What happens when you give an octopus psychedelic drugs? Dr. Gül Dölen discusses her research into psychedelics and the brain.
Neuroscientists are currently researching how psychedelic drugs like MDMA, LSD, psilocybin, ketamine, and ibogaine reveal how our brains work and, ultimately, if they can be used therapeutically. One such researcher is the University of California, Berkeley’s Dr. Gül Dölen, who is investigating how these drugs unlock critical periods in the brain.
“Critical periods are these windows of time where the brain is especially sensitive to the environment around it,” Dölen explained. “When they’re open, typically during development in childhood, you are able to learn easily and well.”
Dölen is a professor and the Renee and Bob Parsons endowed chair in the Department of Psychology, the Helen Wills Neuroscience Institute, and the Berkeley Center for the Science of Psychedelics at the University of California, Berkeley. She’s also an adjunct professor in Neuroscience and Neurology at the Johns Hopkins University School of Medicine.
In her work studying mice and octopuses on psychedelic drugs, she found that the drug “trips” can be key to reopening critical periods of the brain. Her upcoming PHATHOM-Stroke Project (Psychedelic Healing: Adjunct Therapy Harnessing Opened Malleability) will test whether using psychedelic treatment in conjunction with physical therapy will help stroke patients recover motor function, even months or years after having a stroke.
Dölen joined Being Patient founder Deborah Kan in a conversation about her latest psychedelic drug research, critical periods in the brain, and her hopes for future research in this space.
Read or watch the conversation below.
Being Patient: Can you define psychedelic drugs for us and what types are used in the type of research you use?
Gül Dölen: Historically, starting from the 60s and 70s, the definition of psychedelics has been this broad category of drugs that induce an altered state of consciousness. Now that sounds kind of like loosey-goosey, until you sort of dig into the different kinds of psychedelics and you realize how big of a category it is.
When you subdivide based on the flavors of the acute, subjective experience of being in that altered state of consciousness, you can have psychedelics that are like ketamine, which we think of as dissociative psychedelics— like having an out-of-body experience.
Then, a lot of people, when they think of psychedelics, they’re thinking of hallucinogenic psychedelics like LSD, magic mushrooms, and ayahuasca. Then, the most prominent in having only one or two members of this category is the psychedelics that we think of as empathogenic, meaning they induce this very pro-social character [that] people want to cuddle on them. The classic example of that category is MDMA or ecstasy.
Then [the] fourth category, which I’d love to talk about in detail, is oneirogenic psychedelics. These are drugs like ibogaine that induce a dream-like state, this continuous, very long trip. In this case, for ibogaine, [the] trip is characterized by dreaminess.
Being Patient: Do all of these drugs derive from plants, or are some of them laboratory-based?
Dölen: Some of them are chemicals that have been completely synthesized, synthetic compounds that never existed in nature. [For example,] ketamine is a derivative of PCP, and it was synthetically derived. LSD is a completely synthetic chemical, although it was derived from ergot, which is a type of fungus that’s found in plants.
Then MDMA is a purely synthetic chemical, although there are compounds that are similar to it found in nature. People say sassafras might be a natural version of it. Although you know the history of MDMA, it was made in a laboratory, completely synthetic.
Then, we have the plants and the fungi, like the magic mushroom; psilocybin is a good example of that category. Ibogaine comes from the bark of a root of a plant of a tree.
Being Patient: What do we know about how psychedelics have been used throughout history?
Dölen: This is not my area of expertise; just generally, we know that psychedelics have been used across all human cultures for as long as we know of human history. I think people tend to think of it in the Americas, thinking of the Native Americans who are using this, like ayahuasca, mushrooms, and peyote, in their ceremonial practices.
They are using them in both medicinal and spiritual practice. Ibogaine is used indigenously in a country in Africa called Gabon. There’s even some evidence that maybe people were using this in ancient Greek times. Some people have made the argument that psychedelics are part of the ritual wine that the ancient Greeks used, including people like Plato, to go to the other side and learn about death and come back ready to face life.
