New center seeks to understand any ‘magic’ in mushrooms

Interest in psychedelics as therapeutics has risen in recent years, spurred by studies that have found that the once-maligned drugs used in conjunction with therapy can help in the treatment of psychiatric patients. Amid a rush to commercialize a suite of newly developed products, Massachusetts General Hospital (MGH) has begun a new Center for the Neuroscience of Psychedelics to better understand the drugs’ effects on the brain, their mechanisms, and potential for therapeutic purposes. Jerrold Rosenbaum, MGH’s former psychiatrist in chief and Stanley Cobb Professor of Psychiatry at Harvard Medical School, is heading the new center and discussed how it grew out of an insight about rumination as a hallmark of many mental conditions, as well as its promise to help struggling patients desperate for a treatment breakthrough.

Q&A

Jerrold Rosenbaum

GAZETTE: There’s been a lot written about psychedelics in recent years. How did the center get started?

ROSENBAUM: In retrospective, it appears inadvertent. I spent a little less than 20 years as chief of psychiatry at Mass General and toward the end of that term, I was talking to a patient about his suffering, his torment, what was really bothering him. He was very vivid, and I had this “aha” moment. Much of the burden of all the different conditions that we treat in psychiatry, whether it’s OCD, anxiety disorders, addiction, depression, a main source of suffering is a kind of repetitive, stuck, painful dwelling on things: rumination. I made a practice of asking every one of my patients about rumination and found that it was a substantial part of their suffering. I realized that as a field we had not paid sufficient attention to it.

I have a friend who is a passionate advocate for decriminalization and the development of psychedelics as therapeutics. There was a conference on psychedelics at the Broad Institute and he asked me to attend. A pioneering researcher in psychedelic research, Robin Carhart-Harris, presented work describing the impact of psilocybin in fMRIs of the brain. There were changes in what’s called the “default mode network” of the brain, and there are reports of increased activity in the default mode network with people who ruminate. That’s what hooked me: Psilocybin alters the default mode network.

GAZETTE: And the center grew out of that?

ROSENBAUM: I thought this would be cool to study in patients with severe rumination, so I reached out to a company that synthesizes psilocybin, Compass Pathways, and I talked to one of the cofounders, Katya Malievskaia. Our focus on rumination struck her as innovative and appealing, so she agreed to make psilocybin available from the company and later offered some support through a foundation. They also introduced us to a family in California who are passionate about the potential of psychedelics. They lost a daughter to suicide who had been seeking treatment with psychedelics but couldn’t get access to any. We ended up having the resources to fund two neuroimaging studies.

GAZETTE: How hard a sell was it at Mass General, internally?

ROSENBAUM: The approvals were fairly easy. More important has been the MGH culture. People are not siloed in; they don’t worry about collaborating. That’s really true of the Boston ecosystem in general, across MIT, Harvard, the Broad. Lots of those in our biomedical research ecosystem realize that if you work together, everybody is more productive. So it’s easy to reach out to people, and they say, “Sure, I’m in.” There’s a culture of, “We’re happy to work together. We have the tools. That sounds interesting.” There was not a hint of any protective self-interest.

GAZETTE: Does funding have to be private at this point?

ROSENBAUM: It has to be philanthropic for now, but fundraising has been difficult. Some of that’s because of COVID, since we haven’t been able to get out in front of people, but a lot of money is going into commercial opportunities. I can’t tell you how many different versions of psilocybin, for example, are in development in different startups: minor chemical tweaks, novel deliveries, new formulations. Many want to get psychedelics approved or decriminalized, and when I say we need more study of the science, I get more crickets than dollars.

The NIH is not ready to fund much in this area, although they have started, and one would have already had to have done foundational work for proposals to fly. I really believe that there’s potential value to some psychiatric patients and maybe for brain health in general, that will allow people whom we’ve not been able to help to heal or recover.

GAZETTE: But isn’t it still illegal? They’re making these products but it’s speculative at this point, isn’t it?

ROSENBAUM: The FDA [Food and Drug Administration] gave to MAPS [Multidisciplinary Association for Psychedelic Studies], which funds the study of MDMA [3,4-Methyl​enedioxy​methamphetamine, commonly known as ecstasy or molly], and to Compass Pathways, which is doing a Phase 2b psilocybin study, breakthrough status. This indicates that the FDA sees potential and is open to facilitating the process. In the meantime, the DEA [Drug Enforcement Administration] still has most psychedelics as Schedule 1 drugs. You may have a situation where the FDA eventually approves these treatments, and then the DEA will be compelled to reschedule them.

