From politics to the lab: The push for psychedelics in Mass. 

Psychedelics are on a path that could lead them to become an integral part of mental health care in Massachusetts.

Lawmakers are wrestling with a proposed ballot question seeking to decriminalize the use of certain mind-altering substances. It comes at a time of renewed scientific research into their potential for treating a range of conditions, including depression and substance use disorder.

The FDA is expected to weigh in soon on an application for MDMA  — also called ecstasy or Molly — combined with therapy, as a treatment for post traumatic stress disorder. In anticipation of approval, proponents of psychedelic-assisted therapy are training clinicians and creating guidelines for the drug's use.

The FDA also has granted breakthrough therapy designations for psilocybin, the psychoactive compound found in certain mushrooms, as a potential treatment for depression, and has issued draft guidelines for clinical trials of psychedelic drugs.

The use of psychoactive substances has a long history in the spiritual and healing practices of indigenous communities across the globe. Scientific studies have found evidence that psilocybin may help alleviate the fear of death experienced by people with terminal illnesses. Research also suggests it may help treat severe depression for patients who haven't responded to other therapies.

Massachusetts lawmakers heard testimony last month on the proposed ballot question to regulate some psychedelics.

Supporters argued psychedelic plants and mushrooms can help people who haven't found relief through the existing mental health system. They also said some people already consume these substances, so the state should regulate and tax their use to ensure safety and quality.

Opponents of the ballot question told lawmakers decriminalizing a substance doesn't mean it will be safe. They argued there's no conclusive evidence that psychedelics are a beneficial medical treatment, and pointed to studies indicating certain psychoactive substances may be harmful for some patients.

Several physicians and researchers who testified at the hearing were from Massachusetts General Hospital's Center for the Neuroscience of Psychedelics, which was established in 2021 to study psychedelics, including their effects on the brain and how they might be used to create new mental health treatments.

"Our mission is to open a window on new understanding of mental illness and new paths to novel therapeutics," Dr. Jerrold Rosenbaum, a psychiatrist and the center's director, told lawmakers.

WBUR's Deborah Becker sat down with Rosenbaum to talk more about the center's research, and where he thinks the field will go from here. They began by discussing a project that builds on the work of the late Harvard ethnobotanist Richard Evans Schultes, who traveled the world documenting dozens of plants believed to have psychoactive properties.

This interview has been edited for length and clarity.

There are greenhouses on the roof of Mass General Hospital where you'll be growing some of the plants Schultes mentioned, so you can test how these plants affect the brain. What will you be focusing on growing?

"Why nature created plants that would have profound effects on the human brain is unknown, but we're quite certain from the travels and reports and archives of Schultes at Harvard, and the vast ethnobotanical literature mentioning different plants and their uses and properties, that there's more space to explore.

"This is the work led by my colleague, Steve Haggerty, and I'm summarizing. He has curated, really, a list of plants that he thinks have potential — about 50 in number. And he has drilled it down to 11 or 12 to start with that we'll be studying.

"Some of the plants that Steve's interested in are quite common [and] might be in your garden. There are some psychoactive plants that are actually in the mint family, for example. So there's a mixture of interesting plants that people haven't heard of, and plants that people have heard of, but wouldn't have been aware that they had histories of human use, that seemed to have neuropsychiatric kinds of properties."

How do you study them and determine if and how they're psychoactive? How do you test them on someone's brain?

"We can create almost little mini-brains to see how human brain cells respond, and how that is alike or different from the effects of known psychedelics and other psychotherapeutic agents.

Create brains?

"We can grow a tiny little brain of you. We can take skin cells and transform them into stem cells, and evolve them into brain cells and allow them to grow. And really, even though they're tiny, they'll have the five layers of neuronal tissue that we see in the brain. And we can model what it might be like for a human brain exposed to these chemicals.

"I suppose it's possible that you could do observational studies in some cases, although we're not there yet."

The Mass General Hospital Center focuses on researching the biology — how psychedelics affect the brain and the specific parts of the brain. So, what do you look for? Are there specific brain changes that can be observed?

"It's still kind of a fool's errand to say we understand the mechanism of action the way we do, say, with cancer drugs or hypertension drugs. We can observe what psychedelics do. And then we can speculate from that what may account for the changes we see when people use these drugs.

"The leading hypotheses — well there are really several. One is that people have a profound experience and from that experience they learn something new that changes their behavior and sense of self, or perspective on the world.  That's a profound experience. That experience changes things about people.

