How Do Psychedelics Work? Johns Hopkins Researcher Dr. Fred Barrett on the Success of PsychedelicTreatment

One of the most promising — and controversial — fields of research in the realm of mental and physical health is that of psychedelic treatment. Over the past decades, we’ve witnessed a gradual change in the public perception of psychedelics, as they’ve gone from dangerous and illegal drugs to promising substances that can be profoundly helpful for treating mental illness. But there are still plenty of questions, like how do psychedelics work? Are they safe? Who can they help? It’s a huge topic that touches psychology, neurology, integrative and conventional medicine, and federal regulations, among other areas, so it was important that we explore it with one of the foremost experts on psychedelics. Dr. Fred Barrett, cognitive neuroscientist and director of the Center for Psychedelic and Consciousness Research at Johns Hopkins University, joined Adrienne to talk about how psychedelics work, the research behind psychedelic treatment, LSD and psilocybin benefits, and more.

*This is a short clip from Adrienne’s interview with Dr. Fred Barrett. Click here to watch the whole thing.*

You can also listen to the interview on The getWellBe Podcast.

How Do Psychedelics Work?

We know that psychedelics have a powerful effect on the brain, leading people to have what’s colloquially described as a “trip,” during which their thought processes are altered and they may see visual hallucinations. But why, exactly, does this happen? 

“How psychedelics work in the brain is still an area of active research, and there are a lot of interesting ideas out there that may be true. We only have tiny bits and pieces of and fragments of the story with psychedelics, ” Barrett says. He explains that these theories and ideas actually look at two different aspects of how psychedelics work. There’s the acute effects of psychedelics, of what’s actually happening in a person’s brain when they’re “tripping,” and then there are the longer-term effects, of what happens when the drug’s effects wear off. “I like to say, when you go back to paying your taxes and getting stuck in traffic, what changes have occurred that are supporting radical behavior change and mood state change?” Barrett explains. 

He says that we know a lot more about the mechanisms behind the acute effects than the longer-term effects, but there are compelling theories about both. 

One of the earliest theories comes out of research done in Switzerland that looked at brain imaging during psychedelic experiences. In these studies, which included psychedelic compounds like mescaline and psilocybin, researchers found that during psychedelic experiences there was a great increase in activity in the prefrontal regions of the brain as well as the thalamus, which is “a bit of a sensory waystation or switchboard in the brain,” as Barrett puts it. 

“The thalamus is really almost like a filter,” Barrett explains. “If we were to try to attend to all of the sensory information that’s bombarding us constantly throughout our lives, we would be overwhelmed and we would never be able to go about the world attending to things, making decisions, acting appropriately. The thalamus helps us filter some of that stuff out so we can attend to what’s important. So the thought was, the prefrontal cortex provides input to the thalamus to help us decide what’s important to attend to, then the thalamus feeds the important sensory information forward so we can make decisions about it and go about our lives.”

When someone takes psychedelics, however, the psychedelic compounds break down that filter, and that leads to the cortex being overwhelmed with sensory information. This overload of sensory information further breaks down cognitive control, which leads to a flood of information, and all the effects of psychedelics follow from there. “That was one of the earlier models of what’s happening in the brain when we’re having a psychedelic experience,” says Barrett. “I think that model still holds water.”

A more recent theory comes out of functional MRI studies that looked at blood flow and other markers of brain activity during psychedelic experiences. When researchers injected psilocybin intravenously, they saw that there was a remarkable reduction in blood flow and brain activity overall, but this reduction was most concentrated in the regions of the brain called the “default mode network.” 

These MRI studies came on the heels of a theoretical article from a prominent psychedelic researcher suggesting that the default mode network was the seat of the ego. And so, taking those two together, a theory emerged that because psychedelics were turning off the default mode network, this was responsible for the feeling of “ego dissolution” — or when the sense of self disappears — that many people experience when on psychedelics. 

“It’s a compelling idea, and I think it’s an interesting theory that the default mode network is really at the center of psychedelic experiences,” says Barrett. “But the very reasonable alternative hypothesis hasn’t really been adequately addressed: that the default mode network is turning off because all of these other things are turning on strongly. And if you look at all of the studies that have reported a reduction in default mode, almost all of them report similar if not greater effects in other brain networks. So the default mode network doesn’t exist in isolation.”

