Drugs like LSD and psilocybin trigger strong hallucinations, but they can also be therapeutically interesting. Until now, little was known about how the substances work at the molecular level. Now researchers have discovered how LSD and other hallucinogens bind to a specific docking point in the brain, the serotonin receptor 5-HT2A. Their results could help develop new drugs against mental illness.
Hallucinogens expand consciousness, sensory perception, and the sense of self. In the 1960s, drugs like LSD were very popular with hippies; In the early 1970s, most of these psychedelics were banned and have only been available for research purposes with special permission ever since. For a few years, however, it has become apparent that some of the substances could have high therapeutic potential in mental illnesses. Clinical studies suggest that psilocybin, the active ingredient in so-called magic mushrooms, can help against depression under controlled conditions. A positive effect against headaches and against anxiety in palliative patients is discussed for LSD. However, in order to realize the therapeutic potential and reduce possible side effects, it is important to understand the effect at the molecular level.
Molecular cause of hallucinations
A team led by Bryan Roth from the University of North Carolina has now succeeded in using imaging techniques to show how hallucinogens in the brain interact with the serotonin receptor 5-HT2A. This normally serves as a docking point for the brain messenger substance serotonin, which among other things acts as a mood enhancer and “happiness hormone”, but also influences a large number of other brain functions. On the one hand, the scientists carried out a crystal structure analysis for their study. With the help of X-rays, the molecular structure of the proteins involved can be shown. On the other hand, they used what is known as cryoelectron microscopy. In this technique, the discoverer of which was awarded the Nobel Prize in Chemistry in 2017, a sample is examined using an electron microscope at temperatures below -150 ° C. Thanks to the low temperatures, it is not necessary to remove the water from the sample beforehand or to add fixation and contrast agents. In this way, the sample remains close to its original state and a very precise 3D image of the examined structures is created.
The researchers were not only able to show how exactly different hallucinogens bind to the serotonin receptor, but also presented the structure of the entire receptor complex. “These receptors are found in large numbers in the human cerebral cortex,” says Roth. “If they are activated, the nerve cells fire asynchronously and in a disorganized way. We suspect this is a cause of the psychedelic experiences. How these drugs develop their therapeutic effect is still unclear. “
Advances in therapy for depression?
The studies show that various hallucinogens, including LSD and psilocybin as well as the synthetic hallucinogen 25CN-NBOH, which was discovered in 2014, each bind slightly differently to the serotonin receptor. This could be an approach to modify substances in such a way that they are therapeutically effective but have no or less hallucinogenic effects. “Getting a first glimpse of how hallucinogens interact with receptors at the molecular level is an important key to understanding how they work,” says Roth. “Given the remarkable effects of psilocybin on depression, we are confident that our results will accelerate the discovery of new, fast-acting antidepressants.”
Co-author Georgios Skiniotis from Stanford University adds: “The better we understand how these drugs bind to the receptors, the better we will understand their properties in the transmission of signals in the brain. This work doesn’t show us the whole picture, but it is an important piece of the puzzle. “
Source: Kuglae Kim (University of North Carolina) et al., Cell, doi: 10.1016 / j.cell.2020.08.024