Hope For Non-Hallucinogenic Neuroplastogens

A conversation with Joseph Tucker, Ph.D., CEO, Enveric Biosciences

Non-hallucinogenic neuroplastogens are being developed as a potentially safer alternative to psychedelics, with a lower risk of hallucinations. Enveric Biosciences is developing a derivative designed to preserve signaling associated with therapeutic neuroplasticity while potentially reducing hallucinogenic risk.

In this Q&A, Life Science Connect’s Morgan Kohler caught up with Joseph Tucker, Ph.D., CEO of Enveric Biosciences, to discuss Enveric’s preclinical work and their focus on developing non-hallucinogenic neuroplastogenic compounds targeting the 5-HT2A receptor and related serotonergic pathways.

Enveric reported new bioluminescence resonance energy transfer (BRET) assay data demonstrating that its lead candidate, EB-003, activates both Gq- and β-arrestin–mediated signaling downstream of the 5-HT2A receptor. What is the significance of this?

The most important point is that we are no longer just asking whether EB-003 attaches to a receptor. We are examining what the molecule actually does after it reaches the receptor. For many years, neuropsychiatric drug research focused mainly on receptor binding. Scientists asked whether a compound interacted with 5-HT2A and considered that sufficient to make conclusions about its function. We know, however, that receptors are not just simple on/off switches. They are communication centers inside the cell, and the specific signaling pathways they activate can lead to very different biological outcomes.

Our BRET assay lets us directly observe the signaling pathways that turn on after activation of the 5-HT2A receptor. With EB-003, we see activation of both Gq and β-arrestin signaling. This matters because independent peer-reviewed research has already connected these pathways with cellular and network changes associated with antidepressant- and anxiolytic-relevant neuroplasticity in preclinical models. The pathways EB-003 activates are therefore not random. They are pathways the scientific community has linked to therapeutic-related brain biology.

Seen in that context, the BRET findings do more than confirm that the drug reaches its target. They show that EB-003 is operating within signaling networks that have already been studied and reported by other groups to be associated with therapeutic neuroplasticity. From a development standpoint, that helps reduce uncertainty at the mechanism level. We are not relying only on the idea that receptor contact might produce benefit. We are observing activation of signaling routes that independent research has associated with beneficial neuropsychiatric effects in preclinical systems.

This does not guarantee clinical benefit, though, because only human trials can establish efficacy. However, it does strengthen the scientific case for advancing the program. EB-003 is now clearly more than just another compound that hits the 5-HT2A receptor. It is a compound that engages pathways already associated with therapeutic biology, and this strengthens the rationale for evaluating the findings in human clinical studies.

What causes hallucinations in current treatment options? Based on preclinical work for EB-003, has it been shown to avoid hallucinations? 

Hallucinations linked to classic psychedelic compounds are not caused simply by contacting the 5-HT2A receptor. They arise from broader brain network effects, especially changes in sensory processing and communication between brain regions. In other words, hallucinations represent a system-level brain response rather than a single receptor event.

Recent independent research has provided an important advance in understanding this process. Evidence now suggests that different signaling pathways downstream of 5-HT2A can be separated. This has been our working hypothesis since embarking on the non-hallucinogenic neuroplastogen discovery and development program several years ago. It is gratifying to see independent research emerge that supports our strategy. Recent findings suggest that some signaling pathways may be connected to neuroplastic effects, while other signaling, including Gi-related signaling, has been proposed to contribute to hallucinogenic effects. This supports the broader acceptance of the emerging concept that benefit and hallucination may not be inseparable features of the same pharmacology.

Preclinical studies cannot determine whether a person will hallucinate because animals cannot describe subjective experiences. Instead, researchers rely on established translational indicators that historically correlate with hallucinogenic-like pharmacology. One of the most commonly used is the rodent head-twitch response. In our studies, EB-003 did not produce that response at exposure levels where receptor engagement and other pharmacologic activity were observed.

We describe these findings carefully. The head-twitch model does not prove that hallucinations will not occur in humans. It is a supportive laboratory model that helps guide development decisions. When considered together, the pathway-specific signaling profile and the absence of hallucinogenic-like activity in validated animal assays support the hypothesis that therapeutic biology and hallucinogenic effects may be separable. Clinical trials will ultimately determine how this translates in people.

What about Enveric’s approach to this research is unique?

One distinctive feature is how we discovered the molecule. Many programs begin by modifying known psychedelic compounds. We approached discovery differently. We started with a blank-page medicinal chemistry effort, building and testing new molecules step by step until we identified candidates with the biological characteristics we wanted. The goal was a pharmaceutical-style optimization process that designs toward a desired pharmacology rather than adapting a preexisting drug concept.

