Psychedelic without hallucinations
A biosensor based on the serotonin receptor has discovered a non-hallucinogenic psychedelic
Victoria Baranovskaya, N+1
A team of American researchers has developed a fluorescent genetically encoded sensor that is able to identify psychedelic analogues without hallucinogenic effect, which can help in the treatment of depression and post-traumatic stress disorder. In a paper published in the journal Cell (Dong et al., Psychedelic-inspired drug discovery using an engineered biosensor), scientists using this sensor based on a serotonin receptor were able to identify a previously untested substance that has antidepressant properties and does not cause hallucinations.
Serotonin is one of the main neurotransmitters in the human body, which performs a variety of physiological functions. It is also known as 5-hydroxytryptamine, so 5-HT appears in the names of its receptors. For this neurotransmitter, seven families of receptors (5-HT1 – 5-HT-7) are distinguished, which are divided into subtypes. The 5-HT2A receptor, which is one of the subtypes of 5-HT2 receptors, plays a crucial role in the response to antidepressants and hallucinogens such as LSD and psilocybin.
There is increasing evidence that psychedelics can be used in the treatment of various neuropsychiatric diseases, including depression and post-traumatic stress disorder. However, studies show that subjective mystical experiences and hallucinations that accompany the use of psychedelics are not necessary in therapy and can often cause negative effects in people with neuropsychiatric diseases.
Scientists led by Lin Tian, associate professor of Biochemistry and Molecular Medicine at the University of California, Davis, have developed a fluorescent genetically encoded sensor based on the serotonin receptor. This sensor, capable of predicting the hallucinogenic properties of substances, scientists called PsyLight. This is an adapted version of a sensor made by a team led by Ling Tian in 2018 to visualize the release of dopamine.
The PsyLight fluorescent sensor consists of a 5-HT2A receptor and a green fluorescent protein attached to it. When such a modified receptor binds to a hallucinogenic ligand, it changes its conformation, causing increased fluorescence. Non-hallucinogenic molecules that are also able to bind to PsyLight lead to a different fluorescence profile. To test the sensor in vivo, the researchers bred a line of genetically modified mice with the expression of this biosensor.
To test the sensor, 5-methoxydimethyltryptamine (5-MeO-DMT), a relative of dimethyltryptamine (DMT) from Ayahuasca, was selected as an agonist that increases the response of the receptor. Hallucinogens are known to cause characteristic head twitching in mice. Genetically modified animals were injected with 5-MeO-DMT (50 milligrams per kilogram) and PsyLight fluorescence was measured using the method of spectrally resolved fiber photometry. A minute after administration of the drug, a sharp increase in fluorescence with concomitant head twitching was observed in mice. The scientists then injected the mice with a 5-HT2AR receptor antagonist, ketanserin (4 milligrams per kilogram), as a result of which the fluorescent signal decreased.
Figure from the article by Dong et al.
The researchers then evaluated the sensor's ability to distinguish between known hallucinogenic molecules and structurally similar non-hallucinogenic molecules. Scientists tested 83 substances (among them psilocybin, tryptamine, LSD), and for all compounds the sensor reliably predicted the hallucinogenic potential.
After that, the researchers began testing a library of 34 compounds with unknown hallucinogenic potential. It was demonstrated that the smaller molecules 5-FDMT and 5-Cl-DMT were hallucinogenic, and the larger molecule 5-Br-DMT did not cause hallucinations. These three compounds have a very similar structure, despite this PsyLight was able to detect the hallucinogenic potential of the molecules.
The researchers also identified a previously untested molecule AAZ-A-154, which bound to the serotonin receptor without causing hallucinations in mice. Subsequent animal tests showed that this substance had an effect similar to the classic hallucinogenic psychedelics.
In the future, such substances can be used in the treatment of depression, without causing side effects in the form of hallucinations. Recently we wrote about how psilocybin helped people with prolonged depression no worse than antidepressants.
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