Nature: Can it create a "non-psychedelic" compound that is not hallucinogenic but has antidepressant effects

Although recreational use is illegal, psychedelics show great promise
as drugs for treating severe depression and anxiety, alcohol addiction, and other ailments.
Some proponents and scientists argue that true psychedelic journeys — hallucinations and deep emotional experiences — are responsible for
long-term therapeutic effects.
Other scientists speculate that if these drugs could eliminate this effect, only the therapeutic effect would be left
.
Researchers at the University of North Carolina at Chapel Hill, the University of California, San Francisco, Yale, Duke and Stanford have taken an important step
in answering this question.

The study on animal models suggests that it is possible to make a compound that could hit the same target as the hallucinogen — the 5-HT2A serotonin receptor on the surface of a particular neuron — but would not have the same hallucinogenic effect
when given to mice.
The antidepressant effects of this new compound are the same as those of mice taking SSRIs that researchers have long observed over the past 20 years, with two differences: The antidepressant effects of the new compound are immediately and durably lasting
after a single dose.

"We were very surprised that this compound has antidepressant activity similar to ketamine and psilocylline, both of which are rapid-acting antidepressant psychedelic drugs," said co-senior author Dr.
Bryan L.
Roth, a distinguished professor of pharmacology at the University of North Carolina School of Medicine Michael Hooker and director of
the NIMH Psychoactive Drugs Screening Program.
"We're basically doing a chemical experiment to see if we can create a compound to activate 5-HT2A
.
Once we had done this, we decided to experiment
in mice.
”

The compound was patented by Yale University, the University of North Carolina at Chapel Hill and the University of California, San Francisco, and licensed to Onsero Corporation
.

"We don't know if we'll see the same effect
in humans.
" But we want to find out
.
Creating a single-dose, long-acting treatment to help people with refractory depression and other ailments will be game-changers
.
”

The case of psychedelic drugs

When a person eats a magic mushroom, the active ingredient from psilocybin, psilocybin, binds
tightly to the 5-HT2A serotonin receptor on the surface of the neuron.
This receptor is activated for a long time, triggering a cascade of chemical signals
within the cell.
These cells then communicate with other cells in the brain, sending people through a long, strange, hallucinogenic journey that lasts for hours
.
For those who are resistant to treatment, psychedelics can immediately relieve depression and the effects can last for months
.

Ketamine is used in medicine as an anesthetic and also as a tool for
treating severe depression.
In 2019, the FDA approved a prescription version of ketamine called esketamine (Spravato), which is administered through a nasal spray
.
The use of this drug requires the supervision of a medical professional and is expensive
.
Dead vine water is a drink containing two psychoactive plants that has also shown antidepressant effects
in uncontrolled clinical studies.
It is illegal in the United States because one of its active ingredients, N, N-dimethyltryptamine, is also known as DMT
.

Roth said it's hard to scale up these drugs to help millions of people in need because these and other drugs can dramatically alter brain chemicals, to say the least, as risky
as LSD.
A person's experience can be painful, although coming out from the other side feels "cured" of depression, severe anxiety, or addiction
.

There is a class of antidepressants called selective serotonin reuptake inhibitors (SSRIs), which indirectly modulate serotonin signaling, unlike psychedelics that act differently
.
SSRIs can also raise serotonin levels in cells throughout the body, which may be one of the reasons why these drugs cause a large number of
unpleasant side effects.
Although SSRIs cause an immediate increase in serotonin in the brain, people who take these drugs usually don't report antidepressant feelings
until a few weeks later.

"So, there are many more ways to treat depression than simply raising serotonin levels," said Roth, who spent 20 years treating people with
psychosis.
"SSRIs cause changes in the brain, which have an antidepressant effect
.
We don't know exactly what's going on
.
But I know a lot of people whose lives have been changed
by SSRIs and psychotherapy.
”

So the idea is simple: What if scientists could create a compound that selectively hits 5-HT2A receptors, but activates it in a way that alters brain chemicals to treat depression without interfering with this pathway and avoiding the side effects associated with SSRIs?

