In 2016 psychiatrist Benjamin Kelmendi was treating two patients with severe, treatment-resistant obsessive-compulsive disorder (OCD) at a Connecticut mental health center when the patients abruptly disappeared, abandoning their treatment plans without a word of explanation.
Kelmendi, who is now an assistant professor of psychiatry at the Yale School of Medicine, had begun evaluating them as candidates for deep brain stimulation treatment after working with them a few years, he recalled recently.
“And they just stopped showing up for appointments.”
Some months later, both patients resurfaced — looking better than Kelmendi had ever seen them, and they no longer wanted deep brain stimulation. Their reason? They told him that they’d discovered “magic mushrooms.”
“They had participated in some sort of ceremonial therapeutic setting to take psilocybin mushrooms,” Kelmendi said. “It was striking, how much better they seemed. How could a single dose of something have such a remarkable impact? That’s when I first became aware of the use of psilocybin for psychiatric conditions.”
Benjamin Kelmendi
Since then, interest in the psychedelic drug psilocybin — a naturally occurring compound found in some mushrooms — has exploded, with states across the U.S. contemplating, and in some cases passing, regulations to legalize the substance.
Connecticut lawmakers took such a step last spring when the House of Representatives, in a narrow vote, passed a bill to eliminate criminal penalties for possession of less than a half ounce of psilocybin. (The bill, however, ultimately died in the state Senate.)
When it comes to ongoing national debate, Kelmendi is a keen observer. He is co-director of the Yale Program for Psychedelic Science, a multidisciplinary community of researchers investigating the impact and therapeutic potential of psychedelic agents and how they might be used safely.
In recent years he has done research into the potential benefits of psilocybin, with his work touching on broad aspects of safety and efficacy, including most recently the tolerability and clinical effects of repeated psilocybin dosing; and the mechanisms of therapeutic change after psychedelic treatment in OCD.
Much touted research increasingly supports the view that psilocybin can help patients with a range of psychiatric conditions, Kelmendi said. But skeptics worry that the compound could pose unforeseen medical complications and open the door to substance abuse.
In an interview, Kelmendi weighs in on psilocybin’s therapeutic promise, the controversy surrounding it, and why scientific research alone should drive any related public policy.
The interview has been edited for length and clarity.
What are some of the psychiatric conditions that psilocybin shows promise in treating?
Benjamin Kelmendi: Psilocybin has shown compelling evidence in treatment-resistant depression, as well as in major depressive disorder. Results in PTSD [post-traumatic stress disorder] research have been encouraging as well, especially with veteran populations, though the data is not as robust as in depression, so larger trials are ongoing. There’s also some emerging evidence for certain substance use disorders, particularly alcohol use disorder and tobacco use disorder, as well as the work that’s coming from my lab on OCD which shows some really encouraging results. But all these studies so far are small studies, involving 30 to 40 people.
What have your own studies shown?
Kelmendi: We’re just finishing a study now in whichwe worked with over 30 participants with severe, refractory OCD. We treated them with a single dose of psilocybin, and the results are quite encouraging. They showed greater effectiveness than established standard of care treatment, with patients more quickly experiencing relief from a broad range of symptoms. This was only a small pilot study, so it will need to be replicated in larger studies. But for the participants whose symptoms had caused them to resort to a reclusive lifestyle after conventional treatments failed, psilocybin had such a dramatic effect. It’s been very empowering, both for the patients and their families.
Can psilocybin be addictive?
Kelmendi: Like any potent psychotherapeutic compound, there are risks that need to be carefully managed, including risk of misuse and abuse. Our research demonstrates that the potential for serious psychiatric events necessitates comprehensive monitoring infrastructure.
What’s happening at the national level in terms of efforts to decriminalize psilocybin?
Kelmendi: There’s very heterogeneous development in this space. Just in the past year, there have been more than 36 psychedelic health-related initiatives introduced across more than a dozen states, really representing unprecedented legislative activity.
But not all these initiatives are equal, right?
