Interview with cognitive neuropsychopharmacologist, Manoj Doss, on the risk of psychedelic science being oversimplified for the sake of the general public’s understanding, and the study he authored on psilocybin therapy increasing cognitive and neural flexibility.
The Dales Report (TDR): The Default Mode Network (DMN) is a popular, perhaps simplified, explanation for how psychedelics affect the mind, specifically habitual thought. Can you explain the DMN for this who may not be familiar, and take us a step further by highlighting the limitations of the explanation.
Manoj Doss (MD): The Default Mode Network is a set of regions in the brain that tend to communicate with each other. Their activity tends to fluctuate together in sync. Along with some other networks, these are networks composed of regions that are multimodal, so they’re not strictly visual or auditory areas. They’re referred to as “association cortices” where there is an integration of multiple senses. It’s involved in things such as episodic memory, the ides of self or “self-referential processing.” But it’s also involved in the opposite of self-referential processing such as the theory of mind (trying to think about what other people are thinking about). It’s odd that people have focused on the DMN as being strict self-referential processing. The reason being, at least in the psychedelic world, that many people in psychedelic sciences are Freudian psychologists. They need an ego to exist in the brain. The DMN fits that, although it is also thought to be a very social, relevant network. One limitation to this interpretation being particularly important to psychedelic drug action is that it’s involved in the opposite of the self, but the main problem is that there are larger effects found outside the DMN. All drugs seem to impact the DMN, including alcohol, amphetamines, THC, ketamine (although sometimes it has been shown to do the opposite and reduce communication with the DMN). There are also situations in which SSRIs, which have no psychoactive effects, at last in a single dose, have been shown to decrease communication within the DMN. All of these studies are based on what’s known as resting-state functional connectivity. Essentially, looking at the brain when you’re just lying there in the scanner. When you’re comparing people who took a placebo and you’re telling them to “rest” in the scanner, they might rest so well that they fall asleep in the scanner. It’s a weird comparison looking at what happens under a psychedelic when you’re paranoid thinking about what the researcher wants out of you, listening to the weird scanner sounds, and comparing that to a state when you’re essentially asleep. What we need is a task-based fMRI to look at people’s behavior simultaneously with the actual brain activity.
TDR: Is it frustrating for you that psychedelics have gone mainstream because the information has been distilled down for the general public to understand so much so that oversimplification has become misleading?
MD: It’s not so much that it’s not the truth, it’s just that it’s ignoring a lot of other information. I get that we have to distill it for the general public. Just to give you a quick example of how certain scientists need to be more cautious about what they’re saying, and how reporters have to be more cautious about what they’re reporting…when you see brain activity of any sort, there are multiple reasons for it. If you see the amygdala is activated, people automatically think it’s the emotion center of the brain, especially fearful emotions, therefore, someone must be afraid. But you can also get the amygdala activated when you’re happy or you just see salient stimuli. If I were to show you a checkerboard versus a grey screen, you’ll get more activity from the checkerboard because it’s more salient. That alone should tell you, well, what are people doing to get that brain activity?
TDR: You mentioned in an interview in the newsletter, The Microdose, from UC Berkeley, that you’re “baffled” that people aren’t looking into theories of the mind that have been around for centuries. Are you referring to anecdotal evidence or personal stories seeming to outweigh experimental psychology?
Yeah, and I can give you a few examples. I’ve seen almost every psychedelic researcher make this fallacy, which is saying that psychedelic drugs are going to teach us something about consciousness, that for some reason these drugs are important to consciousness, and that they’re “altered states of consciousness.” Wait a minute, all drugs alter consciousness, and all psychological manipulations, minus things like somatic priming, can alter your consciousness. Putting my hand in front of my face is a massive alteration of consciousness, more so than any visuals I might get from a psychedelic. I literally can’t see what’s in front of my face anymore. Clearly, that was biased from people taking the drugs themselves and feeling like these drugs are telling you something about consciousness. Now, feeling that you know something is not the same thing as actually knowing something. In another situation, there was a paper that came out in which they looked at the effects of LSD on emotionality while listening to music. What they ended up showing was that people under LSD found music to be more emotional. This was not interesting to me, at all. If you were to give anybody any stimulus under LSD, they’re probably going to find it more emotional than under placebo. If you give somebody a rock under LSD, they are going to find that to be more emotional than if they weren’t on LSD. Every drug under the sun has been taken at a concert. This was a boring study that I felt was probably biased by personal use. The third example is a difficult one to fully comprehend. It involves something known as a “temporal reproduction task.” Essentially, you see a stimulus on the screen for two seconds and you push a button on a computer for how long you saw the stimulus. In the study examining microdoses of LSD, they showed that people were more likely to push the button for a longer period of time. If the stimulus was on the screen for two seconds, you would now push the button for 3 seconds. They interpreted that as temporal dilation because that’s a concept people use under psychedelic drugs. You sit there for ten minutes and think ‘oh my god, did an hour just pass?” That’s a poor interpretation of what they found because if you thought what was on the screen for two seconds was three seconds, when you push the button down, you’re going to hold the button down for two seconds and think that that’s three seconds and you’ll let go. You should really find that there’s no effect. They failed to mention that there was a microdosing psilocybin study in 2008 that found the opposite. All you can say at that point is that psychedelics make you worse at that task. You can’t say that it’s temporal dilation. People aren’t turning to what’s been done in psychology, data, or even the way to design studies. Instead, they are kind of going off personal use and trying to make things sound sexy when I don’t think they really are.
