Scientists Redesign LSD To Create a Non-Hallucinogenic Antidepressant

Could a subtle tweak to lysergic acid diethylamide (LSD) unlock its therapeutic potential, without the trip?

In a study published in Proceedings of the National Academy of Sciences, researchers at the University of California, Davis (UC Davis) report the creation of JRT – a chemically modified version of LSD that retains its brain-rewiring effects while eliminating hallucinogenic side effects.

The promise of non-hallucinogenic neuroplasticity drugs

Psychedelics like LSD and psilocybin are now the subject of serious scientific investigation for their therapeutic applications. Recent research has shown that these compounds can do far more than alter perception; they can physically reshape the brain. By promoting dendritic growth, increasing synaptic density and enhancing cortical connectivity, psychedelics exhibit powerful neuroplastic effects that may help reverse the structural brain changes seen in conditions such as depression, post-traumatic stress disorder (PTSD), addiction and schizophrenia.

However, these same compounds that regenerate damaged neural pathways also induce profound alterations in consciousness – hallucinations, perceptual distortions and dissociation – that make them unsuitable or even dangerous for many patients. Individuals with schizophrenia or a family history of psychosis are often excluded from psychedelic clinical trials due to concerns that these drugs could exacerbate their symptoms. As a result, a large and vulnerable segment of the population is effectively cut off from a class of therapies that might otherwise be transformative.

The team at UC Davis set out to answer a difficult question: Can you keep the benefits of LSD while removing the hallucinogenic effects that make it unsafe for many patients?

The researchers focused on the chemical structure of LSD itself. Prior studies have suggested that certain parts of the LSD molecule are responsible for triggering hallucinations – specifically, a small chemical group that forms a key interaction with brain receptors. By slightly rearranging the molecule – moving just two atoms – the team was able to disrupt this interaction without affecting the parts of LSD that promote brain cell growth. The result was a new compound, called JRT, which closely resembles LSD in shape and weight but behaves very differently in the body.

“Basically, what we did here is a tire rotation,” said corresponding author Dr. David E. Olson,  professor in the Department of Biochemistry and Molecular Medicine, at UC Davis. “By just transposing two atoms in LSD, we significantly improved JRT’s selectivity profile and reduced its hallucinogenic potential.”

This minor-looking change was chemically complex to carry out. JRT, named after Dr. Jeremy R. Tuck, a former graduate student who was the first to synthesize the compound, couldn’t be made by modifying LSD directly; instead, the researchers had to develop a completely new 12-step synthesis process to build the compound from scratch – a task that took nearly 5 years to complete.

Once synthesized, JRT was tested for how it interacts with different receptors in the brain. It showed strong, selective binding to serotonin receptors, particularly  5-HT2A, which plays a key role in mood and brain plasticity.

Importantly, unlike LSD, JRT showed little to no activity at other receptors such as those for dopamine or adrenaline, which are often linked to side effects like psychosis or cardiovascular stress.

While LSD triggered changes in genes linked to schizophrenia, JRT showed no such effect.

In cultured brain cells, JRT increased the number and complexity of neuron branches, as well as the tiny spines where neurons form connections.

In live mice, a single dose of JRT led to a 46% increase in dendritic spine density and an 18% increase in synapse density in a part of the brain involved in decision-making and emotion. In a model where mice had been stressed to the point of losing brain connections, JRT reversed this damage, bringing their brain structure back to normal.

JRT also did not produce the “head-twitch” response – a widely used indicator of hallucinogenic activity – in mice. When mice were co-treated with LSD, JRT blocked this behavior, suggesting it may actively suppress hallucinogenic activity.

In tests related to mood and cognition, JRT showed strong promise. In a standard test for antidepressant effects, it was ~100 times more potent than ketamine, a fast-acting antidepressant already used in clinical settings. It also helped animals perform better in a learning task that measures cognitive flexibility – the ability to adapt to changing situations, which is often impaired in conditions like schizophrenia.

In a model of amphetamine-induced hyperactivity, JRT reduced abnormal movement in female mice, but not in males – highlighting a potential sex-specific therapeutic response.

JRT’s therapeutic promise and clinical potential

JRT opens up new possibilities for treating difficult-to-manage brain disorders, particularly schizophrenia, where current medications fall short. While existing antipsychotics are generally effective at controlling hallucinations and delusions, they often fail to address other symptoms – such as reduced motivation, lack of pleasure and problems with memory and attention. These so-called negative and cognitive symptoms can have a major impact on a patient’s daily life, and they remain one of the biggest challenges in psychiatric treatment.

JRT’s ability to promote the growth of brain cell connections – combined with its antidepressant and cognition-enhancing effects in animal studies – suggests it could help with these harder-to-treat aspects of schizophrenia. Its effects may also extend to other conditions that involve loss of brain connectivity, including depression, bipolar disorder and neurodegenerative diseases like Alzheimer’s, where parts of the brain gradually shrink or lose function.

JRT may also offer several advantages over current treatments. For example, clozapine – the most effective drug for treatment-resistant schizophrenia – can cause serious side effects like sedation, weight gain and metabolic problems, partly because it acts on a broad range of brain systems. JRT, in contrast, has been designed to act more selectively on serotonin receptors, which are involved in mood and cognition, while avoiding other systems that are often linked to unwanted side effects.

Crucially, JRT appears to avoid the hallucinogenic effects seen with traditional psychedelics like LSD, which are a major barrier to their use in people with psychotic disorders.

“No one really wants to give a hallucinogenic molecule like LSD to a patient with schizophrenia. The development of JRT emphasizes that we can use psychedelics like LSD as starting points to make better medicines. We may be able to create medications that can be used in patient populations where psychedelic use is precluded,” said Olson.

Eventually, the goal is to move toward clinical trials in humans.

“JRT has extremely high therapeutic potential. Right now, we are testing it in other disease models, improving its synthesis, and creating new analogues of JRT that might be even better,” said Olson.

Reference: Tuck JR, Dunlap LE, Khatib YA, et al. Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential. Proc Nat Acad Sci USA. 2025. doi: 10.1073/pnas.2416106122

This article is a rework of a press release issued by the University of California, Davis. Material has been edited for length and content.