Can An Ibogaine Analog Preserve The Therapeutic Potential Without The Trip Or Cardiac Risk?

A conversation between Bob Discordia, Ph.D., CEO, Equulus Therapeutics, and Morgan Kohler

Ibogaine’s anecdotal and clinical signals on cravings, withdrawal, and even PTSD are growing, but the biggest obstacle is that ibogaine itself carries serious cardiac risk (QT prolongation, arrhythmias) and can produce an intense psychedelic experience lasting 10 hours or more, which would necessitate prolonged medical supervision in a clinical setting.

We caught up with Bob Discordia, Ph.D., CEO, to talk about how Equulus Therapeutics is using modern medicinal chemistry to try to capture ibogaine's therapeutic effects in a new molecule without the cardiac liabilities or the prolonged hallucinogenic experience, with the goal of a treatment that could eventually be administered more like a conventional pharmaceutical.

Equulus describes EQL-101 as an effort to decouple hallucinatory pathways from neuroplasticity. From a drug discovery perspective, how are you determining which receptor activities or signaling pathways are responsible for the desired therapeutic effects?

Our approach began with preclinical behavioral outcomes rather than a predetermined receptor target. We asked whether we could identify a molecule that preserved the therapeutically relevant behavioral profile of ibogaine while reducing its hallucinogenic and cardiovascular liabilities. That work led us to identify EQL-101 as our initial development candidate.

We are now conducting focused confirmatory preclinical characterization of EQL-101. We compare its behavioral profile with that of ibogaine and relevant reference compounds, then relate those findings to its receptor and transporter pharmacology, measures associated with neuroplasticity, pharmacokinetics, and brain exposure.

This integrated approach is important because ibogaine is biologically promiscuous, and no single receptor has been conclusively shown to account for its therapeutic effects. Taken together, these studies help us determine whether EQL-101 preserves the therapeutically relevant effects of ibogaine while separating them from its hallucinogenic and cardiovascular liabilities.

What has the structure–activity relationship work on EQL-101 revealed so far about the structural features needed to maintain ibogaine-like efficacy while reducing hallucinogenic activity?

The structure-activity work that produced EQL-101 supports the premise that ibogaine's desirable and undesirable properties can be separated. Focused changes within this chemical class can materially reduce activity associated with hallucinogenic effects while preserving activity in preclinical models relevant to substance use disorders.

The specific structural features and compound-level relationships are proprietary, so we cannot disclose the detailed SAR. At a broader level, however, the work showed that reducing hallucinogenic potential cannot be pursued in isolation. The molecule must also retain the relevant behavioral effects and possess suitable brain exposure, metabolic stability, cardiovascular safety, and pharmaceutical properties.

Those studies established the candidate profile for EQL-101. Our current work is focused on confirming that profile and completing the data package needed to advance into IND-enabling studies.

Cardiotoxicity is one of the major challenges associated with ibogaine. How are you incorporating cardiac safety into the medicinal chemistry optimization process, and what assays or preclinical models have been particularly informative?

Cardiac safety was incorporated into the work that led to EQL-101 and remains central to its confirmatory preclinical characterization. Ibogaine has been associated with cardiac ion-channel inhibition, QT prolongation, and potentially serious arrhythmias. Those risks are particularly relevant in substance use disorder populations, where cardiovascular comorbidities, polysubstance use, and concomitant medications may be common.

MindMed's development of 18-MC generated valuable cardiac-safety information that informs our assessment of both that compound and the broader chemical class. More generally, for any molecule Equulus evaluates for development, we apply a staged cardiovascular assessment beginning with electrophysiology-based ion-channel assays and broader cardiac profiling, followed by increasingly translational experimental systems as the program advances. We would integrate those findings with pharmacokinetic data so that cardiovascular risk is evaluated in relation to the exposures required to produce the intended pharmacological and behavioral effects.

No individual assay establishes cardiac safety. Exposure magnitude and duration, metabolite profiles, and activity across multiple cardiovascular parameters must be considered together. Our objective is to confirm that EQL-101 has a cardiovascular safety margin appropriate for its intended indications and patient population.

The company has described 18-MC as an important reference point for the program. What did the development history and clinical data surrounding 18-MC teach you about designing the next generation of ibogaine analogs?

18-MC provided important evidence that an ibogaine analog could retain activity relevant to addiction without reproducing ibogaine's full pharmacological and experiential profile. In preclinical studies, 18-MC reduced self-administration of a number of addictive substances and attenuated opioid withdrawal behaviors while avoiding some of ibogaine's prominent neurological and cardiovascular effects. Its clinical development subsequently provided valuable human information about safety and tolerability, pharmacokinetics, metabolism, and exposure.

The larger lesson was that separating the hallucinogenic attributes from the desired therapeutic effects was only the first of several challenges in designing a successful next-generation molecule. The candidate must also preserve meaningful biological activity while achieving adequate brain penetration, predictable exposure, an appropriate duration of action, a favorable cardiovascular safety profile, and practical pharmaceutical properties.

