Newly engineered psychedelic shows therapeutic promise without gastrointestinal distress

A recent study published in Science Signaling highlights the potential therapeutic benefits of a newly engineered psychedelic compound for treating depression and anxiety in mice without causing gastrointestinal side effects. Researchers at Virginia Commonwealth University altered the chemical structure of an existing psychedelic drug, creating a variant that targets specific brain receptors linked to mental health benefits while avoiding receptors associated with nausea and physical discomfort.

By combining medicinal chemistry expertise with molecular and behavioral pharmacology, the researchers developed a novel compound called VCU-1012 that activates the serotonin 2A receptor (5-HT2A receptor) while showing minimal activity at the serotonin 3 receptor (5-HT3 receptor). The 5-HT2A receptor is responsible for positive mood and neural adaptability, but most drugs targeting it lack specificity and cause gastrointestinal side effects.

Quipazine, a serotonergic compound first described in the 1960s, was previously investigated for its antidepressant properties but caused significant gastrointestinal side effects due to its activation of the 5-HT3 receptor. The researchers aimed to redesign quipazine to combine its therapeutic benefits with reduced side effects.

After synthesizing several variations of the quipazine molecule, they tested VCU-1012 on human embryonic kidney cells and found that it showed minimal off-target activity at other receptors. To determine if VCU-1012 bypasses gastrointestinal distress seen with the original drug, the researchers tested it on mouse models by feeding them a harmless charcoal solution and measuring how far the charcoal traveled through their small intestine.

Mice injected with quipazine experienced a severe slowdown in digestion, while those given VCU-1012 showed normal intestinal movement. The team also evaluated the behavioral effects of VCU-1012 by measuring head-twitch behavior in mice and found that it prompted a robust increase in head twitches within the first 15 minutes of administration, which was blocked when mice were pretreated with a drug that selectively prevents serotonin 2A receptor activation.

Finally, the researchers tested the antidepressant properties of VCU-1012 and found that it reduced floating time in mice subjected to a forced-swim test, suggesting an antidepressant-like effect. However, in genetically modified mice lacking the serotonin 2A receptor, VCU-1012 had no behavioral effect, indicating that its antidepressant properties rely on the activation of this receptor.