Psychedelic Drug May Help Rewire the Brain to Treat Depression

Growing evidence shows that psychedelics like psilocybin are effective at treating depression, and scientists may finally understand why. Researchers found psilocybin works differently from traditional antidepressants by stimulating and rewiring brain pathways that are less active in the depressed brain.

By rewiring the brain, the antidepressant effects of psychedelics lasted weeks after the initial treatment.

The findings, published in the journal Nature Medicine, suggest psilocybin could help in treating people whose depression has not responded to traditional antidepressants like selective serotonin reuptake inhibitors (SSRI).

Strengthening connections with other brain regions could help with depression and other psychiatric conditions that have fixed patterns of thinking. It may also eliminate the need to take daily medicine as one to two doses was enough to help symptoms.

“You won’t need to dose indefinitely or repeatedly,” David Merrill MD, PhD, a psychiatrist and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center at Providence Saint John’s Health Center who was not involved in the study, told Verywell. “In the trial, they’re showing with two doses a lasting antidepressant effect even when you’re not [actively] using them. It’s the opposite of antidepressants that only show a benefit as long as you take them.”

While psychedelics aren’t slated to replace antidepressants anytime soon, it lends support to the push toward decriminalizing the hallucinogenic drugs for medicinal use across the United States.

Past Evidence of Psilocybin Effectiveness

In recent years, scientists have discovered the benefits of psilocybin for depression treatment. A small 2020 study from Johns Hopkins Medicine showed that two doses of psilocybin combined with psychotherapy reduced depressive symptoms for a month. Half of the patients with major depression also reached remission. When researchers followed up with the same patients, they found the antidepressant effects of psilocybin continued to last one year after the second dose.

How psilocybin fares up against other antidepressants remains poorly understood. An April 2021 study in The New England Journal of Medicine suggested that while psilocybin helped people with severe depression reach remission sooner, there was no significant difference in antidepressant effect between psilocybin and the SSRI Lexapro (escitalopram).

While not published in a journal, a company called Compass Pathways involved in psilocybin-assisted mental health therapy, also released phase 2 clinical data showing one dose of psilocybin significantly reduced depressive symptoms for up to three months.

Merrill said the current data is establishing the evidence for which treatments would work best for different patient populations. “Hopefully, psilocybin will be one of the choices in various interventions,” Merrill said. “Some people may not need a major psychedelic experience or they may have a risk of psychosis with a psilocybin trip. But [for others], combining psychotherapy with psilocybin seems to yield better results than just giving psychedelics as medicine.”

Psilocybin Rewires the Brain to Promote Fluid Thinking

Scientists enrolled people with different levels of depression who recently participated in one of two psychedelic trials. In the first trial, 16 people with treatment-resistant depression knew they were taking psilocybin. People were given a low dose (10 mg) and then a high dose (25 mg) of psilocybin one week later.

The second trial involved people with major depressive disorder who were told they would receive psilocybin but were unaware of the dosage. People were randomly selected to receive 25 mg of psilocybin or Lexapro that served as the placebo. Twenty-one people received the placebo. Throughout the trials, all participants received psychotherapy.

The research team took brain scans of every trial participant before and after treatment. In the pre-treatment scans, the brains of participants showed a fixed pattern of thinking. The brain connections inspired a rigid thought pattern, characterized by obsessively pondering over the same thought over and over again and being extremely self-focused. Because the depressed brain encourages rumination, it is difficult for people to change their thought processes.

People who took psilocybin reported better outcomes in depression severity after both trials. The researchers observed improvements in cognition and being more emotionally open. The changes in people’s depressive symptoms lasted three weeks after researchers followed up on their second dose. Meanwhile, people who were given the SSRI antidepressant showed temporary improvement before reverting back to a rigid pattern of thinking.

Psilocybin was associated with changes in brain connectivity. The results suggest psilocybin may affect the brain differently from traditional SSRIs.

“Basically the brain is connected in a more functional way,” Merrill said. “It’s a remarkable study and I was struck from the milder antidepressant effect from the SSRI and that there were no changes in the brain network organizations from these antidepressants.”

The study authors propose psilocybin works to decrease higher cognitive brain areas that are hyperactive in depression and foster stronger connections in other disconnected brain regions. Promoting connectivity throughout the brain may have made it easier for people with depression to have flexible thinking and change their mindset.

“This study is arguably saying that the real game-changer is going to be the psychedelic experience because it’s qualitatively different than the antidepressant,” Merrill added. “And this is part of the convincing evidence that psilocybin may be a truly different way to treat major mental illness because of the positive effects it has on the brain.”

Researchers hypothesize that psilocybin disrupts the function of 5-HT2A receptors, which become hyperactive in the depressed brain. By stopping the connections, psilocybin may give the brain an opportunity to create other connections.

“In previous studies, we had seen a similar effect in the brain when people were scanned whilst on a psychedelic, but here we’re seeing it weeks after treatment for depression, which suggests a carry-over of the acute drug action,” Robin Carhart-Harris, PhD, the director of the Neuroscape Psychedelics Division at the University of California, San Francisco, and the senior author of the study, said in a press release.

More Research Is Needed

The study findings indicate psilocybin has great potential, but there are some limitations. The trials were highly controlled meaning the researchers created a trial design that limited other outside variables that could affect the results.

But in the real world, it is possible other factors could affect psilocybin’s effectiveness such as a person’s past history with psychedelics or comorbidities.

The study was also conducted on a small sample size, making the data prone to variability and bias when doing statistical analyses. It is possible that psilocybin’s benefits could be impacting people with severe depression the most and that adding more people with less severe depression into the mix could make the benefits less significant overall.

Merrill said he would be interested in seeing how psilocybin would affect older adults—almost one-third of people with treatment-resistant depression are more likely to be older—and younger people whose brains are still developing.

“We’re still in early research and we’re still studying the effects,” Merrill said. “It’s not legalized federally but we’re hopeful we are headed towards more widespread, accessible, and safe clinical use.”

Merrill expects psilocybin to be approved for the treatment of depression by the FDA within the next one to three years.

But currently, psilocybin is not legal, and Merrill discourages people from self-medicating with psilocybin or other psychedelics because it increases the risk of a “bad trip” and other safety issues with dosing.