How do you distinguish between simply removing an undesirable pharmacological effect and genuinely preserving the mechanism responsible for ibogaine’s therapeutic potential?

That distinction was central to the identification of EQL-101. Removing activity at a receptor associated with an undesirable effect does not, by itself, establish that the therapeutically relevant biology has been preserved.

We therefore required EQL-101 to demonstrate more than a reduced hallucinogenic profile. It also had to retain activity in preclinical behavioral models relevant to addiction, achieve appropriate central nervous system exposure, and produce effects distinguishable from sedation, motor impairment, or generalized behavioral suppression.

We then consider whether the behavioral findings are supported by the molecule's pharmacology, brain exposure, and effects in assays related to neuroplasticity. Convergence across those different types of evidence gives us greater confidence that we have preserved a therapeutically relevant phenotype rather than simply removed an unwanted effect.

Our definition of success is therefore not simply "ibogaine without hallucinations." It is an ibogaine-inspired therapeutic profile in a molecule designed to offer substantially improved safety and a more practical treatment experience.

What preclinical models are you using to establish that EQL-101 can reproduce the relevant anti-addiction or neuroplasticity effects of ibogaine, and how do you assess whether those findings are likely to translate to humans?

Preclinical behavioral pharmacology was instrumental in identifying EQL-101 as our initial development candidate. Drug self-administration models are particularly important because they measure voluntary drug-taking behavior rather than a passive response to drug exposure. Our program includes models involving highly relevant contemporary substances, including fentanyl and methamphetamine.

We assess not only changes in drug taking but also the selectivity and persistence of the response. We also determine whether the observed effects can be separated from sedation, motor impairment, or generalized suppression of motivated behavior. That work is complemented by cellular and molecular assessments related to adaptive neuroplasticity.

Translation requires connecting efficacy to exposure. We therefore relate behavioral effects to plasma and brain pharmacokinetics, the duration of pharmacological coverage, and relevant safety margins. Animal models cannot establish clinical efficacy, but convergence among behavioral, biological, pharmacokinetic, and safety findings can provide a strong, testable rationale for clinical development.

How important have CNS drug-like properties, such as brain penetration, metabolic stability, exposure, and receptor occupancy, been in optimizing EQL-101? Have any of those properties created unexpected challenges during lead optimization?

These properties were fundamental to identifying EQL-101 and remain central to its confirmatory preclinical characterization. Potency in an isolated assay has limited value if a molecule cannot achieve appropriate brain exposure, has an unsuitable duration of action, or requires an impractical dose.

Iboga alkaloid chemistry creates a multidimensional optimization challenge. A change that improves metabolic stability may also prolong exposure to an unwanted target, while one intended to improve pharmaceutical properties may adversely affect brain penetration. We therefore evaluate these properties together rather than maximizing any single parameter.

The challenge has been less about encountering one unexpected obstacle than managing these interdependencies. Having identified EQL-101 through its behavioral activity, we are now confirming how that activity relates to brain and plasma exposure, metabolic stability, duration of action, and safety. The objective is not the highest brain concentration or the longest half-life but the right exposure for the right duration, with sufficient separation from cardiac and other off-target effects.

As EQL-101 moves toward IND-enabling studies and planned first-in-human dosing, what are the key scientific questions that still need to be answered before you can be confident that the molecule has achieved the desired balance of efficacy, safety, and drug-like properties?

EQL-101 has been identified as our initial development candidate. We are now conducting focused confirmatory studies to complete the data package supporting advancement into IND-enabling development.

The central remaining question is whether EQL-101 has a sufficiently robust therapeutic exposure window: one in which it produces the intended central pharmacology and relevant behavioral effects at exposures adequately below those associated with cardiovascular, neurological, or other liabilities.

We are therefore confirming the reproducibility and selectivity of its behavioral effects, refining its exposure-response relationships, assessing its cardiovascular safety margin, and establishing that it can be manufactured reproducibly for clinical development.

We also want the preclinical work to inform the first-in-human study by identifying useful pharmacokinetic and pharmacodynamic measures. Our objective is to enter IND-enabling development with a candidate for which efficacy, safety, and developability tell one consistent scientific story.

About The Expert

Bob Discordia, Ph.D., is cofounder, president, and CEO of Equulus Therapeutics. He has more than 30 years of pharmaceutical and biotechnology experience, including 26 years at Bristol Myers Squibb, where he held important roles in the development and commercialization of Taxol^®, Baraclude^®, and Eliquis^®. He subsequently served as chief operating officer and head of pharmaceutical development at Corbus Pharmaceuticals. His experience spans drug discovery through commercialization, with expertise in pharmaceutical development, CMC, global development and supply networks, and intellectual property development. At Equulus, he applies that experience to advancing novel therapeutics for substance use disorders and other serious CNS conditions.