DemeRx is launching the first U.S. clinical trial of an ibogaine-derived drug candidate, marking a pivotal moment for a controversial psychedelic long sidelined by safety concerns.
With new federal support for psychedelic therapies, ibogaine has entered the spotlight. But the drug’s unclear mechanism and history of potentially fatal cardiotoxicity pose significant risks for drug developers. At DemeRx, executives are banking on a better safety profile for active metabolite noribogaine, which in late April was cleared by the FDA for the first in-human testing in the U.S.
“I’m flippin’ ecstatic,” DemeRx CEO and founder Deborah Mash told BioSpace at the time. “We’re primed and ready to go,” with plans to launch a Phase 2 trial in alcohol use disorder early next year.
The federal approval follows growing momentum in states such as Texas, Mississippi, West Virginia, Oklahoma and Tennessee that had introduced laws to support ibogaine clinical trials. And just days before DemeRx received the FDA go-ahead, President Donald Trump signed an executive order aimed at accelerating the development of psychedelic therapies for serious mental conditions. Compass Pathways, Usona Institute and Transcend Therapeutics each ended up with FDA Commissioner’s National Priority Vouchers (CNPVs)—which shorten review periods from as long as a year to just 1–2 months—for psychedelic drugs in late-stage development.
By contrast, neither ibogaine nor any derivative of the classic drug has ever before been tested in humans in the U.S. Sourced from an African shrub, ibogaine has historically been used by indigenous people in West Central Africa. The drug’s effects vary, but the most intensive psychoactive experience generally lasts about 24 to 36 hours. Like other psychedelics, ibogaine is thought to promote neuroplasticity and has garnered attention for potential use in veterans with post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI), as well as for substance use disorders.
Ibogaine has attracted significant attention, particularly from the political right. The executive order came shortly after podcaster Joe Rogan shared information with Trump about ibogaine’s potential benefits for opioid use disorder, the pundit said.
Rogan said he first learned about ibogaine’s potential for treating addiction and helping veterans from a friend involved in the Texas Ibogaine Initiative. He then discussed the drug on several podcast episodes and ultimately texted Trump some of the evidence of its efficacy. According to Rogan, Trump responded, “Sounds great. Do you want FDA approval? Let’s do it.” Not long after, Rogan appeared in the Oval Office standing behind the president as he signed the executive order on psychedelics.
In addition to directing the FDA to issue CNPVs for psychedelics assets, the order instructed the regulator as well as the Drug Enforcement Administration to develop a pathway under the Right to Try Act for eligible patients to access psychedelic drugs, including ibogaine compounds.
But besides the potential benefits, ibogaine is also known for its neurotoxic and cardiotoxic effects, which can be associated with severe complications and even death. As of 2022, 33 deaths after ibogaine use had been recorded in published literature.
“It’s very risky. There’s a reason why none of the drug companies that we cover have brought something like it forward, and it’s because of the safety concerns,” Patrick Trucchio, biotech analyst and managing director at H.C. Wainwright, told BioSpace.
While ibogaine’s safety profile has kept both investors and scientists at bay, DemeRx is developing an active primary metabolite of the drug that the company says isn’t associated with any psychoactive effects. Dubbed noribogaine, the compound lacks the “trip” effects of ibogaine and reduces the safety risk, according to DemeRx. The biotech aims to prove noribogaine’s safer profile in an alcohol interaction trial that will run slightly ahead of a Phase 2 study in alcohol use disorder.
While those results are still some time away, the president’s spotlight has buoyed the investor base for the approach, CEO Mash said, pointing to “an inflection in incoming investor interest” in DemeRx the week following the executive order.
The company plans to raise $25 million in a series B financing set to close this quarter, cash that will fuel the two upcoming trials, with the midstage launch planned for early next year, Mash said. Ultimately, the biotech considers noribogaine a potential “pipeline in a drug” asset given its potential antidepressant and anti-anxiety effects, with plans to launch Phase 3 trials in 2028, she explained.
While the federal policy shift may be turning investors’ heads, it isn’t a regulatory free pass, Patrick Trucchio, biotech analyst and managing director at H.C. Wainwright, told BioSpace. Although investigational new drug clearance is a key first step, it doesn’t prove a drug is safe, effective or likely to win approval, he said. “For an ibogaine analog, the first key milestone is Phase 1 trial safety, especially cardiac safety,” Trucchio explained.
“They’re not lowering the evidentiary bar,” he said of the FDA. “These companies are still going to have to run Phase 1, 2 and 3 trials. There’s not going to be some sort of red carpet rolled out.”
Baggage and fear
The biggest safety concern with ibogaine is heart damage or dysfunction, also known as cardiotoxicity. The most reported adverse effects tied to ibogaine are “marked QT interval prolongation”—a delay in the heart’s electrical reset after each beat—and “malignant ventricular arrhythmias,” which are life-threatening abnormal rhythms, according to a recent study published in Molecules.
The drug’s toxicity profile has created “baggage and fear,” Dalibor Sames, a chemistry professor at Columbia University with more than 20 years of ibogaine research under his belt, said in an interview. “I think that’s why ibogaine was really treated separately from other psychedelics, and it has not really progressed.”
DemeRx’s Mash has been trying to get ibogaine into the clinic for decades, even receiving the FDA go-ahead to run the first clinical trial of the drug in 1993. But the company had to abandon its U.S. efforts after struggling to raise enough money.
