Researchers May Have Created LSD-Analogs that Treat Depression Without the Trip

Researchers at the Shanghai Institute of Biochemistry and Cell Biology may have created LSD analogs that can treat depression without the trippy hallucinations — in mice anyway. 

Their paper in the journal Science is the latest piece of evidence suggesting it could be possible to provide many of the therapeutic effects of traditional psychedelic experiences, but without the potential risks and costly monitoring required for lengthy trips. If proven safe and effective in humans, such “no-trip psychedelics” could potentially deliver relief from depression and other mental health conditions to millions more people than could traditional psychedelics. 

“We are evaluating the compounds for their drug-like properties in other preclinical experiments,” Jianjun Cheng, one of the study authors, wrote in an email. “Our goal is to identify a preclinical drug candidate.”

But it’s not yet clear if Jianjun and his colleagues’ findings in mice will translate to primates or humans, or if his team’s explanation for the compounds’ effects — that they bind to different parts of brain receptors than do drugs like LSD — will prove true in future replication studies. 

Furthermore, given the progress of for-profit companies like Compass Pathways, and non-profit organizations like the Multidisciplinary Association for Psychedelic Studies (MAPS), in conducting clinical trials of traditional psychedelic therapies such as psilocybin and MDMA — not to mention psilocybin mushroom legalization in Oregon — it’s likely “no-trip” psychedelics will take a back seat to full trip psychedelics for the time being. But work like that of Jianjun’s team nevertheless opens the door of possibilities a bit wider for psychedelic therapies, and could help scientists better understand how all psychedelic compounds actually work in the brain, trip or no trip involved. 

Scientists have long theorized that many psychedelics work their magic by binding to and activating the 5-HT2A receptor in the brain, a complex of proteins normally activated by the neurotransmitter serotonin and triggering a cascade of subsequent signaling within a neuron. Substances like psilocybin, DMT, and portions of the more complex LSD molecule all closely resemble serotonin, allowing them to fit into and activate the 5-HT2A receptor like an accidentally matching puzzle piece. Compounds that activate a receptor are known as agonists. 

But while serotonin and LSD both bind to a site known as the “orthosteric binding pocket” on the 5-HT2A receptor, Jianjun, and his team may have discovered a different area on the receptor where compounds can bind. 

“They found through some of their structural biology studies this idea of the ‘extended binding pocket,’” said Ryan Gumpper, a structural biologist and post-doctoral researcher at the University of North Carolina who is familiar with the paper, but not involved in the research. “Then they designed some new drugs that targeted that [extended binding pocket] and they’re saying they are non-psychedelic. That’s the main takeaway of the paper.”

The research team created multiple compounds similar to LSD, including two they call IHCH-7079 and IHCH-7806. In tests with mice, IHCH-7079 and IHCH-7806 failed to elicit head twitching behavior that scientists have established as a sign of psychedelic effects in the rodents. But the new compounds also reduced mouse behaviors associated with depression. The researchers hypothesized that the binding of the compounds at the extended binding pocket, along with related changes in signaling after activating the receptor, is what allowed the therapeutic effects to be split from the traditional psychedelic effects. 

The kind of functionally altered compound-to-receptor binding that Jianjun and his colleagues show in the paper is sometimes called biased agonism, meaning the compound binds to a receptor, but in a way that triggers a different than typical response through only partially activating the receptor or altering subsequent signaling. In opioid painkiller research, for instance, scientists have found that certain biased agonist opioid drugs may trigger pain relief when binding to opioid receptors, but present less risk of respiratory depression and overdose. 

IHCH-7079 and IHCH-7806 may well be biased agonists of the 5-HT2A receptor, but Gumpper said he is uncertain about the way the models in Jianjun’s paper explain how the compounds are acting. 

A structural biologist with a background in using X-rays to uncover the molecular structure of viruses, Gumpper joined the Bryan Roth lab at the University of North Carolina in 2020 specifically because of work the lab published in 2017 elucidating the structure of LSD bound to another serotonin receptor, the 5-HT2B receptor (one of the Roth lab researchers on that 2017 project, Sheng Weng, is the principal investigator on the new paper in Science). 