They’ve been used in a variety of different ways. I should also say that there is some evidence that animals also like psychedelics. There are the stories of the reindeer and goats. Animals interact with psychoactive compounds and possibly even like them.
There’s some evidence that they do like them, although what [is it like] for a mouse, goat, or reindeer to experience that sort of “god-like” sense we often have on psychedelics? Who knows, but certainly, they’re around, and they have been for all of our evolutionary history.
“Just generally, we know that psychedelics
have been used across all human
cultures for as long as we
know of human history.”
Being Patient: How did you start studying psychedelic drugs and the brain?
Dölen: I’ve always been interested in psychedelics— since I was in college, actually, even before that. I designed my own major in college. It was comparative perspectives on the mind, and I was interested in understanding, from a philosophical perspective, from a neurobiological perspective, from a comparative religions perspective— what is consciousness? How [do] we experience the world, and what are the mechanisms for that?
I remember when I was taking philosophy classes and neuroscience classes — this is now 30 years ago, almost— feeling despondent that I would never in my lifetime, get at these big questions and get the big answers to things like, “What is consciousness?” I made peace with it by saying, “I’ll just stick to the smaller problems like learning and memory and curing diseases because that seems like we could tackle those problems in my lifetime.”
[With psychedelic drugs,] you take a pill, and then suddenly the world, your conscious experience of the world, is so radically altered that it seemed to me that it would be sort of key to getting at these bigger philosophical problems of mind-body-consciousness. I had it in the back of my mind.
At the time, we were still very much in the middle of the drug war [and] it was still looked upon as not serious science to pursue things that relate to psychedelics. Frankly, we just didn’t have the same framework of understanding the brain at that time for me to have even known where to begin on trying to understand what psychedelics were doing in the brain, so I back-burnered it.
I was interested, but I didn’t pursue it until I opened my own lab about 10 years ago. I opened my own lab at Johns Hopkins. At Johns Hopkins at the time, there was the person who had originally started my department, Saul Snyder, [who] was a pioneer in psychedelics research.
He discovered one of the receptors that is thought to be the way that LSD works. For example, he’s discovered many of the receptors in the brain, including the one that LSD binds to. He was very supportive of this idea that now might be the right time to kind of come back and look at psychedelics. It took a long time for me to come back to it, but I’m still interested in those big problems.
“You take a pill, and then suddenly the world,
your conscious experience of the world,
is so radically altered that it seemed
to me that it would be sort of key to
getting at these bigger philosophical
problems of mind-body-consciousness.”
Being Patient: Do psychedelics help with neuroplasticity in the brain?
Dölen: I’m so glad you asked this question, because it’s a word that gets thrown around a lot in a lot of contexts, and people use it differently depending on what they’re talking about. As a synaptic physiologist, somebody who uses techniques like wholesale patch clamp recording, I have a very specific definition of synaptic plasticity, but if you ask the average doctor, they basically mean anything that changes over time, which I don’t like. It’s not very precise.
The way that I define synaptic plasticity is the change in the response properties of a synapse in response to a specific [stimulus.] So, it’s thought to be the mechanism for learning and memory. [There are] a lot of different kinds of plasticity, and plasticity can go wrong in a lot of different diseases.
It’s not the case, for example, that all plasticity is good, just like not all growth is good growth. Under the right developmental circumstances, it’s great to grow, but under cancer circumstances, growth is not a good thing. Similarly, with synaptic plasticity, yes, it’s important for learning and memory, but it’s also too much of it; what I call hyper-plasticity is associated with disease states like addiction and possibly autism.
There’s also some evidence that it’s involved in the formation of tumors in the brain, so we want to be careful not to sort of get excited and say, “Oh, plasticity, plasticity, plasticity,” and be more specific about what we mean by that.
Being Patient: What type of plasticity are we talking about when learning a new thing like an instrument or a language?
Dölen: Just to introduce this idea early in the conversation, what I want to kind of get people to start thinking about is that plasticity itself is the ability to induce plasticity. It’s very different at different stages of development.
When you’re a kid, you’re able to learn from the world easily. You’re learning languages, you’re learning visual stimuli, you’re learning how to ride a bike, you’re learning all of these different things, and it kind of comes easily. This is why we say, “Kids are like sponges. They pick up everything.”