The last theory that Barrett brings up is one that he’s actually researching himself, and it centers on a little-known region of the brain called the claustrum. Barrett explains that the claustrum is one of the most highly interconnected brain regions, but it’s only active for brief periods of time. “The claustrum only seems to be transiently active at the transition from doing something easy to doing something difficult,” Barrett says. “We believe that the claustrum may be responsible for essentially allowing us to switch brain network states from one state to another to respond to changing demands in the environment.”

Through their research, Barrett and his colleagues have found that the claustrum is one of the brain regions that most highly expresses the serotonin 2A receptor, which is the receptor that all classic psychedelic drugs bind to. This means that psychedelics have a profound effect on the claustrum, and that effect is that the claustrum’s activity becomes significantly reduced and it communicates less with other brain regions. “So this may be the first step in the disorganization of the brain that could occur during psychedelic experiences,” he says. 

All of the theories, Barrett says, speak to “the potential of psychedelics to disrupt our ability to maintain and control our brain network state space, which then leads to all of the other effects.” 

The Promising Potential of Psychedelic Treatment

All those other effects, it turns out, can have some powerful positive implications for treating mental health issues, and this potential has led to a boom in research around psychedelic treatment.

When someone takes psychedelics, they enter a chaotic brain space — described by the different theories above — in which they don’t have the control over their mindset that they’re used to. “And it could be that in this brain state, our previously learned maladaptive mental behaviors that keep us in a rut of negative rumination or that drive us to make certain negative assumptions about our relationships or our place in the world, that for a short period of time, these don’t have control over us anymore,” says Barrett. “And that allows us to really entertain other ideas about how all of this should work or who we are or what that means.” 

This idea feeds into the prominent theory that psychedelics allow our entrenched belief systems to relax (a state referred to as “the entropic brain”), and that when this happens, new possibilities open up. “Some form of relaxation of our prior beliefs leads us to a state in which we can entertain new beliefs that then take hold and have purchase in our minds,” he explains. 

In patients who are suffering from a mental health problem, like depression or substance use, they get stuck in what Barrett describes as “a maladaptive application of metacontrol.” In layman’s terms, this means that rather than being able to think flexibly and make choices based on their environment, their brain remains in a very stable place where it continually makes the unhealthy choice. “This can be described behaviorally in terms of compulsive drug-seeking within patients who are suffering from substance use disorders or stuck in loops of negative rumination in patients who are suffering from mood disorders,” he says.

Psychedelic experiences, Barrett says, throw us into a radically flexible state that allows us to relearn the value of flexibility on a molecular, neural, and psychological level. “We’ve shown some evidence for this in our patients treated for major depressive disorder,” he says. “We’ve shown careful behavioral evidence that these patients, after treatment with psilocybin, have a notable increase in the capacity for cognitive flexibility, for thinking more adaptively, or for changing the way you think about yourself.”

Barrett adds that both behavioral evidence and careful questionnaires of people who were administered psychedelic drugs show that these substances can have a profound impact on mental state, and that this holds true both for both people being treated for mental health problems and healthy controls. “People often report encountering some unexpected and deeply, personally meaningful psychological insights that they’ve encountered during this experience that then kind of feeds their healing process, whatever that ends up being,” he says. 

“Even healthy individuals who undergo these experiences can find an increase in well-being and life satisfaction and relief from anxiety or other mood states that are wearing on them. It may be that those insights are what’s driving the storytelling about healing and well-being that follows these experiences.”

Psychedelic treatment takes this research and formalizes it. Though psychedelics are still federally illegal, they can be used in clinical trials, and there’s a standard protocol for administering psychedelic treatment in these settings. First, Barrett says, people are screened to ensure that they feel safe and are prepared as much as possible for the experience. While they’re having the psychedelic experience, they’re in the presence of two trained therapists with whom they’ve had several sessions leading up to the trip. After the acute effects of the psychedelics have worn off, they then work with these therapists to integrate the experience into their lives and help them move forward.