But when Gumpper looked at Jianjun’s paper, something seemed off with the researchers’ models of psilocin, LSD, serotonin, the 5-HT2A receptor, and a well-known non-psychedelic LSD analog called lisuride. 

X-ray crystallography is a technique for mapping the density of molecules by shining X-ray light on them to create something like a pattern of light and shadow called an electron density map. The “ball and stick” models of molecules familiar to anyone who has taken a chemistry class, Gumpper said, are derived from these maps. 

When he looks at the maps and the models Jianjun’s team used in the paper, Gumpper isn’t sure they match each other very well. 

“If somebody tries to use those for other drug discovery purposes, like some sort of computational pipeline, they could just go down the wrong path,” he said. “Just from my perspective as a structural biologist.”

Asked about Gumpper’s criticism, Jianjun stood by his team’s electron density maps.

“The resolutions were not perfect, but good enough to support our models,” he wrote in an email. 

Another structural biologist, Stanford’s Georgios Skiniotis, argued that the maps and models used by Jianjun’s team were fine, but that the necessarily incomplete nature of X-ray crystallography still led him to withhold judgment about the paper’s structural explanation for the effects of IHCH-7806 and IHCH-7806 pending further research. 

“Any [molecular] structure is not an absolute truth,” Skiniotis said. “Any structure is just a snapshot.” 

Looking at the model of psilocin bound to the 5-HT2A receptor in the paper, in particular, he said the structure looks to him as if the “snapshot” Jianjun’s team took caught psilocin in the act of  migrating toward the usual orthosteric binding site, rather than binding to an extended binding pocket. It’s possible for example, Skiniotis added, that a fatty acid present as part of the experimental conditions could have gotten in the way of the psilocin, preventing it from reaching the usual orthosteric binding site. 

Ultimately, he said, he’s not sure about the existence of an extended binding pocket, or that IHCH-7079 and IHCH-7806 work their effects through binding there, but “that doesn’t mean it doesn’t exist.” It may just take future studies attempting to replicate the findings to determine if the structures modeled by Jianjun’s team do indeed determine the mechanism through which IHCH-7079 and IHCH-7806 are acting.

Ambiguity around how psychedelic compounds actually work in the brain is, after all, the default, with neuroscience only now coming close to determining how classical psychedelic compounds like LSD work their magic. In the same way, the effectiveness of IHCH-7079 and IHCH-7806 at relieving signs of depression (in mice) doesn’t depend on an accurate understanding of their molecular structures. 

And, Gumpper pointed out, It’s certainly not necessary to understand the details of how a drug works before taking it through a successful clinical trial.

“As long as you’ve already proven safety and some sort of efficacy in mouse models or rat models — or other non-primate human models — you can take it into clinical trials without necessarily having to know exactly the potential mechanism because it’d be therapeutically useful,” he said. 

A number of companies are developing compounds they also hope will provide the psychiatric benefits of psychedelics — rapid alleviation of depression, post-traumatic stress disorder, or help with addictions — but without the trip. Delix therapeutics, founded by University of California Davis Professor of chemistry David Olson, is pursuing dozens of novel no-trip psychedelic compounds the company hopes will promote neural healing, for instance. And Better Life Pharma is pursuing a non-psychedelic LSD analog long used to treat cluster headaches, 2-bromo-LSD, for treating depression. 

In academia, the Roth lab where Gumpper works has been pursuing just such a drug with funding from the US Department of Defense (Skiniotis’s lab at Stanford is also involved in the work, although to a lesser degree than the Roth lab). It’s possible, he said, that no-trip psychedelics could be entering clinical trials within five years. 

But that doesn’t mean that work on underlying mechanisms shouldn’t continue or isn’t ongoing. The Roth lab, for instance, has been working on the underlying mechanisms of both traditional and new, no-trip psychedelics since before the Department of Defense grant. 

“I think the ultimate question would be, what makes each of those compounds hallucinogenic versus something that’s not?” Gumpper said. “Something like psilocybin is similar to serotonin, and so what makes those big differences?”