Chemists at the University of California, Davis did something that borders on the molecular equivalent of pulling off a magic trick. They moved two atoms within the intricate structure of LSD—a drug notorious for unlocking surreal dimensions of consciousness — and turned it into something else entirely.
The new compound, dubbed JRT, retains the therapeutic potential of LSD for mental health but without the hallucinations.
The LSD-derived drug could crack open the door to psychedelic-inspired treatments for a group long left outside it: people with schizophrenia or a family history of psychosis, where conventional psychedelics pose serious risks.
A Trip-Free LSD
Psychedelics like LSD and psilocybin have re-emerged in recent years as promising treatments for depression, PTSD, and addiction. But their use remains sharply limited. One reason: they alter perception in ways that can destabilize vulnerable patients, especially those at risk for psychosis.
At the same time, these drugs also belong to a rare class of molecules called psychoplastogens. These are compounds that promote the growth of cortical neurons and help rebuild the brain’s circuitry. That’s a property scientists are eager to harness. In disorders like depression, schizophrenia, and substance use, neurons in parts of the brain shrink and lose connectivity. Psychoplastogens offer a way to regrow them.
So, how do you keep the brain-healing effect of LSD without the sensory fireworks?
The answer came in the form of a subtle redesign. Instead of modifying LSD beyond recognition, the researchers at UC Davis made a minimal change. They restructured LSD’s ergoline backbone just slightly, removing its ability to form a key hydrogen bond with a serotonin receptor protein in the brain.
This new drug, JRT, is a “constitutional isomer” of LSD — meaning it has the same atoms, just arranged differently. It binds to the same receptor (5-HT2A) but doesn’t activate it in the same way. The result is a partial agonist: a compound that gives you some effects, but not the full psychedelic plunge.
Powerful Without the Perils
To test whether JRT could still promote brain plasticity, the team turned to a set of classic neuroscience tools. In the lab, they treated cortical neurons with JRT and watched as the cells sprouted longer, more complex dendrites — the branches that help neurons communicate.
In mice, a single dose of JRT increased dendritic spine density in the prefrontal cortex by 46%. It also boosted the number of synapses — the tiny junctions between neurons — by 18%. These changes mirror those seen after a dose of LSD, ketamine, or other fast-acting antidepressants.
But when researchers ran JRT through behavioral assays, the differences from LSD became clear.
The head-twitch response in mice, for example, is a reliable proxy for whether a compound is likely to cause hallucinations in humans. Unlike LSD, which triggers this behavior at low doses, JRT had no such effect — even at high doses.
“(+)-JRT possesses lower hallucinogenic potential,” the researchers conclude in their study.
They also found that JRT didn’t impair sensory gating (as measured by prepulse inhibition), didn’t cause hyperactivity, and didn’t mimic behaviors seen in psychosis-like states. And when it came to gene expression in the brain, JRT didn’t alter schizophrenia-linked genes the way LSD did.
Perhaps the most exciting part of JRT is how it performed under stress.
In mice exposed to chronic stress, a model of depression and anxiety, the compound reversed cortical atrophy. In the forced swim test, a classic readout of antidepressant effects, even small doses of JRT encouraged active coping behavior.
And in the sucrose preference test, which gauges anhedonia (loss of pleasure), two spaced doses of JRT restored normal behavior in stressed animals.
What’s more, JRT showed signs of improving cognition. In reversal learning tasks, where animals must adapt when the rules change, stressed mice normally struggle. But a single dose of JRT restored their ability to shift strategies.
These findings suggest JRT may help with not just mood symptoms, but also the cognitive and motivational deficits common in conditions like schizophrenia.
Redesigning a Psychedelic Future
The idea of non-hallucinogenic psychedelics may sound contradictory and even boring to some. But several groups have already developed analogues of psilocybin, ibogaine, and mescaline that retain therapeutic properties without perceptual distortion.
JRT adds to that list — and stands out for how little was changed. By tweaking just two atoms, the researchers preserved LSD’s power to regrow neurons while eliminating its high.
The compound doesn’t touch dopamine receptors, unlike many antipsychotics, and avoids the sedation and weight gain often caused by drugs like clozapine. Its affinity for serotonin receptors is highly selective.
Still, questions remain. Long-term safety, effects in humans, and its interactions with the 5-HT2B receptor will need thorough investigation.
The findings appeared in the Proceedings of the National Academy of Sciences.
