The Neuroscience of Psychedelic Drugs: Your Brain on Psilocybin With Frederick Streeter Barrett

Psychedelic drugs have long been exiled to the fringes of medicine, dismissed as recreational drugs with limited therapeutic potential. That all changed with the breakthrough therapy status granted last year to psilocybin, the active compound found in psychedelic mushrooms, for its ability to rapidly reverse treatment-resistant depression. This has led to an explosion of interest in the field, with new institutes opening and new disorders identified as targets for psychedelic therapy. In our latest interview series, we discuss the potential of psychedelics to revolutionize clinical neuroscience with thought leaders in the field.

Fred Barrett is an Assistant Professor of Psychiatry and Behavioral Sciences at Johns Hopkins University in Baltimore. In this interview, we discuss his work with the active component of magic mushrooms, psilocybin. Fred explains how this compound affects the brain, its potential to combat visceral pain, and its links to so-called mystical experiences.

Ruairi Mackenzie (RM): Could you tell us about psilocybin’s mode of action on the brain?

Fred Barrett (FB): This goes back to the very beginning of research for psychedelics, through the ‘70s and then ‘80s and ‘90s as well. People have been thinking about this for decades.

I think there are a couple of interesting hypotheses, but two in particular which are not necessarily independent or mutually exclusive hypotheses. One of the hypotheses was that psilocybin-related drugs essentially alter thalamic gating. So, what the hell does that mean? Here’s a crash course.

The thalamus is almost like a switchboard for sensory information being transmitted to higher cortical areas. The thalamus acts as a gate if you will in many instances. It’s responsible for routing sensory information and in that duty it’s also responsible for holding back some sensory information. It’s often under the direction of higher prefrontal and executive cortices and so depending on what you need to pay attention to, the routing through the thalamus will change to attend to one or another sensory stimulus or modality. This is what happens in a normal healthy waking conscious brain.

Some of the experiences people have with psychedelics include an almost overwhelming sensorium and the cognition that you’re sensing things with psychedelics that you don’t normally sense. I’m hopefully not getting too scandalous by saying this but I think that if you were to really look for the “reducing valve” that Huxley was talking about, it would be the thalamus. It reduces the sensory information coming through to your cortex. The hypothesis was that psychedelics reduce the gating of the thalamus. They impair the thalamus’s reduction of sensory information and open the valve. That’s an interesting hypothesis; one of the things working against that hypothesis is that there are no serotonin 2A receptors in the thalamus [5-HT2A receptors are central to the action of psilocybin], but that’s okay because the thalamus undergoes top-down control from a number of other cortical regions that do have lots of serotonin 2A receptors.

One of those areas is the prefrontal cortex. Another theory that came up around this time was that psychedelics increase activity in the prefrontal cortices or they somehow inhibit the top-down control of the prefrontal cortices on other sensory and sub-cortical regions.

This is, like I said, not mutually exclusive, it could be that both are working together. It could be that. Evidence has been generated for both hypotheses. Studies back in the mid-'90s found evidence across several different psychedelic substances that there was a relative increase in frontal activity and a decrease in other cortical activity and most recently Katrin Preller, from Franz Vollenweider’s group, has published a couple of papers that have shown a vast alteration of the connectivity of the thalamus to other cortical brain regions. These are two hypotheses that seem reasonable. They’re not likely to explain everything that goes on with psychedelics but they are very likely to explain at least some of the sensory aspects as well as some of the feelings of loss of control that people experience when they’re under the acute effects of psychedelics, and some of the cognitive changes.

RM: Is there evidence that psilocybin could have a role in minimizing pain and suffering in illness?

FB: That’s the story that came out of some cancer studies that were published where the explicit aim to see if we could reduce suffering, emotional pain, psychological pain and suffering. That brings up an interesting additional potential pathway which is for the direct treatment of pain, like physical visceral pain. There are reasons to think that psilocybin and related drugs may have anti-nociceptive properties.

