Psilocybin studies may lead to ‘revolutionary’ shift in cancer-related depression treatment
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For centuries, psychedelic plants and fungi have been harvested and explored for medicinal purposes.
Swiss chemist Albert Hofmann’s 1938 synthesis of lysergic acid diethylamide (LSD) and his subsequent isolation and synthesis of the “magic mushroom” compounds psilocybin and psilocin ushered in a period of extensive scientific inquiry into the possible benefits of these agents. However, government intervention effectively halted much of this research by the 1970s and 1980s, and the “war on drugs” reinforced the stigma around psychedelics.
The past decade has seen a resurgence of research into the therapeutic use of psychedelic drugs. In particular, psilocybin has been studied extensively for its potential to alleviate anxiety and depression associated with cancer and its treatment. Dozens of clinical trials are evaluating psilocybin’s potential to provide relief for patients experiencing severe anxiety and depression.
This proliferation of new research may be partly attributable to Michael Pollan’s bestselling 2018 book, How to change your mind: What the new science of psychedelics teaches us about consciousness, dying, addiction, depression and transcendence, according to Anna C. Beck, MD, director of supportive oncology and survivorship at Huntsman Cancer Institute and professor and director of the university supportive and palliative care program at University of Utah School of Medicine.
“Michael Pollan’s book brought these kinds of drugs back to the forefront, and a lot of the initial trials have been very exciting. Research on these psycholytic agents has exploded,” Beck, who conducted a study on the effects of psilocybin in reducing existential fear in patients with cancer, told Healio | HemOnc Today. “There have been problems with some of the research, as well, and much of that is centered around the fact that psilocybin is not legal in the United States. It’s been difficult to do the same sorts of trials that we would do for a new cancer treatment.”
Healio | HemOnc Today spoke with researchers and pharmacology experts about the potential of psilocybin for treatment of cancer-related depression and anxiety, barriers to clinical study and development of psychedelics, and how this therapy might one day be incorporated into cancer centers across the United States.
‘Very experiential’
Of the more than 100 clinical trials of psilocybin listed on clinicaltrials.gov, many pertain to treatment-resistant depression and anxiety, although it is being studied for a wide range of other indications, including alcohol use disorder, anorexia, Lyme disease, migraine and caregiver burnout.
Anxiety and depression are common among patients who have been diagnosed with cancer and are undergoing active treatment. If left unaddressed, these mental health issues often persist after the patient has completed treatment and transitioned into survivorship. Individuals who are terminally ill may struggle with a more intense, “existential” distress related to the prospect of their mortality.
Jai N. Patel, PharmD, BCOP, CPP, chair of cancer pharmacology and pharmacogenomics and associate professor in the division of hematology/oncology at Levine Cancer Institute at Atrium Health, as well as a HemOnc Today Editorial Board member, frequently manages antidepressant and antianxiety medications for patients with cancer. He said in many of these cases, traditional antidepressants such as selective serotonin reuptake inhibitors (SSRIs) prove insufficient.
“Unfortunately, over half of patients don’t respond to our conventional pharmacologic therapies for depression,” Patel told Healio | HemOnc Today. “It may take two, three or four trials before we find a drug that can work. I think this is an opportunity for patients who don’t respond very well to those kinds of therapies to have an option that, at least in the limited data so far, does seem to show some long-term benefits, even out to 12 months and later in a substantial number of patients.”
Psilocybin is distinctly different than traditional antidepressants in that it is always administered in conjunction with psychotherapy, according to Manish Agrawal, MD, medical oncology specialist and co-director of clinical research at Aquilino Cancer Center in Rockville, Maryland.
“Most SSRIs are pills that aren’t necessarily combined with therapy,” Agrawal, who wrote an article for The Washington Post about the benefits of psilocybin in relieving depression and anxiety in patients with cancer, told Healio | HemOnc Today. “And most [talk] therapies aren’t being combined with a medicine, so this is very novel. SSRIs are aimed at adjusting brain biochemistry, but they’re not necessarily trying to give you insight or get to the root of what’s happening.”
Although the exact mechanism of psilocybin on the brain is not fully known, Agrawal said psilocybin interacts with the brain’s 5-hydroxytryptamine receptors.
“We also know that on functional MRIs, different parts of the brain get connected that weren’t previously connected,” Agrawal said. “There are still paradigms that are being worked out as far as what is happening, but what people report is that they have insight. They are able to step out of their usual thinking and get a larger perspective on their life. They can make some sense of it in a way that is very experiential, and that seems to stay with them.”
