Altering Perceptions on Psychedelics

Jerry Rosenbaum was intrigued when he first heard about the effect that psilocybin—the hallucinogenic compound found in certain species of mushrooms—was purported to have on the brain’s “resting state,” what neuroscientists call the default mode network. Associated with daydreaming and thinking about the past or the future, the default mode network encompasses any neural function that has some bearing on our autobiographical tendencies.

“Given the nature of the results, I was eager to learn more,” recalls Rosenbaum, the Stanley Cobb Professor of Psychiatry at HMS.

The information that grabbed Rosenbaum’s attention was being delivered by Robin Carhart-Harris, a Hugh Grant-esque young Brit speaking remotely from the United Kingdom to participants at a 2018 conference on psychedelics at the Broad Institute in Cambridge, Massachusetts.

Carhart-Harris, a psychologist and head of the Centre for Psychedelic Research at Imperial College London, was describing recent neuroimaging research out of his lab demonstrating that when people take psilocybin at low doses, the default mode network becomes less active. That is, the drug appears to tame self-reflection and all but ruin rumination, that obsessive mental state characterized by excessive, repetitive thoughts.

“I often say that rumination is self-reflection gone awry,” says Sharmin Ghaznavi, an HMS instructor in psychiatry and an attending psychiatrist at Massachusetts General Hospital. Rumination is a hallmark cognitive symptom of depression.

Last November, a pharmaceutical company announced promising, although not yet published, results from a clinical trial of psilocybin’s effect on severe depression. The researchers found that nearly 30 percent of the participants given 25 milligrams of the compound were in remission three weeks after treatment, compared to less than 10 percent of those in the control group. The study’s findings were generally considered encouraging by researchers in the field. At the time of its completion, it was the largest randomized, controlled, double-blind trial of psilocybin to have been conducted.

Ghaznavi and Rosenbaum are among those who see promise in the findings and note that they would be especially compelling if the drug being studied were a traditional antidepressant. But psychedelics research is in its early stages and the threshold for results being judged impressive is high. “There’s so much we still have to learn,” Ghaznavi says.

Anne St. Goar, MD ’79, a researcher and psychedelic therapist, also attended Carhart-Harris’s talk and remembers Rosenbaum’s enthusiasm. They went out to dinner with a few peers afterward and batted around some ideas.

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“Seeing evidence of decreased default mode network activity really piqued Jerry’s curiosity,” St. Goar says.

That dinner provided the initial spark for the Center for the Neuroscience of Psychedelics at Massachusetts General Hospital. Launched in early 2021, the center aims to assess how psychedelic substances could be used to improve the treatment of mental illnesses like depression, anxiety, substance abuse, eating disorders, phobias, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD).

“We really want to understand what is happening in the brain, from molecular to cellular to network and beyond,” Rosenbaum says. “What happens that allows people to improve and recover? And what sustains that?”

A constellation of researchers as interconnected and electrified as the neural networks many of them study has emerged not just at Mass General but throughout the HMS ecosystem and beyond. With expertise in multiple fields—from palliative care to psychiatry to law—these experts have a dedicated interest in piecing together the ways psychedelic therapies could transform medicine imminently, and maybe permanently.

Rebirth of interest

Their efforts seem timely. With the counterculture movement of the ’60s and ’70s and the antidrug movement of the ’80s receding into our collective past, the stigma associated with psychedelics has waned significantly. Scientists, mental health professionals, legislators, and the public at large are becoming increasingly fascinated by the possibility that psychedelics could alleviate some of the most extreme varieties of human psychological disease. Important studies, once frozen by the strictures placed on certain hallucinogens under the 1971 U.S. Controlled Substances Act, are being given a second life through philanthropically funded research initiatives at Yale, Johns Hopkins, and the University of California’s San Diego and Berkeley campuses. In January, the National Institutes of Health hosted a groundbreaking, free virtual workshop on psychedelics as therapeutics for some 1,500 attendees.

A psychedelic renaissance is upon us from a commercial standpoint, too. According to one analysis, the market for psychedelics could be worth $7 billion by 2027. JAMA reported that as of January 2022, there were more than 50 publicly traded companies in this space, with at least three U.S. companies valued at more than $1 billion. And bills are being introduced in state legislatures across the country—from Washington and California to Pennsylvania and Maine—to legalize medical psilocybin, decriminalize it, or both.

