By Adam Piore
For most of his adult life, Aaron Presley, age 34, felt like a husk of a person, a piece of "garbage." He was trapped in a reality that was so excruciatingly tedious that he had trouble getting out of bed in the morning. Then, all at once, the soul-crushing, depressive fog started to lift, and the most meaningful experience of his life began.
The turning point for Presley came as he lay on a psychiatrist's couch at Johns Hopkins University, wearing an eyeshade and listening through a pair of Bose headphones to a Russian choir singing hymns. He had consumed a large dose of psilocybin, the active ingredient in what's more commonly known as magic mushrooms, and entered a state that could best be described as lucid dreaming. Visions of family and childhood triggered overwhelming and long-lost feelings of love, he says, "like heaven on earth."
Presley was one of 24 volunteers taking part in a small study aimed at evaluating the effectiveness of a combination of psychotherapy and this powerful mind-altering drug to treat depression—an approach that, should it win approval, could be the biggest advance in mental health since Prozac in the 1990s.
Depression, often characterized by feelings of worthlessness, profound apathy, exhaustion and persistent sadness, affects 320 million people around the world. In a typical year in the U.S., roughly 16 million adults, or 7 percent, suffer from a depression-related illness such as major depression, bipolar disorder or dysthymia. Roughly one-third of those who seek treatment won't respond to verbal or conventional drug therapies.
Magic-mushroom therapy is offering some hope for these hopeless cases. In the Hopkins study, published last year in JAMA Psychiatry, the therapy was four times more effective than traditional antidepressants. Two-thirds of participants showed a more-than 50-percent reduction in depression symptoms after one week; a month later, more than half were considered in remission, meaning they no longer qualified as being depressed.
Larger clinical trials underway in the United States and Europe are aimed at winning regulatory approval. Two studies that have enrolled more than 300 patients in 10 countries were given "breakthrough therapy" status in 2018 and 2019 by the U.S. Food and Drug Administration (FDA), which will now expedite its review of the results. If the trials succeed, new protocols that combine psilocybin with psychotherapy in a clinical setting for the treatment of depression could be established quickly. Treatments could appear in clinics as early as 2024.
The rehabilitation of psilocybin as a medical treatment raises some concerns. Some scientists worry about the drug, which can induce psychosis in some people, becoming widely available outside of clinical settings. And they are loath to see a repeat of the 1960s embrace of recreational LSD, which caused much harm and set research into psychedelics back decades.
But many scientists in the mental health profession believe that the risks pale against the potential benefits, which include not only effective treatments for depression but also a new understanding of the neural basis of many mental health disorders. "We're convinced that the effects of these drugs are pretty profound and that there is a story that will be relevant to understanding new approaches to brain disease," says Jerrold Rosenbaum, a Harvard Medical School professor, former psychiatrist-in-chief at Massachusetts General hospital and leader of its new Center for the Neuroscience of Psychedelics.
Although psychedelic drugs have been used by indigenous populations for millennia, they only entered the western medical mindset in 1943, when Albert Hoffman, a chemist at the Swiss pharmaceutical giant Sandoz, accidentally ingested a compound called lysergic acid diethylamide, or LSD. He promptly entered "a dreamlike state" and hallucinated "an uninterrupted stream of fantastic pictures, extraordinary shapes with intense kaleidoscopic play of colors." Hoffman became convinced LSD might have some use in medicine and psychiatry.
Not long after, a Manhattan banker named R. Gordon Wasson took a trip to Oaxaca, Mexico, sampled psilocybin mushrooms, and published a 15-page account of his psychedelic experience in Life magazine, introducing the American public to the power of the plants.
Psychiatrists were soon reporting therapeutic benefits. By the 1960s they had dosed more than 700 alcoholics, half of whom subsequently stayed sober for at least a couple months. Other researchers discovered that the drugs were helpful for anxiety, depression, the existential angst of terminal cancer patients, and other mental health disorders—provided they were administered under supervision.
Psychedelic drugs lost their legitimacy soon after the counter-culture embraced them for recreation, triggering a spate of suicides, mental breakdowns and bad trips. Federal research funding dried up. Over the years, however, a few groups in the U.S. and abroad continued to conduct experiments on mice and map out the strange molecular-level gymnastics that give psilocybin its ability to so profoundly alter human perception.
