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Drugs like magic mushrooms and LSD can act as powerful and long-lasting antidepressants. But they also tend to produce mind-blowing side effects that limit their use.
Now scientists report in the journal Nature that they’ve created LSD-based drugs that appear to relieve anxiety and depression – in mice – without inducing the usual hallucinations.
“We found that our compounds had essentially the same antidepressant activity as psychedelic drugs,” says Dr. Bryan Roth, study author and professor of pharmacology at UNC Chapel Hill School of Medicine. But, he says, “they didn’t have any psychedelic drug-like action.”
This discovery could eventually lead to drugs for depression and anxiety that work better, work faster, have fewer side effects and last longer.
The hit is just the latest involving triple versions of psychedelic drugs. A previous effort created a hallucination-free variant of ibogaine, which is made from the root bark of a shrubby plant native to central Africa known as the iboga tree.
“It’s very encouraging to see multiple groups approaching this problem in different ways and coming up with very similar solutions,” says David E. Olson, a neuroscientist in chemistry at the University of California, Davis, who led the ibogaine project. .
An unexpected find
The new drug comes from a large team of scientists who did not start looking for an antidepressant.
They had built a virtual library of 75 million molecules that include an unusual structure found in a number of drugs, including the psychedelics psilocybin and LSD, a migraine drug (ergotamine) and cancer drugs including vincristine .
The team decided to focus on molecules that affect the brain’s serotonergic system, which is involved in regulating a person’s mood. But they still weren’t looking for an antidepressant.
Roth remembers that during a meeting, someone asked, “What are we looking for here anyway?” And I said, well, at least we’ll have the best psychedelic drugs in the world.
As their work progressed, however, the team realized that other researchers were showing that the psychedelic drug psilocybin could alleviate depression in humans. And the effects could last a year or more, possibly because the drug helped the brain rewire itself in a less depression-prone way.
“The [were] really interesting reports of people getting great results after just a few doses,” says Brian Shoichet, study author and professor in the department of pharmaceutical chemistry at the University of California, San Francisco.
The team therefore began to refine their search to find molecules in their library that could act in the same way.
In the end, they chose two.
“They had the best properties,” says Shoichet. “They were the most potent, and when you gave them to a mouse, they entered the brain in the highest concentrations.”
Both molecules were also “extremely effective” in relieving symptoms of depression in mice, Roth says.
How to tell when a mouse is tripping
Scientists have shown that a depressed mouse tends to give up quickly when placed in an awkward situation, such as hanging from its tail. But the same mouse will continue to struggle if given an antidepressant drug like Prozac, ketamine, or psilocybin.
The mice also continued to struggle when they got the experimental molecules.
But they showed no signs of a psychedelic experience, which usually causes a mouse to twitch its nose in a distinctive way. “We were surprised to see that,” Roth says.
The team says they need to refine these new molecules before they can try them in humans. One reason is that they seem to mimic LSD’s ability to increase heart rate and raise blood pressure.
But if the approach works, it could overcome a major barrier to using psychedelic drugs to treat depression.
Currently, treatment with a psychedelic requires medical supervision and a therapist to guide a patient through their hallucinatory experience.
It’s an impractical way to treat millions of people with depression, says Shoichet.
“The company would like a molecule that you can get prescribed and just take and you don’t need a guided tour for your trip,” he says.
Another advantage of the new approach is that the antidepressant effects would occur within hours of taking the drug and could last for a year or more. Medications like Prozac and Zoloft often take weeks to work and need to be taken every day.
Psychedelic-based drugs “bring us closer to a cure, rather than just treating the symptoms of the disease,” says Olsen.
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