Psychedelic drugs, such as the magic mushroom component psilocybin or the sedative ketamine, are now being widely explored for their therapeutic potential. Whilst the mechanisms that these drugs exploit remain unsolved, their side effects are clear – at therapeutic doses, these compounds induce hallucinations that require their use in a controlled clinical setting.
A new technology developed by researchers at the University of California Davis promises to fast-track the development of compounds that could exploit psychedelics’ therapeutic action without hallucinogenic side effects.
The research behind the tool has been published in Cell.
The mood molecule behind psychedelics
The antidepressant citalopram, the antipsychotic clozapine and the party drug MDMA might seem worlds apart, but all three rely on the neurotransmitter serotonin to exert their effects. Why this molecule has such striking effects on mood remains something of a mystery, says Lin Tian, senior author of the study and an associate professor in the Department of Biochemistry and Molecular Medicine at the University of California, Davis (UC Davis) in a press release. "Serotonin reuptake inhibitors have long been used for treating depression, but we don't know much about their mechanism. It's like a black box.”
To better understand the dynamics of this molecule, Tian’s lab developed a sensor system called psychLight. This system, a customized version of a tool the lab developed in 2018, consists of a serotonin 2A receptor (5-HT2A) attached to a fluorescent tag. When mice are genetically modified to express this sensor, researchers can follow the release of serotonin while the animals move around and perform tasks.
Simulated structure of psychLight. Credit: Dong et al
Tian’s team collaborated with the lab of David E. Olson, an assistant professor in the Department of Chemistry at UC Davis, who specializes in the 5-HT2A receptor. The researchers determined that psychLight could be reliably used to measure serotonin release after the administration of psychedelic compounds. In parallel, they could assess whether the compounds were inducing hallucinogenic side effects in the mice. Having established their tool, the collaborators ran a series of compounds with unknown hallucinogenic potential through the system.
Out of 34 compounds, 2 molecules, both related to the ayahuasca compound 5-MeO-DMT, were shown to activate the 5-HT2A receptor and initiate hallucinogenic activity. A third compound, AAZ-A-154, which had never previously been recorded in a publication, was shown to bind the receptor without inducing any hallucinatory activity.
Next steps for a novel compound
Subsequent behavioral testing in mice dosed with AAZ-A-154 showed striking results. Testing the presence or absence of a condition like depression in a rodent model is challenging, but the team were able to show that the new compound could improve performance in these tests in much the same way as ketamine. This psychedelic drug’s derivative, esketamine, is now licensed for treatment-resistant depression by the US Food and Drug Administration.
Even if AAZ-A-154 passes safety testing and is cleared to be trialed in humans, it will have to reckon with the reality that, of the few psychedelic compounds to be tested for antidepressant potential in humans, none have shown clinical efficacy in the absence of hallucinations.
Beyond the goal of developing new psychedelics, the technology behind psychLight has the potential to revolutionize drug discovery. It can be adapted to other receptors in the same family as 5-HT2A, a grouping termed the G protein-coupled receptor (GPCRs). Drugs targeting these receptors make up over a third of all FDA approved medications. “This technology,” concluded Tian, “Could open the door to discovering better drugs without side effects and studying neurochemical signaling in the brain."
1. Dong C, Ly C, Dunlap LE, et al. Psychedelic-Inspired Drug Discovery Using an Engineered Biosensor. Cell. 2020. doi:10.2139/ssrn.3745934