I don’t think it makes sense for psychedelics to continue in Schedule 1. When you talk about harm to self or harm to others, they’re way down the list, below things you can buy in your pharmacy or that your doctor can prescribe. They’re not addictive, though they do create an intense emotional experience that can be distressing if people are not prepared for it or if it’s not done with the right mental set and in the right setting. But millions of people have used these substances. For thousands of years, they’ve been used by various populations, especially indigenous cultures, as part of rituals and spiritual experiences. Some of these substances may have some brief cardiac stimulation, but otherwise, they’re remarkably safe and non-addicting. They were banned, at least in part, because in some situations they were misused, but I don’t think the misuse is the full story as to why they were banned. An example of misuse was a government agency trying to see if they could brainwash people. There were political reasons for making them Schedule 1 and illegal.

GAZETTE: What has been the key development that turned things around in recent years? Was it the foray into psychedelic-assisted psychotherapy that showed results and safety?

ROSENBAUM: I think there are a lot of different elements. Some individuals have been laboring long and hard, making connections and appealing to people for support of changing the restrictions, while others — potential future influencers — were having personal experiences that changed their beliefs. Rick Doblin, with MDMA, the founder of the Multidisciplinary Association for Psychedelic Studies, MAPS, has been an unrelenting pioneer in this area. Although there are countless individual testimonials and many small and often poorly controlled studies, current studies are finally using larger samples and better methods. There was a recent report on MDMA and assisted therapy for PTSD, published in Nature Medicine a couple of weeks ago, which was a solid study. There is a usual criticism: Can you truly blind whether you’re on a study drug or the placebo, given the powerful experience one has? But nonetheless, all the small studies, all the testimonials — I think 30 million people who have been on psychedelics are alive today — all point in the same direction: that these have powerful effects on the brain in creating a unique perceptual or emotional state, and not all psychedelics are the same.

The focus on psychotherapy was helpful in that the claim that it is not psychedelics themselves that are therapeutic, but the drugs create a state where psychotherapy, processing of emotional material and past traumas, can be handled so that you can be free of them. If managed well, you can make profound changes in how people think, feel, and behave — in some cases abruptly after years of suffering. And, at least for somewhat short-term follow-up, that effect seems relatively durable. Finally, there’s much formal research, going back to the ’60s. A lot of very serious scientists felt that drugs like LSD had the potential for treating some of the most difficult-to-treat conditions, like alcoholism and other forms of addiction. There were studies in the ’90s that revealed that people faced with terminal illness, given a treatment with psilocybin, came to feel at peace and those who were still living months later, the vast majority continued to manifest reduced anxiety and depression. So there’s longstanding and consistent supportive evidence out there if you review it.

But I think the biggest influence was Michael Pollan’s book “How to Change Your Mind” because like me and many, he started out as a skeptic. He just set out to learn the history, interview the people. He got intrigued and acquired much information that not only changed his mind but those of many others.

GAZETTE: I wanted to loop back to rumination, since it’s an important part of the center’s story. Is rumination the thing that makes clinical depression different from ordinary depression, the thing that makes people feel trapped?

“Many want to get psychedelics approved or decriminalized, and when I say we need more study of the science, I get more crickets than dollars.”

ROSENBAUM: Rumination is not unique to depression and, in depression, people have other sources of distress. They lose their energy and their motivation, have an inability to experience pleasure, it interferes with their ability to sleep, they may have significant total body inflammation — aches and pains and so forth. Rumination is one feature of depression, but it’s not unique to depression.

Think of it as being stuck in recurrent thoughts that torment you. They’re not obsessions per se because they vary. It could be about something someone said, something you didn’t do, something self-deprecatory, but your mind just can’t move away from it. You’re basically stuck, and your own thinking is causing you torment. You can’t distract yourself; you can’t stop it. Some people say it’s like faux problem-solving — you just never get the answer. Everybody ruminates a little. We all have events in our lives where you realize, “Oh, my God, I wore two different socks,” or whatever it would be. You feel humiliated and embarrassed.

Humiliation is a pretty foundational human fear. John Cleese once said it was the goal of every British citizen to get safely in his grave while avoiding humiliation. We all ruminate a little, but with depression, you have heat-seeking missiles for it. You find stuff about yourself or about things in the past or things more recently, and it’s kind of torture. But addicts ruminate, eating-disorder patients ruminate, OCD — rumination crosses over. People who are depressed and are better, when I ask them, “Do you still ruminate?” They say, “Yeah, but not like that. I can distract, and it doesn’t get bad.” They almost see it like taking their temperature. When they start ruminating more, then that’s the signal that they’re going to relapse. But I don’t know if it’s just an epiphenomenon or whether that’s what’s driving it.