As you get older, it becomes much harder to learn new things. That’s why there’s the adage, “You can’t teach an old dog new tricks,” because the ability to induce plasticity is harder as you get older.
That phenomenon of the plasticity of plasticity, or the change in the ability to induce plasticity, actually has a name— it’s called meta-plasticity. What we think that psychedelics are doing, or is not inducing plasticity by themselves, but rather changing the ability to induce plasticity. Meta-plasticity is what we think psychedelics are doing, and they’re sort of restoring to the old brain that ability to induce plasticity similar to the way that it was as kids.
“Meta-plasticity is what we think
psychedelics are doing, and they’re
sort of restoring to the old brain that
ability to induce plasticity similar to
the way that it was as kids.”
Being Patient: Do you think this is because psychedelics are subconsciously taking away the inhibitions that we’ve learned as we’ve matured?
Dölen: A little bit. Just to give you another framing of this, instead of using plasticity, because there are all these different types and different contexts for it, I like to focus on the concept of critical periods. Critical periods are these windows of time where the brain is especially sensitive to the environment around it. When they’re open, typically during development in childhood, you are able to learn easily and well.
That concept has been around for almost 100 years in neuroscience, and it’s been so important to neuroscience, this idea of critical periods that something like 7000 papers have been published on the topic of critical periods. Three Nobel prizes have been given in trying to understand the mechanisms underlying critical periods.
All of that study is inspired by the fact that we understand that our ability to reopen critical periods in adulthood, that being limited is why we’re so bad at curing diseases of the brain. Now, in trying to understand the mechanism for these critical periods, we’ve come up with lots of different mechanisms in those 7000 papers. You can imagine there are lots and lots of different ideas about what constrains critical periods and what enables their reopening, and one of them is inhibition.
Neurons of the brain come in two basic varieties: excitatory and inhibitory. There has been this idea out there that as the brain matures, that inhibitory network gets more solidified and constrains memories, but that’s not the only thing. The other idea that people have had around why critical periods close is this idea of meta-plasticity, and then a third major category is the maturation of the extracellular matrix that supports the space between neurons and regulates the availability of transmitters and their precursors.
Being Patient: In studying critical periods and psychedelics, you started in mice, and now you’re studying octopus. Tell us about that.
Dölen: Yes, that’s true. Let me back up and say that when I first started my lab, some people were studying psychedelics in humans. I remember going to a conference, [where] some very well-known researchers were there, and they were basically poo-pooing the idea that you could get anything interesting out of studying animals.
[This is] because, to these people’s minds, the whole revived interest in psychedelics is all about therapeutics and humans. “We don’t really need to understand the mechanism,” was the way that they were talking, “Because they work, and so who cares how they work? They just work.”
They were very much pushing the idea that the really interesting part of psychedelics is stuff that’s only unique to humans, like, “Who cares what a mouse seeing God looks like anyway,” [that] it’s not an interesting question. I was very much opposed to both of those lines of thinking because I had just come off of another clinical trial that I was tangentially related to that had failed, I think, partially because we didn’t understand the mechanism.
I also know that almost everything that people think they know about the brain, they actually know about a mouse brain, and then it’s been extrapolated to human brains through correlation studies with imaging, but that the mechanistic insights come from humans.
The mechanistic insights that people think they’re getting by giving humans psychedelics and then putting in a brain scanner, looking at default mode networks, amygdala, and all of these different brain regions and saying, “Look, the signaling is going up and down, so now we understand how psychedelics work in a human.” [I wanted to prove] that those insights were essentially wrong, and the reason I think that they’re wrong is because an octopus doesn’t have any of those brain regions.
It doesn’t have a cortex, it doesn’t have a default mode network, it doesn’t have a nucleus accumbens, or an amygdala, and yet, if you give an octopus MDMA, it will do the same pro-social behavior that a human or a rat does. What this tells us is that the mechanistic insights that we’re getting at the anatomical level aren’t giving us the core basic mechanism that’s happening to enable these processes.
