Scientists strip down the LSD molecule to find the exact parts that trigger hallucinations

A recent study has successfully stripped down the complex chemical structure of LSD to pinpoint exactly which parts of the molecule cause hallucinations and which parts might be harnessed for therapy. By testing these simplified molecules, scientists identified a specific structural combination that produces antipsychotic effects in mice without triggering a hallucinogenic trip. The research was published in PNAS.

Lysergic acid diethylamide, commonly known as LSD, is a powerful psychedelic drug that alters perception, mood, and cognitive processes. It exerts its effects primarily by interacting with specific proteins on the surface of brain cells called serotonin receptors. One of these, the serotonin 5-HT2A receptor, is widely recognized as the main trigger for hallucinogenic experiences. It is also responsible for promoting neuroplasticity, which is the brain’s ability to grow and rewire itself.

Classic psychedelics tend to activate a broad array of targets in the brain and body. This wide-ranging activity was detailed in a study covered by PsyPost in 2025, which demonstrated that these compounds engage many different signaling pathways. Activating some of these pathways can lead to unwanted physical side effects. For instance, a 2011 review noted that when drugs stimulate a receptor known as 5-HT2B, it can lead to a dangerous thickening of the heart valves.

To develop safe psychiatric treatments from psychedelics, scientists aim to modify these molecules so they no longer activate the 5-HT2B receptor or cause hallucinations. To measure hallucinogenic potential in the lab, researchers observe mouse behavior. Specifically, a 2020 study demonstrated that the intensity of a rapid side-to-side head movement in mice, known as a head-twitch response, closely matches the potency of hallucinogenic effects in humans.

LSD has a highly complex, four-ring chemical skeleton known as an ergoline core. Because of this complexity, modifying its structure to isolate its therapeutic benefits has been historically challenging. A research team that included lead author Andrian G. Basargin and senior author David E. Olson sought to systematically deconstruct LSD.

“The synthesis of ergolines like LSD is quite challenging,” Olson, director of the Institute for Psychedelics and Neurotherapeutics at the University of California, Davis, told PsyPost. “By creating simpler analogues, we were able to determine which structural features of LSD were responsible for which pharmacological properties.”

By removing different rings from LSD’s four-ring core, the researchers aimed to identify the absolute minimum structural requirements needed to trigger hallucinogenic effects, and to discover simpler, safer variations of the molecule that might treat mental health conditions. “This information is critical for medicinal chemists to develop optimized medicines,” added Olson, a professor of chemistry and biochemistry who leads the Olson Lab.

The researchers used a process called function-oriented synthesis to create nine simplified versions of LSD. These new compounds were stripped down to possess only three, two, or one of the original four chemical rings found in LSD. To evaluate how these structural changes altered the drugs’ effects, the team first tested the compounds on lab-grown cells engineered to express different human serotonin receptors. They measured how tightly each compound bound to the receptors and how strongly it activated them.

Next, they tested the compounds in mice. They administered varying doses of each compound to groups of three to four female mice and used an automated magnetic system to track their head-twitch responses. In separate tests, they also placed the mice in an open-field arena and administered a dose of amphetamine, a stimulant that increases dopamine release and causes hyperactivity, to see if the new compounds could calm the animals.

The team found that the complete four-ring structure of LSD is necessary for the drug to maximally activate the 5-HT2A receptor. Every simplified molecule they tested had a weaker ability to bind to and activate this receptor compared to the original LSD molecule. By stripping the molecule down, the scientists pinpointed the exact structural components responsible for a psychedelic trip. They found that a two-ring combination corresponding to the “A” and “D” rings of the original LSD molecule was the bare minimum required to induce the characteristic head-twitch response in mice.

“If you delete certain structural elements of LSD, you can still produce psychedelic effects,” Olson explained. “This is analogous to determining that you can remove the roof of a car, windshield, doors, etc. and it can still drive.”

Removing a specific part of the molecule called the “D” ring resulted in a three-ring compound named UCD0094. This modified version showed a drastically reduced ability to activate both the hallucinogenic 5-HT2A receptor and the heart-risk 5-HT2B receptor. However, it maintained a strong ability to activate the 5-HT2C receptor, a target that is associated with antipsychotic and anti-addictive properties. The authors suggest UCD0094 could be a strong candidate for developing drugs that promote brain plasticity without causing hallucinations.

An even simpler, two-ring compound called UCD0076 demonstrated unique promise. UCD0076 showed almost no ability to activate the hallucinogenic 5-HT2A receptor, but it strongly activated the 5-HT2C receptor. When tested in mice, UCD0076 did not induce head twitches. Instead, it behaved like an antipsychotic medication. At high doses of 31 milligrams per kilogram, pretreating the mice with UCD0076 prevented them from having head twitches when they were subsequently given a known hallucinogen.

In the open-field tests, UCD0076 successfully reduced amphetamine-induced hyperactivity in a dose-dependent manner. The findings indicate that by selectively targeting the 5-HT2C receptor, this simplified molecule can suppress behaviors linked to psychosis. These findings align with research covered by PsyPost in 2025, which found that slightly modifying LSD’s structure can eliminate its hallucinogenic effects while producing a therapeutic, antipsychotic-like compound capable of healing damaged brain circuits.

However, not all of the new molecules behaved in live animals exactly as they did in isolated cells. For instance, a synthesized compound named UCD0179 appeared to be a potent activator of the 5-HT2A receptor in cell cultures, but it failed to trigger head twitches in mice.

“We were surprised that UCD0179 did not produce hallucinogenic effects in vivo given its in vitro profile,” Olson said. “This really speaks to the importance of a drug reaching its target in sufficiently high concentrations.”

As with all research, there are a few things to keep in mind regarding this study. First, the majority of the new compounds were tested as racemic mixtures, meaning they contained a blend of two mirror-image versions of the molecule. Because receptors in the brain often respond differently to exact structural shapes, testing isolated, pure versions of these molecules might yield slightly different results regarding their potency.

Additionally, the head-twitch response is a reliable indicator of hallucinogenic effects in rodents, but mice are not humans. It is always possible that a compound might affect human perception in ways that animal behavior cannot fully capture. The researchers also noted that LSD interacts with a wide variety of other targets, including dopamine and adrenergic receptors. Future studies will need to explore how these newly synthesized molecules interact with this broader array of brain targets to fully understand their safety and potential side effects.

“Our long-term goals are to use this information to develop better medicines for treating neuropsychiatric and neurodegenerative conditions,” Olson concluded.

The study, “Deconstruction of lysergic acid diethylamide,” was authored by Andrian G. Basargin, Andras Domokos, Joseph J. Hennessey, Isak K. Aarrestad, Rohini Sambyal, Yara A. Khatib, Johanna Krüger, Lee E. Dunlap, Samuel J. Carter, Isabella A. Rebek, John L. McKee, Serena S. Schalk, Min Liu, James C. Fettinger, Monica A. Gonzalez, Abhay Potluri, Dean J. Tantillo, Oliver Fiehn, John D. McCorvy, and David E. Olson.