derived hallucinogen, works remains unclear, but Columbia University’s Dalibor Sames and colleagues proposed a new theory on June 15. Their recent study suggests that ibogaine impacts serotonin signaling through a broad transporter network rather than targeting a single molecule, introducing the concept of “matrix pharmacology.”
Sames said this could explain why ibogaine has shown potential for treating serious mental health conditions while also being linked to more than two dozen deaths. "What we found over and over is that ibogaine doesn’t fit into the standard pharmacological scientific paradigms," Sames said. "Ibogaine is defining a new category, and we need a new term, and that’s where the matrix pharmacology comes in." He further explained that traditional drug development relies on drugs binding strongly to single targets, but with ibogaine, "the interactions are weak, and there are many." He called it "a new logic."
This information may be valuable for companies like DemeRx and Gilgamesh Pharmaceuticals as they work to develop safer analogs of ibogaine. DemeRx recently received clearance from the Food and Drug Administration for the first U.S. trial of an ibogaine-derived drug.
Safety concerns remain significant due to cardiotoxicity risks associated with ibogaine use. In a 2021 analysis of 24 datasets involving 705 individuals who received either ibogaine or its primary metabolite noribogaine, two deaths were recorded. A previous paper from 2016 examined 27 deaths following use of the substance. Forensic toxicology studies have detected both compounds throughout the body after overdose or fatal exposure; noribogaine is known to persist longer in the system.
Pre-existing cardiovascular conditions likely contributed to many reported fatalities, according to post-mortem data from one analysis published in Clinical Toxicology in 2016; however, eight patients who experienced cardiac effects had no such history. Another recent study published in Molecules noted arrhythmic events at both modest and high doses of ibogaine.
Sames said there is still much work ahead before scientists fully understand how molecular changes affect toxicity: “We’re not there yet. We need better tools, but we’re developing those tools to understand: this changes this effect.” Despite these uncertainties about mechanism and safety profile, DemeRx and Gilgamesh continue efforts toward creating safer drugs based on the compound.
