The Psychedelic Rx

Charles Grob

This was always an obscure, niche area,” Dr. Grob says of his scientific explorations of the therapeutic value of psilocybin, an active chemical in magic mushrooms; MDMA, the party drug better known as ecstasy or molly; and ayahuasca, the Amazonian plant hallucinogen employed as a religious sacrament by indigenous cultures for centuries. “For the most part, the field consisted of myself and a few friends. What we’re seeing now is astonishing.”

Dr. Grob, director of child and adolescent psychiatry at Harbor-UCLA Medical Center and a member of the Jane and Terry Semel Institute for Neuroscience and Human Behavior at UCLA, is referring to the growing embrace of drugs long associated with the counterculture, and which are, for the most part, still illegal outside of tightly controlled research settings. Interest in studying psychedelics for mood disorders, addictions and other difficult-to-treat conditions has soared in recent years amid tantalizing hints of their transformative capabilities, particularly when combined with psychotherapy.

How to Change Your Mind, the bestseller published in 2018 by UC Berkeley journalism professor Michael Pollan about the new science of psyche - delics, thrust the issue into the public sphere. Seemingly every week, another mainstream news outlet covers the practice — thus far unsupported by science — of “microdosing” psychedelic drugs. More than half-a-dozen cities, including Oakland and Santa Cruz in California, have decriminalized plant psychedelics, and in November 2020, voters in Oregon passed a ballot initiative making it the first state to legalize psilocybin and regulate its use by adults. The National Institutes of Health has joined for-profit and philanthropic enterprises in beginning to fund studies of psychedelic treat - ments. And some of the world’s most prestigious universities have launched research programs — several University of California campuses among them, including UCLA, where the Semel Institute’s UCLA Psychedelic Studies Initiative will bring to bear the expertise of faculty from across the campus.In the immortal words of the Grateful Dead: What a long, strange trip it’s been.

Dr. Walter S. Dunn (left) and Dr. Thomas B. Strouse.

“Astonishing” could also apply to the evidence — albeit early — of the benefits of high-dose psychedelics, particularly psilocybin and MDMA, in the treatment of conditions that include depression, obsessive-compulsive disorder, alcohol abuse, smoking addiction and eating disorders. MDMA-assisted psycho - therapy for the treatment of severe post-traumatic-stress disorder is on the verge of becoming the first psychedelic treatment to win approval of the U.S. Food & Drug Administration (FDA). That milestone comes on the heels of a Phase 3 clinical trial run by the nonprofit Multidisciplinar y Association for Psychedelic Studies, which found that with three MDMA-assisted therapy sessions, 67% of patients no longer met criteria for a PTSD diagnosis and 33% showed complete remission. For the placebo group, the findings were 32% and 5%, respectively. The US-based nonprofit Usona Institute has an ongoing Phase 2 trial assessing the efficacy of psilocybin in the treatment of major depressive disorder. Similarly, the UK-based biotech company COMPASS Pathways expects to begin a Phase 3 trial for its psilocybin-assisted psychotherapy for treatment-resistant depression.

Dr. Grob’s work, which has contrib - uted seminal findings that demonstrate significant improvement in mood and quality of life among patients with advanced-stage medical illnesses following psychedelic treatment, underpins much of this current research. “For many patients, these drugs appear to function as existential medicine, facilitating a renewed sense of purpose and meaning,” he says. “Individuals come out less fearful of death, less isolated and withdrawn, and they are more engaged with family and friends.”

Building on those conclusions, Dr. Grob and his colleagues at HarborUCLA and the UCLA Semel Institute are now collaborating with researchers at UC San Francisco on a multisite clinical trial using the psilocybin-treatment model — which augments the “trip” with psychotherapy by specially trained professionals before, during and after — for people with end-stage illnesses who are experiencing severe demoralization.

NEARLY ONE-IN-FIVE ADULTS IN THE UNITED STATES — approxi - mately 53 million people — live with a mental illness, a public-health crisis that is compounded by the COVID-19 pandemic. While existing medications and psychotherapy help many, an estimated one-third of patients are considered treatment-resistant, and another third experience improve - ment but not complete remission. Even when effective, psychotherapy and medication work slowly, and the drugs have sometimes debilitating side effects. And when it comes to development of new medications, the process is painfully sluggish. The last major development in psychophar - macology was the introduction of selective serotonin reuptake inhibi - tors (SSRIs) more than 30 years ago, in the 1980s and ’90s.