GAZETTE: Are there specific psychedelics that the center is starting with? And are there others that you see in the future?

ROSENBAUM: Right now, our only funded studies are with psilocybin. We have a proposal that we would love to get funded with MDMA and our Home Base program with Gulf War veterans. We are in discussion with a variety of other sources involving DMT (dimethyltryptamine) or N, N-DMT, or 5-MeO-DMT. DMT is the active ingredient in Ayahuasca and 5-MeO DMT is what you get from licking a certain toad. The Steve Haggarty lab and the Jacob Hooker lab together are working on a novel psychedelic, also plant-based and entheogenic. We’re open to others. We were just in conversation with a company that makes thin film wafers of psychedelics. And we were talking about the possibility of a microdosing study in chronic anxiety.

Steve Haggarty is interested in ethnobotany and, in particular, the Richard Schultes legacy. He’s interested in discovering what the psychoactive substances are in some of those plants [used by native peoples] that were never really known. Perhaps we could use DNA technology to extract from now old, dried-out specimens [collected by Schultes] some of the chemical substances that accounted for their reported effects. The indigenous peoples whom Schultes met with used them for different things, for memory problems, for getting ready for the hunt, for spiritual reasons. So one potential area is this ethnobotanical exploration.

If resourced, I think we can do amazing things. We’ll be able to take fibroblasts from patients in studies, grow mini versions of their brains in a dish and study their brains’ unique perturbations or responses to different psychedelic agents to explain the effects that we see in vivo, or why some respond and others don’t. There’s even a hope that we’ll be able to do precision psychedelics, that we’ll be able to know which substance might be better for which person.

There are things to understand and we’d like to understand them. If we do, we think we can enhance how these substances are used, design new therapies that take advantage of that knowledge, knowledge that may have less baggage or be more efficient or delivered better.

GAZETTE: Clearly, science has lagged behind the experiences of millions who’ve used psychedelics. Is that experience useful in any way or are you really starting from scratch?

ROSENBAUM: It’s not useful for the various juries that we have to present our case to, but it’s very compelling when you talk to people. I had an outreach from a person who I worked with years ago who wanted to report to me his experience with psilocybin. He also had a family member, whom I had previously met because of psychiatric history. He said, “I saw you’re doing this and I have to tell you that I’ve done journeys. I had lifelong anxiety issues and really for the last year, my world is so different, I just have so much more peace. And you remember my family member? After years of psychotherapy, he did some journeys and he’s just a completely different person.”

Maybe I don’t hear from the ones who would say, “I took it, and it was the worst thing in my life,” but these testimonials make me optimistic. They make me hopeful. It’s quite clear from those reports and it’s quite clear from the neuroimaging, that we are profoundly, at least temporarily, disrupting brain and connectivity. And that many who have undergone this experience in a controlled setting experience a meaningful change in emotional state. With the tools we now have, it shouldn’t remain a mystery to understand why that happens.

GAZETTE: When I first heard about this research several years ago, I remember thinking, “This is interesting though it probably isn’t going anywhere,” but in talking to you, you sound almost sure that within a few years, there’s going to be something before the FDA and/or FDA approval, even.

ROSENBAUM: I’m sure they’ll have enough data that it could be approvable.

GAZETTE: So is this not really speculative anymore? You seem convinced that something’s going on, and it’s a matter of figuring out what it is, getting the documentation and putting it forward. Is that an accurate assessment?

ROSENBAUM: I think so. There is a vast amount of commercial investment in developing psychedelics as novel therapeutics. But before there is “Big Psychedelics” in big pharma, as we have seen recently with cannabis, we very much need to get a better handle on the neuroscience of psychedelics.

GAZETTE: If things progress as you hope, might the center need a physical location at some point?

ROSENBAUM: If and when these agents are approved, there will be a need for specialized spaces for therapeutic administration as well as for further research. We are already challenged with creating suitable space for the currently approved studies.

GAZETTE: So you’re not ruling out a potential treatment arm one day, depending on the outcome of the studies?

ROSENBAUM: I think we’ll have to, if these are approved. Even now, we’re getting five to 10 appeals a day from people who are not sure what we do but really want us to help them. There’s lots of demand for relief. People are hopeful — I’m hopeful — but we still have much to understand and prove.

Interview was lightly edited for clarity and length.