The next wave of psychedelics focuses on brain rewiring without the trip
by Bree Foster is a science writer at
Drug Discovery News
By separating therapeutic neuroplasticity from hallucinations, new psychedelic-inspired molecules could make treatment safer and more accessible.
For decades, psychedelics like psilocybin and N,N-dimethyltryptamine (DMT) have intrigued scientists and clinicians with their ability to rapidly reshape the brain and
improve mental health. Clinical trials have shown promise for conditions ranging from
depression and
anxiety to
post-traumatic stress disorder (PTSD), but there is still a potential downside.
Their hallucinogenic effects can be intense and overwhelming, with dosing sessions that last for hours and outcomes that often depend on an individual’s mindset and environment. As a result, patients typically require close supervision in clinical settings, guided through the experience, and monitored for adverse psychological reactions. These constraints limit how widely such treatments can be used and pose significant challenges for commercialization.
Now, a new wave of biotech companies, including
Enveric Biosciences,
Delix Therapeutics, and
Mindstate Design Labs, is racing to redefine what psychedelic-inspired medicine can look like. Rather than centering treatment around a guided psychedelic experience, these companies are working to separate the brain-rewiring benefits of these compounds from the hallucinations themselves. By teasing apart the molecular pathways that drive therapeutic neuroplasticity from those that trigger hallucinations, researchers aim to create drugs that are scalable, easier to administer, and reduce treatment burden.
“Early on, many assumed the hallucinatory experience itself was the therapy. What we and others began to question was whether that was really true. Our view, from the start, has been that most biological effects are separable,” Joseph Tucker, CEO of Enveric Biosciences, told
DDN.
“If you understand the molecular mechanisms in enough detail, you can isolate the therapeutic benefit from the hallucinatory effects.”
Building a library from scratch
Instead of simply modifying existing psychedelic molecules, Enveric started from the serotonin core and built a library of entirely new compounds. Beginning in 2020, the team designed and tested more than a thousand molecules, searching for ones that could promote neuroplasticity while avoiding hallucinogenic effects.
“Most of the molecules we made were hallucinogenic, and many that weren’t didn’t have any effect. It was a lot of trial and error, but this process ultimately allowed us to identify candidates that appear to safely deliver the brain-rewiring benefits in animal models,” Tucker explained.
Each candidate was rigorously tested in vitro and in animal models. The team used a specialized assay called the head-twitch response in mice as a preclinical behavioral proxy for hallucinogenic activity. By iteratively testing, discarding, and optimizing, they narrowed their library to a handful of promising molecules.
The result was EB-003, a neuroplastogen designed to open a window of brain plasticity while stabilizing circuits that regulate emotion and behavior.
The science behind the effect
Most psychedelic molecules are promiscuous, meaning they hit many different serotonin receptors at once. With 14 receptor subtypes, most compounds engage multiple receptors and pathways, creating unpredictable effects. This pharmacological complexity is why existing psychedelic therapies are typically administered under clinical supervision, and why traditional pharma has historically aimed for more selective, well-defined targets.
Classic psychedelics — like lysergic acid diethylamide (LSD), psilocybin, and DMT — produce their hallucinatory effects largely through the 5‑HT2A receptor, which can activate multiple signaling pathways. Recent research
published in
Nature has now described two distinct signaling pathways downstream of 5‑HT2A, which appear to separate therapeutic from hallucinatory effects.
This insight has helped to explain EB-003’s preclinical profile. EB-003 is a partial agonist at the 5-HT2A receptor and also engages the 5-HT1B receptor. This dual mechanism, according to Tucker, may allow the molecule to promote adaptive rewiring in the brain while keeping the experience non-hallucinogenic.
Emerging research suggests that 5-HT1B receptors may play a key role in stabilizing neural circuits. A study
published in
Nature Communications found that serotonin and psilocybin activate 5-HT1B receptors to suppress cortical signaling, pointing to a modulatory role for 5-HT1B in brain network function distinct from the classic effects of psychedelics.
“Neuroplasticity gives the brain a chance to rewire,” Tucker said.
“But you want to rewire it in a beneficial, stable way. Activating 5‑HT2A alone opens the door to brain rewiring, but without much direction. That's why, our hypothesis is, pairing it with a second receptor matters. In our case, 5‑HT1B helps stabilize brain circuits, so you’re guiding change in a controlled, positive way rather than triggering something unpredictable.”
Partial agonism adds another layer of control. Most psychedelics are full agonists, meaning that they will activate a receptor more strongly as the dose increases. However, partial agonists have a built-in ceiling. Even at higher doses, receptor activation plateaus.
“This is important because it allows you to dose high enough to get the neuroplasticity benefit without triggering unwanted effects,” Tucker explained.
Promising preclinical results
According to Tucker, EB-003 has shown striking effects in preclinical studies. In animal models, the compound produced rapid and durable improvements in behaviors related to anxiety, depression, and PTSD — sometimes observable within just half an hour of administration.
“From a preclinical point of view, it hits the two things people get excited about in this field — fast onset and durability,” Tucker said.
“The next step is making sure those effects translate to humans.” He noted that the durability observed in rodents was comparable to that seen with classical psychedelics in similar preclinical assays, while lacking hallucinogenic-like behaviors.
The combination of speed and durability addresses a major limitation of many current psychiatric treatments, which can take weeks to show effects and often require continuous dosing. By opening a controlled window of neuroplasticity, EB-003 may allow the brain to relearn more adaptive patterns of thought and behavior with a fraction of the treatment burden.
Equally important, EB‑003’s non-hallucinogenic profile in preclinical models may make it more amenable to outpatient or at-home administration, potentially avoiding some of the logistical and regulatory complexities associated with traditional psychedelic therapies. While human safety and efficacy remain to be determined, this characteristic positions EB‑003 as a compound that could eventually support more scalable and accessible approaches to mental health care — a direction already being explored in the field, as seen by the
FDA’s clearance to allow at-home administration of Delix Therapeutic’s neuroplastogen, DLX-001.
The future of mental health treatment
As Enveric prepares to advance EB-003 into human trials later this year, the company’s work reflects a broader evolution in psychiatric drug development. By targeting neuroplasticity while minimizing hallucinatory effects, compounds like EB-003 are designed to reduce treatment burden and may ultimately offer a more practical approach to a range of mental health conditions. While classic psychedelics may continue to have a role for select patients, the future of neuropsychiatric therapeutics may increasingly emphasize compounds that balance therapeutic impact with real-world clinical application.