“We have serious chronic illnesses for which our treatments are imper - fect,” says Thomas B. Strouse, MD (RES ’91), medical director of the Stewart and Lynda Resnick Neuropsychiatric Hospital at UCLA, who is spearheading the Psychedelic Studies Initiative. “And there is at least the suggestion that many of these [psychedelic] substances may be quite safe, with people getting lasting benefit from single episodes of treatment. If that’s true, that could be a big change.”

The buzz around psychedelics stems not just from the idea that they represent a new approach, but also from results of studies hinting at the potential for fast, dramatic and enduring improvements in patient populations that haven’t fared well with conventional treatments. “What’s intriguing is to hear testimonials from patients who talk about their lives being changed,” says Walter S. Dunn, MD (RES ’14), PhD, a UCLA psychiatrist and Semel Institute faculty member who has advised the FDA on psychiatric drugs. “They don’t just say ‘I got over my depression’ or ‘my PTSD is better.’ It’s, ‘I’m seeing the world in a whole new light.’ We don’t have much long-term data in the literature, but we know that at six months or a year, people are sustaining their remission after one, two or three treatments, whereas with standard medications, patients have to continually take them to stay well.”

Dr. Dunn and others in the field are quick to stress that more research is needed to understand both the benefits and the potential risks of utilizing psychedelics to treat mental disorders. “What’s really exciting is that we’re bringing modern clinical trials and other techniques to understand compounds that have been used by humans for thousands of years,” says Joshua D. Woolley, MD, PhD, who directs the Translational Psychedelic Research Program at UC San Francisco and has worked on a number of clinical trials of psychedelic treatments. “The studies look very promising in that you can get big changes in many conditions, but we still have a lot to learn.”

Among the most fundamental questions is why psychedelics would be so effective in so many patients across a wide swath of psychiatric conditions. The working hypothesis involves the ability of psychoactive compounds to recapture the brain’s state of neuroplasticity, inviting new connections and ways of thinking to emerge. When assisted by a skilled psychotherapist, the theory goes, these changes in the brain’s chemistry enable people with mood or substance-use disorders to break free from negative thought loops — known in the mental-health fields as rumination.

“These medications seem to allow people to change habits or patterns of behavior that aren’t easily changed,” Dr. Woolley says. “If that’s true, it has profound implications, because many psychiatric illnesses involve people getting stuck in a way of thinking or dealing with feelings. We know talk therapy is effective for many things, but it’s slow, and it’s not easy. If you could reopen a critical learning period and then augment the psychedelic treatment with talk therapy, that could have a big impact.”

Mark Geyer, PhD, is another UC resea rcher with long exper ience working in this field; he co-founded the Psychedelics and Health Research Initiative at UC San Diego to study the potential of psilocybin and related compounds in treating pain and promoting healing. Dr. Geyer likens psychedelic therapy to a “rebooting” of the brain’s circuitry, resulting in a reprogramming of cognitive and emotional processes. “Someone asked me how a medication with such a short half-life could produce such a long effect,” Dr. Geyer says. “Well, look at PTSD. A singular event can have an enduring impact.”

For Dr. Grob, some of the most striking findings have been in patients with alcohol-use disorder. Treatments using psychedelics, first in the 1950s and 1960s, and more recently in research at New York University with psilocybin, have shown robust effects for a condition that is notoriously difficult to tame. “Even in the earlier studies, the researchers noted that the most-therapeutic outcomes were among patients who had what was described as a mystical-level experience — a psycho-spiritual epiphany that seemed to have catapulted them into a new sense of purpose and meaning to their lives,” Dr. Grob says. “It harkens back to what William James, the father of American psychology, said in the early 1900s: The best treatment for dipsomania is religiomania. He was talking about spontaneous religious experience — but when you’ve got a psychedelic treatment model, you can reliably predict that this will be part of it.”