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Key to the action of the drug is its ability to bind to a special class of tiny proteins that protrude from the surface of many brain cells and detect passing chemical signals—in this case the neurotransmitter serotonin. What made the active molecules in LSD and psilocybin so powerful was a quirk in their geometry that caused the chemicals to get stuck in these proteins—known as serotonin 5H 2A receptors—and linger for hours, rather than quickly washing out as normal neurotransmitters would. Once the chemical was wedged inside a the receptors, it began to wreak havoc on the cell's internal signaling, causing some neurons that normally wouldn't fire to pop off like firecrackers, and prompting others to go dark.
These insights didn't come close to explaining the deep questions scientists had about the drugs—why, for instance, they elicit deep spiritual experiences?—which could only come with human trials. In the early 1990s, after a campaign of lawsuits and lobbying by psychedelic advocates, the FDA re-evaluated psychedelic drugs and other "drugs of abuse" and indicated it would be open to applications to study them.
Clinical trials on mystical experiences, terminally ill cancer patients and addiction came in the mid-2000s from such prestigious institutions as New York University, UCLA and Johns Hopkins. Meanwhile, brain-scanning tools helped document the remarkable effects of the drugs on the brain. In recent years, a clearer picture of how these drugs work their magic—and why they might work as a therapy for mental disorders—has begun to emerge.
The Mystical Brain
Both LSD and psilocybin profoundly disrupt the normal communication patterns in the brain—researchers can detect these changes using brain scanners that show which areas of the brain appear to be active simultaneously or in quick succession (suggesting which ones are communicating). In particular, they seem to interfere with the connectivity and functioning of networks of brain structures involved in planning, decision making and associative thinking—many of the high-level circuits we rely upon to interpret and make sense of the world. The drugs also seem to interfere with the functioning of the thalamic reticular nucleus, a structure close to the center of the brain that regulates the volume of sensory signals, allowing us to focus our attention on some inputs and block out others.
Robin Carhart-Harris, a neuroscientist who recently moved from Imperial College London to U.C. San Francisco, has articulated one of the most widely cited theories on how the drugs induce transformative experiences. He believes it stems from their ability to somehow shut down a specific constellation of brain structures known as the "default mode network." This network is most active when our mind wanders—when we are daydreaming. It gives us that voice we hear in our heads, which is often hyperactive in depressed and anxious patients who are tormented by negative thought loops.
Some scientists think of the default mode network as the neural correlate of Freud's "ego," that portion of human personality we experience as the "I" that remembers, evaluates, plans, helps integrate our outer and inner worlds and provides the mental filter through which we experience and interpret our moment to moment experience. Aaron Presley's experience shows how this network can go awry. Prior to his treatment, Presley recalls, he routinely told himself he was a waste of space and there was no hope of getting better. This repetitive, unproductive thinking, or "faux problem solving," is known in the field of psychiatry as "rumination." According to Harvard's Rosenbaum, rumination plays a key role in mental health conditions like depression, addiction and obsessive-compulsive disorder, or OCD.
For Presley, the psilocybin experience caused his unhelpful rumination to cease. It knocked the critical, domineering voice in his head off-line. He glimpsed a level of self-acceptance and a sense of agency in his own life that he did not know was possible.
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Charles Raison, a psychiatrist from the University of Wisconsin-Madison who specializes in depression, explains such experiences in Freudian terms. With the ego knocked offline, Freud's unconscious is given free rein to express itself, often revealing inner truths and deep insights that those taking the drugs might normally be blind to.
"The idea psychedelics liberate some of these powerfully valent, deeper emotional areas of the brain—the limbic areas involved in memory and emotion—to have their say is consistent with what people are reporting," says Raison, who also serves as director of clinical and translational research for Usona Institute, a nonprofit that is leading a clinical trial of psilocybin. "They are often overcome by these really, really powerful emotions that are surprising, as if they're coming from the outside but yet seem completely credible and utterly believable. These areas are liberated and get their day in court."
None of this, however, explains perhaps the most enduring mystery of these drugs—what Raison calls "the holy grail," and others have referred to as the "black box" or the "hand wave" in our current scientific understanding.
Many brain disorders are defined by a "narrowed mental and behavioral repertoire" that confines those who suffer from them to "suboptimal patterns" they cannot break out of," says Matthew Johnson, a professor of psychiatry and behavioral sciences at Johns Hopkins and one of the coauthors of the depression study Aaron Presley participated in. These "suboptimal patterns" manifest as behaviors, such as ruminative thinking and a reflexive expectation that things will go badly, and they also manifest physically in abnormal brain activity. Many mental health disorders are characterized by aberrant brain activity, in which populations of specialized neurons, known as circuits, get stuck in rigid communication patterns and lose the ability to communicate effectively with other brain circuits. The brain loses the flexibility and the nimbleness that would allow it to respond to and interpret new situations and react accordingly. We become sick.
