A new bioluminescent sensor can identify substances that provide the clinical benefits of hallucinogenic drugs for depression, substance use disorder and other conditions without hallucinogens' intense psychoactive side effects, allowing researchers to find potential psychiatric treatments more efficiently.
The team of scientists at the University of California, Davis, and other institutions who developed the detection system, known as "psychLight," have already located one chemical of interest, known as AAZ-A-154, that shows promise in activating some of the same pathways as psychedelic substances without prompting hallucinations, as detailed in a study published Wednesday in Cell.
According to the new paper, the sensor aims to identify "profound functional differences between compounds that share a high degree of structural similarity," by isolating the 5-HT2A receptor, which is thought to mediate the hallucinatory properties of psychedelic drugs. Using psychLight, researchers can watch how these serotonin receptors react to different types of hallucinogens, both in highly controlled test-tube conditions and in living organisms, such as mice.
The current methods for identifying whether a particular chemical induces hallucinations are often costly and inefficient; psychLight saves time by allowing researchers to identify substances of interest earlier in the drug-development pipeline.
"Before this paper, the only way you could really determine if a compound was going to produce hallucinations or not was to give it to a person or to give it to a rodent and do specific behavioral tests that would tell you whether or not it was likely to produce hallucinations," David Olson, an assistant professor in the department of chemistry at UC Davis and one of the paper's co-corresponding authors, told The Academic Times. "We want to limit the number of animals used in research, and we want to try to increase the throughput. That's what this asset allows us to do." Olson is also co-founder of a private experimental-pharmaceutical company that he thinks may someday benefit from this research.
The portion of the brain's serotonin 2A receptor that is monitored by the sensor is already the target of antipsychotic medications such as clozapine, as well as traditional hallucinogenic compounds such as LSD. PsychLight may also help researchers better understand the serotonin dynamics of living creatures, allowing them to track 2A receptors in real time using technology that is already available in most biology labs across the country, the researchers explained.
Put simply, "When the sensor binds to the drug, it makes a different number of photons compared to the areas not binding with the drug," Lin Tian, an associate professor in the department of biochemistry and molecular medicine at UC Davis and one of the paper's co-corresponding authors, told The Academic Times. "So, as long as you have equipment that counts the difference of photons, you'll be able to have a readout of the distinct confirmation of the receptor."
Powerful hallucinogens such as psilocybin mushrooms, LSD and MDMA have been used to treat post-traumatic stress disorder, depression and substance use disorder. And in 2019, a derivative of ketamine, typically administered as an anesthetic, was approved by the FDA for use in people whose depression had been resistant to other treatments. But these substances present a practical problem: The use of hallucinogenic compounds in high concentrations can cause drastic changes in one's perception, requiring close monitoring by doctors for eight to 12 hours in a highly controlled setting. And, so far, only a small fraction of patients who could benefit from hallucinogen-like drugs have been given the opportunity to undergo clinical trials for them.
Although scientists are still unsure about the exact mechanisms by which hallucinogenic drugs work, a leading theory suggests that psychedelics' unique properties can cause certain areas of the brain to rapidly rewire themselves, especially in the prefrontal cortex — a phenomenon known as brain plasticity. Olson's lab aims to identify other psychoplastogens, which can reactivate damaged neurons, so as to one day develop drugs that need to be administered only once — or several times — in order to permanently alter brain regions. That would mark a significant improvement over more traditional selective serotonin reuptake inhibitors used to treat depression and anxiety, which can take four to six weeks to build up in one's system — a critical period of time for someone in the midst of a mental health crisis.
AAZ-A-154, the substance of interest that was isolated in the study, showed promising results in an animal model. "Like psychedelics, it can promote neuronal growth, and it can lead to long-lasting beneficial behavioral effects after a single administration" without accompanying hallucinations, Olson said. The researchers tested their results by delivering the compound to mice, which experienced a reduction in depression-like symptoms, similar to those mice that had taken other types of hallucinogens. The compound did not cause any of the hallmark behavioral signs of hallucinatory-like experiences in mice, such as head twitching, that are typically caused by DMT and other hallucinogenic compounds.
Because their psychoactive properties may affect the brain pathways in ways that mirror the hallucinations seen in psychotic illnesses, traditional hallucinogens may worsen symptoms of serious mental illnesses, such as schizophrenia. But a compound that acts in the same way as hallucinogens without the debilitating psychoactive side effects could pave the way for new antipsychotic medications that are more effective than what is currently available and do not have any devastating side effects, the researchers explained. "One of the hallmarks of schizophrenia is a loss of dendritic spines in the prefrontal cortex," Olson said. "And so, having a nonhallucinogenic drug that could affect this receptor is extremely exciting and has a lot of potential."
But in a result they consider just as exciting as the possibility of identifying new compounds, the team says its sensor can also help researchers better understand how serotonin works in the brain, answering a mystery that has stumped scientists for decades.
"Serotonin is this neuromodulator that is said to be involved in everything, but responsible for nothing. And that probably has a lot to do with the fact that we just don't have really good ways of understanding how it modulates brain function," Olson said. "And so, we hope that this sensor could shed some light on that."
The study "Psychedelic-inspired drug discovery using an engineered biosensor," published April 28 in Cell, was authored by Chunyang Dong, Calvin Ly, Lee E. Dunlap, Maxemiliano V. Vargas, Junqing Sun, Arya Azinfar, David E. Olson and Lin Tian, University of California, Davis; In-Wook Hwang and Won Chan Oh, University of Colorado School of Medicine; and William C. Wetsel, Duke University Medical Center.