BY THE TIME DR. GROB ENTERED COLLEGE, IN THE LATE 1960s, the consciousness-expanding properties of LSD and other psychedelics had become an article of faith in the growing coun - terculture movement, fueled by the works of authors such as Ken Kesey, Tom Wolfe and Aldous Huxley; musicians such as Jimi Hendrix and the Jefferson Airplane; and leading movement figures such as Harvard University psychologist Timothy Leary.

But it wasn’t until Dr. Grob was out of college, in the early 1970s, that he learned about research from the previous two decades suggesting a role for these substances in psychiatry. “I was working at a sleep-research laboratory, and one of the doctors had a library in his office of everything that had been written on psychedelics, including all the treatment studies up to that point,” Dr. Grob recalls. “I saw how much this could teach us about the brain and mental illness, and I decided this was what I wanted to do.”

He enrolled in medical school, only to find that psychedelics research had become verboten. “It was taboo,” Dr. Grob says. “Every month, I would go to the medical school library, look up in Index Medicus terms like halluci - nogen, lysergic acid diethylamide [LSD], psilocybin, whatever, and there was never anything new.”

The use of psychoactive plants for spiritual and physical healing purposes by indigenous cultures dates back centuries, but it was only in the 1950s and 1960s that Western medicine began taking interest. In the course of those two decades, more than 1,000 articles were published in the peer-reviewed literature, and tens of thousands of subjects participated in studies of the therapeutic value of LSD and psilocybin for conditions that included depression, anxiety and alcohol abuse. Among the LSD-clinic attendees were Hollywood luminaries as bright as actor Cary Grant, who reportedly said after his many experiences with the drug, “At last, I am close to happiness.”

But the counterculture’s love affair with psychedelics produced a backlash. By the early 1970s, the FDA had stopped approving studies and the substances were classified as Schedule I, defined as “drugs with no currently accepted medical use and a high potential for abuse.” Through the ’70s, ’80s and most of the ’90s, research on psychedelics as therapy was almost non-existent. Dr. Grob remembers psychiatry turning its back on the field, as well. As a secondyear medical student, he chose to present to his class on a study in which patients with terminal cancer were treated with psychedelics to reduce their anxiety. “I was excited, wondering what questions my classmates and professors would ask,” he recalls. “Not a single hand went up. I got the sense I wasn’t supposed to talk about this.”

The field cracked open again, ever so slightly, in the 1990s, but activity remained limited until the early 2000s, when the tide began to turn with a Johns Hopkins University study of psilocybin in healthy volunteers, a study led by Dr. Grob at Harbor-UCLA on psilocybin treatment for patients with terminal cancer who had anxiety, a study at the University of Arizona using the drug for treatment-resistant OCD patients and the first research into MDMA as therapy for chronic PTSD. With funding still hard to come by, a group of physicians and scientists with an interest in psychedelics research, including Dr. Grob and UC San Diego’s Dr. Geyer, established the nonprofit Heffter Research Institute in 1993. The goal was to attract philanthropic funding for high-quality studies that would demonstrate therapeutic value sufficient to ignite a new era of government support. The institute served as both reviewer and financial backer of many of the pivotal clinical studies of psychedelic therapies that were published, beginning in 2011. “We would identify worthy projects and investigators, then go out and find donors who would fund them,” Dr. Geyer explains. “We also had a considerable influence on the quality of the work, because we had to rehabilitate psychedelic science after the backlash. We were told we needed to be holier than the Pope.”

Dr. Geyer’s research group was among a handful to continue receiving government funding for laboratory studies of the behavioral and neurobi - ological effects of psychedelics during the dormant period. He originally was drawn to the field after reading Huxley, intrigued by the notion of “doors of perception,” as the author described in his book by that name about his expe - rience on mescaline in the early 1950s. Through much of his career, Dr. Geyer studied psychedelics to gain a better understanding of the workings of the brain. Now, in leading UC San Diego’s initiative, he is part of the first study investigating psilocybin’s potential in the treatment of phantom limb pain — pain perceived in the area where an arm or leg has been amputated — with plans to also examine psychedelic therapy for complex regional pain syndrome. “It’s amazing, even to those of us who have always thought there is legitimate reason for scientific scrutiny of these compounds, to see the crossdiagnostic clinical efficacy being found in preliminary data,” he says.

