LSD-Like Drug Relieves Depression and Anxiety in Mice

An accidental discovery

A new study published in Nature may overcome one of the hurdles of therapeutic psychedelics: lengthy hallucinations, which some people can find terrifying and anxiety-inducing. But the discovery came about by accident.^[1]

The international team of scientists wasn’t necessarily looking for an antidepressant when they built a virtual library of 75 million different compounds with a common molecular motif—tetrahydropyridine (TPH). The TPH structure shows up in the psychedelics LSD and psilocybin (magic mushrooms) but also in the migraine drug ergotamine and the cancer medications vinblastine and vincristine.

Seeking a drug candidate, they scanned the library for a THP derivative that could bind to a model of the brain's serotonin 5-HT2A receptor. That’s the receptor that LSD and psilocybin bind to. It’s also connected to mood.

They ultimately identified 17 molecules that ‘dock’ on the receptor. Around this time, other researchers were uncovering the powerful and long-lasting antidepressant effects of similarly structured psilocybin. 

"There [were] really interesting reports about people getting great results out of [psilocybin] after just a few doses,” Brian Shoichet, an author of the study and professor of pharmaceutical chemistry at the University of California, San Francisco, told NPR.

How do you know if a mouse is depressed?

After further testing, these researchers settled on two candidate compounds and optimized them so they bind even more strongly to the 5-HT2A receptor. They then administered the compounds to depressed mice.

How do you tell if a mouse is depressed? They give up when put in an uncomfortable situation, such as being dangled by their tails. When given the antidepressant Prozac or ketamine or psilocybin, hallucinogens with antidepressant properties, they keep struggling.

The mice given the novel compounds kept struggling, a sign that they were no longer depressed. In fact, the compounds reduced depression-like symptoms at doses that are 20 times lower than doses of Prozac. Those effects were also much longer lasting. A single dose could ease a mouse’s depression for 14 days.

Or tripping?

The mice also didn’t display hallucinogenic symptoms such as nose twitching and excessive locomotion that are seen with LSD and psilocybin. The compounds also didn’t seem to activate the same reward pathways as those drugs, reducing the potential for abuse.

It’s thought that the new compounds don’t elicit hallucinations because they selectively activate the 5-HT2a receptor and have only limited activation at other receptors that may be responsible for the hallucinogenic effects of psychedelics.

That tweak could make psychedelic-based treatments for depression much more accessible.

Currently, in trials of the still-unapproved treatments, patients need to be closely supervised and guided through the psychedelic experience by a therapist. These trips can be lengthy—as long as 12 hours for LSD—increasing the cost to the healthcare system. Patients can also have strong negative reactions, colloquially called bad trips.

Without those hallucinations, patients can simply be given a pill and sent home.

"Society would like a molecule that you can get prescribed and just take and you don't need a guided tour for your trip,” Shoichet said.

The molecules still need to be refined before they can be tested in people. But they’re promising. 

Psychedelics are also being considered as treatments for addiction, PTSD, OCD, and many other mental health conditions.