Yet Stephen Haggarty, an HMS associate professor of neurology and scientific director of chemical neurobiology for the Mass General center, thinks something special is happening at Harvard.

“In the twenty-five years I’ve been at Harvard I haven’t seen anything that has as much potential to connect the faculty of arts and sciences, the medical school, the divinity school, and even the law school,” says Haggarty. “We have an amazing world-class community of investigators across the whole spectrum.”

Out of the ashes

When it comes to psychedelics, though, Harvard also has a troubled past. The psychologist and psychedelic advocate Timothy Leary was a Harvard professor who, from 1960 to 1962, partnered with his colleague Richard Alpert (later known as Ram Dass) on the Harvard Psilocybin Project. Their efforts were methodologically, and ethically, ambiguous at best: Faculty members and administrators expressed alarm that the researchers often conducted their experiments while under the influence of psilocybin themselves, that they were sloppy in their research design, and that, in addition to using volunteer graduate students in their research, Alpert administered psilocybin to an undergraduate off campus. Harvard ultimately fired Leary and Alpert in 1963.

Haggarty wants to refocus the narrative. He recalls Richard Evans Schultes, a former Harvard professor, pioneering environmentalist, and scientist who researched medicinal plants in Mexico and the Amazon region and who is now known as the father of ethnobotany. Schultes started out as a scholarship student at Harvard College, initially interested in medicine. Yet his focus shifted after he took the class Plants and Human Affairs an experience that led to his spending a summer in Oklahoma with the Kiowa people studying the use of the cactus peyote, a source of mescaline. During a long career that included several positions at Harvard, Schultes formed ties with Indigenous knowledge-keepers, chemists, psychiatrists, and others in an attempt to elucidate the medicinal and cultural value of psychoactive plants.

“He laid a foundation of interdisciplinary science that we’re trying to bring back to life,” Haggarty says.

We really want to understand what is happening in the brain, from molecular to cellular to network and beyond. What happens that allows people to improve and recover?

Franklin King, an HMS instructor in psychiatry and director of education and training at the Mass General center, says that changing the narrative goes beyond just rethinking Harvard’s history. It will also entail reflecting on the difference between treatment and healing, the definition of “cure,” and the doctor-patient relationship.

“Most people who are really invested in this work have some kind of commitment to changing the paradigm underneath it,” he says. He acknowledges, however, that it may be a long time before we can safely integrate hallucinogens into therapeutic practices.

King points out that psychedelic drugs have long been an accepted part of many of the world’s cultures—and that recent adopters of psychedelic-assisted therapy must take care not to appropriate the strategies and assume they are immediately compatible. “Nonordinary states of consciousness have been integrated into communities in most civilizations other than the dominant civilization of the West for the past two millennia,” King says. “That is not a commentary on whether these drugs will be safe or not safe in some future theoretical situation. We’re a different culture.”

Test and measure

Arguably one of the biggest factors in making psychedelic research more accepted in the United States and elsewhere is the knowledge that psychedelics produce no neurotoxic effects at the doses administered in clinical trials. In fact, neuroscientists are observing that, when taken in a controlled setting, these substances are beneficial to the brain, especially for people who have certain psychiatric disorders. Landmark studies in 2014 and 2016 showed that LSD and psilocybin alleviated existential anxiety in patients with life-threatening illnesses for up to a year after beginning the treatment. Other studies have shown that ketamine may strengthen neurons against the damage from chronic stress by preventing synapses from being flooded with glutamate, an amino acid that, in excess, withers dendrites. And researchers continue to investigate whether psychedelics are useful as anti-inflammatory agents.

In general, scientists seem to agree that the primary reason psychedelic drugs trigger nonordinary states of consciousness is that they bind to a particular receptor in the brain, which promotes the release of serotonin, dopamine, oxytocin, and other chemical messengers into synapses. What experts don’t understand is how these temporary experiences produce long-
lasting, positive neural change.