You can think of two obvious hypotheses why that might be, one is that there are some kind of biomechanical anti-nociceptive effects; maybe psilocybin alters ascending nociceptive pathways or alters periaqueductal gray, all the brain stem-mediated pain receptor-type mechanisms, that there’s some effect on these mechanisms that reduce pain. I collaborate with an anesthesiologist at the Bayview Medical Center here at Hopkins. When we first started collaborating and I told him what I was doing with psychedelics, he said, “Have you studied pain, because I’ve seen patients in the ER who say they’ve taken acid and they can’t feel a thing. They’re hitting their heads against the wall, maybe got into a car accident, they don’t feel anything!” Isn’t that fascinating? Frankly if we need people to be under the acute effects of psychedelics to have them not experiencing pain, then that may really limit the potential application of these drugs in pain reduction.

Another hypothesis; a big part of pain can be catastrophizing. To the degree that psychedelic drugs can alter our view of our relationship of the world around us, to the degree that psilocybin can reduce anxiety and put us at ease and allow us to be present and at peace with the state of our lives. That maybe reduce catastrophizing which can have a direct impact on pain and suffering. There are certainly some more psychological theories and hypotheses about what psychedelics are doing, a couple of theories that maybe psychedelics increase psychological flexibility. Maybe psychedelic experiences increase an individual’s insight into their life and their relationships. Maybe psychedelics allow people to identify and then jettison undesirable behaviors in their lives. All of these things can load on to the factor of reducing pain and suffering through lots of different ways. Researchers around the world I think are really piling onto this to see if the way they understand psychology and the way they understand the mind and their theories apply to psychedelics. It seems like all of these things may be at play so I think we have a really interesting future ahead of us in seeing what really shakes out.

RM: Could you briefly outline the relationship between psilocybin and mystical or religious experiences?

FB: Early on in the study of psychedelic experiences there were a number of people who seemed to think that there was a clear relationship between psychedelic experiences and what might be described as mystical experiences. It seems to me that mystical and religious experiences can be two different things. There’s a philosopher of religion, Walter Stace, who scoured all the literature he could find to try and identify examples of what might be a mystical experience. From that he developed a philosophical model of mystical experiences where he identified six or seven factors, depending on how you read it, of mystical experience.

These being:

• Deeply felt positive mood
• Sacredness
• Reverence
• Ineffability
• Timelessness and spacelessness
• Internal or external unity
  
  

External unity being the feeling of oneness with everything around you and internal unity being a bit deeper in that with external unity you may still say, “I am one with everything” and then with internal unity, you say, “There is only one, there’s nothing, there are no differences.”

One of the early researchers in psilocybin was Walter Pahnke who was an investigator here in Maryland, at Spring Grove Psychiatric Centre and Maryland Psychiatric Institute. Walter wanted to understand if he could evoke religious experiences with psilocybin. Are you familiar with the Good Friday experiment? He conducted this experiment at the seminary associated with Harvard University and he recruited a number of seminary students. Before attending this Good Friday Mass, he gave half of the individuals in the study a high dose of psilocybin and the other half a high dose of Niacin and everybody went into church and participated in this Mass. There are lots of amazing features of the study.

There are a lot of completely problematic features of the study too, but after everybody got out of mass and came down from their experience, he had everybody complete a questionnaire to try and quantify in some way the dimensions of the experiences people had. He based this questions on Stace’s work. He asked questions that probed and targeted each of these potential features of mystical experience. His theory being that that’s what psychedelics do, they evoke a mystical experience, so why not put this in a religious context to maximize the potential that we get the experience in seminary students.

RM: Research was… different back then.

