New Theories and Findings From The Frontier of Ibogaine Research
As a young professor at Columbia University in the early 2000s, Dalibor Sames taught his students how to synthesize iboga molecules. “I just found them interesting, and the structure was very beautiful,” Sames says. “I didn’t really know consciously at the time that they were these remarkable medicines.”
Today, as head of a team focused on developing “paradigm-changing therapeutics” in the chemistry department at Columbia University, Sames is leading one of several U.S. labs developing analogs of the powerful plant medicine. Ibogaine, the primary active compound in iboga plants, is considered by many to be the most powerful psychedelic, known for its 12-hour peak period and impact on substance abuse and different types of trauma. If mismanaged, its cardiotoxicity is also potentially lethal.
In 2019, Sames co-founded Gilgamesh Pharmaceuticals to develop synthetic analogs to several psychedelic drugs. In 2024, Gilgamesh received a $14 million grant from the National Institute on Drug Abuse to develop its heart-safe ibogaine analog. Last August, 2025, pharmaceutical giant AbbVie announced it would be spending up to $1.2 billion to acquire Bretisilocin, a fast-acting tryptamine created by Gilgamesh to treat major depressive disorders.
In a paper published late last month in the Journal of the American Chemical Society, Sames and his colleagues investigated how various iboga molecules affect the brain. The researchers developed several synthetic iboga analogs. Then they used lab-grown human cells, rat brain tissue, and live mouse brain slices to track how the analogs interact with proteins that transport neurotransmitters into and out of nerve cells. By tagging the proteins they were interested in with fluorescent markers, the researchers were able to see how the various synthetic iboga compounds changed neurotransmitter storage and recycling at synapses.
“Ibogaine defies classical paradigms of pharmacology that we teach in school and in graduate schools,” Sames says. “It has its own logic.”
Iboga And The Brain’s Messaging Factory
Several researchers around the world have begun to see ibogaine as a sort of Swiss Army knife for treating many different conditions. Researchers have shown that the drug, known for its effects lasting up to 24 hours, the longest psychoactive period of any psychedelic, can penetrate the cycles of addiction and help liberate minds hijacked by PTSD and traumatic brain injury. Recently, case reports of patients experiencing recovery from Parkinson’s and multiple sclerosis after taking ibogaine have emerged. What began as a sacred plant medicine in Africa hundreds of years ago is now the subject of a highly capitalized public health movement, with tens of millions of dollars being devoted to ibogaine research in Texas and Arizona in 2025.
“When we look at [ibogaine], it’s a molecule with remarkable clinical effects, with an unknown mechanism of action, and a beautiful molecular structure,” says Sames. “It also has a serious adverse effect. So it’s perfect for a chemist because we have things to fix.”
For more than twenty years, Sames has been studying the molecules found in the various species of the iboga plant, including ibogaine and its longer-lasting metabolite, noribogaine. Like many addiction researchers, he was struck by the drug’s ability to disrupt the cycle of addiction quickly, interacting with a range of messaging systems in the brain that go beyond the classical 5-HT2A serotonin receptors, and how it managed to do so.
When the brain is transmitting messages from one neuron to another, it depends on specialized proteins called monamine transporters (MATs) to sort and ship the messages out of one cell to another. Noribogaine affects how multiple important neurotransmitters, including dopamine, serotonin, and norepinephrine, are stored, released, and recycled in the brain all at once.
The researchers found that noribogaine inhibits the carrier proteins for serotonin and another important molecule, VMAT2. VMAT2 acts inside neurons, packing neurotransmitters into vesicles and shipping them out to other cells. With noribogaine, the uptake into these vesicles is limited. This combination of abilities in a single molecule doesn’t fit neatly into existing drug categories, so the researchers proposed a new one: “synaptic reuptake inhibitors.”
“Think of it like a factory assembly line making light bulbs,” says Christopher Hwu, a fifth-year chemistry graduate student at Columbia University and a co-author of the paper. “In order to produce a bulb that’ll be sold in stores, you need to source the raw materials into the factory first… The factory [synaptic vesicles carrying VMAT2] is trying to package and hold everything until it’s ready to be shipped to stores. Eventually, these small factories will approach the cell surface, bud, and distribute the different ornaments they’ve packaged, releasing their contents into the extracellular space.”