“It doesn’t have a cortex, it doesn’t
have a default mode network, it doesn’t
have a nucleus accumbens, or an
amygdala, and yet, if you give an
octopus MDMA, it will do the
same pro-social behavior that
a human or a rat does”
Being Patient: What are these pro-social behaviors, and what does this mean in terms of what’s happening inside our brain?
Dölen: Octopuses, despite what you might have seen on a Netflix special about octopuses cuddling men who are going through divorces, aren’t particularly social. The vast majority of them are, of the 300 or so known species, asocial. If you put two of them in the same tank, they’ll kill each other.
Some are sort of socially tolerant. They won’t kill each other, but they’re not like hanging out and doing anything together, either. What we found is that if we gave octopuses MDMA, then we could measure their likelihood of wanting to spend time in a chamber that contains another octopus versus not.
Because the species we chose is asocial, they spent almost as far away from the other octopus as possible. 30 minutes after they received the MDMA, they spent most of their time on the side that had the other octopus. The other octopus was underneath the inverted flower pot because if it didn’t work, we didn’t want them to kill each other, so we had to protect the other animal in case it didn’t work. They didn’t measure their specific social interactions, just how much time they spent.
Being Patient: Why is this important? Some of your studies have been about stroke therapy. Is this related to that, or is this completely separate?
Dölen: It started out completely separate, but I think now we’re getting excited about how they might be related. To give you a sense of that, let me jump ahead to the mouse studies because I think that will help us connect the dots between the human, mouse, and octopus.
My lab studies social behaviors, and so we were interested in what happens to the ability to form social groups across development. We have this hunch from human studies that teenagers are much more susceptible to peer pressure.
They care a lot about their social interactions, and that period of time when they’re learning from their social peers is important for developing things like culture and hierarchy, knowing how to give gifts, and what color acid wash jeans to wear, all of those things that we as humans care a lot about, but then you outgrow it.
As an adult, thankfully, you know you can wear comfortable mom jeans because they’re comfortable without worrying so much about what your peers think about you. We had this sense that it was changing over development, and we wanted to define this period of social development more empirically.
We can’t do that kind of experiment on humans because it takes too many people. It’s massively expensive to look at so many different ages and individuals. We did it in mice, and we used a different assay, not the one I described for the octopus, a learning assay for social learning.
We found that the juvenile mice, indeed similar to humans, are much more sensitive to and learn from their social environment very robustly. As the animals get older, that learning goes away, and so that is defined as a critical period for social reward learning, which was, by itself, a really exciting discovery.
[This is] because it was the first time we could finally start looking at the mechanisms underlying things like why teenagers are so much more susceptible to peer pressure, how that relates to drug addiction, [and] all of those kinds of questions.
At the time, we thought, “Well, there are these clinical trials where people are saying that MDMA is so good for treating PTSD. Wouldn’t it be amazing if the reason that MDMA was working so well in those human clinical trials is that by the time adults get around to going to therapy for their PTSD, you know, those critical periods have closed, and what MDMA is actually doing is reopening that social reward learning critical period and enabling people to form that therapeutic bond to their therapist and love themselves again, just because you’ve reopened this critical period.”
When we made that discovery and published it in a Nature paper in 2019, the way we ended that paper was, “Yep, we figured it out. MDMA restored social reward learning and, of course, it did so because MDMA is this pro-social drug.” It induces pro-social behaviors in mammals and induces it in octopuses. It’s just all about the social, social, social.
Then, my postdoc did another control experiment. That control experiment was to say, “Okay, well, MDMA is this very unique drug in terms of pro-social behavior, but it’s closely related to a couple of other drugs, too.” On the one hand, it’s related to the methamphetamine class of psychostimulants.
We looked at cocaine, and we asked whether or not cocaine reopens this critical period, and it doesn’t. We were like, “Okay, great. It’s really specific to the pro-social effects,” but then my clever post doc, Romain Nardou, also did another control. He said, “MDMA is also related to the psychedelics group. Let’s look at some of the other psychedelics.”
