Considerable effort has been made in recent years to evaluate—or in some cases, reevaluate—psychedelic drugs for potential use as therapeutics to treat, among other things, psychiatric disorders such as depression, PTSD, and anxiety.

None of this research so far has led to the approval by the U.S. Food and Drug Administration of any “classical” psychedelic drug (such as LSD, psilocybin, or DMT) for any medical purpose, despite a number of clinical trials suggesting promise in specific applications and under specific conditions of administration. Among the lingering concerns are those relating to the hallucinogenic properties and abuse potential of these drugs, which continue to be listed by the U.S. government as prohibited Schedule I substances.

Even as clinical testing continues, these issues have inspired research in two directions, both driven by the hope that ways can be found to modify psychedelic compounds to render them safe (or safer) to use for medical purposes. Some, including David E. Olson, Ph.D., Director of the Institute for Psychedelics and Neurotherapeutics at the University of California, Davis, have tried to modify psychedelics chemically to produce related compounds that are non-hallucinogenic yet retain therapeutic properties.

Another approach, just reported in the journal Science, is to closely investigate the neural and circuit mechanisms though which psychedelics exert their effects. The hope in this work is to see whether the brain cells and circuits that drive hallucinogenic effects are perhaps distinct from those that drive specific therapeutic effects.

The new research was led by 2021 BBRF Young Investigator Christina K. Kim, Ph.D., also of UC Davis, whose grant project was devoted to this objective. Dr. Olson is a co-author of the new paper. In the current research, the idea of decoupling putative beneficial effects of psychedelics from their hallucinogenic effects, Dr. Olson explained, isn’t, as it has been in some of his prior work, “a matter of chemical compound design. Rather, it’s a matter of targeting neural circuity.”

Drs. Kim, Olson and colleagues used a sophisticated technology in mice to apply genetics-based tags to neurons in the brain’s medial prefrontal cortex (mPFC). This is an area where past research shows that psychedelics engage the serotonin system, generating powerful “plasticity” effects. Plasticity, which is the basis of learning and memory among many other operations in the brain, refers to the ability of neurons to modify the strength of their connections—in this case, substantially increasing (rather than inhibiting) connectivity.

The psychedelic drug that the team administered to their mouse-subjects is called DOI, a well-studied compound that modifies a receptor type called 5-HT2A (5-hydroxytryptamine 2A) that is part of the large serotonin receptor family.

In the minutes immediately following DOI administration, while mice were experiencing hallucinogenic effects (evident in their head-twitching behavior), the team used a technology called scFLARE2 to tag neurons in the mPFC that had been activated by the drug. These tags could be “placed” in the very short time window in which the drug is most active—a matter of minutes.

The tags enabled the researchers to molecularly profile the activated neurons, and also, in subsequent experiments, to selectively manipulate their firing using optogenetics, a technology co-developed by BBRF Scientific Council member Karl Deisseroth, M.D., Ph.D., and colleagues that renders specific neurons sensitive to laser light of a specific color.

The experiments revealed a psychedelic-responsive network of neurons in the mouse mPFC that included many neurons that expressed the 5-HT2A receptor, but, importantly, not only these cells; the network extended beyond the population of cells bearing the receptor.

This was a crucial discovery that helped the team determine that the hallucinogenic effects of the drug and its long-observed capacity to reduce anxiety-like behaviors are not inextricably bound together but may in fact be distinct, in terms of neural circuity.

Long after the hallucinogenic effects of DOI administration had ended in the mouse-subjects, the team found it was possible to use optogenetics to reactivate the neural network initially activated by the drug, and in so doing, restore the anxiolytic, or anxiety-reducing effect of the drug when it was originally administered. This reactivation of tagged neurons, in fact, took place the day after the drug had been administered.

“It is important to realize that the cells we are tagging and reactivating extend beyond just those that express the [5-HT2A] receptor for the drug,” Dr. Kim said. “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.” It is not yet known if stimulation of the same neurons even further after the initial administration of the drug will result in anti-anxiety effects.

The team noted that while DOI is a potent psychedelic, it is not being considered as a potential therapeutic in the clinic. The point of the study was to dissect the basic circuit mechanisms that enable one psychedelic to exert both hallucinogenic but also anti-anxiety effects. Discovering circuity that specifically mediates the anti-anxiety effect in the case of DOI may be possible to extend to studies of other drugs and other impacts—for example, the anti-depressive or fear-extinguishing impact that some psychedelics have been reported to have in clinical tests. These potentially could reveal circuitry that might be specifically targeted in future therapies.

The technologies used in the current study are enabling researchers to elucidate precisely how psychedelic drugs affect the brain and induce specific behavioral effects. This is what is needed, said Dr. Olson, “to ultimately develop targeted therapeutics with better safety profiles.”