“The deepest neuroscience question here is the basis of that persistence,” Haggarty says. His lab is searching for clues about what happens after a psychedelic agent targets its receptor. If he and his colleagues can trace the resulting domino effect on the brain’s circuitry and figure out which aspects help catalyze the therapeutic response, they could uncover new pharmacological strategies for more effectively targeting or circumventing the receptor altogether. Since psychedelics appear to reawaken the brain’s neuroplastic potential, prompting a “childlike” state of openness and wonder, they are an enticing lens through which to explore more than psychiatric disease.

“It’s all about the potential to make a broad impact by looking at basic mechanisms and transdiagnostic processes,” Rosenbaum says.

To begin to characterize these basic mechanisms, Ghaznavi has initiated a Harvard-based human study involving psychedelics. It will use neuroimaging to analyze the effects of psilocybin on brain networks involved in rumination. Rosenbaum and Ghaznavi also hope a study by colleagues will move forward; it will investigate how MDMA (ecstasy), when paired with mindful self-compassion, influences symptoms of PTSD and feelings of loneliness among veterans with the treatment-resistant disorder.

Experts in the field are particularly excited about MDMA because so much work has been done on it. Within the next two years, scientists and advocates are likely to succeed in securing FDA approval of MDMA for clinical use. Such a milestone would be due in large part to the efforts of MAPS, the Multidisciplinary Association for Psychedelic Studies, founded in 1986.

St. Goar was a therapist for the first phase 3 trial, sponsored by MAPS, of the effects of MDMA-assisted psychotherapy for individuals with severe PTSD. Study participants, 90 percent of whom had previously contemplated suicide, engaged in three preparatory therapy sessions with two trained therapists, and then underwent three eight-hour sessions over the course of three months, during which they took MDMA or a placebo and talked with the same two therapists. Between MDMA sessions, the participants had weekly therapy, starting the day after each MDMA session and continuing for a few weeks after the last MDMA session. Overall, including the therapy, the treatment took four months.

The results, published in Nature Medicine in May 2021, made headlines: Two months after treatment, 88 percent of participants with severe PTSD experienced a clinically significant reduction in PTSD diagnostic scores, compared to 60 percent of placebo participants. Additionally, 67 percent of participants who had received MDMA no longer qualified for a diagnosis of PTSD, compared with 32 percent in the placebo group.

Positive findings from a second phase 3 trial, which is currently underway, could usher in further research into psilocybin, LSD, mescaline, ayahuasca, and other psychedelics.

“What we’re going to see is an explosion of clinical trials done in other populations,” Haggarty says. “What’s been established is that the molecules are generally well tolerated and can be delivered safely, and that the clinical world is developing new paradigms to optimize such care.”

Walk with me

The importance of the therapist’s role in creating the right conditions, or what experts refer to as “set and setting,” for psychiatric improvement cannot be overstated, St. Goar says. And because it differs from regular psychotherapy, it requires special training.

“Therapy is a crucial part of this,” she says. “We’re not talking about just giving patients the medicine and telling them to go home and take it. It’s vital that the therapy is strong and supportive.”

MDMA may be especially helpful for treating severe PTSD over other disorders because it brings about feelings of emotional communion: one study demonstrated that octopuses become more social when given MDMA. In a therapeutic setting, emotional communion often translates to patients with PTSD openly sharing their experiences, reliving their traumas by talking about them, and then feeling a surge of self-compassion that allows them to separate from their past and move forward. The therapist provides a safe setting and acts as a nonprescriptive guide throughout the therapeutic session.

“One of the issues right now is how to train enough therapists to do this work,” St. Goar says. She recently worked with Janis Phelps, the director of the California Institute of Integral Studies, to create a Boston cohort for Phelps’s training program. This year, 120 people from the Boston area completed the program. But St. Goar says that more must be done to build an infrastructure for what many see as an inevitable wave of new medicinal approaches ahead.

Therapy is a crucial part of this. We’re not talking about just giving patients the medicine and telling them to go home and take it. It’s vital that the therapy is strong and supportive.

“It’s not the kind of training that leads to an automatic job,” she says. “Right now, the only way you can administer these medicines legally is through a research protocol.”

Yvan Beaussant, an HMS instructor in medicine and a palliative care physician at Dana-Farber Cancer Institute, is also trained in psychedelic-assisted therapy. He’s been researching the effect of psychedelics on demoralization in patients with serious illnesses and has begun a pilot study to assess how psilocybin-assisted therapy could be integrated into serious-illness care. He says that it’s critical to think about how to implement therapist training and certification programs into hospice care.

