Psychedelic-Inspired Anxiety Treatments Could Avoid Hallucinations

A new study using mouse models indicates it may be possible to develop psychedelic-based treatments for anxiety that do not induce hallucinations. Researchers at the Institute for Psychedelics and Neurotherapeutics (IPN) at the University of California, Davis, identified that anxiety-reducing and hallucinogenic effects of psychedelics may activate separate neural circuits, rather than being inherent to the chemical structure of these compounds.

Key neural circuits tied to anti-anxiety effects in mice

To test for anti-anxiety effects, the research team used two behavioral assays: the elevated plus maze and the marble-burying test. In the elevated plus maze, mice with heightened anxiety preferred enclosed arms, while less anxious mice were more likely to explore open arms. Similarly, in the marble-burying test, anxious mice compulsively buried marbles. Psychedelic treatments such as 2,5-dimethoxy-4-iodoamphetamine (DOI) generally reduce marble-burying and encourage open-arm exploration, indicating reduced anxiety in mice.

The study revealed that these anxiety-related behaviors changed six hours after dosing, even as hallucinogenic markers, such as head-twitch responses in mice, diminished. This temporal distinction between effects suggests that separating the anti-anxiety properties from hallucinogenic responses may be possible by targeting specific neural pathways.

“In the past, we did this using chemistry by making new compounds, but here we focused on identifying the circuits responsible for the effects, and it does seem that they are distinct”

Dr. David E. Olson

Highlighting neural activity with scFLARE2 technology

To understand which neural pathways were responsible for these effects, researchers used a technique known as scFLARE2, which enabled tagging of specific neurons in the medial prefrontal cortex (mPFC) – a brain region associated with anxiety regulation in mice. This molecular tagging revealed that DOI activates a neural network that extends beyond the primary receptor often linked to psychedelic effects, the serotonin 2A receptor (5-HT2AR).

“We thought that if we could identify which neurons activated by DOI were responsible for reducing anxiety, then we might be able to reactivate them at a later time to mimic those anti-anxiety-like effects."

Dr. Christina Kim

The team’s findings indicate that while 5-HT2AR-expressing cells initiate the effect, other neurons in the mPFC are subsequently activated, suggesting a broader network involvement. The anti-anxiety effects, therefore, seem to rely on an interconnected network of neurons, not solely those with 5-HT2AR expression.

Optogenetic reactivation for continued therapeutic effects

With scFLARE2’s neuron tagging in place, researchers applied optogenetics to re-stimulate the specific neurons linked to anxiety reduction. When these cells were reactivated with light, anxiety-like behaviors decreased in mice, evidenced by both reduced marble-burying and increased exploration of open arms in the maze.

To further refine their understanding of the neural circuitry, the team conducted single-nucleus RNA sequencing to classify neuron subtypes within the DOI-responsive network. Among nine neuron groups, three showed heightened activity. While some of these neurons expressed 5-HT2AR, others did not, indicating that DOI-induced changes may occur through a cascade where initial serotonin receptor activation leads to further downstream effects across a broader network.

Implications for future treatments

Although DOI is not under clinical investigation as a therapeutic drug, this study underscores the importance of understanding psychedelics' basic neurocircuitry. By pinpointing specific circuits involved in anxiety reduction, the study supports the potential for developing targeted treatments that mitigate anxiety without hallucinogenic side effects. The Institute for Psychedelics and Neurotherapeutics aims to use these findings to better understand how psychedelics interact with the brain’s networks, potentially informing future therapeutic approaches.

“Understanding which neural circuits psychedelics activate to elicit their effects is the kind of basic science needed to ultimately develop targeted therapeutics with better safety profiles.”

Dr. David E. Olson

Reference: Muir J, Lin S, Olson DE, et al. Isolation of psychedelic-responsive neurons underlying anxiolytic behavioral states. Science. 2024. doi: 10.1126/science.adl0666

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