The entire project took 7 years and began in Roth's lab to address the complex chemical structure of serotonin receptors, including what psychedelic compounds look like
when they bind tightly to them.
This alone took years and was funded
by a grant from the National Institutes of Health.

In 2020, the Defense Advanced Research Projects Agency (DARPA) provided Ross and his colleagues with $26.
9 million in funding to develop new drugs that are effective and rapid in treating depression, anxiety, and substance abuse without major side effects
。 Ross was awarded this high-risk, high-reward project through his expertise, experience, and collaboration with experts in the field, including at Nature paper author Brian Shoichet, Ph.
D.
, from the University of California, San Francisco, and others
at Duke University, Icahn School of Medicine at Mount Sinai, and Stanford University.

Years of collaborative science

Combinational chemistry expert Dr.
Jonathan Ellman, co-author Dr.
Danielle Confair, now a senior scientist at AstraZeneca, led a work to develop a series of reactions that, under different starting materials, could theoretically create billions of new compounds with slightly different chemical structures
.
In this study, Ellman and Confair focused on the chemical reaction of synthesizing tetrahydropyridine (THPs), which exist in nature and are fundamental components of many compounds, including drugs
.

They then used computational simulations with UCSF's co-first author Anat Levit, Ph.
D.
, and co-senior author, Dr.
John Irwin, to lock in specific THP-based virtual compounds that most likely bind to 5-HT2A only on specific neurons, similar to how bare capsin binds to these receptors, but with a difference enough to potentially avoid dramatic psychedelic effects
.

"For us, this project was an opportunity from the beginning to expand the new virtual library
with the 75 million elaborate molecules in the Elman lab.
It was only when we started to see unusual signals from new compounds and the amazing permeability they made into the brain that we as a team began to think that these compounds could have interesting effects
.
"

The University of North Carolina lab, then led by co-first author Dr.
Kuglae Kim, selected and tested several actual compounds to see how they bind to serotonin receptors
in cell culture.
This part also took several years
.
Receptors are complex and delicate strings of perfectly localized proteins
.
Observing how compounds act on them is a laborious process involving a variety of experimental techniques, including X-ray crystallography
.

Through each experiment, Roth and colleagues at the University of North Carolina learned more nuances about the compound's relationship with 5-HT2A
.
Shoichet's team then used this knowledge to tweak their computational chemistry design, creating another virtual compound
that Roth Labs created in the real world.

This iterative process produced some compounds, enough for Roth's lab to test in mouse models, essentially to see if the compounds bind to 5-HT2A in animals, just as
they did in lab dishes.

"What we saw was completely unexpected," Roth said
.
"This compound not only binds to the 5-HT2A serotonin receptor as we imagine, but also has the same antidepressant effects as ketamine, but does not have the same hallucinogenic effects
.
"

While the researchers couldn't be sure whether the mice were depressed or hallucinating, they could study the drug's effects — biological effects on mice — and then observe their behavior
.
For decades, researchers have used standard tests — forced swimming tests, tail suspension tests, novelty inhibition feedings — when testing the action of compounds
.
Similarly, the researchers used standard mouse models of psychotropic drug action, which have been validated for decades
.
Mice have specific behaviors after taking hallucinogens, just as humans do when they stumble
.

When Dr.
William Wessel's Duke lab gave the new compound to mice, the team observed that the antidepressants worked the same way, but not the same psychoactive drugs
.

"It is very noteworthy to us that this compound is effective for all mouse models after a single dose and has a long-lasting effect, similar
to psilocybin," Roth said.
We were lucky
.
We know we're not over
yet.
”

Whether this or other similar drugs can actually provide a one-dose, long-lasting antidepressant effect for people with refractory depression, severe anxiety, and other conditions remains to be determined
.
But this study suggests it's
possible.