Using this approach to psychedelic treatment, “we’re seeing some really remarkable effect sizes in treating patients with mood disorders and substance use disorders,” says Barrett. “And now there are a wide range of studies that are being conducted in a greater number of indications.” Some of those indications, he says, include using psychedelics to treat obsessive compulsive disorder, Alzheimer’s, dementia, post-treatment Lyme disease syndrome, and more.

Exploring Psilocybin Benefits

One of the most promising psychedelic substances is psilocybin, which is the active ingredient in psychedelic mushrooms. Like most psychedelics, psilocybin is not approved as a medicine and so can’t be prescribed to patients, but given the many psilocybin benefits, Barrett believes this may change soon. 

“My expectation and the expectation of many is that once we get enough data, once the phase three clinical trials are approved, it’s possible the FDA may approve psilocybin for the treatment of major depressive disorder at that point,” he says. “It’s likely that people will begin to set up clinics to offer psilocybin therapy for patients with depression.”

Barrett says that most of the documented benefits of psilocybin so far have to do with it as a treatment for depression, but that there needs to be more research into how long these benefits last and how replicable they are. “If the effects that we found in our clinical trial of 50% remission from depression for at least a year after treatment, if that’s real, if that sustains scrutiny and interrogation, that’s predictive of how this will work in the real world,” Barrett says. “Then, gosh, that’s 16 or 20 hours of therapy, and the cost of that pales in comparison to the lifetime cost to the individual in society for someone suffering from depression.” 

This means that, despite the fact that each session of psychedelic treatment involves two licensed professionals, pre- and post-session therapy, and a psychedelic trip of six to 12 hours, treatment with psilocybin or other psychedelics actually winds up being much more efficient and cost-effective than traditional psychotherapy.

What’s more, Barrett says, psilocybin benefits almost certainly extend beyond depression. “One of the interesting things about all of this is that we don’t know what the limits to the space are,” he says. “I absolutely don’t believe we should expect it to be a panacea. But I do think there’s a great potential for treatment of mood and substance use disorders at the very least with psilocybin.”

Barrett sees us standing on the precipice of huge discoveries and massive changes when it comes to the field of psychedelic medicine, but cautions that we shouldn’t get ahead of ourselves because of our excitement. “There are still a million questions we haven’t answered. We’re still early on in this,” he says. “I think we can still be excited, because the effects are so large so far. But we’re not there yet.”


Watch the full interview with Dr. Fred Barrett to learn how he got into the field of psychedelic research, how more conventional psychiatric treatments fall short, the research being conducted into psychedelics and chronic Lyme disease, his thoughts on natural psychedelics like psilocybin versus synthetic psychedelics like MDMA and ketamine, how regulations and access are impacting the field of psychedelic research, who should absolutely not try psychedelic research, what he thinks about newly developed psychedelic treatments that take out the “tripping” aspect of the drug, and much more.

You can also listen to Adrienne’s interview with Dr. Fred Barrett on The getWellBe Podcast.

What’s your take on psychedelic treatment? We’d love to hear your thoughts in the comments below!



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  2. Carhart-Harris, R L, and K J Friston. “The default-mode, ego-functions and free-energy: a neurobiological account of Freudian ideas.” Brain : a journal of neurology vol. 133,Pt 4 (2010): 1265-83. doi:10.1093/brain/awq010
  3. Madden, Maxwell B et al. “A role for the claustrum in cognitive control.” Trends in cognitive sciences vol. 26,12 (2022): 1133-1152. doi:10.1016/j.tics.2022.09.006
  4. Barrett, Frederick S et al. “Psilocybin acutely alters the functional connectivity of the claustrum with brain networks that support perception, memory, and attention.” NeuroImage vol. 218 (2020): 116980. doi:10.1016/j.neuroimage.2020.116980


The information contained in this article comes from our interview with cognitive neuroscientist Dr. Fred Barrett. Dr. Barrett is Associate Professor of Psychiatry and Behavioral Sciences at Johns Hopkins School of Medicine, and director of the Center for Psychedelic and Consciousness Research. He received his PhD at the University of California, Davis, and has been conducting psychedelic research at Johns Hopkins since 2013, during which time he has published many peer-reviewed articles and received several notable grands, including a 2017 NIH grant that was the first federally funded research into psychedelics since the 1970s. You can learn more about Dr. Barrett here.

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