Scientists Develop Rapid-Acting Antidepressants Similar to LSD but Without Hallucinogenic Effects

Clinicians and researchers have been showing more interest in psychedelics for the treatment of mental disorders, such as depression, in recent years. However, there have been serious safety concerns over them. Scientists from China have now developed similar compounds that seemingly do not produce hallucinations. LSD Tripping

The World Health Organization (WHO) estimates that depression affects around 280 million people globally. In the U.S., about one in every four persons is believed to suffer from mental or neurological disorders each year. These disorders increase the tendency for someone to kill himself or herself.

There are therapies for depression, but these do not work in most cases. Psychedelics have been observed to be more helpful but their use often comes with awful side effects.

Researchers reported in the new study published in Science a strategy that enables the development of non-hallucinogenic compounds capable of producing antidepressant effects of psychedelics. These LSD relatives could lead to availability in the future of psychedelic analogs that do not require painstaking monitoring.

LSD stands for lysergic acid diethylamide. It is one of the most powerful psychedelics existing.

How psychedelics work

More and more doctors are becoming open to the idea of using psychedelics for the treatment of mental disorders. Clinicians and researchers think they offer great promises as psychiatric therapies. There has been a special interest in a compound called psilocybin in recent years as many psilocybin treatment centers are becoming available around the world.

Granted a “breakthrough therapy” status in 2019 by the US Food and Drug Administration (FDA), psilocybin comes from the mushroom genus Psilocybe. Phase II clinical trial results show that a single dose of the compound can help deal with depression for months. It can drastically improve symptoms within a day of dosing.

Similarly, a 2021 trial showed that 3,4-methylenedioxymethamphetamine (popularly called Ecstasy or E) can be useful for treating post-traumatic stress disorder (PTSD).

It is not entirely clear how these hallucinogens work. Scientists are uncertain whether the drugs’ hallucinogenic effects are just side effects or have therapeutic significance.

Psilocybin, LSD, and other psychedelics are believed to convert into pharmacologically active forms and bind to 5-HT2AR receptors in the brain. These are receptors for the brain’s chemical serotonin.

Serotonin 2A receptors are a type of G-protein coupled receptor (GPCR). When acted on, they set off many cellular responses and also enlist proteins known as beta-arrestins, which control GPCR activity.

Previous research in patients revealed that psychedelics work strongly on not only the GPCR pathway but also the beta-arrestin pathway.

Previous work by Dr. Sheng Wang, who led this study, showed that LSD fits into the orthosteric binding pocket (OBP) within a serotonin receptor.

Eliminating hallucinations

Researchers have shown a greater interest in finding a way to alter psychedelics and create analogs that retain therapeutic effects and produce no hallucinations. That was also the focus of this work.

In this study, Wang and his fellow researchers from the Shanghai Institute of Biochemistry and Cell Biology created six novel crystal structures of substances including psilocin (the pharmacologically active form of psilocybin), LSD, serotonin, and the non-hallucinogenic psychedelic lisuride.

The team carried out behavioral studies in mice to examine how hallucinogenic the drugs were. They looked out for head twitches and freezing responses, which are indicative of hallucination and depression.

The scientists were somewhat surprised to observe that some compounds, including psilocin, reached the extended binding pocket (EBP). They found in test animals that compounds occupying more EBP than OBP seemed to produce anti-depressive effects. Such compounds stirred up beta-arrestin activity and reduced GPCR activity

Wang’s team repeated the behavioral tests using psychedelic analogs that they created with the hope of interacting more with the EBP than the OBP. The researchers observed that two of the compounds named IHCH-7079 and IHCH-7806 did not produce head twitches. The compounds also reduced freezing responses.

Further research is needed to confirm the therapeutic benefits and side effects of these compounds before they can be available for use in humans. However, this study represents a major stride in the quest for non-hallucinogenic psychedelic analogs for clinical uses. It highlights a strategy that can be used to develop fast-acting drugs for depression.