He started with LSD, and uh-oh, suddenly LSD was reopening it. Nobody’s doing 30-person cuddle puddles on LSD. This was a fly in the ointment of our grand theory that this MDMA was working because of the pro-social effects. What it suggested instead was that this altered state of consciousness that’s common across all psychedelics is really how this critical period reopening is happening.
“Suddenly LSD was reopening it…
What it suggested instead was that
this altered state of consciousness that’s
common across all psychedelics is really
how this critical period reopening is happening.”
Being Patient: How did you get from that point, with your mouse and octopus studies on critical periods, to studying strokes and psychedelics?
Dölen: I’ll skip a bunch of the details, but basically, what we figured out is that all psychedelics, whether they’re pro-social or not, [can] reopen this critical period. Because it doesn’t matter whether they’re pro-social, we thought, “Maybe these drugs are those master keys for unlocking all kinds of critical periods.”
It’s not [only] about social. There are a lot of critical periods that have nothing to do with social behavior. There’s a critical period for vision, there’s a critical period for touch, and there’s a critical period for motor learning. That critical period for motor learning briefly reopens when you have a stroke. It stays open for about two months.
If, after you have a stroke, you do not get enough physical therapy, it closes back up again, and then you’re done. You’re not going to get a lot of benefit from more physical therapy once that critical period closes.
We thought, “If we’re right that these are the master keys for unlocking critical periods, then we should be able to unlock other critical periods.” My lab right now is very focused on the idea of reopening the critical period for motor learning after stroke to kind of get back that ability of physical therapy to be able to restore motor function.
“There’s a critical period for vision,
there’s a critical period for touch, and
there’s a critical period for motor learning.
That critical period for motor learning
briefly reopens when you have a stroke.”
Being Patient: Is there a critical period for memory? In the future, could this be applied to neurodegenerative diseases like Alzheimer’s?
Dölen: Probably not, unfortunately. I would love to be the person who solves Alzheimer’s, both for myself and for everybody else I know out there who has it or has a family history of it. To me, it seems that the neurodegenerative processes that are causing those diseases, once their neurons are dying, we don’t believe that psychedelics are causing more neurons to be generated. I don’t have a huge amount of hope that in those cases, in those neurodegenerative diseases, that psychedelics are going to be able to bring back those memories.
Being Patient: In terms of micro-dosing psychedelics, are there any brain health benefits?
Dölen: We looked at microdosing in our studies, and found no evidence that microdosing [can] reopen critical periods. Whatever microdosing is doing, it’s either so below the detection threshold of what we are measuring that it’s not something that we can study in this way.
I will also caution you that a lot of the double-blind clinical trials around microdosing have failed to show any difference, and there might be some effect of a big placebo effect happening there. The other thing I would just say, I’m not sure that there’s nothing to microdosing.
I think that people have a response to it. What I would caution is that it seems that microdosing, people build up a tolerance to it, right? Even people who are avid believers in microdosing will say that, after doing it for a couple of months, the effects wear off. Mechanistically, I think that that probably relates to, you know, this is triggering something similar to what SSRIs, or what drugs like Prozac are doing to the brain.
Just by flooding the synapse with too much serotonin, they’re causing the receptors to get internalized. That receptor internalization is probably responsible for the fact that you have to take higher and higher doses to have the microdosing work after some amount of use.
I am much more in favor of macro-doses than microdoses. I feel like the real therapeutic potential of psychedelics is in having big trips that reopen critical periods and enable these windows of time where you can get a lot of either psychological or, in the case of our stroke studies, physical therapy to work better.
“I feel like the real therapeutic potential of
psychedelics is in having big trips
that reopen critical periods”
Being Patient: When you say higher doses, how much do people have to be given to see an impact based on the animal studies you’ve researched?
Dölen: What we discovered from the mouse studies is that the duration of the open state of the critical period is proportional not to the dose of the psychedelic but to the duration of the trip. If you’re taking a psychedelic like ketamine at the psychedelic dose, which is much less than the anesthetic dose of ketamine, but if you’re taking a psychedelic dose of ketamine, that trip is going to last something like 30 minutes to two hours.