“The only way I heard about psychedelics in medical school was through classes about addiction and substance abuse,” he says. “I hope that in medical, psychology, and chaplaincy curriculums there will be more opportunities for training.”

Amanda Kim, a psychiatry resident at Brigham and Women’s Hospital, runs an affinity group through the Boston Psychedelic Research Group that serves as a community for clinical trainees to share their perspectives on psychedelics and brainstorm ways to pursue their interest in this area.

“One thing we’re trying to do is advocate for some type of training opportunity for psychedelic-assisted therapy that’s accessible to clinical trainees,” Kim says. “Although a few psychedelic training programs exist, they have limited capacity and can be expensive, making them out of reach for many clinical trainees. As these therapies become approved for clinical use, there is going to be a bottleneck of trained professionals who can deal with these powerful substances. Having more people, especially coming straight out of training, who are knowledgeable about psychedelics will be very important for the future.”

In addition to the problem of how to scale therapist training, a number of infrastructural elements face practitioners who hope to someday roll out these medicines. For example, it remains to be seen how insurance companies would reimburse these treatments, and more research needs to be done on what specific therapeutic contexts are most helpful.

Alex Simon, an advisor to the Mass General psychedelics center, regularly organizes programs to help philanthropists, investors, and others become familiar with the current research around psychedelics. While his mission is to galvanize support for this work and identify structural barriers to its growth, he also wants to caution people against thinking that psychedelics are a silver bullet.

“This is a space that has extraordinary promise for helping a lot of people,” Simon says. “I would encourage anyone involved to maintain enthusiasm but marry it with a level of rigor and sobriety that will mitigate the risk of disappointment or of over-promising.”

Plans and possibilities

While Simon is working to understand the evolving psychedelics ecosystem, some researchers are probing other aspects of the use of psychedelics.

King is building education programs, and Haggarty is starting to examine the question of whether psychedelics can be a gateway to precision medicine. Specifically, he’s inducing patient-derived pluripotent stem cells to become neurons and glia, then studying the resulting neural interactions in the lab to document neuroplasticity changes at the molecular, cellular, and circuit level. Someday, he says, the field might arrive at very precise predictions and descriptions of how each patient responds to different psychedelic drugs.

That’s a positive step for neuroscience as a whole, according to Simon. “Using these compounds and healing modalities could open up a much larger arena of understanding the brain,” he says.

Others grapple with how the economic model for psychedelic-assisted therapy will unfold and with issues related to inclusion.

“As psychedelic-assisted therapy becomes more of a reality, it’s going to be very important to ensure there’s equity of access,” Kim says. “If research shows that these types of treatments can be helpful for everyone, they should be accessible to everyone.”

Ensuring widespread availability means understanding that each patient comes to these drugs with a story. No matter their background, respecting a patient’s individual experience during any such therapy session is paramount.

“One of the great potentials and risks of psychedelics is that they bring people into a space of greater vulnerability, self-discovery, and authenticity,” says Beaussant. “This is the soul of psychedelic-assisted therapy, and we want it to be preserved. This is a human encounter that acknowledges the joys and difficulties of being human and requires the highest of ethical standards.”

Allison Eck is the executive communications manager in the HMS Office of Communications and External Relations.

Information for top image: In 1799, while in Haiti to “secure his family’s plantations,” French national Michel Etienne Descourtilz was arrested and pressed into service as a physician under Jean-Jacques Dessalines, a leader in the rebellion that secured Haiti’s independence. When not tending the wounded, Descourtilz collected plant specimens from the tropical forests in the area that now forms the border between Haiti and the Dominican Republic. That project supplied the material for his eight volumes on the natural history of the region’s flora. In 1827, he published yet another taxonomic text, the Atlas des champignons: comestibles, suspects et vénéneux. The book contained the lithograph used at the top of this story and other lithographs by artist A. Cornillon. Champignons Suspects features many of the mushroom species that we now know have psychedelic properties.

Images: from the Atlas des champignons: comestibles, suspects et vénéneux, M.E. Descourtilz, 1827 (top); John Soares (Ghaznavi, Rosenbaum, St. Goar)