Brian Anderson, MD, MSc, became interested in the therapeutic potential of psychoactive compounds during the dark period for psychedelic research, and he remembers being surprised to learn that it was mostly anthropologists and botanists, rather than psychiatrists, seeking to understand the use in indigenous settings of substances that could have such powerful effects on thoughts and emotions. After seeking counsel from Dr. Grob while an undergraduate, he pursued medical school and training in psychiatry, with an eye toward investigating psychedelic medicines as potential treatments.

“I was struck early on by the capacity of these substances, when used as adjuncts to psychotherapy, to enhance how people perceive meaning in their lives and in the events around them,” says Dr. Anderson, now a psychiatrist at UC San Francisco and an investigator with the recently established UC Berkeley Center for the Science of Psychedelics.

Dr. Mark Geyer, Dr. Joshua Woolley and Dr. Brian Anderson.

As a postdoctoral scholar under the mentorship of Dr. Woolley at UC San Francisco from 2018 to 2019, Dr. Anderson conducted a pilot study of psilocybin-assisted group therapy for older, long-term AIDS-survivor men experiencing demoralization. Although the study was designed only to test the safety and feasibility of the therapy, the researchers observed clinically significant improvements. Dr. Anderson is now collaborating with Dr. Grob on the Harbor-UCLA study of individuals with end-stage illnesses, which seeks to determine if psilocybin in combination with psychotherapy not only reduces depression and anxiety, but also enhances patients’ sense of meaning. “Some of the best outcomes of clinical trials using psychedelic-assisted therapy have been among patients in an end-of-life palliative-care setting, where they’re coping with finding new sources of meaning when old sources of understanding what’s important in life have been shifted or challenged by their illness,” Dr. Anderson says.

AS THE MOMENTUM FOR INVESTIGATING THE THERAPEUTIC POSSIBILITIES OF PSYCHEDELICS builds, and researchers begin to make up for lost time, they face the reality that even when the funding is there, it’s a tricky field of study. For one, the Schedule I designation of the drugs they are investigating raises regulatory hurdles, including the need to obtain a special license from the U.S. Drug Enforcement Administration to secure the substances. But beyond that, designing double-blind, randomized placebo-controlled trials — considered the gold standard in clinical research, wherein volunteers are arbitrarily assigned to receive either the expermental treatment or an inactivesubstance, and neither the research subjects nor the researchers know who is in which group — can be thorny. “For the most part, people know if they’re on a psychedelic drug as opposed to a placebo,” says Dr. Dunn, who is leading the West Los Angeles VA Medical Center site for multicenter trials of psilocybin-assisted psychotherapy for PTSD and smoking cessation.

Recruiting subjects for such studies hasn’t been difficult — there is considerable interest in participating, Dr. Dunn notes. But that raises its own challenge: a phenomenon where functional unblinding and participant expectations collide. “People come in excited to be part of these studies and hoping to receive the psychedelic. If they realize they received placebo because it is obvious they didn’t have the psychedelic experience, they’re going to be disappointed, and their depression might worsen,” Dr. Dunn says.

The modern studies also represent a departure from traditional medication trials in that they typically combine the psychedelic with psychotherapy. In the current model, that means a substantial investment of resources — generally six-to-eight hours of therapy beforehand with two psychotherapists to prepare for the drug session; six-toeight hours under the influence of the drug, guided by the therapists; and six-to-eight hours of sessions over the following weeks for subjects to discuss the psychedelic experience and how they might incorporate changes based on insights gained. Emphasis is placed on ensuring the subject has the right mindset and that the environment for the drug session is soothing — more living room than doctor’s office, with comfortable couches, beanbag chairs, rugs, artwork and plants. The professionals who deliver the 20-or-so hours of therapy before, during and after the drug treatment undergo extensive training to learn how to work with patients experiencing intense and challenging memories and emotions, and how to harness those experiences therapeutically.

