Proprietary assays demonstrate dual Gq and β-arrestin signaling at 5-HT₂_A, pathways linked in peer-reviewed studies to antidepressant and anxiolytic effects

A recent independent Nature study reports that distinct signaling pathways support mechanistic separation of therapeutic benefit from hallucinations

Enveric Biosciences (NASDAQ: ENVB) (“Enveric” or the “Company”), a biotechnology company advancing novel neuroplastogenic small-molecule therapeutics to address psychiatric and neurological disorders, today announced new mechanistic data demonstrating that its lead candidate, EB-003, activates both Gq- and β-arrestin–mediated signaling downstream of the 5-HT₂_A receptor. Multiple independent, peer-reviewed studies have previously shown that selective activation of 5-HT₂_A receptor, by either Gq-biased or β-arrestin–biased agonists, can independently produce antidepressant- and anxiolytic-like effects in preclinical models, suggesting that therapeutic benefit can arise from activation of either pathway.

The new data was generated using proprietary bioluminescence resonance energy transfer (BRET) assays. Enveric developed and validated in-house BRET assays to characterize EB-003’s intracellular signaling profile because commercial assays capable of reliably measuring pathway-specific 5-HT₂_A signaling were not available. The data demonstrate biologically relevant engagement of both Gq and β-arrestin pathways.

Enveric’s new data also indicate that EB-003 exhibits a modest preference toward β-arrestin over Gq signaling relative to serotonin, the native ligand of the receptor. Ongoing research is exploring the mechanistic significance of this apparent bias. Importantly, both pathways appear to be engaged at levels consistent with biological relevance.

Independent Academic Findings Support Pathway Separation

A recently published study in Nature employing BRET assays and complementary techniques provides additional mechanistic clarity regarding signaling downstream of 5-HT₂_A.¹ The study reports that Gi signaling downstream of 5-HT₂_A was required for hallucinogenic effects in the experimental models evaluated, while Gq signaling mediated antidepressant- and anxiolytic-like benefits in preclinical systems. These findings indicate that therapeutic benefit and hallucinations may arise from distinct intracellular pathways.

“Growing mechanistic clarity around 5-HT₂_A signaling strengthens confidence in the scientific foundation of our platform,” said Joseph Tucker, Ph.D., CEO of Enveric Biosciences. “Our proprietary BRET assay data show that EB-003 engages signaling pathways that prior peer-reviewed studies have linked to antidepressant- and anxiolytic-like effects in preclinical models.”

Dr. Tucker continued: “Independent academic research further suggests that hallucinogenic effects may arise from a distinct Gi-mediated mechanism. Those findings are consistent with our strategy of designing non-hallucinogenic neuroplastogens intended to deliver therapeutic benefit without the safety, monitoring, and scalability constraints associated with psychedelic compounds. Enveric is planning additional BRET testing of EB-003, including of the Gi pathway, to further characterize its unique signaling mechanisms.”

EB-003 is being developed to be a non-hallucinogenic neuroplastogen intended to support streamlined treatment paradigms, including potential at-home administration. The Company continues to advance EB-003 through IND-enabling studies.

About Enveric Biosciences

Enveric Biosciences (NASDAQ: ENVB) is a biotechnology company focused on developing next-generation, small-molecule neuroplastogenic therapeutics that address unmet needs in psychiatric and neurological disorders. By leveraging a differentiated drug discovery platform and a growing library of patent protected chemical structures, Enveric is advancing a pipeline of novel compounds designed to promote neuroplasticity without hallucinogenic effects. Enveric’s lead candidate, EB-003, is the first known compound designed to selectively engage both 5-HT₂_A and 5-HT₁_B receptors with the potential to deliver fast-acting, durable antidepressant and anxiolytic effects with outpatient convenience.

For more information, please visit www.enveric.com.

Forward-Looking Statements

This press release contains forward-looking statements and forward-looking information within the meaning of applicable securities laws. These statements relate to future events or future performance. All statements other than statements of historical fact may be forward-looking statements or information. Generally, forward-looking statements and information may be identified by the use of forward-looking terminology such as "plans," "expects" or "does not expect," "proposes," "budgets," "explores," "schedules," "seeks," "estimates," "forecasts," "intends," "anticipates" or "does not anticipate," or "believes," or variations of such words and phrases, or by the use of words or phrases which state that certain actions, events or results may, could, should, would, or might occur or be achieved. Forward-looking statements may include statements regarding beliefs, plans, expectations, or intentions regarding the future and are based on the beliefs of management as well as assumptions made by and information currently available to management. Actual results could differ materially from those contemplated by the forward-looking statements as a result of certain factors, including, but not limited to, the ability of Enveric to: develop EB-003 as a non-hallucinogenic neuroplastogen intended to support streamlined treatment paradigms; conduct additional BRET testing of EB-003, including of the Gi pathway; finalize and submit its IND filing to the U.S. Food and Drug Administration; carry out successful clinical programs; achieve the value creation contemplated by technical developments; avoid delays in planned clinical trials; establish that potential products are efficacious or safe in preclinical or clinical trials; establish or maintain collaborations for the development of therapeutic candidates; obtain appropriate or necessary governmental approvals to market potential products; obtain future funding for product development and working capital on commercially reasonable terms; scale-up manufacture of product candidates; respond to changes in the size and nature of competitors; hire and retain key executives and scientists; secure and enforce legal rights related to Enveric’s products, including patent protection; identify and pursue alternative routes to capture value from its research and development pipeline assets; continue as a going concern; and manage its future growth effectively.

A discussion of these and other factors, including risks and uncertainties with respect to Enveric, is set forth in Enveric’s filings with the Securities and Exchange Commission, including Enveric’s Annual Report on Form 10-K and its Quarterly Reports on Form 10-Q. Enveric disclaims any intention or obligation to revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

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