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Falling for Psychedelics

People are trying them. The media is touting them. But scientists say we need to know more about how they work and when they can help.

March 2023

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Falling cards

Trisha Suppes kneels to open an 1,800-pound safe. The door swings open, revealing nothing more than a handful of mostly empty prescription bottles, with just one little white pill remaining.

“I never thought I’d be doing this,” says the physician-scientist, who has more than 20 years of experience studying mood disorders. 

Across the hall is the pill’s destination: the university’s “dosing room,” which sits near Page Mill Road on the edge of campus. It’s legal despite the illegal drugs taken there—so far, psilocybin, the active ingredient in magic mushrooms, though that could soon expand to include MDMA, aka Ecstasy or Molly. There are soft lights, a white noise machine, and a bed with poofy pillows. All in all, it looks very calm. And Suppes? Well, she looks a bit harried. The stress of managing more than three years of regulatory paperwork necessary to run this trial—a joint effort of the VA Palo Alto Health Care System and Stanford—may have added a few gray hairs. Getting volunteers for the study, on the other hand, was easy. Veterans, many “at the end of their rope” after decades of depression, lined up for the 15 available slots.

“So, I’m here, pacing,” Suppes, ’73, says. “No, really, I find I walk about a mile and a half during the dosing. I wasn’t aware I was doing it, but then my Apple Watch started telling me: Oh my gosh, I really am pacing. It was like, ‘Oh my God, we are giving psychedelics to veterans. What could possibly go wrong?’”

Indeed, there are risks to psychedelic medicine. But of the veterans who participated—taking a single dose of psilocybin with two therapists at their side—40 percent reported a significant positive impact from the drug. Only one reported that his depression worsened, temporarily. A few described their “trip” as life-changing. 

Trisha SuppesTrisha Suppes

“What the drug does is take you right to the most dark place and the most light place,” says Paul G., a study participant and retired Marine who has lived for years with treatment-resistant depression, severe PTSD, and anxiety. “It was a blessing. I felt enormous relief. It gave me hope back.”

Curiouser and Curiouser

After years of stigmatization and criminalization, a new era in psychedelics research has arrived, but whether the use of these mind-altering drugs moves forward on a wave of hype or of evidence-based science remains to be answered. Classic psychedelic drugs, such as psilocybin and LSD, along with drugs with similar hallucinogenic properties—including MDMA and ketamine—make frequent headlines as therapeutic cure-alls for everything from PTSD to treatment-resistant depression to addiction, along with obsessive-compulsive disorder and anxiety associated with terminal illness. 

“Unless you live under a rock, you’ve probably heard about the class of therapeutics broadly known as psychedelics,” said Boris Heifets, an assistant professor of anesthesiology and a psychedelics researcher, at the Stanford Center for Precision Mental Health and Wellness symposium on campus in September. (Although not all drugs under study are psychedelics, the terms psychedelics and psychedelic medicine are commonly used to describe the field.) “There’s been a groundswell of interest, along with decriminalization efforts, but very little is known about how they work or even, I would say, whether they work. The studies are hopeful but very small.”

The promise of these fast-acting drugs—that they can save lives, sometimes with a single dose—comes at a time when the United States faces increasing rates of depression and anxiety, not to mention a public that loves fast solutions. Nearly 1 in 10 American adults had at least one depressive episode in the past year. Suicide is a leading cause of death in the United States. At the same time, there aren’t enough mental health professionals and we aren’t developing many new medications. The few groups of psychiatric drugs we do have for depression and anxiety can take weeks or months to work—and the first-line drugs improve symptoms for only 40 to 60 percent of patients.

“I do think the field of psychiatric drug development is stalled,” says Suppes. “Hope matters, and that’s part of why the media is going so crazy.” It’s no wonder that people are craving quicker, more effective treatments. Some are microdosing—using a less-than-therapeutic dose to treat a mental health condition, without evidence of its efficacy—or even taking full doses of psychedelics without medical supervision. For their part, governments are starting to inch ahead of research. Australia will begin allowing limited psychiatric use of MDMA and psilocybin this summer. Oregon and Colorado have removed state controls on the medicinal use of psilocybin. But if these drugs are to become standard U.S. medical treatment, researchers will need to show the federal government that they are safe and effective.

