Can Psychedelics Be Redesigned To Avoid Nausea and Treat Depression?

Psychedelics are rapidly changing the mental health landscape by providing faster relief than traditional treatments.

Now, a team from Virginia Commonwealth University has developed a redesigned molecule that separates the therapeutic benefits of psychedelics from the unwanted side effects, such as nausea.

In preclinical tests, the compound successfully promoted brain plasticity and relieved anxiety symptoms without causing digestive issues. The results were recently published in Science Signaling.

Separating the benefits of psychedelics from their side effects

Modern medicine is re-evaluating psychedelics as a powerful alternative to traditional antidepressants for patients with depression, anxiety, and addiction.

“These agents appear to be fast-acting and require fewer administrations compared to clinically used antidepressants,” said the authors of the latest study.

However, these drugs face a hurdle before widespread use: their potent side effects. Patients often experience hallucinations and uncomfortable gastrointestinal side effects, such as nausea and vomiting.

“All known psychedelics also interact with off-target receptors. This lack of selectivity raises concerns about potential secondary and, in principle, unwanted side effects during preclinical and clinical testing,” the authors explained.

The antidepressant benefits of psychedelics come from activating the serotonin 2A receptor (5-HT2A), but these side effects are a result of the same drugs also activating the serotonin 3 receptor (5-HT3 receptor).

To study these pathways, researchers have previously used a compound called quipazine, a molecule that was initially investigated as a potential antidepressant but was never taken to market due to its gastrointestinal side effects.

Scientists needed a way to separate the positive therapeutic mechanisms of these compounds from their negative physical side effects.

In the new study, the team deconstructed the quipazine molecule to find the structural features that trigger the 5-HT3 receptor. They aimed to engineer a distinct chemical version that can treat depression through 5-HT2A activation, while leaving the 5-HT3 receptor untouched.

Engineering a selective psychedelic antidepressant scaffold

The researchers created an analog to quipazine, called VCU-1012, by identifying the nitrogen atom responsible for binding to the 5-HT3 receptor and modifying it. They then tested this design using in vitro cell-based models and mice to track changes in behavior, gut health, and brain structure.

Laboratory assays confirmed that VCU-1012 partially activated the 5-HT2A receptor but caused no activity at the 5-HT3 receptor. Computer models showed that the compound sat inside the receptor pocket differently than regular serotonin.

The team then tested VCU-1012 in mice.

The drug caused a head-twitch response, which is a behavioral sign that a psychedelic compound is active in the brain. When the 5-HT2A receptor was blocked, the twitching stopped.

The compound did not disrupt gut movement during tests.

Longer-term effects were also observed: after 24 hours, the immediate psychedelic reactions had worn off, but the mice still showed reduced signs of depression and anxiety.

Brain scans identified that the drug increased the number of stable connections between brain cells in the frontal cortex, and these structural changes did not occur in mice lacking the 5-HT2A receptor.

The clinical potential and limitations of targeted psychedelic antidepressants

This study acts as a proof-of-concept that scientists can design novel psychedelic drugs without the standard side effects.

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“Our findings establish the quinazoline core as a previously unrecognized scaffold for developing psychedelics, demonstrating translationally relevant preclinical effects on structural neural and behavioral plasticity without undesired side effects,” said the authors.

Despite these results, the compound has limitations that require investigation. When screened against 40 receptors, VCU-1012 attached to unintended targets, including the norepinephrine transporter and the serotonin 2B receptor. Overactivation of the latter is linked to heart issues.

The drug also relies on a single biological pathway, and when tested on 5-HT2A receptor knockout mice, the behavioral benefits disappeared. Chronic depression and long-term antidepressant use can desensitize or downregulate an individual’s 5-HT2A receptors. If a patient has a low baseline density of these receptors, a single-pathway drug might fail, whereas broad-spectrum psychedelics, such as psilocybin, hit multiple serotonin targets simultaneously.

Future studies must determine whether binding to the extra targets could lead to increased heart risks during long-term use. Researchers also need to explore whether the compound works differently in male and female subjects.

Even so, the study provides a roadmap for developing safer psychedelics.

“By expanding our understanding of how subtle modifications to the ligand structure influence receptor pharmacology, this work sets a foundation for the rational design of serotonergic psychedelics with improved therapeutic windows,” the team concluded.

Reference: Younkin J, Bansode AH, Saha S, et al. A new psychedelic quipazine analog targets 5-HT2A receptors without activating the 5-HT3 receptors that mediate side effects. Sci Signal. 2026. doi: 10.1126/scisignal.adw6055

This article is a rework of a press release issued by the American Association for the Advancement of Science (AAAS). Material has been edited for length and content.