The power of group therapy
Agrawal, who acknowledged that initially he had been skeptical about the use of psychedelics in improving cancer-related depression and anxiety, discussed the 8-week psilocybin study he and colleagues conducted at his institution. The study enrolled 30 patients with cancer at any stage.
“That was a difference from previous studies — we also enrolled patients with curable cancer vs. only patients facing the end of life,” he said. “It was also done in a cancer center rather than in a specialized psychiatric hospital, where these studies are usually conducted.”
The researchers treated four patients at a time, Agrawal said. The process consisted of group preparation the day before treatment, during which a therapist explained what to expect and how to optimize the treatment benefits. On treatment day, patients received a 25 mg standard dose of psilocybin, accompanied by group therapy. Agrawal emphasized that the therapy session doesn’t use the same approaches seen in traditional cognitive behavioral therapy.
“This is different in the sense that we’re not leading the person into talking about cancer or death or how they feel about their families,” he said. “It’s more about trusting whatever is arising — whatever their subconscious minds are bringing up for them to look at. There’s a certain intuitive trust. We don’t spend much time analyzing during the treatment.”
A week after the treatment, patients attended another session in which they discussed and evaluated their experience. During this session, they dig deeper and attempt to understand the meaning of their experience.
Agrawal said unlike with traditional antidepressants, the feelings associated with psilocybin tend to last beyond the physical effects of the drug.
“One of the more powerful effects of this treatment is that it feels very real — very experiential in their thoughts, emotions and bodies,” he said. “So, that feels much more real than an intellectual concept. That feeling seems to stay with them — the sense that they have experienced something important that they can take some insight from.”
Psilocybin appears to be unique in its ability to address “existential distress” in patients with both treatable and terminal cancer. However, this distinctive effect is not an official diagnosis and, therefore, not a primary focus of the study, Agrawal said.
“The trials have historically had a heterogeneity of diagnoses, like anxiety, depression and existential distress, but Diagnostic and Statistical Manual of Mental Disorders only recognizes depression and anxiety, and that’s what FDA drug approval would be based on,” he said. “That’s why our trial was specifically for depression.”
In the study, 82% of patients had more than a 50% decrease in their depression scores as measured by the Montgomery-Åsberg Depression Rating Scale, or MADRS, Agrawal said. Additionally, more than half of these participants had complete remission of their depression at 8 weeks.
Agrawal called the findings “profound,” noting that additional follow-up is being planned.
“We’ve just initiated a yearlong follow-up,” he said. “Even when the study ended, people wanted to keep meeting. Many of them continue to meet once a month.”
Beck and her colleagues are also conducting a psilocybin trial at Huntsman Cancer Institute. The methodology, designed by psychiatrist Paul Thielking, MD, chief scientific officer of Cedar Clinical Research, also involves treatment with psilocybin in conjunction with group psychotherapy. Prior to the treatment day, participants have three 2-hour preparatory sessions in which they discuss goals and expectations.
“Although this is a study of psychedelics, it’s also a study specifically of psychedelic group therapy,” Beck said. “Most of the previous studies with psilocybin have been one-on-one trials — a therapist with a patient. So, we are trying to show that a group environment confers additional therapeutic benefit. Group treatment is also much more practical — you can treat more patients without compromising efficacy.”
On psilocybin treatment day, patients spend the day in the infusion room in reclining chairs with their individual therapists, but still as a group, Beck said. After the treatment, they attend three 2-hour sessions, during which they discuss and process their experiences on psilocybin and influence one another.
“It’s a pilot trial, so our initial intent is to see if it’s feasible. We haven’t yet analyzed all the data,” Beck told Healio | HemOnc Today. “However, it’s been very much smooth sailing. We’ve had very robust interest in the trial among patients at Huntsman Cancer Institute, as well as from patients around the country, so recruitment has not been difficult. We also have not had any significant or unexpected adverse outcomes. Just being part of this trial and witnessing the dosing sessions has been a very gratifying experience.
Barriers and concerns
Although psilocybin appears to be well-tolerated in studies so far, additional study is needed to determine its safety for use in patients with cancer. Because psilocybin acts on the serotonin receptors of the brain, Patel said it could cause adverse effects if given in combination with drugs that also stimulate serotonin production. He cited serotonin syndrome, a condition caused by an excess of serotonin and characterized by vomiting, seizures or cardiac issues.