"Another thing that happens that's not unique to psychedelics but it is very rapid and profound, is an induction of synaptogenesis [or the formation of new connections between neurons in the brain] and dendritic growth, what's called 'neuroplasticity.' This occurs with learning and exercise, antidepressants and other things. But with psychedelics, it seems to be that you sort of get a surge, and we think that may be an important part of how psychedelics allow people to change.

"The other thing you see about the effects of psychedelics in neuroimaging is that you see a massive disruption in brain connectivity. Parts of the brain that communicate with each other normally no longer connect for a while. The analogy that I think people like to use most, it's a little bit like rebooting your computer when you have a software problem and it resets."

Why is that important for mental health?

"Somebody who's severely ruminating [or dwelling on negative thoughts], or has obsessive-compulsive disorder or stuck thinking, it's almost like a reset. At least for a time, you've changed that state of a stuck loop of recurrent thinking that you can't get out of. It doesn't happen for everybody, but it does happen. So there's something about all these changes in connectivity — new connections, disruption in old ones and then the reset — that seems to allow some people to feel relief.

The last time we spoke, when the center first launched in 2021, you said there might be some clinical studies done at Mass. General.

"When we opened recruitment to a small neuroimaging study of 20 subjects with treatment-resistant major depression offering a single treatment with psilocybin, hundreds of patients responded, suggesting that there is a large number of patients who are eager for access to psychedelic treatment. [This study is still ongoing.]

"There's a study that's probably finishing up in June which is exploring a novel, or at least novel in this space, psychotherapy that we think will be good to use with psychedelic-assisted therapy — particularly within substances like MDMA — called 'mindful self compassion.' And we're doing a pilot study with veterans which would pair a psychedelic or psychedelic-like drug with very intensive therapy."

Billions of dollars are already being spent to get in on what some expect to be a "psychedelic gold rush." The substance MDMA is expected to soon receive final FDA approval to treat PTSD, so that drug could be on the market soon. And federal regulators have opened the door to start testing  psilocybin, or "magic mushrooms," to help with treatment-resistant depression.

So there is a lot of hype that these substances can provide relief for people with various mental health issues.

"I believe that these molecules that we're exploring in the psychedelic space will provide additional tools for treating people that we haven't been able to help. So I do believe there'll be a useful addition to the pharmacopeia. I don't know that they'll be as miraculous as some people feel. They've been transformational and miraculous for some, and those people have become profound advocates, even to the point of, I think, proselytizing."

Some doctors have told Massachusetts lawmakers not to allow the proposed ballot question to go forward. They say the research isn't there yet on who might be helped by psychedelic therapies and how to ensure that they're administered safely. What do you say about those concerns?

"There are potential harms to be considered, even if its only a small number of people who use these drugs. I believe general access to these agents will come to pass, but we need to be mindful of excessive optimism and the risk of diminished caution."

Do we know who should not use psychedelic therapies?

"We strongly believe that the substances offer risk to a subgroup of people. What accounts for that, and the biology of the risk, is not clear. But the groups that we are concerned about are those with either a family history or personal history of psychotic disorder, including people with schizophrenia, a family history of schizophrenia, people with bipolar disorder who have had mania, or family history of bipolar disorder. There area a lot of stories, many anecdotes but perhaps a small percentage of users who have triggered the onset of their psychosis."

The proposed Massachusetts ballot question would do something similar to what was implemented after the ballot question allowing the recreational use of cannabis. Is this the model that should be followed with psychedelics?

"I don't think it'll ever be quite as open as cannabis where anybody can go to a dispensary and purchase these substances. I think there'll be regulated places where people probably could buy psychedelics and that will probably be expensive. But on the other hand, you can grow your own mushrooms, and so I do think that we will eventually allow people to access these things because millions of people do anyway.

"And many people find it very helpful and certainly less harmful overall than many things that people are allowed to access."

Some [people] expect there will be psychedelic drugs on the market very soon. Do you think we'll see shelves full of different types of psychedelics?

"I think companies are looking at psychedelic substances, different versions of them, and coming up with their own proprietary version. And there's not going to be room on the shelf for all these different psychedelics. It's a little bit like we saw with SSRIs [a class of drugs typically used as anti-depressants], we ended up with, like, six SSRIs, and they all became multi-billion dollar drugs, and they just had the subtlest of differences between each other. So, we'll see that with psychedelics."