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“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.”
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 fadewithin a few weeksafter starting an antidepressant, but sexual side effects such as reduced libido and difficulty with orgasm can last for months or even years. Inrare cases, sexual dysfunction can persist even after stopping the antidepressant.
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“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 toemotional 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.’”
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 theTimothy Leary eraof the 1960s.
In small clinical trials, synthetic versions of the psychedelic have shown benefits in tacklingcluster headaches,anxiety,anorexia,obsessive-compulsive disorderand various forms ofsubstance abuse.
TIL Limited Stock Buy or Sell ✌️【Earnings Growth】✌️ Accurate stock market predictions with real-time stock indices, futures data, and global market trend analysis. Achieve stable growth and avoid losses by staying ahead with our expert recommendations. 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 isseverely depressedmost of the time.
Breakthrough status is a designation that can fast-track the road to FDA approval and is given to drugs that “demonstratesubstantial improvementover available therapy,” according to the agency.
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In 2024,lysergic acid diethylamide, better known as LSD, won FDA breakthrough status for treating anxiety. It’s also inclinical trialsfor depression.Smallerclinical trials forless well-knownpsychedelics arealso underway.
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“We have no idea how these drugs will fare in a much larger population of people,” said Harvard’s Madras.
“To say that psilocybin is going to be the magic bullet that will solve the problems of depression, I think, is irresponsible at best and hazardous at worst.”
Psilocybin works on a different part of the brain than antidepressants, expert says. The psychedelic zeros in on the brain’s ruminative area, where thoughts run in a circular wheel of negativity many find hard to stop. Brain scans taken before, during and after people are tripping on psilocybin show the brainbecomes desynchronized—disrupting those negative thoughts and allowing people to see themselves differently.
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“People begin to feel, understand and appreciate that their brain can change and they can escape from their depression,” Nutt said. “They can look through a door to a different way of thinking, and they can then walk through the door afterwards.”
Integrating those new insights into daily behavior that lasts, however, is the key to long-term success in fighting depression, experts say. That’s why studies on psilocybin have used trained therapists during the hallucinogenic trip, along with therapy sessions before and after the experience.
“The psychedelic experience opens up this sort of critical period where your brain is more open, sprouting new brain cells, somewhat like a child’s brain,” Raison said.
“But what if you get in a car wreck or your husband leaves you the next day? What if it alters your mental status in ways that make you want to fly so you jump off a bridge? It doesn’t happen often, but that’s the risk.”
Psychedelic therapists sometimes do reportadverse outcomes,such as difficulty adapting to life post-treatment and a worsening of anxiety and ruminative brooding, the very conditions psychedelics are supposed to help. Even if such reactions are rare, Raison said, they point to the larger problem of prescribing psilocybin — or any other psychedelic — to the general population.
“Let’s say only 2% or 3% of people get really screwed up after a trip,” he said. “If you have 20 million people doing a trip, it’s a problem. These agents are really powerful.”
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“This is the first time anyone has looked at the longer-term behavioral effects of psilocybin compared to something else — and probably the only time anyone will ever do a long-term comparison of psilocybin to an SSRI,” said Raison, who was not involved in the study. “For that reason alone, this research matters.”
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“The brains of people on psilocybin had increased flexibility, a greater ability to switch between different brain states,” said Nutt, who was a coauthor on the study.
TIL Limited Stock Buy or Sell ✌️【Earnings Growth】✌️ Free break-even services with personalized investment plans. Quickly recover from losses, avoid risks, and achieve steady growth with expert stock predictions and real-time market updates. Nutt and his team published the six-month results of the same group of patients inSeptember. While both psilocybin and escitalopram showed comparable improvement in depressive symptoms, people who took psilocybin reported greater joy in their lives — a significant plus in keeping depression at bay.
“Psilocybin outperformed escitalopram in several measures of well-being — meaning in life, work and social functioning,” said lead researcher Tommaso Barba, a doctoral candidate at Imperial College London in a statement.
However, critics pointed out that people in the psilocybin arm of the trial were allowed to seek out additional therapy and even start antidepressants between the administration of psilocybin and the six-month check-in — behaviors that could have also contributed to improvement.
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“The more flexible a patient’s brain was three weeks after one trip, the better their outcome on depression at six months,” Nutt said. “There’s a biological, physiological change in the brain as a result of psilocybin — which you can see at three weeks after a trip — that predicts clinical outcome.
Harvard’s Madras and other critics said a good deal about psilocybin and other psychedelics must be sorted before any could ever become a new treatment option for mental health.
“For one, clinical trials have focused on a restricted population. In some of the studies, 1,000 people are interviewed, and 50 are selected,” said Madras, who wasn’t involved in the escitalopram study.
“Why? Because they have to screen out people who might be susceptible to a psychotic break — anyone with family history of suicide, psychosis or bipolar disorder,” she said.
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In fact, Madras said, adverse effects are such a concern that researchers in psychedelic clinical trials often actively recruit people who have successfully taken psychedelics in the past.
TIL Limited Stock Buy or Sell ✌️【Earnings Growth】✌️ Free stock market analysis and data updates to help you select the best investment portfolio. Achieve steady growth and avoid losses with expert predictions and real-time market insights. Then there’s the issue of blinding. In gold standard randomized clinical trials, patients are not supposed to know if they received a drug or a placebo, a fake pill designed to mimic the active ingredient in the treatment being tested.
If a drug is significantly more helpful than the placebo, that’s a good indication the positive effect isn’t due to a patient’s expectation of getting better and the clinical trial is a success.
However, finding a placebo that fools people into thinking they are on a hallucinogenic trip has proven challenging. In a study using psilocybin for alcohol substance abuse, for example, some 95% of those involved correctly guessed whether they weretaking psilocybin or the placebo.
TIL Limited Stock Buy or Sell ✌️【Earnings Growth】✌️ Real-time stock indices and futures data to help you seize the best investment opportunities. Analyze market movements with precision and grow your portfolio with expert stock predictions. Then there’s the issue of cost. It’s yet to be determined if the intense therapy needed to bolster success with a psychedelic drug such as psilocybin will be affordable to the many depressed people who need it, Raison said.
“That’s the $1,000 question: How will this be brought to scale, and who will pay for it?” he said. “What’s it going to take for insurance to cover a treatment that’s administered say, two to three times a year that might cost $15,000 versus generic Prozac (fluoxetine), which costs five bucks a month?
“It is clear psychedelics work and have protracted benefits that we don’t yet understand,” Raison added. “But how that’s going to translate into long-term effectiveness against depression and how the health care system might deliver these at scale is still unknown.”
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