“The funding did not materialize, and one of the major reasons, I think, was the fear of these adverse effects,” Sames said.
Already in the business of ibogaine treatment, Mexico-based Beond takes the safety concerns very seriously. Before a patient is approved for therapy, the company collects detailed medical records and runs a variety of lab tests, founder and CEO Tom Feegel explained. Once the patient gets the green light and arrives at the clinic, Beond runs all the tests again before beginning treatment.
Then, during the acute phase of the ibogaine experience, patients are hooked up to an EKG, blood pressure cuff and pulse oximeter, plus an IV with electrolytes—principally of magnesium and potassium to help mitigate cardiac risks, the CEO continued. Those protocols stay in place for at least 12 hours after all biomarkers have returned to baseline.
“[Ibogaine] has to be delivered in a therapeutic manner that requires a high standard of care in a hospital-grade environment,” Feegel said. “I don’t think that that is up for debate at all.”
Making a safer medicine from ibogaine
While Joe Rogan–promoted ibogaine likely won’t take flight with U.S. regulators any time soon, its analogs may offer a more viable path to market. That’s the hope of DemeRx as it advances noribogaine to the clinic.
“We know that many of the beneficial aftereffects of ibogaine are likely due to the active metabolite,” Mash said, meaning noribogaine should still carry the same therapeutic value. But it doesn’t have the same observed psychedelic side effects, she explained. “Noribogaine is simple. Noribogaine is not a hallucinogen. It is not metabolized. . . . It’s very safe [and] well tolerated.”
In addition to preclinical studies, Mash pointed to a Phase 1 study of the drug that DemeRx recently completed in the U.K. for alcohol use disorder. In the multiple ascending dose trial of 55 healthy volunteers, noribogaine was safe and well-tolerated, according to DemeRx. The drug did show a dose-related QTc increase, but the effect wasn’t large enough to be considered clinically relevant, the company said.
“It’s all dose related, any QT,” Mash explained. “There are plenty of QT-prolonging drugs that are approved for use,” she said, citing methadone, which is approved to treat chronic pain and opioid use disorder and is known for extending the QT interval.
Not all researchers agree that noribogaine is safer than ibogaine itself, however. A 2016 analysis published in Clinical Toxicology found that noribogaine may carry less neurotoxicity risk than the plant-derived compound but is “at least as harmful to cardiac functioning,” in part because it remains in the system for days—much longer than ibogaine does. A separate 2016 study found noribogaine to be well tolerated in opioid-dependent patients, with the most frequent treatment-emergent adverse events being changes in light perception, headache and nausea.
The reality is that noribogaine is extremely understudied.
“We see them as complementary, in part because we’ve never been able to study them separately,” Feegel said of ibogaine and noribogaine. “Now it seems like there’ll be opportunities to study noribogaine as the primary substance, and we’ll see how that creates a different therapeutic model—or if it does at all.”
To advance in the clinic, DemeRx’s planned U.S. studies will have to demonstrate clean data with a manageable cardiac safety profile, Trucchio said.
“The FDA’s primary concern is safety,” Trucchio continued. “If there is a signal like this cardiotoxic signal that causes death, I can’t envision a scenario where the FDA approves that drug.”
Moreover, he added, if safer psychedelic or neuropsychiatric treatments become available—such as Compass Pathways’ late-stage synthetic form of psilocybin or Definium Therapeutics’ lysergide tartrate—ibogaine and its analogs may fall to the wayside. “These are already, from a safety perspective, much more favorable compounds,” Trucchio pointed out.
That said, if an ibogaine analog can slash QT liability, avoid serious arrhythmia risk, temper the acute experience and still show efficacy, he continued, that would be “a much more investable path.”
Psychedelics tailwinds could buoy ibogaine’s chances
While it may be a long road for noribogaine or any other ibogaine derivatives, the recent executive order “signals that FDA and the broader federal government are open to seeing psychedelic and psychedelic-adjacent medicines advanced for serious neuropsychiatric conditions,” Trucchio said. Plus, the FDA’s policy shift may also encourage more investment and thus more research and development in the space.
While there are psychedelics deeper in the clinic than noribogaine, biopharma’s R&D efforts in the field are still relatively new. “The real work of optimization hasn’t really been done with psychedelics because they’ve been illegal for so long,” Trucchio said.
The “holy grail” of psychedelic drug development would be circumnavigating the trip while still gaining the therapeutic benefit, Trucchio said. “How do we get the most efficacy with the fewest side effects?”
For Sames, ibogaine presents both a formidable challenge and a significant opportunity. He views the drug as the “parent,” with drug developers creating “many children” that make up a whole new category of therapeutics. Noribogaine is one of the few existing children. Another lives at Gilgamesh Pharmaceuticals, a neuroscience biotech Sames helped form. The company, which recently executed a deal with AbbVie, is developing a preclinical “cardiac-safe ibogaine analog” called GM-3009 for substance use disorders, PTSD and TBI.
“It’s structurally very similar to noribogaine and ibogaine,” Sames said, adding that early studies in cultured human cardiomyocytes suggest the drug may bypass ibogaine’s cardiac risks.
Gilgamesh is continuing to refine its development process, with the possibility of creating “many more generations” of the candidate.
“It’s a learning experience,” Sames said. “It really is a novel molecular entity.”
