In 2013, Kerry Pappas was diagnosed with stage 3 lung cancer. She endured surgery, chemotherapy and radiation, and then went back to her regular life. But she was struggling. “I felt paralyzed with anxiety—not only with the thought of death, but how to move forward in my life,” she recalls.
A friend told her about a Johns Hopkins University School of Medicine study in which researchers were studying psilocybin (the compound in hallucinogenic “magic” mushrooms) to treat cancer-related distress. Not long after, Pappas found herself in Baltimore, swallowing a dose of psilocybin while a social worker on the Hopkins research team guided her through the experience.
Overall, it wasn’t the enjoyable trip she’d expected. “I was plunged into the darkest, most despairing landscape,” she recalls. At first, in her altered state, she felt she was being shown a truth: that life was meaningless. Eventually, though, a glittering jewel emerged from the bleakness, accompanied by the words “Right here. Right now.”
“I recognized that the jewel was me. I have worth and meaning,” Pappas says. “And those words—‘right here, right now’—are still my mantra today.”
It took Pappas some time to process what she’d seen. But she came away transformed. Since the treatment, she’s faced serious challenges, including the cancer metastasizing to her brain. She says she’s been able to face those setbacks as they come. “I live right here, right now. I’m not scared or full of anxiety,” she says. “The experience transformed my inner perspective on a cellular level. All these years later, I’m truly living.”
Since Pappas’s experience with psilocybin in 2013, the field of research on psychedelic drugs has grown rapidly. The U.S. Food and Drug Administration (FDA) has granted “breakthrough therapy” designation to two medical research organizations studying psilocybin to treat depression, allowing them to fast-track development of the treatment. Meanwhile, a growing number of psychologists and their colleagues are studying psychedelics as potential treatments for other disorders including addiction and anorexia.
The research is still young, and sample sizes for most studies are small, but early studies hint that psychedelics combined with psychotherapy may lead to lasting changes in emotional well-being and mental health.
“In a single six-hour session, participants can have experiences that they interpret as being profoundly meaningful, with enduring positive changes years later,” says Roland Griffiths, PhD, founding director of the Johns Hopkins Center for Psychedelic and Consciousness Research. “There’s something profoundly important about these experiences.”
Enduring benefits
Research on the potential benefits of psychedelic drugs has a long but interrupted history. Drugs in this class—including psilocybin, mescaline (peyote), DMT and LSD—act on the serotonin 2A receptor, producing hallucinogenic experiences. In the mid-20th century, scientists began studying whether these drugs could treat problems such as addiction and end-of-life distress. But the drugs developed a negative reputation in the backlash against the counterculture of the 1960s, and research dried up after Congress classified the substances as schedule 1 drugs in 1970 and made them harder to access for research.
In the late 1990s, after becoming interested in meditation and altered states of consciousness, Griffiths convinced Johns Hopkins and the FDA to let him study psilocybin. In early work, he and his colleagues showed that psilocybin could be administered safely in healthy volunteers and produce experiences that the volunteers described as among the most meaningful events in their lives. “The results were so striking, it was a course correction for my career,” he says.
His team then began studying patients like Pappas who were facing distress from a life-threatening cancer diagnosis. They conducted a randomized double-blind trial and found a single high dose of psilocybin in combination with therapy led to large decreases in depression and anxiety and increases in optimism, life meaning and quality of life. At a follow-up six months later, 80% of participants continued to show clinically significant improvements in depression and anxiety (Journal of Psychopharmacologyopens in new window, Vol. 30, No. 12, 2016). Other labs found similar results. In a double-blind trial, Stephen Ross, MD, at New York University (NYU), and colleagues also showed that single-dose psilocybin led to rapid and enduring reductions in anxiety and depression among participants with life-threatening cancer (Journal of Psychopharmacologyopens in new window, Vol. 30, No. 12, 2016).
In light of such results, the field is blossoming. In 2019, Johns Hopkins and Imperial College London both launched centers devoted to psychedelics research. Meanwhile, research labs across the United States have begun exploring the compounds to treat a variety of mental health problems. Most modern research has been on psilocybin, though some labs have begun studying LSD and DMT. (Drugs like ketamine and MDMA are sometimes described as psychedelics, but they have different modes of action and different safety profiles than classic psychedelics.)
Many of these new studies are exploring psilocybin as a treatment for addiction. In one ongoing clinical trial, Michael Bogenschutz, MD, a professor of psychiatry at NYU, and colleagues are studying psilocybin to treat alcohol dependence. In a pilot study, they found that psilocybin increased abstinence in participants with alcohol dependence (Journal of Psychopharmacologyopens in new window, Vol. 29, No. 3, 2015). Psilocybin has also been shown to help smokers quit. In an open-label pilot study, Matthew W. Johnson, PhD, at Johns Hopkins, found that nine of the 15 smokers in the study who received psilocybin were still abstaining from cigarettes at least 16 months later (American Journal of Drug and Alcohol Abuseopens in new window, Vol. 43, No. 1, 2017). That’s noteworthy, considering evidence that only about 20% of people who use the nicotine patch or nicotine lozenges are still not smoking a year later (Baker, T.B., et al., JAMAopens in new window, Vol. 315, No. 4, 2016).
Other researchers have shown that psilocybin can be an effective treatment for some people with depression. In an open-label trial, Robin Carhart-Harris, PhD, at Imperial College London, and colleagues tested single-dose psilocybin in 20 people with treatment-resistant depression. Nineteen completed the trial, and all of them showed initial improvements in depression. Five weeks later, nine patients had marked reductions in depressive symptoms, and another four met the criteria for remission. The improvements were still evident at a six-month follow-up (Psychopharmacologyopens in new window, Vol. 235, No. 2, 2018).
