Exploring Psilocybin as a Potential Future Antidepressant Medication
The anticipated victor: The substance that delivers the optimal outcome at six months in the struggle against depression, which impacts more than 300 million individuals globally.
The stakes are high for psychedelic clinical trials — there's an urgent need for a more effective medical solution in the fight against depression, particularly treatment-resistant depression. Of the nearly 9 million people with major depression in the United States who have tried medication, approximately 2.8 million are speculated to be resistant to multiple antidepressants.
"I'm familiar with a case of an individual who tried 17 different drugs and none of them worked," said psychobiologist Dr.Bertha Madras, director of the Laboratory of Addiction Neurobiology at Harvard Medical School’s McLean Hospital in Belmont, Massachusetts.
"Even electroconvulsive therapy failed," Madras said. "It's heartbreaking when you simply can't help a person get out of bed and engage in life."
Antidepressant advantages and disadvantages
For a significant number of people, antidepressants have been a lifesaver, 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 instances, 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 advantage when it comes to emotional numbing, 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 the crowd favorite — arguably the most popular of a lineup of psychedelic drugs that last saw their heyday in the LSD 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.
Not everyone in the field is convinced that psilocybin — or any other psychedelic — will survive FDA scrutiny. In August, the agency surprised researchers by rejecting MDMA as a treatment for PTSD, sending its maker back to conduct another clinical trial that could take years.
“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 operates on a distinct area of the brain compared to antidepressants, as suggested by an expert. This psychedelic substance zeroes in on the brain's rumination zone, where thoughts spin in a continuous loop of negativity, often proving difficult to halt for many individuals. Scans performed before, during, and following psilocybin use reveal the brain loses synchronization —interfering with these negative thoughts and enabling individuals to view themselves differently.
According to Nutt, individuals begin to understand, feel, and appreciate that their brain can change, allowing them to break free from their depression. They perceive an opportunity to shift their perspectives, and subsequently, they can actually do so.
The key to achieving long-term success in combating depression, as indicated by experts, is by consistently integrating these new insights into daily behavior. Consequently, studies on psilocybin have involved trained therapists throughout the hallucinogenic trip, along with sessions before and after the experience.
Raison remarks that the psychedelic experience creates a state where the brain becomes more receptive, generating new brain cells similar to a child's brain. However, he cautions that potential adverse consequences could arise, such as challenges adapting to normal life post-treatment and an escalation of anxiety and rumination, which are conditions psilocybin is intended to help alleviate.
Regardless of how rare such reactions may be, Raison points out that they highlight the concerns associated with dispensing psilocybin or any other psychedelic to the general population.
Promising yet unconclusive findings
The aforementioned research contrasting psilocybin and escitalopram was a double-blind, randomized controlled trial that involved 59 patients with either moderate or severe depression. Half of the patients received two 25-milligram doses of psilocybin separated by three weeks, while the other half received a 1-milligram dose of psilocybin along with six weeks of escitalopram. Both groups underwent roughly 20 hours of psychotherapy.
As Raison, who was not involved in the study, notes, this research is significant due to its examination of the long-term behavioral effects of psilocybin in comparison to something else, and it could potentially be the only research to ever make a long-term comparison of psilocybin to an SSRI.
At six weeks, there was no significant difference in depression scores between the two groups. However, brain scans revealed a different narrative.
According to Nutt, a coauthor on the study, the brains of individuals using psilocybin demonstrated enhanced flexibility, a higher ability to transition between various brain states.
Nutt and his team published the six-month results of the same group of patients in September. Both treatments—psilocybin and escitalopram—showed comparable improvements in depressive symptoms, although individuals using psilocybin reported higher levels of joy in their lives—an advantageous factor for maintaining depression in check.
Although critics pointed out that individuals in the psilocybin arm of the trial had the opportunity to engage in additional therapy and even start antidepressants between the administration of psilocybin and the six-month check-in—behaviors that could have contributed to improvement—the study found that individuals who exhibited the least depression at six months were those who responded best to psilocybin on brain scans at six weeks.
“The more flexible a patient’s brain was three weeks following a trip, the better their outcome on depression at six months,” Nutt said. “There’s a biological, physiological alteration in the brain due to psilocybin—which can be observed three weeks following a trip—that predicts clinical outcome. However, before we can definitively say that it's a fact, it should be replicated.”
Future challenges
Harvard's Madras and other critics emphasized that significant aspects related to psilocybin and other psychedelics need to be addressed before they can potentially become new treatment options for mental health.
Madras, who was not involved in the escitalopram study, explained that clinical trials have primarily focused on a limited population. In some studies, 1,000 individuals are interviewed, and only 50 are selected.
“Why? Because they need to screen out individuals who might be vulnerable to a psychotic break—anyone with a family history of suicide, psychosis, or bipolar disorder,” Madras said.
Additionally, she pointed out that adverse effects are such a concern that researchers in psychedelic clinical trials actively enroll individuals who have had successful psychedelic experiences in the past.
Furthermore, the issue of blinding in gold standard randomized clinical trials must be addressed. Patients should not be aware if they received a drug or a placebo, a dummy pill designed to mimic the active ingredient in the treatment being tested.
If a drug is significantly more effective than the placebo, that would be a strong indication that the positive effect isn't due to a patient's expectation of improvement, and the clinical trial would be deemed a success.
Finding a decoy that dupes individuals into believing they're experiencing a hallucinogenic journey has proved to be quite difficult. Take the instance of a study utilizing psilocybin for alcohol addiction, where an astounding 95% of participants successfully identified if they were ingesting psilocybin or the dummy substance.
Regarding affordability, it's uncertain if the extensive therapy required to boost success with a psychedelic drug like psilocybin will be within reach for the numerous depressed individuals who require it, Raison mentioned.
"That's the million-dollar question: How will this be scaled up, and who will shoulder the cost?" he questioned. "What's it going to take for health insurance to cover a treatment given, say, two to three times a year, and could potentially set you back $15,000, as opposed to generic Prozac (fluoxetine), which costs just five dollars monthly?"
"It's indisputable that psychedelics are effective and deliver lasting advantages we're yet to fully grasp," Raison concluded. "But how will this translate into long-term efficacy against depression, and how the healthcare system might deliver these at scale, remains to be seen."
The use of psilocybin in clinical trials shows promise for individuals with treatment-resistant depression, as indicated by the FDA's "breakthrough therapy" designation for three synthetic psilocybin versions in 2018 and 2019. implementing a holistic approach, including therapy sessions before and after the experience, can help individuals integrate these new insights into their daily lives, potentially leading to long-term success in combating depression.
Regarding overall wellness and health, integrating psilocybin into treatment regimens could offer an alternative approach for individuals struggling with depression, particularly those who have not responded to traditional antidepressants. This wellness-focused approach could help individuals to improve their quality of life and mental health, potentially aiding in the reduction of depression symptoms and enhancing overall well-being.