At Stanford, a dozen or so psychedelic researchers see the promise of these drugs, but also potential peril. MDMA and ketamine both have addictive properties. The hallucinogenic effects of LSD and psilocybin can cause “bad trips” that lead to psychotic states or—if used without supervision—dangerous actions. Researchers are collaborating across disciplines and departments, including through the Wu Tsai Neurosciences Institute and the Stanford Psychedelic Science Group, to understand the mechanisms at work in these drugs and to guide the future use of therapeutic psychedelics based on solid science. This means finding evidence-based answers to such questions as: Which drugs should be used for which patients? How important is the setting, and the use of therapists, to achieve results? Can safer, better versions of these drugs be developed? There is much to be determined about how to responsibly deliver these drugs outside of labs, according to the researchers. “We need to understand how these therapies work,” Heifets says. “They are racing through the regulatory approval pipeline.”

Boris HeifetsBoris Heifets

There is a fear that individuals and state and local governments will get ahead of scientists and federal regulators, bringing to a halt the current explosion in psychedelic research at universities and in scientific labs around the world. Which is part of what happened the first time around. In the mid-20th century, psychedelics were the subject of serious scientific study. But in the 1960s, regulatory changes and a backlash against counterculture recreational use of psychedelics paved the way for new antidrug laws. At present, LSD, psilocybin, and MDMA are all classified as Schedule I drugs by the federal government, meaning they have no currently accepted medical use, a lack of accepted safety for use under medical supervision, and a high potential for abuse. They can, however, be used in federally approved research studies. Seeing positive results from early trials, the FDA has designated MDMA and psilocybin as “breakthrough therapies” to expedite their development as treatment, and MDMA could earn the agency’s approval for therapeutic use within a year or two. A version of ketamine, a Schedule III drug due to its lower potential for abuse and its routine medical use (as an anesthetic during surgery), is already approved for medical use outside of clinical trials. 

Today’s psychedelic researchers hope the public will wait a little longer for science to provide answers, before something bad happens and the promise of psychedelic therapy slips, once again, back underground.

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Psilocybin chart

Psilocybin

Other name: Magic mushrooms

History: A chemical found in more than 100 mushroom species and used for millennia in Indigenous communities in Mexico and Central America as part of celebrations, healing rituals, and religious ceremonies. Investigated by psychiatrists in the 1950s and 1960s before the 1971 Controlled Substances Act designated it a Schedule I drug. 

Effects: Increased positive mood, hallucinations, and an inability to discern fantasy from reality. Causes alterations of thought and of the perception 
of time. Panic reactions and a psychotic-like episode can occur, particularly at a high dose. 

How scientists think it works: Classic psychedelic compound that, like LSD, activates serotonin receptors in the brain. Unclear how the neuronal mechanisms cause hallucinogenic or antidepressant effects, as well as how those effects are related to each other. 

Studied at Stanford for: PTSD, depression

Down the Rabbit Hole

On a Sunday in mid-July, Paul G. flew from northern Virginia to Palo Alto for five days to participate in Suppes’s psilocybin trial of veterans with treatment-resistant depression. He traveled with his girlfriend and brought along his service dog, Ellie Jo. He’d hit another low point in his long mental health struggle when a news article caught his interest: Psilocybin in a different clinical trial had helped a veteran like him. Paul considers himself a rule follower. Other than smoking a little pot in high school, he had never used illegal drugs. But he had gotten to the point, he says, where he was ready to try something as “radical” as magic mushrooms. “I come from a law enforcement background,” explains the former Marine infantryman and FBI agent. “I’d never done anything like this before.”

A 51-year-old divorced father of three, Paul is 6 feet, 5 inches tall, fit, and imposing. His go-to workout is pumping iron—his kids jokingly refer to him as “the K-Mart version of the Rock.” During tours in Iraq and Afghanistan, he saw his share of combat. But he was a tough guy, and tough guys just tough things out.

So when Paul started having nightmares and uncontrollable bouts of crying four years after he left the Marine Corps, he didn’t know what was going on. “It had never happened before and it was terrifying,” he says. Thus began years of misery: cycles of nightmares and insomnia, heart-pounding anxiety, and depression. On two occasions, he was unable to get out of bed for days at a time. “At one point I was taking the antidepressant Zoloft, Wellbutrin, Adderall, and they had me on benzodiazepines for sleep,” he says. The antidepressants helped but only for a while. The other medications created a seesaw dynamic—one pill to fall asleep, another to wake up. Nothing was solving the problem. “I was desperate for some daylight,” he says.