“Using [psilocybin] with something that enhances and increases serotonin activity can cause issues related to serotonin,” Patel said. “There are pain medications that can increase serotonin — tramadol is one. Even commonly used nausea medications like [ondansetron] can increase serotonin. As providers, we need to be cognizant and aware of issues related to serotonin syndrome.”
The fact that psilocybin currently is illegal represents another barrier to its development and regulatory advancement.
“It is certainly harder when the drug you are testing is a Schedule I and requires a special license,” Beck said. “In that sense, it certainly is different than a lot of phase 1 cancer trials. Psilocybin has had a checkered past for how it was perceived and used back in the ’60s and ’70s, and ultimately it was made illegal. Everything that’s happened lately with cannabis has made it more possible for something like psychedelics to be brought back into conventional medicine.”
In terms of studying psilocybin and other psychedelics, it may be difficult for researchers to use current measures to assess the mechanism of these drugs, Agrawal said.
“Some of it is, we have to figure out how to measure what it is doing,” he said. “It may be that many of our metrics and outcome tools are not geared to capture what we’re seeing happening with psilocybin.”
He added that the emergence of psilocybin analogs onto the market might also complicate researchers’ ability to study these substances comparatively.
“The question becomes, ‘how are we going to measure those?’” Agrawal said. “How do you compare something like psilocybin with something like LSD or an analog or [3,4-methylenedioxymethamphetamine]? So, we need to be more specific and precise in terms of what we’re trying to capture as an outcome measure, and how that varies from substance to substance.”
Integration into cancer centers
Agrawal, who co-founded an institution called Sunstone Therapies that conducts its psilocybin studies within the cancer center, said oncologists have traditionally been focused on the physical aspects of treating cancer, perhaps at the expense of quality of life.
“As oncologists, we just weren’t trained for this — the focus has been on the physical symptoms, the chemotherapy, radiation and surgery,” he said. “I think in many ways, we’ve neglected the psychospiritual issues. After practicing for 20 years, I realized that this is a huge unmet need.”
At Aquilino Cancer Center psilocybin is administered at the Center for Healing, housed on the third floor with chemotherapy and a surgical suite. Agrawal said he could envision such services being incorporated in other cancer centers, as well.
“You’d have chemotherapy, radiation and then there would be psychedelic therapy, all in the same center,” he said. “Some others might say we are stretched too thin and we should just focus on treating the cancer.”
At this point, Patel foresees psilocybin being used in situations where traditional antidepressants are unsuccessful.
“I see it being used possibly under a breakthrough designation, where the patient has exhausted all standard-of-care options,” he said. “However, I could see it being considered for wider use as more data come out.”
Psilocybin and other psychedelics have the potential to improve patient quality of life in a manner that is commensurate with the tremendous advances in patient survival, according to Agrawal.
“We have so many great drugs — during my career, there have been more drugs approved than during any previous 20-year period,” he said. “People are living longer, and yet the quality of life is only marginally better. To have something like this, which can truly impact how people live and how the feel — that would be revolutionary.”
References:
- Agrawal M, et al. Abstract 12097. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
- ClinicalTrials.gov. Study of psilocybin enhanced group psychotherapy in patients with cancer (HOPE). Available at: clinicaltrials.gov/ct2/show/NCT04522804. Accessed Oct. 12, 2022.
- Doblin RE, et al. J Psychoactive Drugs. 2019;doi:10.1080/02791072.2019.1606472.
- Dos Santos RG, et al. Risk Manag Healthc Policy. 2021;doi:10.2147/RMHP.S300656.
- Pollan M. How to change your mind: What the new science of psychedelics teaches us about consciousness, dying, addiction, depression, and transcendence. Penguin Books. 2019.
For more information :
Manish Agrawal, MD, can be reached at Sunstone Therapies, 9905 Medical Center Drive, Suite 350, Rockville, MD 20850; email: manish.agrawal@sunstonetherapies.com.
Anna C. Beck, MD, can be reached at University of Utah Health, 82 1100 E #403, Salt Lake City, UT 84102; email: anna.beck@hci.utah.edu.
Jai N. Patel, PharmD, BCOP, CPP, can be reached at Atrium Health, 1021 Morehead Medical Drive, Charlotte, NC 28204; email: jai.patel@atriumhealth.org.
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Agrawal M, et al. Abstract 12097. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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