The treatment of depression has improved dramatically over the last half-century. The introduction of selective serotonin reuptake inhibitors (SSRIs) in the late 1980s was truly life-changing for millions of Americans.

But for the 30 percent of people who have treatment-resistant depression, that hope is often dashed when those and other available medications and therapies don’t work, don’t work well enough, or just have too many side effects. Now something as life-changing as SSRIs may be on the horizon for those patients too: therapeutic psilocybin.

Psilocybin is a naturally occurring alkaloid that is found in several types of mushrooms and is best known for its recreational use.

Researchers from Johns Hopkins University School of Medicine have been studying its potential therapeutic effects for 20 years, and recently reported some of their findings in JAMA Psychiatry. In a small study, they found that two doses of psilocybin, given with supportive psychotherapy, produced a rapid, significant, and long-lasting reduction in depressive symptoms.

Bottom Line Health spoke with Natalie Gukasyan, MD, medical director of the Johns Hopkins Center for Psychedelic and Consciousness Research, to learn more about this study and her team’s work.

What is the most exciting part of this research?

Unlike antidepressants, which can take weeks or months to have an effect, we’re seeing that people had strong antidepressant effects within a few days of taking psilocybin. Further, while antidepressants must be taken daily, our research suggests that this treatment can be delivered just once or twice to produce long-lasting benefits for many people.

How does psilocybin reduce depression?

Psilocybin appears to have a biological effect as well as effects from the subjective experience. Biologically, it works on the serotonin 2A receptor, which is important for mood regulation. While the main group of antidepressants (SSRIs) also work on serotonin, they do it differently: Those medications increase the amount of serotonin that is available to bind to cells, whereas psilocybin attaches directly to the serotonin receptor. When the drug latches to the receptor, patients have a subjective experience characterized by substantial changes in mood, perception, and thinking that lasts for four to six hours. Brain imaging studies show that there are also changes in parts of the brain that control the emotional response beyond the period of immediate drug effects.

Psychedelic drugs, such as psilocybin, also change the function of the default mode network. This is a circuit in your brain that is likely involved in your sense of self. In people with depression, this network may be overactive. Psychedelic drugs appear to change how the parts of the brain in that network communicate with one another, and one study found that such changes were associated with improvements in depression.

What role does the subjective psychedelic experience play?

The subjective experience is different for everyone, which makes it difficult to predict. In the many psilocybin studies that we do, we use standardized questions to ask people about their experiences. People report feelings of oneness and connection, as well as mystical, spiritual, and religious experiences. In about 25 to 30 percent of sessions, people report a challenging experience during which they feel anxiety, distress, or dysphoria. But even when the immediate experience is challenging, the overall effects of the treatment tend to be positive. Many people emerge feeling like they have gained new psychological insight or a new perspective on a situation. Right now, we are conducting larger clinical studies to see if these effects are observable in bigger patient populations.

Can we expect to see medical psilocybin anytime soon?

This is currently a schedule 1 substance, which means that it is designated as a drug that is not known to have medical benefits and is associated with risks. We are now releasing data that shows that it does, in fact, have medical benefits and that it has minimal risk when administered in a monitored setting with proper screening and careful patient selection.

The U.S. Food and Drug Administration has granted breakthrough therapy status to two companies to speed up the drug development and review process for psilocybin. While the early results have been promising, we are still at least several years away from having the level of evidence required to make this treatment available outside of research settings.