Photo of Leanne WilliamsLeanne Williams

On that Monday, Paul was sent to the Stanford Center for Cognitive and Neurobiological Imaging in the psychology building on the Quad. In addition to the psilocybin trial, he’d agreed to be part of a tandem study led by clinical neuroscientist Leanne Williams, a professor of psychiatry and behavioral sciences whose lab is running brain imaging studies on participants dosed with psilocybin, MDMA, or ketamine. The plan was to scan Paul’s brain function in an fMRI machine twice—the day before his dosing and the day after—to measure any changes in his brain circuitry. “The challenge of the explosion of interest for therapeutic psychedelics,” Williams says, is “how do we identify who is going to benefit?” A psychiatrist doesn’t want to give mind-altering drugs to a patient if they won’t work or might cause harm. Williams’s goal is to use brain scans in advance of treatment to diagnose the problem and help determine the best path forward.

Illustrations of spilled tea and flying cards

‘I could see the beauty inside of me. I think that is something I have denied my whole life.’

On Tuesday, Paul arrived at the dosing lab. He took a sip of water from a cup, downed the white pill, pulled on black eyeshades, and with music playing in the background, lay back and waited for something to happen. For the first 30 minutes, nothing. And then, well, something did. 

“I started seeing everything really vivid and intense, brights and darks,” he says. These visual changes were accompanied by a feeling of anguish. “Here’s the thing that totally blew my mind. Almost simultaneously, one part of me sees this desperate bleak blackness, the other part of me sees what I can only describe as a beautiful dazzling light.” So beautiful, he says, that he couldn’t look at it. “I could see the beauty inside of me. I think that is something I have denied my whole life, the internal awesomeness of life.” Throughout the experience, he talked to the therapists by his side, sharing the visions in his mind. They comforted him and put a hand on his arm when he asked. He told them about the bodies of the dead Marines that appeared to him. Those images helped him create new ways of thinking about his past and present, new stories that have helped him change his many negative patterns of thought, he says. 

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3,4-Methylenedioxymethamphetamine (MDMA) chart

3,4-Methylenedioxymethamphetamine (MDMA)

Other names: Ecstasy, XTC, Molly

History: Synthetic drug made in 1912 as an intermediate chemical in the production of a medication to stop blood loss. Became a popular recreational drug before it was placed on the list of Schedule I drugs in 1985.

Effects: Produces both amphetamine-like stimulation and mild hallucinations. Provides an experience that is mellower than with other hallucinogenic drugs, creating feelings of empathy. May enhance fear extinction, resulting in a shift in perspective and improved ability to process traumatic memories. May provide insight into cognition, emotional regulation, and coping strategies. Causes dopamine release that is linked to addictive behaviors. 

How scientists think it works: Technically not a psychedelic but an entactogen; triggers the release of an array of neurotransmitters, such as serotonin, oxytocin, and dopamine, that might alter social perception. 

Studied at Stanford for: PTSD and OCD, focusing on MDMA-induced serotonin release for its prosocial effect.

We’re All Mad Here

Plant-based hallucinogens have been integral to the spiritual practices of Indigenous communities around the world for more than 5,000 years. The story of their beginnings in Western medicine starts in 1938, when Swiss chemist Albert Hofmann, working for a pharmaceutical company, synthesized a new substance called lysergic acid diethylamide (LSD). It didn’t interest him much until five years later when, while resynthesizing it, he accidentally absorbed some through his skin. 

Thus began the world’s first acid trip, said Giancarlo Glick, a resident in psychiatry and behavioral sciences, in a lecture to about 200 students in the winter 2022 course Introduction to Psychedelic Medicine. So, Glick continued, Hofmann started to feel weird, a little bizarre. “He decides to self-experiment and a few days later, intentionally takes a dose of the drug. He starts to feel woozy and uneasy. He perceives a stream of fantastic pictures, a kaleidoscopic play of colors. He thinks he’s dying. But when the trip ends, he’s left with a sense of well-being that lasts for several days.” 

Photo of Giancarlo GlickGiancarlo Glick

Hofmann “feels vibrant, positive, present, and finds this notable, so he told his pharmaceutical company, and the company does what pharmaceutical companies do: patents and packages it,” Glick said. Samples were sent to medical centers and universities worldwide to promote research into the drug’s possible benefits. The prospect launched more than two decades of research and exploration of psychedelics in hundreds of studies.

