Opinion | Psychedelics for Depression: Can They Work Without Hallucinations?

“To get the kinds of persisting benefits that we’re seeing, which are weeks, months, even over a year later, that would seem to suggest that there’s some kind of cognitive shift or changes to one’s meaning-making that are going on,” said David Yaden, an assistant professor of psychiatry and behavioral sciences at the Johns Hopkins Center for Psychedelic and Consciousness Research.

People participating in psychedelic studies often say the experience was among the most meaningful of their lives, on a par with the birth of a child or death of a parent. Many report feeling a sense of connectedness with the universe. “This psilocybin journey was the single most transformative experience of my life,” Mr. Fernandez wrote in a Medium post in 2018. “It forced me to reconcile with the mortality of being human. It alleviated my anxiety and gave meaning to my life.”

It is this existential catharsis and the personal insights that accompany it that Dr. Yaden and others believe are so important to people’s healing. Backing up the theory, several studies have found that the feelings of connectedness and meaningfulness and the mystical-type experiences people have during their trip correlate with their therapeutic outcomes.

Regardless of which side is right, the pursuit of an answer to how psychedelics treat depression brings scientists one step closer to understanding not only how to relieve the symptoms of mental illness, but also potentially how to remove them. That’s because the truly revolutionary vision of both psychedelic therapy and its non-psychedelic chemical cousins is to take the medications not on a daily or weekly basis, but only once or twice and potentially be healed for good. “Wouldn’t it be wonderful if we had a drug that you can take at bedtime and you woke up the next day and you were no longer depressed?” said Dr. Bryan Roth, a professor of pharmacology at the University of North Carolina, Chapel Hill, who is also working to develop non-hallucinatory psychedelic compounds.

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Beginning in the 1960s, scientists thought that depression resulted from having low levels of the neurotransmitter serotonin in the brain, and traditional antidepressant drugs, such as selective serotonin reuptake inhibitors, worked by correcting that chemical imbalance. But there were holes in this hypothesis. Most notably, S.S.R.I.s raise serotonin levels immediately, but symptoms of depression typically don’t alleviate until several weeks after starting the medication.

A new theory emerged in the 1990s and early 2000s that depression, as well as anxiety and PTSD, may stem from the loss of synapses in the brain — the connections between neurons. Scientists discovered that people with depression have less volume in regions of the brain important for mood, executive control and feelings of reward. Chronic stress and genetics are thought to contribute to the atrophying of neurons and their connections.