Oregon made history on November 3, becoming not just the first U.S. state to legalize psilocybin, the psychoactive compound in “magic mushrooms,” but also the first jurisdiction in the world to lay out plans for regulating the drug’s therapeutic use.

The next day, on the opposite coast, Johns Hopkins University researchers published results from the first randomized controlled trial of treating major depressive disorder with synthetic psilocybin. Their study, published in JAMA Psychiatry, found 71 percent of patients experienced a “clinically significant response” (an improvement that lasted at least four weeks after treatment). And 54 percent met the criteria for total “remission of depression.”

At the U.S. federal level, psilocybin remains a completely prohibited Schedule 1 Drug, defined by the Drug Enforcement Administration as having “no currently accepted medical use and a high potential for abuse.” But the state-level ballot measure and positive study results broaden the legal circumstances and settings in which the potent psychedelic can be used for mental health therapy.

“Our goal was to move psilocybin out of the medical framework so we could provide access to anyone who might safely benefit,” meaning to allow its use by counseling therapists and not just by doctors in a hospital, says therapist Tom Eckert, co-author of the Oregon Psilocybin Therapy Ballot Measure, which passed with more than 1.2 million votes (55.7 percent). Although Oregon is not the first place in the U.S. to loosen restrictions on psilocybin—the cities of Oakland, Denver, Ann Arbor and Washington, D.C., voted in the past two years to effectively decriminalize the drug—it is the first to offer a framework for legal therapeutic use. “This is very different from decriminalization, which only seeks to lower the penalties for possession,” Eckert notes. “We want to bring this therapy out from the underground and into [safe therapeutic environments].”

Such use will be tightly regulated, however: only licensed therapists and manufacturers will be allowed to grow the mushrooms or extract psilocybin from them, or to synthetically produce the drug, set up a psilocybin therapy center or provide therapy. There will be no dispensaries selling mushrooms for recreational use, as exist for cannabis in California and 15 other states. People must be over 21 to receive the drug, and may only consume it at a licensed facility with a certified therapist present. And Oregon will not be opening any legal psilocybin therapy centers until 2023 at the earliest, as the measure requires a two-year consultation with lawmakers.

The Oregon vote is the latest step in what many see as magic mushrooms’ march to become “the next marijuana”: a natural therapeutic and mood-altering compound gaining mainstream acceptance in a regulated market. Since 2015 psilocybin retreats have been allowed to operate in the Netherlands, where dozens of them cater to affluent tourists. Even there the drug exists in a legal gray area, however: psilocybin mushrooms are illegal, but “truffles” (clumps of the fungus’s subterranean root-like filaments) are legal.

PSYCHEDELIC MEDICINE

The potential benefits of psilocybin, LSD and other psychedelics were widely explored by psychiatrists in the 1950 and 1960s, before such drugs leaked from the lab and were embraced by the counterculture. A subsequent backlash led to a strict prohibition of legitimate research for the next four decades. But in recent years, a handful of dogged psychiatrists have revived the field. A Johns Hopkins 2006 double-blind study (meaning neither trial participants nor researchers knew if a subject was receiving psilocybin or placebo), published in the journal Psychopharmacology, demonstrated that psilocybin could give healthy volunteers “experiences having substantial and sustained personal meaning.”

“What is different about psilocybin, compared to other mood-altering drugs or pharmaceuticals, is the enduring meaning and belief changes that can occur. People feel ‘reorganized’ in a way they don’t with other drugs,” says Johns Hopkins neuropharmacologist Roland Griffiths, lead author of the initial 2006 study as well as the latest one on depression. “It’s almost like reprogramming the operating system of a computer.” Griffiths now leads the new, $17 million-funded Center for Psychedelic and Consciousness Research at Johns Hopkins Medicine.