Kelmendi: No, they vary widely in their scope as well as in their sophistication. I’ve categorized them into three approaches. We’ve seen one of these approaches in Oregon and Colorado, where they’ve established regulated access to psilocybin — and you don’t need a medical referral — through licensed facilitators and service centers. They’ve established a regulated framework for production, distribution, and use with some measure of quality control, as well as health care provider training.
Then you have a less well-known approach, which we’ve recently seen in New Mexico’s Medical Psilocybin Act, which authorizes use for specific, qualifying, conditions under the care of physicians or other healthcare providers.
And the third approach, which we saw here in Connecticut last spring, involves simple decriminalization measures that are more about reducing penalties for individuals found in possession of small amounts of the substance, without creating any medical access framework.
What is the difference between “decriminalization” and “legalization”?
Kelmendi: When it comes to understanding these bills, it’s important to know the difference. Connecticut’s proposed bill was around decriminalization, which typically involved reducing criminal penalties to civil infractions while maintaining an underlying prohibition. Legalization measures generally aim to open the door to health care providers utilizing psilocybin as a medical treatment.
What do you feel would be the most beneficial legislation?
Kelmendi: While we do have preliminary data showing efficacy for use of psilocybin across many psychiatric conditions, we’re still in the early stages. I think we should be aiming for FDA-approved medical access with specific protocols. Our five years of research at Yale has shown that these substances can offer significant therapeutic benefits when administered in controlled clinical settings with proper safeguards and trained professionals.
The risks can be mitigated when the substance is administered and guided by trained health care professionals with established dosing protocols based on clinical trials, as well as integration within an existing health care infrastructure. I’m very much in line with use that is guided by validated protocol to ensure safety.
What are some common misconceptions about using psychedelics as medication?
Kelmendi: One, with respect to legislation, is that decriminalization provides therapeutic access. At least in Connecticut, there has so far been no mention of creating regulated medical treatment pathways.
But the biggest misconception that I run into quite frequently is confusion over the difference between recreational and therapeutic use models. The data from clinical trials that shows some clear efficacy in therapeutic purposes is translated into this belief that taking mushrooms in a recreational context is going to generate the same results. These are powerful psychoactive compounds that require careful administration. This context is just not being clearly conveyed.
There’s this notion that it’s a fun, easy thing to do. You just eat the mushrooms, and you feel better.
Kelmendi: Absolutely, and the reality is far from it. When these compounds are properly administered, it’s in a health care setting, and patients require two days of preparation and education beforehand. It’s a big production. The day of the dosing is an eight-hour day, and patients typically are not in the position to drive after, so they need to ensure they have a safe ride home. Medical staff remains available to them for 24 hours.
If this space is going to develop as a medical treatment, it will fall within the psychiatric intervention model — like we see with the use of ketamine for depression — where there will be a specialized facility and staff that has been trained to work with this intervention.
Benjamin Kelmendi and staff in a treatment room.
What has been the biggest surprise to you in this research?
Kelmendi: For me, it’s been the disconnect between policy development and research evidence. As researchers, we spend so much time ensuring safety, and we believe these substances have potential. But we have also demonstrated that they need to be administered in a carefully designed setting that optimizes success and minimizes risk. These are the findings that need to inform policy. Any legislative framework should align with the clinical research findings and best practices that demonstrate safety and efficacy. I remain optimistic that Connecticut and other states will develop frameworks that harness the therapeutic potential while maintaining appropriate safeguards.
Looking ahead, what’s next for the Yale Program for Psychedelic Science?
Kelmendi: We’re expanding our research in several critical directions. With support from the State of Connecticut, we recently launched a groundbreaking study examining how psilocybin therapy can address functional impairment, helping people not just feel better but actually return to work, rebuild relationships, and reclaim their lives.
We’re also deeply committed to serving those who serve us. Our current work with military veterans has been so promising, we’re launching an innovative group therapy model, recognizing that the shared experience of service creates unique therapeutic opportunities. We’re also extending this approach to healthcare workers and first responders — populations that have carried extraordinary burdens, especially during the pandemic.
These initiatives represent a continuation of over 60 years of Yale leadership in this field. With the state’s partnership now, we’re not just studying these compounds — we’re building the evidence-based frameworks that will ensure they can be safely and effectively integrated into mental healthcare.
