What experts say about taking psilocybin as an alternative treatment for depression
In an artist's rendition of an actual brain on psilocybin, the red and yellow hot spots are where the brain is firing at the height of the psychedelic trip.
The matchup: Two doses of psilocybin, the active ingredient in “magic mushrooms,” against a six-week course of the popular antidepressant escitalopram, often sold as Lexapro or Cipralex. Escitalopram is one of a class of antidepressants called selective serotonin reuptake inhibitors, or SSRIs.
The projected winner: The drug that produces the best outcome at six months in the battle against depression, which affects more than 300 million people worldwide.
The stakes are high for psilocybin clinical trials — there’s a pressing need for a more effective medical solution in the fight against depression, especially treatment-resistant depression. Of the nearly 9 million people with major depression in the United States who have tried pharmaceuticals, 2.8 million are estimated to be resistant to multiple antidepressants.
“I am aware of a case of a person who tried 17 different drugs and nothing worked,” said psychobiologist Dr. Bertha Madras, director of the Laboratory of Addiction Neurobiology at Harvard Medical School’s McLean Hospital in Belmont, Massachusetts.
“Even shock therapy failed,” Madras said. “It’s a terrible thing when you simply cannot help a person to get up out of bed and engage in life.”
Antidepressant pros and cons
For a good number of people antidepressants have been a blessing, at least at the beginning of treatment, said Dr. Charles Raison, a professor of psychiatry and human ecology at the University of Wisconsin School of Medicine and Public Health in Madison.
“I always start by saying, ‘Thank God, we have them.’ Many people can say, ‘Wow, I was pulled out of a pretty deep hole,’“ said Raison, who is also the director of the Vail Health Behavioral Health Innovation Center in Colorado where psilocybin is studied.
But for up to a third of depressed patients, antidepressants fail to work at all. Even for those who do find relief, “the benefits tend to fade in some fairly reasonable percentage of people over time,” Raison added. “Then there’s the side effects, many of which don’t get much better long term.”
Initial reactions such as nausea or headaches often fade within a few weeks after starting an antidepressant, but sexual side effects such as reduced libido and difficulty with orgasm can last for months or even years. In rare cases, sexual dysfunction can persist even after stopping the antidepressant.
That’s one problem that psilocybin doesn’t have, said psychedelics researcher David Nutt, director of the neuropsychopharmacology unit at Imperial College London’s division of brain sciences.
“If you have just one trip and get better, there’s no drug in you day after day and no long-term sexual side effects,” Nutt said.
Psilocybin also has the edge when it comes to emotional blunting, which is the tendency of antidepressants to diminish not only depression but also enjoyment in life.
“This is such a consistent finding in studies, it’s become the theory of how antidepressants work — they suppress the brain’s supersensitive stress center and allow it to heal,” Nutt said.
“However, the pleasure center of the brain can also be dampened, and we know that because when we put people on antidepressants in the brain scanner, they don’t respond as much as to happy faces,” he added.
“Some people don’t like that. They say, ‘I don’t enjoy life as much. I’m not depressed anymore, but I’m not as happy.’”
The top psychedelic contender
In the search for a new alternative in treatment, psilocybin entered the ring as a fan favorite — arguably the most popular of a lineup of psychedelic drugs that last saw their heyday in the Timothy Leary era of the 1960s.
In small clinical trials, synthetic versions of the psychedelic have shown benefits in tackling cluster headaches, anxiety, anorexia, obsessive-compulsive disorder and various forms of substance abuse.
Still, psilocybin’s highest accolades have come from the drug’s apparent success in treating depression. Three versions of synthetic psilocybin have received the US Food and Drug Administration’s “breakthrough therapy” designation — in 2018 for treatment-resistant depression, which is diagnosed when people have tried and failed multiple antidepressants — and in 2019 and 2024 for clinical depression, diagnosed when a person is severely depressed most of the time.
Breakthrough status is a designation that can fast-track the road to FDA approval and is given to drugs that “demonstrate substantial improvement over available therapy,” according to the agency.
Another key contender, MDMA, or 3,4-Methylenedioxymethamphetamine, commonly known as Molly or Ecstasy, shows promise in treating post-traumatic stress disorder, or PTSD, but hasn’t been directly studied for depression.
In 2024, lysergic acid diethylamide, better known as LSD, won FDA breakthrough status for treating anxiety. It’s also in clinical trials for depression. Smaller clinical trials for less well-known psychedelics are also underway.
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