Could psychedelics become a new generation of treatments for depression and other psychiatric disorders? This question is no longer confined to basic research. Several therapies based on classical psychedelics have advanced into late-stage clinical development and have reported encouraging results. DT120, an LSD-based candidate, and COMP360, a synthetic psilocybin formulation, have both received Breakthrough Therapy designation from the US Food and Drug Administration.

Despite this progress, a key challenge remains: how can the rapid and long-lasting therapeutic effects of psychedelics be preserved while minimizing acute hallucinogenic experiences and the practical demands of supervised dosing? Addressing this question will be crucial not only for the further development and regulation of these therapies, but also for making them safer and more accessible.

In a study published in Nature Neuroscience, a research team led by Prof. WANG Sheng from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences, in collaboration with Prof. CHENG Jianjun at the iHuman Institute, ShanghaiTech University, integrates receptor signaling and ligand-binding kinetics to define the temporal features of downstream 5-HT_2AR pathways.

The study links the instantaneous peak of Gα_q/Ca²⁺ signaling to hallucinogenic-like responses, while cumulative β-arrestin signaling over time supports sustained antidepressant-like effects, establishing a pharmacological strategy for separating the two.

A growing body of evidence suggests that classical psychedelics such as LSD and psilocybin can produce rapid and sustained antidepressant effects. Unlike conventional antidepressants, which often take weeks of continuous treatment to produce clear benefits, psychedelics may lead to longer-lasting behavioral improvements after a single dose.

Recent progress in non-hallucinogenic compounds targeting the 5-HT_2AR has further established this receptor as a promising therapeutic target. However, the respective contributions of its downstream signaling pathways to antidepressant efficacy and hallucinogenic effects have remained unresolved.

WANG's laboratory has long investigated how the therapeutic and hallucinogenic actions of psychedelics might be dissociated. In earlier work with the Cheng laboratory, the team developed IHCH-7086, a β-arrestin-preferring partial agonist of 5-HT_2AR that produced rapid antidepressant-like effects in mice without detectable hallucinogenic-like responses. That study was published in Science in 2022.

Building on this earlier work, the researchers used structure-guided ligand optimization to develop IHCH-8134. They then investigated whether enhancing β-arrestin activity could lead to more durable antidepressant-like effects.

In cell-based signaling assays, IHCH-8134 robustly and preferentially activated β-arrestin without detectable Gα_q/Ca²⁺ activation. The compound produced rapid and sustained antidepressant-like effects in mouse models of depression. It did not elicit detectable LSD-like behavioral responses in mice or cynomolgus monkeys, and no comparable impairment of motor coordination or cognition was observed. Experiments using 5-HT_2AR- and β-arrestin-deficient mice further showed that the sustained antidepressant-like effect depended on 5-HT_2AR and downstream β-arrestin signaling.

The researchers then examined classical psychedelics from the perspective of ligand-receptor binding kinetics. LSD dissociated from 5-HT_2AR substantially more slowly than psilocin. After one low dose of LSD, a fraction of the drug therefore remained bound to the receptor, allowing subsequent doses to build on the existing level of receptor engagement. By contrast, the rapid dissociation of psilocin limited the accumulation of receptor occupancy and downstream signaling during repeated low-dose administration.

Further analyses revealed that signal "peaks" and signal "accumulation" were associated with different biological outcomes. A high concentration of a psychedelic produced both a Gα_q/Ca²⁺ peak and a β-arrestin peak. The rapid and strong Gα_q/Ca²⁺ response exceeded the threshold associated with hallucinogenic-like behavior, whereas the area under the β-arrestin signaling curve was sufficient to support a sustained antidepressant-like effect.

With repeated low doses of LSD, each Ca²⁺ response was below the behavioral threshold and did not cause Ca²⁺ signal accumulation. At the same time, prolonged receptor engagement arising from slow dissociation allowed β-arrestin signaling to build progressively to a level associated with a sustained antidepressant-like response.

In animal experiments, repeated low-dose LSD did not induce detectable hallucinogenic-like responses in the behavioral measures used in mice or cynomolgus monkeys, while producing sustained antidepressant-like effects in mice. Repeated low-dose psilocybin likewise produced no detectable hallucinogenic-like response. However, because its active metabolite psilocin dissociated rapidly, the regimen did not generate sufficient cumulative β-arrestin signaling and did not produce the sustained antidepressant-like effect observed with LSD.

The study also found that pretreatment with repeated low-dose psilocybin reduced the hallucinogenic-like responses subsequently induced by a high dose of LSD or psilocybin, without diminishing the antidepressant-like effect of the high-dose treatment. This result provided additional evidence that the two classes of effects can be separated at the signaling level.

Taken together, the findings bring ligand structure, receptor-binding kinetics, signaling bias and dosing strategy into a unified mechanistic framework. They point to two complementary routes for separating hallucinogenic-like responses from sustained antidepressant-like effects: designing non-hallucinogenic compounds that efficiently activate β-arrestin, and optimizing drug exposure for slowly dissociating psychedelics so that β-arrestin signaling accumulates while Ca²⁺ peaks remain limited.

This framework provides testable pharmacological principles for the future design of drug candidates and clinical translational research, and may guide the development of safer treatments for psychiatric disorders with sustained therapeutic benefits.