In contrast, something like psilocybin at a psychedelic dose of psilocybin, not a microdose, but a psychedelic dose of psilocybin, that trip is going to last somewhere between three to five hours. MDMA the same thing, three to five hours. LSD, a little bit longer, [at] eight to 10 hours. ibogaine is the rock star of the group because a trip on ibogaine lasts anywhere from 36 hours to 72 hours.
It’s an extremely long trip, and proportional to those durations of the trip, we know that ketamine reopens the critical period for social learning for about 48 hours. It’s closed by a week. MDMA and psilocybin reopened the critical period for about two weeks, which was closed by three weeks. LSD opens [it] for three weeks, closed by four weeks. Ibogaine is open for four weeks and beyond. We haven’t looked further than that. For me, this provides an explanation for why people are going down to Mexico or Brazil to do ibogaine.
Being Patient: What are your thoughts on Ayahuasca for brain injuries like CTE?
Dölen: Our working model is that when one brain region gets injured, another brain region nearby can take over that function and remap, relearn, or repurpose nearby brain regions to take over that function. The reason we think that is because we know from things like phantom limb, where the working model is when you lose an arm, it’s the nearby part of the brain, the cortex, that maps the nearby jaw right next to the arm.
Those neurons that are normally mapping the sensory information from the jaw can get repurposed to also map the lost arm, and that’s why you can kind of rub on the jaw and get some relief from the pain that comes from losing a limb.
Basically, the brain gets tricked into thinking that it’s in a constant state of flex, and that’s painful. We think that similarly, following a traumatic brain injury or following a stroke, if you get restoration of function, like through a cochlear implant, then it’s not that the neurons are growing over again, or that there’s, a resprouting of neuronal dendrites or anything, but rather that nearby brain regions can get remapped or repurposed by through mechanisms of meta-plasticity to those functions.
“Our working model is that when one brain
region gets injured, another brain region nearby
can take over that function and remap, relearn,
or repurpose nearby brain regions
to take over that function.”
Being Patient: Where are we in psychedelics research in terms of helping people who might have a stroke or might have a brain injury? How far away are we from really understanding some of those answers so that if they do work, people can indeed get help?
Dölen: Science is hard, but you are tougher. That’s what my postdoc friend used to tell me when I was struggling with experiments. It’s hard, and we have a long way to go. I know that there are a lot of people hoping for quick answers here, but I do want to caution and ask for people’s patience on this because we can have good clinical evidence.
For example, the clinical evidence from the MDMA-assisted psychotherapy trials, those experiments, took a long time to collect that data [and] to do the experiments. We’re still in the process of trying to get approval, I would say that beyond just the clinical data, though, I’m going to make my push again to understand the mechanisms.
If we hadn’t understood this mechanism, we never would have thought of stroke, right? Because the critical period explanation doesn’t necessarily fit with the “hug your therapist” kind of pro-social explanation we originally thought we were getting in.
The other major thing, and I think that this is an exciting moment in psychedelics. For 50 years or so, we’ve been working under this assumption that there are biochemical imbalances in the brain. So, depression is just a biochemical imbalance in serotonin, and all we have to do is increase or mess around with serotonin a little bit, and poof— depression is cured.
What the psychedelics are really teaching us, besides these specific mechanisms that I’m talking about, I think more generally, careful clinical trials are revealing that the biochemical imbalance model of neuropsychiatric disease is probably wrong and that we need to be thinking of these diseases as [being] of learning and memory.
I think that the fact that if you take MDMA and you go to a rave, you’re probably not going to cure your PTSD, but if you take MDMA and you go to a rave, maybe you’re going to do better on motor learning because you’ve paired the right type of learning to this window of opportunity, this open state of the critical period that enables that learning and memory to happen.
Understanding disease in this way is a radical shift in how we approach diseases in general, but specifically neuropsychiatric diseases. I think [this] gets us away from this idea that you take a pill, you go home, you spend the rest of your life medicalized on that bill, and rather offers an opportunity to offer cures to people, where you take the drug two or three times, you have an insight, you practice, you do the physical therapy, and then your function is restored. That, I think, is very hopeful for those of us who are in the field.
Katy Koop is a writer and theater artist based in Raleigh, NC.