"When the drug wears off and it's all gone, somehow that leads to re-set and these brain networks go back to a healthier pattern," says David Nichols, a retired Purdue University chemist, who has been studying the molecular biology of psychoactive drugs for more than 50 years. "And that's the big question I think psychiatrists are going to be looking at for a long time. What's that re-set mechanism?"
In recent years some scientists have begun to uncover evidence that suggests one tantalizing possibility—that the drugs might somehow prompt the brain to release growth agents that not only send a global signal that allows the cells of the brain to rewire themselves and forge new connections. That the drugs may even catalyze the brain to begin regenerating itself.
In one study, researchers at the Yale School of Medicine used a laser-scanning microscope to peer into the brains of mice. In particular, they observed "dendritic spines," the branch-like projections on the end of neurons that allow them to communicate with neighboring brain cells. Chronic stress and depression are known to reduce the number of these neuronal connectors and cause existing ones to shrivel. When Yale researchers took a bunch of stressed-out, depressed mice with shriveled dendrites and fed them psilocybin, their dendrites bloomed.
Remarkably, this rewiring of the brain after a single dose appears to be long lasting: a month afterwards, the psilocybin-fed mice had 10 percent more neuronal connections than before they had taken the drug. The increased density of these crucial neuronal connectors had observable benefits: mice showed behavioral improvements and increased neurotransmitter activity.
"These new connections may be the structural changes the brain uses to store new experiences," says Yale's Alex Kwon, associate professor of psychiatry and neuroscience and an author of the paper.
Other groups who have exposed human brain cells to the drug in petri dishes report a growth of new brain cells—a process called "neurogenesis." One theory is that the drugs ability to wedge serotonin receptors in the "on" position for an extended period of time somehow kick off a series of chemical reactions that prompts neurons to release hormone-like signals that stimulate neurogenesis
If scientists can reverse engineer and map out these chemical reactions, says Harvard's Rosenbaum, they could shed new light not just on what goes wrong in various brain disorders but also develop new treatments for many intractable brain disorders that have been difficult to treat.
A Night and Day Difference
As Presley lay on his psychiatrist's couch, he wasn't thinking about his blooming dendrites or his Freudian id. He was a seven-year-old kid again, sitting in a church pew with his family during a Sunday sermon. He and his two brothers were trying to make one another laugh.
"I could actually feel my brothers on either side of me—and just how fun it was," he recalls. "And I just felt how much love I have for my brothers and my parents. It's one of those moments where you make each other laugh until you cry."
The church scene morphed into other visions. Presley saw his own funeral, that of his parents, and those of others he loved (all of whom were still alive). He traced a possible future with his girlfriend. He sobbed so hard it felt as if he'd been kicked in the stomach, and conversely felt his body flood with pure joy and gratitude. Presley knew what he was experiencing wasn't technically real. But the scenes were so detailed, so infused with passion and meaning, they felt real.
When it was all over, after he'd processed it with his Hopkins facilitators, something had shifted. In the weeks and months that followed, the visions of joy and meaning he'd glimpsed became his guide stones. He joined a musical choir, because singing gave him joy. He shaved his beard and his head and once again began attending social events. He made an effort to reconnect with old friends and family members. With the aid of Hopkins therapists who were on hand to help "integrate" his experience, he made to-do lists of actions he could take if—or when—the darkness returned: Call a friend or loved one, go to a climbing gym, lift weights, sing, play the piano, reach out to experts in academia and initiate conversations about their work.
"I was so tired, so drained," he recalls of his time before the treatment. "It felt like I was underneath a huge weight. And all of a sudden, that's lifted. It's, like, night and day difference."
Such transformative experiences are common in the cozy, dimly lit offices of mental-health professionals, with their soft couches, Buddha statues and landscape paintings. Mary Cosimano, director of facilitator services at the Johns Hopkins Center for Psychedelic and Consciousness Research, has taken part in more than 475 sessions with volunteers in clinical trials. The individual experiences vary widely but share some common themes.
One volunteer taking part in a study of psilocybin to treat anorexia experienced a feeling of being held and accepted by a higher being—"resting in the arms of God"—which gave her a sense of peace and may have helped her to let go of her need to control so many aspects of her life. Another volunteer described feelings of worthlessness that made her afraid to speak with anyone at her job. In one session, she had a vision of herself at work. She watched her coworkers become "really, really little," and then ate them. The experience left her with the sense that "we are all connected, all one." When she returned to work she felt like an equal with her co-workers and was able to treat them as peers.