“Unlike most of psychiatry, in which talk therapy and psychopharmacology are related but separate, in this case they’re combined,” Dr. Woolley says. “In part, that’s because if you’re giving highdose psychedelics to people with mental illness to take by themselves, without someone to help them process the experience, you can have bad outcomes. If you think about it, millions of people use psychedelics out in the world, and they’re not all cured of their depression or substance-use disorder. We think it might require this combination of the psychedelic drug and the psychosocial intervention to have the best outcomes.”

The drug ketamine may offer an instructive comparison. Though not a classic psychedelic, at high doses, ketamine can produce hallucinations, and it is believed to enhance neuroplasticity. Its antidepressant properties were discovered in the 2000s; it has been used off-label ever since, and in 2019, a ketamine-de - rived drug won FDA approval for treatment of drug-resistant depres - sion. But ketamine has mostly been studied apart from psychotherapy, and while it produces a fast-acting, mood-elevating effect, that tends to wear off within days or weeks. “It’s easy to argue that, in the case of the psychedelic-assisted psychotherapies, it’s the therapy that’s the driving force in terms of patients getting better, with the psychedelics supercharging that process,” Dr. Dunn says. THE FORM IN WHICH PSYCHEDELIC THERAPY WILL BECOME LEGALLY AVAILABLE remains an open question. Most psychotropic drugs currently in use to treat conditions like depression, anxiety and psychosis can simply be picked up at a local pharmacy with a prescription and taken at home. If psychedelics, on the other hand, require the supervision of a trained psychotherapist when administered, along with the intensive preparation and integration before and after the experience, both the high cost and the limited supply of trained providers could limit the number of people able to receive the therapy. “There isn’t a lot of know-how about these substances in the mental-health profession, and training people to work with them is going to take time,” Dr. Anderson says.

That assumes that individuals won’t go rogue and seek to medicate themselves with the drugs, either on their own or under the care of untrained therapists. “There’s always been an underground,” Dr. Grob says. “Some of these practitioners know what they’re doing, others don’t. I’m not a big fan of underground treatment.” UC San Diego’s Dr. Geyer also worries that as word continues to spread about the promise of psychedelic therapy that is demonstrated in the studies, more people will take the drugs outside of medical supervision. “This is not some - thing you should try at home,” he says.

Yet, many already are. An increas - ingly popular use of psychedelics involves microdosing. The idea is to take a small enough amount every few days so as to capture the mental-health benefits without feeling the high — in essence, using the psychedelic like a standard antidepressant medication. But psychedelic-medicine researchers point out that microdosing hasn’t been studied, so there is no data to suggest it works, or that it doesn’t have adverse effects.

The classic psychedelic drugs aren’t addictive, and there is little risk of lethal overdose. Used as they are being currently studied, with one or two supervised doses, they may, in fact, prove to be safer than less-potent drugs prescribed for long-term daily use, Dr. Geyer notes. Concerns about the drugs are more psychological. The clinical studies have mostly excluded individuals with schizophrenia or bipolar disorder, along with those with a first-degree relative with one of the conditions; the risk level for these populations will require further study. Outside of the setting of a clinical trial, people have, in rare cases, likened their negative psychedelic experiences to PTSD, or they have reported that the experience brought on existential crises.

FOR MUCH OF DR. GROB’S CAREER, OBTAINING FINANCING FOR HIS PSYCHEDELIC STUDIES was nearly impossible. “We would have to scrape by with minimal funds. I’d have to work pro bono,” he says.

That’s changed in a big way, but now Drs. Grob and Geyer, who co-founded the Heffter Institute to help drum up support for the research, worry about the rapid growth of for-profit companies entering the field. They are concerned that an emphasis on maximizing returns on investments will lower safety standards.

Indeed, at a time when t h e momentum is on the side of decriminalizing psychedelics and once again exploring their therapeutic use, some want to seize the moment and press on the gas pedal, while those who remember how the first wave of interest ended are more likely to urge restraint. “This field was shut down for decades because of the excesses in the culture,” Dr. Grob says. “Now we have a remarkable window of opportunity, and we have to be cautious about opening things up too quickly. We need more research to demonstrate the utility of these drugs under optimal conditions, and to spell out what those conditions are.”