In the 1950s, research showed promising results using LSD to treat alcohol dependence. High doses of LSD produced “mystical” experiences that scientists believed were necessary for successful treatment. Other researchers treated anxiety and depression using LSD as part of psychotherapy. Still other studies showed that psychedelics reduced anxiety and distress associated with terminal illness.

But beginning in the mid-1960s, increased federal oversight of drug trials and prohibitive legislation at state and federal levels effectively ended all major psychedelic research programs. California and Nevada were the first states to outlaw LSD in response to media reports of bad trips, psychoses, accidental deaths, and suicides. As other jurisdictions followed, public opinion of psychedelics changed as well. Most scientific labs stopped researching them. The few who continued the work did so in “the psychedelic underground,” as Michael Pollan calls it in his 2018 bestseller, How to Change Your Mind: What the New Science of Psychedelics Teaches Us About Consciousness, Dying, Addiction, Depression, and Transcendence

Illustration of a falling teapot, tea cup and the white rabbit.

‘The idea is that people are in this altered state and may be more able to confront difficult topics.’

The renaissance in research began in the 1990s, slowly at first, then gaining speed in 2006, after Johns Hopkins scientists published a study noting the safety and positive effects of a single dose of psilocybin. That and subsequent Johns Hopkins guidelines for safe hallucinogen research helped to revive studies worldwide. Some of today’s research builds upon those midcentury theories that hallucinogenic experiences aid in healing. A trip might help the brain reorganize thought patterns to find new ways of processing anxiety, depression, or trauma, says Laura Hack, an assistant professor of psychiatry and behavioral sciences who treats veterans with PTSD and depression.

Photo of Laura HackLaura Hack

“During psychedelic therapy, the idea is that people are in this altered state and may be more able to confront difficult topics,” Hack says. The ideal outcomes of talk therapy are similar. But therapy alone can’t always do the job. “It can be very difficult to think about traumatic memories during therapy,” Hack says. “You relive the trauma. Dropout rates for trauma-focused therapies can be as high as 50 percent because it’s so hard.” With the addition of psychedelic treatment, the patient still remembers the trauma but it no longer induces the same symptoms. “Because of the effect of the drug, combined with therapy, the patient feels safer, the pain gets softened, you are able to create new memories,” Hack says. Sometimes, she adds, the results are nearly instant.

Through the Looking Glass

The day after his psilocybin dosing, Paul G. returned to the imaging lab and climbed back into the white fMRI machine for his post-dosing brain scans. He flew home the next day, hoping the before-and-after images of his brain he’d left behind might expand scientists’ minds.

Williams got to analyzing. “What we observed with Paul’s scans were too many connections in an area of the brain called the default mode network,” she says, referring to a part of the brain in which increased connectivity can result in brooding and in negative self-thoughts. “I think of the analogy of when you are in your car, in neutral and just idling,” Williams says. “You are trying to go somewhere, but the car is just stuck.” In Paul’s post-dosing scans, the default mode network is less connected—in other words, unstuck. “It’s visible, the change.” 

There are other ways of reducing that hyperconnectivity of brain regions over time, including mindfulness meditation, exercise, and antidepressants. But what’s unique to psychedelics is how rapidly such a dramatic change can happen.

While psilocybin can affect the default mode network, MDMA (the drug associated with prosocial feelings of friendliness and empathy) appears to work in multiple areas of the brain, including the amygdala, part of the limbic system that encompasses some of the oldest regions of the brain, Williams says. The amygdala is known to elicit fear in the face of potential threats, activating the fight-or-flight reaction. If it stays switched on, it can result in some forms of persistent depression or PTSD. “With MDMA we see a striking reduction in that region,” Williams says. “People say they feel a deeper understanding, gratitude, a connecting with the planet. I think of psilocybin as dissolving that hyperfocus on internal thoughts and MDMA as dissolving these defenses.”

Early results of these studies demonstrate positive correlations between the drugs and changes in the brain, but they’re not enough to show causation, she says. More evidence is needed at a molecular and cellular level to prove that the drugs are responsible for these changes—and not, for example, a comfy couch, the therapist in the dosing room, or the good old placebo effect. 

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Ketamine chart

Ketamine

Other names: K, Special K

History: First synthesized in 1962 and used as anesthesia. Gained popularity as a club drug and in 1999 was designated a Schedule III drug. A version of the medication is sometimes used to treat chronic pain and depression.