Dr. Charles Grob, a professor of psychiatry and biobehavioral sciences at UCLA, who worked with terminal cancer patients in the early 2000s, says many of the patients he worked with emerged from the experience with a newfound ability to focus on the present moment.
Most of his patients came in experiencing high levels of existential distress, demoralization, depression and anxiety. After the psilocybin treatments, they often left with a newfound sense of peace and a determination to spend the rest of their days connecting with loved ones and making the most of the time they had left.
Often when we become seriously ill, he explains, "we lose that part of the identity, which is so vital for our function, and this kind of treatment process seems to re-establish that sense of meaning and identity anchored in who one has been in the past," he says. "You no longer feel cut off and kind of marooned from your old sense of self. We found that this in many respects was existential medicine."
Cosimano emphasizes that the trip itself is just part of the clinical protocol. At Johns Hopkins, and in most of the trials currently underway, what happens afterwards is just as important. After their sessions are over, volunteers are asked to write "session reports," sometimes simply bullet-pointing their experiences. They then read the reports to their facilitators, who help the volunteers explore what the experience meant to them and how they might integrate the insights into their daily lives.
"If you don't do something with what you experience, it's just going to go back to the way you were before," says Cosimano. "It is a discipline. It's something that you have to make a commitment to."
A Heavy Mandate
If the drugs are ever to make it into the clinic and help actual patients, advocates will have to avoid the mistakes of the past. Many of those pushing the therapies believe it is important to distinguish between abuse of the drugs outside the clinic and the experiences of those who use the drugs in a tightly-controlled, supervised, safe therapeutic setting.
This mandate weighs heavily on George Goldsmith, one of the founders of Compass Pathways, the publicly-traded London-based biotechnology company conducting a 22-site, 10-country study with 233 patients who meet the diagnostic criteria for "treatment resistant" depression. Goldsmith has a personal connection to the issue: He and his wife Ekaterina Malievskaia discovered psychedelic therapy while searching for a cure for her mentally ill son and committed themselves to taking it out of the shadows.
In designing the trial, he and Malievskaia conferred closely with regulators—indeed, a British regulator first suggested they design their first trial to treat drug-resistant depression. They have also recruited a board of well-respected advisors that includes Tom Insel, former director of the U.S. National Institute of Mental Health, Paul Summergrad, former head of the American Psychiatric Institute, and Sir Alasdair Breckenridge, the former Chair of the UK's Medicines and Healthcare Products Regulatory Agency.
"I'm of the opinion we need innovation in this space," Insel says.
Insel worries about these efforts being overtaken by other events. In the U.S., an active movement to decriminalize psilocybin has picked up momentum in recent years, with voters in Denver, Oakland, Santa Cruz, Washington, D.C., and Somerville and Cambridge in Massachusetts voting in favor. Although the drugs remain illegal under federal law, he worries what might happen if they become widespread outside the clinic. Without supervision, psychedelics can accelerate the onset of psychosis in those who are vulnerable to it. That could lead to the kind of tragedies and bad publicity that derailed the drug in the past.
The gold rush for treatments, however, has already begun. Hundreds of new biotechnology companies are raising money for therapeutics and research groups studying the compounds for clinical use have exploded to well over 100.
The therapy Compass is proposing includes a protocol designed to ensure the drugs can be taken safely and experts are on-hand to help should a patient begin to feel overwhelmed. Patients are screened, required to attend preparatory meetings with a therapist, supervised and monitored during their dosing sessions and attend follow-up sessions aimed at integrating their experiences.
If the FDA approves the therapy, it is likely to do so with special provisions stipulating that the drugs cannot be taken outside the clinical setting, are carefully controlled and can only be administered by a trained healthcare professional.
"Quite often, you can have a very challenging experience and still have a lot of benefit," Goldsmith says. "I don't think that a bad trip is necessarily a bad experience. It's a challenging experience. It's content you may not want to look at, but it actually could be quite therapeutic to do so. And that's why it's important to have the therapist present. In the wild, God knows what happens."
In the proper clinical settings, however, the therapy may be able to help many people who have resisted other therapies. Three years after his Hopkins experience, Aaron Presley's depression still comes back sometimes. But when it does, it no longer overwhelms him, and he knows what to do to climb out of it. The experience inspired him to reach out to his parents and brothers to connect more deeply. He is more open about personal stuff he previously would have avoided discussing, he says.
"I realized it's possible to have a set of actions and activities, just the right combination and sequence, that produces ideal features for myself. And I have the agency to be able to make it happen. I found my passions again, what really motivates me deep down inside."