Another difference is our pharmacological design. EB-003 acts as a partial agonist at 5-HT2A while also acting as an agonist at 5-HT1B. Independent research suggests that simultaneous activation of 5-HT1B signaling may influence the biological response associated with 5-HT2A activation and has been proposed to contribute to neuropsychiatric-relevant effects in preclinical models. Psychiatric disorders involve brain circuits rather than single targets, so engaging more than one relevant receptor may lead to more consistent pharmacodynamic effects.

A third distinguishing aspect is methodology. We rely heavily on functional testing. We use not only receptor binding panels but also intracellular signaling measurements, receptor engagement assays, and translational behavioral models to guide decision-making early in discovery. The objective is to align chemistry, cellular biology, and translational pharmacology before clinical testing rather than discovering problems later.

Overall, our strategy is less about advancing a psychedelic derivative and more about building a modern neuropsychiatric therapeutic candidate using contemporary pharmacology tools.

What current treatment paradigms exist and how does Enveric hope to change that?

Current treatment approaches generally fall into two categories.

Traditional antidepressants and anxiolytics, such as SSRIs and SNRIs, are usually taken daily and often require several weeks before full benefit appears. Many patients improve with them, but response rates vary and a significant number of patients do not achieve adequate symptom relief. Even for those who do, the side effects associated with these pharmaceuticals can lead to compliance challenges.

Another category includes rapid-acting approaches, such as ketamine-based treatments and investigational psychedelic-assisted therapies, that remain under clinical development. These approaches can produce rapid improvement in some patients, but they frequently require monitored administration and extended clinic visits because of acute psychoactive effects. That creates practical challenges for providers, clinics, and patients.

We believe EB-003 may offer scalability advantages for patients. When we refer to scalability in real-world practice, we mean whether a therapy can be used widely within typical healthcare settings. A treatment requiring specialized facilities, continuous supervision, or long observation periods may help patients but can be difficult to implement broadly. Our development goal is to pursue candidates that may produce rapid neuroplasticity-associated biological effects while potentially fitting within ordinary prescribing and monitoring practices, if clinical trials support that outcome. If supported by clinical data and regulatory review, this could potentially allow use outside specialized clinical settings, including at-home usage.

I want to emphasize that clinical data will determine the final use of EB-003. The working hypothesis is that separating therapeutic biology from intense acute psychoactive effects could enable treatment approaches that are more accessible to patients and healthcare systems.

What are the big picture takeaways from this research?

The first takeaway is mechanistic support for our lead drug candidate. The BRET assays show that EB-003 activates specific intracellular signaling pathways downstream of 5-HT2A, and independent studies have reported that these same pathways contribute to neuroplastic and neuropsychiatric-relevant effects in preclinical research. The importance is therefore not only improved clarity of mechanism but also that the mechanism itself has been supported by multiple outside studies.

The second takeaway is differentiation within the field. Neuropsychiatric research is moving toward pathway-level pharmacology, meaning scientists are identifying which signals are linked to therapeutic benefit and which are linked to unwanted effects. Our findings align with the broader scientific direction suggesting that therapeutic outcomes and hallucinogenic effects may be separable.

The third takeaway is increased development confidence, not proof of clinical success. These findings do not demonstrate safety or efficacy in humans because only clinical trials can establish that. They do provide a stronger rationale for clinical advancement. EB-003 is not only engaging a relevant receptor but doing so in a manner consistent with emerging understanding of therapeutic signaling in the brain.

Overall, the research reflects a broader shift in neuropsychiatric drug development toward mechanism-guided design. By intentionally selecting signaling pathways, future treatments may be designed to optimize therapeutic potential while reducing undesirable acute effects. EB-003 represents our attempt to contribute to that progress.

About The Expert

Joseph Tucker, Ph.D., is a seasoned executive who has built several publicly traded biotechnology companies. He was a founder and CEO of Stem Cell Therapeutics. Trillium Therapeutics acquired Stem Cell Therapeutics in 2013. Tucker has also held the position of coFounder and CEO of Epimeron Inc., a University of Calgary start-up acquired in the creation of Willow Biosciences Inc. At Willow, he served as executive chairman and COO. Prior to founding companies, Tucker was a healthcare analyst with two investment banks and has also worked in technology commercialization for a university technology transfer office. He received his Ph.D. in biochemistry and molecular biology from the University of Calgary.