Dozens of other scientific reports in the past 15 years have built on the 2006 study, demonstrating psilocybin’s helpfulness for a variety of mental health conditions. In a 2016 paper in the Journal of Psychopharmacology, Griffiths and his team found that more than 80 percent of patients with a terminal cancer diagnosis experienced a “significant decrease in depressed mood and anxiety” after psilocybin combined with psychotherapy. In the same year, other researchers published the first study demonstrating psilocybin’s potential to alleviate “treatment-resistant depression” that was not relieved by mainstream antidepressants. British researchers at Imperial College London described in The Lancet Psychiatry the “marked and sustained improvements” in 12 patients suffering from this form of depression. This study, however, had no control (placebo) group. The latest randomized controlled trial from Johns Hopkins tested the drug in a double-blind study on 24 people suffering from major depressive disorder, which affects an estimated 300 million people worldwide. Roughly 20 percent of Americans will experience this form of depression at some point in their lives; by comparison, treatment-resistant depression is estimated to affect fewer than 5 percent.

In 2019 the U.S. Food and Drug Administration granted “breakthrough” status to a company called Compass Pathways to study the use of psilocybin—in conjunction with psychotherapy—for treatment-resistant depression. This means the FDA recognises that the research “demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy,” and that research and development will be “expedited.”

“I welcome the broadening of the indications, because I think psilocybin is likely to be effective in a range of disorders,” says David Nutt, author of the initial 2016 study on psilocybin and depression, and director of the neuropsychopharmacology unit in the division of brain sciences at Imperial College London. “However, it is critical that we have proper screening to protect people who might be vulnerable due to psychotic predispositions.”

Rachel Aidan, a professional therapist and CEO of Synthesis Group, a Netherlands psilocybin retreat center now looking to expand operations to Oregon, agrees. “As excited as we all are about the power of these compounds, the reality is that they are NOT for everyone,” she says. “Right now we just need to keep our heads down to learn from the situation in Oregon, and plan carefully for the future so we don’t rush into legalization. We don’t want to recreate the 1960s and the backlash that ensued.”

AN ANTIDEPRESSANT ALTERNATIVE

Because psilocybin is thought to be most effective when given in combination with psychotherapy, the cost (possibly involving a dozen or more hours of therapy sessions) could remain in the thousands of dollars for the near future—and even more if the treatment involves synthetic psilocybin. Nonetheless, many hope the latest study will lead to psilocybin treatment being viewed more as a first line of defense for depression, rather than a quirky option for people who are desperate after conventional treatments fail. Psilocybin appeals to many because of the treatment’s rapid and sustained effects, combined with the lack of unpleasant side effects such as weight gain and loss of libido, which are typically associated with widely prescribed SSRI antidepressants.

“This isn’t about selling people a box of pills. This is about exploring a new way to deal with depression by going into the underlying issues,” says Rosalind Watts, a psychologist who was formerly clinical lead on the psilocybin for depression study at Imperial College London. “It’s not that this is better than antidepressants—it’s just better for some people. Some people will still prefer antidepressants because they are simply more convenient. It just makes sense to have different options, and for us to understand that different things work for different people at different times.”

Watts has now left Imperial to operate as the clinical director at Synthesis, where she works to develop psilocybin therapies outside of medical academia. “Rather than conduct more small trials,” she says, “I wanted to help set up something for people to access psilocybin therapy now.”

Actions like this by clinicians around the world are nudging psilocybin from a fringe treatment toward mainstream medicine. As Rick Doblin, founder and executive director of the Santa Cruz, Calif.–based Multidisciplinary Association for Psychedelic Studies, puts it: “Our long term goal is mass mental health.”

Johns Hopkins and Imperial researchers have already planned more psilocybin studies for a range of difficult-to-treat conditions, hoping to harness the drug’s ability to “unblock” people by shifting perspectives, catalyzing insights and changing problematic and habitual mindsets and behaviors. Studies on anorexia, obsessive-compulsive disorder, smoking cessation, opiate addiction and post-traumatic stress disorder are all in the works.

Griffiths, however, is wary of efforts to rush the drug out from tightly regulated settings. “I’m sympathetic to people who are impatient, but we don’t want to end up in a situation where people underestimate the potential risks of using these compounds. They do have significant risks, such as panic, anxiety and dangerous behavior,” he says. “In Oregon, the devil is in the details in how things will unfold.”