TDR: Let’s talk about the study you authored: psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder.
The study examined psilocybin’s effects on two concepts related to neuroplasticity: cognitive flexibility and neural flexibility. These are important terms to know because you found, and I quote, “that greater baseline neural flexibility was associated with less improvements in cognitive flexibility.” Please explain the relevance of this.
MD: The concept of cognitive flexibility is being able to adapt to one’s environment, and then there is neural flexibility, which is variability in the brain’s activity. For a while, people thought that more noise in the brain was a bad thing, and it can be. For example, if you’re trying to pay attention, it’s not good to have constant back and forth patterns of activity. But there are situations where it is adaptive to be searching through all the possible states that your brain can go through. This is where neural flexibility has been linked, to some degree, to cognitive flexibility. What we found was that one week after the second dose of psilocybin for patients with major depressive disorder, keeping in mind that this was a moderately high dose and then a really high dose, their brain became more flexible, there was more variability in terms of how the brain was communicating within itself, as well as greater cognitive flexibility. What was interesting was that the relationship between those two wasn’t really a one-to-one mapping. It’s not that those who got greater increases in neural flexibility got greater increases in cognitive flexibility, rather, it was the opposite. If you had greater neural flexibility by the end of your second dose of psilocybin, you actually had the least benefits in cognitive flexibility. There are many potential interpretations of this. It could just be an error due to the way we measure cognitive or neural flexibility. The other possibility is what’s known as an inverted-U. If you have a little bit of a good thing or a moderate amount of a good thing, it can potentially enhance your performance to a certain extent. Stress, for example. A little or moderate amount of stress might help you get your work done. But if you get overloaded, you’ll be an anxious mess and won’t get anything done.
TDR: And that can be applied to coffee or alcohol too. What’s the myth? A glass of wine per day can be good for you?
MD: Exactly. The glass of wine is a controversial one. Some people say you don’t need a single glass. I don’t mind having a glass of wine a day, and I feel like I’m doing alright. Neural flexibility has been shown in people with schizophrenia, and even relatives of patients with schizophrenia have higher neural flexibility. What we’ve shown is that although most people did improve their cognitive flexibility, perhaps we were a little bit past the most beneficial range of neural flexibility to see the maximum benefit.
TDR: Was the intention of the study to find the sweet spot in relation to incorporating psilocybin into therapy?
MD: That was definitely a secondary measure. The main intention of the study was just to see how it improved depression. It’s well known that patients with depression have impairments in cognitive flexibility. It seems to be paired with many disorders, including addiction. This was a marker to see if we could actually see improvements, especially because, at last acutely under the effects of psychedelics in animal models as well as humans, you actually get impairments in cognitive flexibility.
TDR: There is so much information coming out right now about psychedelics. We have a lot of investors who come to The Dales Report to see where the industry is going. Based on what you know today, what’s your best guess for where the future of psychedelics is headed?
MD: I could be completely wrong on this, but right now there are a lot of people trying to make patents on psilocybin. I think psilocybin is just one drug. There are 500+ drugs out there. One thing that’s going to happen is looking into other drugs that might be more beneficial for certain disorders, and looking at combinations of drugs, perhaps even combining different hallucinogens like ketamine and psilocybin, or MDMA and psilocybin, or sedatives and psychedelics, which might be beneficial for some people. Or combining brain stimulation with psychedelics. Or what you do with that neural flexibility might be what’s important here. For example, while acutely under the influence, people just lie on a couch with eyeshades on. It could be the case that certain types of queuing of memories or therapies could be useful. Or after the trip is over, when there is still neural flexibility one week later, it might be important to do certain types of therapy beyond just checking in with people.
TDR: A Zoom call with your therapist the next day might not necessarily be the most effective for capitalizing on that window of plasticity?
MD: It might be if it’s the right therapy, but in our studies, participants come in the day after, and it’s not just a Zoom call. Right now, it’s a lot like “mom and dad” checking in on you rather than having evidence-based psychotherapy. People talk about all different kinds of therapies, music and dance being some. I think [it could be effective] to combine things like that after or during psychedelics therapy. Although, during high doses, it’s important that people don’t injure themselves.