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Polarized light micrograph of serotonin.

Crystals of the neurotransmitter serotonin (polarized light). Psychedelic drugs bind to serotonin receptors in the brain.Credit: Michael W. Davidson/Science Photo Library

Scientists in search of psychedelic drug treatments have developed a way to determine whether a molecule is likely to cause hallucinations, without testing it on people or animals.

Growing evidence suggests that psychedelic compounds, which are active in the brain, have potential to treat psychiatric illnesses such as post-traumatic stress disorder (PTSD), but researchers are trying to find out whether there is a way to keep the beneficial properties of these drugs without the hallucinogenic side effects, which can complicate treatment.

It is currently almost impossible to predict whether a potential drug will cause hallucinations before it is tested on animals or people. “That really slows down drug discovery,” says David Olson, a chemical neuroscientist at the University of California, Davis.

To address this, a team led by Olson and neuroscientist Lin Tian, also at Davis, designed a fluorescent sensor to predict whether a molecule is hallucinogenic, based on the structure of a brain receptor targeted by psychedelics. Using their approach, the researchers identified a psychedelic-like molecule without hallucinogenic properties that they later found had antidepressant activity in mice1.

The discovery adds “more fuel for the fire” of efforts to make drugs from psychedelic-like molecules without side effects, says Bryan Roth, a molecular pharmacologist at the University of North Carolina School of Medicine in Chapel Hill.

Psychedelic potential

Studies seem to show that some psychedelic drugs can relieve the symptoms of chronic mental illnesses, including addiction, PTSD and severe depression, possibly by helping the brain to create new connections between neurons. Ongoing clinical trials are attempting to use the magic-mushroom compound psilocybin, LSD (lysergic acid diethylamide) and MDMA (3,4-methylenedioxymethamphetamine, also known as ecstasy) to treat various psychiatric disorders.

But these drugs’ hallucinogenic properties make them difficult to administer, because the recipients require constant supervision, and the hallucinatory effects can be a challenging experience. Some researchers are now looking for psychedelic-like molecules that retain the therapeutic potential without the trippy side effects.

Psychedelic drugs cause hallucinations when they interact with receptors in the brain that normally bind to serotonin, a neurotransmitter that affects mood. But not all molecules that bind to serotonin receptors cause hallucinations, says Olson. His team’s sensor is based on the structure of a particular serotonin receptor called 5-HT2AR, which changes shape when a molecule binds to it. The degree to which it changes dictates whether hallucinations are produced.

The sensor links the receptor with a green fluorescent protein that lights up with different intensities according to the receptor’s shape. It acts like “a radar for hallucinogenic potential”, says Tian, allowing the researchers to directly interrogate how a molecule binds to 5-HT2AR, and whether that binding causes the receptor to activate.

Molecular screening

The researchers wanted to see whether they could use the sensor to predict a molecule’s hallucinogenic properties. They started by screening a group of 83 compounds with known psychedelic profiles and scoring them according to how much light the sensor emitted when bound. For all compounds, the assay reliably predicted hallucinogenic potential, says Olson.

Then the researchers applied the test to 34 compounds with unknown psychedelic profiles. They identified a molecule called AAZ-A-154 that they predicted could interact with a serotonin receptor without causing hallucinations. Mice given AAZ-A-154 did not exhibit head twitching, which is associated with hallucinations. The molecule also seemed to alleviate symptoms of depression in mice with a genetic mutation that decreases their ability to feel pleasure.

Although it’s still unclear how AAZ-A-154 might work, the method of its discovery is an “innovative approach” to looking for non-hallucinogenic psychedelics, says Roth.

The sensor technology is still a long way from decoupling psychedelic medicine from hallucinatory side effects, cautions Robert Malenka, a psychiatrist and neuroscientist at Stanford University in California. It’s difficult to translate hallucinatory drug effects in mice to those in people, and although the identification of AAZ-A-154 is a good proof of the sensor concept, he says, the use of this technique in molecular screening needs to be developed further.



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