FB: Yeah, much different. An interesting point in our history is that one of the investigators at the time, in Spring Grove and Maryland Psychiatric was Bill Richards. There are lots of interesting digressions here we could go down but of course the psychedelic research program eventually closed. Bill went about his life as a therapist and when Roland Griffiths here at Hopkins reignited the psychedelic research, well started his first study he was fortunate enough to get Bill Richards to come and be the clinical director of that first study. Bill basically started, picked up where they left off. And so, since the beginning of our program we’ve been following that thread of using the framework of mystical experiences to describe the unique phenomenology of psychedelics.

It may have been a terrible error in marketing, in that the word mystical itself can bring up all kinds of misconceptions in people, “Oh it’s mystical, you can’t describe it. It’s something that can’t be described while you’re trying to study it, or mystical in a sense that it’s like the initiation of a religion, “Only a few can get to this place.” Or that it’s religious, you have to be a Judeo-Christian or be from a given tradition to understand it.”

It really, at its heart, transcends religious definitions and boundaries. A mystical experience, despite the scary-sounding name, is actually somewhat of an operationally-defined construct [meaning that the way it will be measured can be articulated] . In psychology we’re really excited about operational definitions. What’s your operation definition for attention? People will argue about that. Lots of people might be able to agree on basics. What’s your operational definition of memory? That’s a little bit more concrete. What’s your operational definition of decision making? These are things that you have to operationally define before you experimentally interrogate them.

We don’t ask people did you have a mystical experience? We have a questionnaire that systematically addresses each of the theoretical domains that Stace proposed. The original version of our questionnaire that we started using in 2000 hit all of Stace’s domains. More recently, Catherine McLean from survey data and I from experimental data did some real hardcore psychometric evaluation of the questionnaire and we pared it down at least from the way that the questions and responses behaved. It seems like there really are four factors. People who felt positive mood, ineffability, timelessness and spacelessness and a general what we call mystical factor which includes external, internal and sacredness questions.

We have this study and questionnaire. Every good psychologist has a questionnaire, right? It has good reliability; it has validity and has a nice, well-behaved factor structure. We use this as a heuristic framework for trying to describe the profound, wild experiences that people have with these drugs. We recently completed a [psychedelic dosing] study on individuals who have a long-term meditation practice and by and large these were people who were following Buddhist practices, although many of them wouldn’t self-identify as Buddhist because they didn’t like the idea of self-identifying as something. Certainly not Western Judeo-Christian or people of the book type of religious folk.

They were able to, without using the term mystical – a lot of them bristled at the term mystical – but they were able to complete this questionnaire in such a way that comported quite well and quite beautifully with all of the other responses we’ve got in other studies. So, do you believe in religion, do you believe in mystical experience? That doesn’t matter, fill this questionnaire out. Did your sense of time and space deteriorate. Were you able to orient yourself in space and time? Did you experience joy or peace or love? How well are you able to describe the experience using words? Can you agree with the following statements: I felt at one with everything around me; boundaries between self and other began to erode? Things like that. Yeah to all of them? Mystical experience.

Do we want to call it a religious experience? I mean people can have religious experiences with these drugs but I think at the end of the day what that really is, is an attempt by an individual who may have a religious predisposition to try to make sense of it using whatever language they have available to them, or whatever frameworks they have available to them. The interesting thing with that is that if you ascribe to a certain tradition, that doesn’t mean you’ll see imagery in your [psychedelic] session related to that image and that tradition. Christians have seen Hindu imagery, Hindus have seen Christian imagery, that’s a brief example.

We’ve recently completed a study that I wasn’t involved in with giving psilocybin to religious professionals, with the acknowledgement that many religious professionals experience some pretty deep and profound burnout in their ministry. The question being can psilocybin help people to recover from that burnout, reignite the faith?

There have been studies in this relationship between psilocybin and mystical experience or religious experience, I’d say from the very beginning. What we’ve found is that strength of mystical experiences as we’ve operationally defined it actually seems to mediate the effect of psilocybin on depression and anxiety. The statement really is that the subjective effects are important in realizing the therapeutic outcomes.

Interviews have been edited for length and clarity