His lab is now running a larger study comparing psilocybin therapy with a conventional antidepressant for treating severe depression. Two U.S. medical research organizations—COMPASS Pathways and the Usona Institute—are conducting trials of psilocybin for treatment-resistant depression and major depressive disorder, respectively, after receiving the “breakthrough therapy” designation from the FDA.
Elsewhere, researchers are looking at psilocybin to treat problems including anorexia, demoralization in long-term AIDS survivors and depression in people with early Alzheimer’s disease. “One of the most interesting features is that it appears as though psychedelics may be useful for treating a variety of psychiatric and behavioral conditions or disorders,” Griffiths says. “The prospect of transdiagnostic applicability is tantalizing—and unlike any medication approaches that we currently have in psychiatry.”
Set and setting
Some research suggests that nonclinical use of psychedelic drugs is even associated with better mental health among the general population. Peter Hendricks, PhD, a professor of psychology at the University of Alabama at Birmingham, and colleagues gathered data from the National Survey on Drug Use and Health and found that people who reported using psychedelics at any point in their lifetime had lower odds of psychological distress during the past month, and lower rates of suicidal thinking and suicide attempts in the past year (Journal of Psychopharmacologyopens in new window, Vol. 29, No. 3, 2015).
That study doesn’t show a causal link, however. Indeed, it’s possible that people with better mental health are more open to experimenting with these drugs. And Hendricks and other researchers are not suggesting people experiment on their own. For maximum mental health benefits, they say, therapy is a key part of the process. “There’s a big difference between taking a psychedelic drug at a music show when you’re 17 and don’t know what to expect and taking it in a therapeutic setting while working with a therapist to address a specific issue,” Hendricks says.
All of the recent trials of psychedelics follow the “set and setting” model developed in the 1960s. The setting is often a comfortable room with soothing lights and music. Set describes the mindset a person brings to the experience. For an optimal mindset, participants typically have several counseling sessions with a psychologist or social worker before and after the psilocybin dose to help them prepare and then to process what they saw and felt. The therapist also sits with the patient for the six or so hours that the drug is active to guide them through it.
“The experience provides the possibility of change, but change doesn’t just occur by itself,” Bogenschutz says. “It’s very different from other pharmacotherapies in the sense that we’re looking at this as a way to facilitate a psychotherapeutic process.”
With the right set and setting, these interventions seem to open the door to dramatic change. People often describe a mystical experience, marked by a sense of interconnectedness and the feeling that the experience is more true than everyday consciousness. Researchers have also found that people who report a mystical experience are more likely to derive meaning and enduring benefits from the event (Johnson, M.W., et al., Pharmacology & Therapeuticsopens in new window, Vol. 197, No. 1, 2019).
There’s some evidence that psychedelics may produce these benefits by making the brain more malleable. Carhart-Harris and colleagues used fMRI to look at brain activity in people with treatment-resistant depression who participated in a trial of psilocybin-assisted therapy. They found that activity in the brain’s default mode network decreased during the acute phase of psilocybin but showed greater than normal activity one day later, along with improvements in participants’ moods (Scientific Reportsopens in new window, No. 7, 2017). The default mode network is a network of interacting brain regions thought to be active when people are focused inward rather than on the outside world.
“Psilocybin seems to increase interactions across different brain areas and networks that don’t normally speak to one another. It opens a window of neuroplasticity during which brain networks can be changed,” Griffiths says.
Cautious optimism
While researchers are excited about the possibilities of psychedelics, they’re also circumspect. The drugs themselves are quite safe, says Hendricks. “We know of no data that psychedelics are addictive, and there are no withdrawal symptoms—but they can be used in a dangerous or inappropriate context,” he says.
People can become frightened and disoriented and behave dangerously—in an altered state of mind, jumping out a window or running into traffic is a real possibility. And without a therapist to help them frame the experience in helpful ways, people might be left unsettled or even traumatized, Griffiths says.
Others are concerned that the drugs could trigger enduring psychotic illness in people at risk of schizophrenia. Though there is no hard evidence, there are anecdotal reports of people experiencing a psychotic break after using hallucinogenic drugs—that’s why modern researchers exclude participants at elevated risk of serious mental illness.
Even in healthy people, the results are promising but preliminary. Psychedelics researchers warn that it’s too soon to draw firm conclusions, much less to recommend these drugs outside clinical research settings. “Those of us doing this research are interested in making a change to mental health treatment models to improve the lives of those who are suffering, but there’s still a lot we don’t know,” Hendricks says.
Among the open questions is how best to conduct therapy sessions before, during and after a psychedelic dose. So far, investigators have implemented best practices that emerged during research in the 1960s, but none of the modern research has focused on the therapy itself.
Nevertheless, the field is moving forward, with more and more labs studying psychedelics and a number of clinical trials underway. Though public funding has so far been scarce, private donors have kept the research afloat, and researchers are hopeful that large funders such as the National Institutes of Health will begin supporting the work in light of the positive trials. The renewed interest in psychedelics is a welcome development, says Charles Grob, MD, a psychiatrist at the David Geffen School of Medicine at the University of California, Los Angeles, who studies psychedelics to treat mood and anxiety disorders. “Psychopharmacology really hasn’t developed any novel treatments in some time. There’s a sense the field has stalled,” he says. “Now, after almost half a century of quiescence, the field is resonating with the potential that the psychedelic model may have value. The question is: Are we ready for a new paradigm in mental health?”