Understanding VMAT2 could provide insights into treating conditions such as catalepsy, where the muscles stiffen into an immobile posture. For example, the drug Tetrabenazene or TBZ is used to treat spasms in Huntington’s disease patients by reducing dopamine levels in the brain, but this FDA-approved treatment is known for causing severe side effects. Like Tetrabenzine, ibogaine blocks VMAT2. “What’s exciting to me,” says Hwu, “is that we can mimic that capability [VMAT2 inhibition] with iboga compounds, but in a way that’s fundamentally different from a drug [TBZ] with major drawbacks.”
In recent years, ibogaine analogs and noribogaine have been investigated by the biotech industry. According to Sames, he was inspired to study iboga molecules, in part, by the work of Dr. Deborah Mash, a pioneer in ibogaine research credited with co-discovering noribogaine in the 1990s. Between 1996 and 2003, Mash treated some 200 patients in St. Kitts and Nevis, and catalogued ibogaine’s unique ability to act on messaging systems in the brain. “The introduction of this new Synaptic Reuptake Inhibitors (SynRIs) category is an important contribution,” Mash says, “and something ibogaine researchers can be excited about. [Sames] is articulating the next big questions about ibogaine and noribogaine that scientists in this field will be exploring for years to come.”
There is still a debate over whether or not ibogaine should be molecular tinkered with at all. The iboga plant has been used in spiritual contexts for millennia in Gabon, but the interest in funding and developing next-gen ibogaine analogs supports the Western scientific drive for treatments that can be given with the lowest possible risk tolerance. Other noted ibogaine researchers, including Mash and David Olson, have started their own companies to develop analogs.
“Getting ibogaine to the clinic, I think, is highly urgent, and it’s doable,” said Sames. “That would be step one in the ibogaine field. And step two is for analogs… You could argue we don’t really need to know the mechanism that well, as long as you stay close to the original ibogaine… But then, for the future generations of the iboga therapeutics, go deeper.”
In their paper, Sames and his team develop a new concept to try to explain how ibogaine might be working. This new framework, which they dub “Matrix Pharmacology,” suggests that iboga compounds influence multitudes of downstream processes. These include the release of neurotransmitters by inhibiting and modulating the proteins that carry them in and out of cells, blocking or antagonizing ion channels. This amplifies the number of signaling pathways in the long relay races of communication within and between cells in the brain.
The team’s observations that iboga molecules do not cause catalepsy while still blocking dopamine and other neurotransmitters show that, at a minimum, iboga-based molecules are doing something beyond the explanation of traditional neuropharmacology. “When I first read the paper, the first thing that came to my mind about the title was the 1999 movie, The Matrix,” Mash tells Lucid News. “And then I asked myself, does the concept explain ibogaine’s therapeutic or transdiagnostic potential at this time. There’s something very exciting happening here, but for now, that concept for me is more ‘Fi’ than ‘Sci.’”
“The matrix pharmacology theory is a critical conceptual shift, at least in my lab, but I believe also for the entire ibogaine field,” Sames added. “We need a new framework for how to think, design, and interpret experiments and studies with iboga therapeutics. Ibogaine defies classical pharmacology; it engages, restores, and re-aligns the nervous system in a manner we have not seen before. It is a paradigm shift.”
A Researcher Takes The Medicine
Just before the start of the new year, Sames traveled to Mexico to take ibogaine for the first time. He is the first Western pharmacology researcher at a major research institution to do so publicly.
“I’ve been objective for 20-plus years, and scientists cultivate a healthy skepticism,” Sames says. “If you’re claiming to be making discoveries, it has to be supported by data, the data has to be reproducible. That’s one of the hallmarks of the scientific method – how we do science – reproducibility. While in the subjective realm, it’s typically the uniqueness, or irreproducibility, of subjective experience that is meaningful and likely therapeutic.”
Psychedelics as medicine are a cultural dark matter. They exist in a space between hardcore science and spirituality that presents a risky frontier for researchers, offering opportunities to treat challenging conditions while occasioning mysticism in an empirically driven environment. “One can slip very quickly right out of the scientific method and lose footing, and or be discredited by the mainstream scientific establishment,” Sames says. “But as we’ve seen over and over in human affairs and in science, these interfaces, these frontiers, that’s where new things come from.”