Effects: At lower doses, can alter one’s sense of time and space, induce a feeling of calm or relaxation, and relieve pain. At higher doses, can induce a dissociative state, rendering some people unable to interact with the outside world. 

How scientists think it works: Technically not a psychedelic but a dissociative anesthetic; acts on receptors for the neurotransmitter glutamate, among other targets, which may play a role in regulating mood. 

Studied at Stanford for: Suicidal ideation, depression, OCD

Off with their Heads

Heifets, the anesthesiologist, grew up hearing frightening things about psychedelics—that LSD made you go crazy and that users thought they could fly, sometimes jumping to their deaths. As for MDMA? He was told it would put holes in your brain and drain your spinal fluid.

“It was totally misrepresented,” Heifets says. Despite these dire predictions, he experimented with both LSD and MDMA as an undergraduate at Yale. “I had life-changing experiences with MDMA, being able to connect with people in a way I had never been able to connect before,” he says. “I felt like I was truly myself. It was powerful.” The experiences so moved him that he went on to study anesthesiology and neuroscience, fields that have provided him a particular expertise for understanding altered brain states. In 2013, while finishing his anesthesia residency at Stanford, he began studying MDMA in the lab of Robert Malenka, a professor of psychiatry and behavioral sciences who had been studying related topics since 2008. Heifets opened his own lab in 2020. The two have published several studies on topics such as MDMA’s mechanisms within the brain and separating out its therapeutic properties from its addictive ones. Another study shows how the environment for administration of psychedelics, including the setting and the use of a therapist, is important for their therapeutic success.

Photo of Robert MalenkaRobert Malenka

“This is how modern psychedelic neuroscience works,” says Malenka, PhD ’82, MD ’83. Animal, human, and cellular studies come together with advanced technology, such as genetic engineering and tools to manipulate brain circuits, to help scientists home in on “which synapses and brain pathways these drugs are modifying, to mediate their powerful behavioral effects,” he says. 

Heifets is focused on connecting clinical trials (which determine safety and efficacy of a drug) with cellular and molecular studies of neural circuitry (which aim to reveal how that drug works). From there, he wants to discover how to create better, safer medicines based on ketamine, MDMA, and psilocybin by separating the molecular upsides from the downsides, assuming they can be disentangled.

Heifets sees “a lot of opportunity for real good from these compounds, but there’s also a whole lot of collateral to avoid,” he says. In trials, participants are screened for a personal or family history of psychotic disorders, and a therapist or other support person establishes a rapport with them. “Rushing the drugs to market before safety guidelines are in place opens up the possibility of risks that currently are controlled under scientific settings.”  

Every Adventure Requires a First Step

When Williams called Paul G. with the results of his brain scans, they made perfect sense to him. His psychedelic trip, he believes, altered his brain. “My thinking about life in general has changed quite a bit,” he says, as has his approach to mental health. He no longer takes any psychiatric medications, and he meditates more. “I am kinder to myself for sure. I understand that my decisions in the past don’t define me or my life.”

Certainly, the visions he experienced during his psilocybin dosing made a difference: While he relived gruesome combat experiences, Paul says he left with a new perspective. One Marine’s death had haunted him for decades. “I loved him like a brother,” Paul says. “I saw him [in the vision], and he did speak 
to me: ‘Hey, you know, I’m dead. You’re not helping me. You’ve gotta let me go.’ And then I could let go of him.”

The experience was exhausting, with his body clenching and sweating, he says. He cried. It was like he’d been wrestling with himself for six hours straight. But afterward, there was a load off his back, he says—of punishment, guilt, and self-hatred. 

He’s used the time since to reevaluate those experiences, to refashion his life. “I take a bit more time to appreciate things around me and the people in my life. I’m not in the same rush I used to be, if that makes sense.” As for volunteering in the trial, he would most definitely choose to do it again. “It was not a fun experience,” he says. “But after, I felt so good. I felt free, unencumbered, hopeful, happy. It had been years living in a personally imposed hell. There is still a fear, like ‘When is the other shoe going to drop?’ But it’s been months now, and I feel good. I feel strong. I’m much better.” 


Tracie White is a senior writer at Stanford. Email her at traciew@stanford.edu.


Photo credits, from top: Courtesy Trisha Suppes; Steve Fisch/Stanford Medicine; Christophe Test/Stanford University; Jordan Emont/Courtesy Giancarlo Glick; Courtesy Laura Hack; Wu Tsai Neuroscience Institute/Stanford University

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