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.
When you think about psychedelics, 3,4-Methylenedioxymethamphetamine (MDMA), also known as Ecstasy, isn’t what first comes to mind. Whilst this commonly used party drug’s status as a psychedelic is still debated by some in the field, MDMA has, alongside more “traditional” psychedelics, become a hot topic in neuropharmacological research, and received its own “Breakthrough Therapy” status from the FDA for treatment of post-traumatic stress disorder (PTSD). Its therapeutic potential for neurological disorders has attracted attention from researchers and ravers alike. In this first interview of our series exploring the Neuroscience of Psychedelics, we talk to Johns Hopkins Associate Professor Gul Dölen, who has spent years exploring the effects of MDMA on the mammalian (and more recently, cephalopod) brain.
Ruairi Mackenzie (RM): In a recent paper, you exposed octopuses to MDMA. Could you tell us why?
Gul Dölen (GD): Years ago, people had started to suspect that psychedelic drugs might be acting on the serotonergic system and specifically MDMA had been shown to be interacting with a protein called the serotonin transporter or SERT. Most people have heard of this transporter by another name because they’ve heard of drugs like Prozac, which is a blocker of the serotonin transporter. Prozac makes serotonin available in the synapse by preventing the serotonin transporter from vacuuming extra serotonin from the synapse. Because Prozac blocks that action it makes more serotonin available.
What MDMA does is it reverses the direction of the serotonin transporter. Instead of vacuuming up the serotonin, it is spewing it out into the synapse. It’s not just making more serotonin available, but it’s actually pushing more serotonin into the synapse. That was the main mechanism that people had focused on for the last couple of decades. When we studied the octopus we just wanted to know whether an animal which is evolutionarily so distant from humans – our last common ancestor was over 515 million years ago – would have the same serotonin transporter, similar enough that if we gave the animals MDMA it would cause the animals to behave in a way that is recognizable to the way that we know MDMA makes humans and other mammals behave.
What was super exciting for us was that when we gave MDMA to the octopuses, they spent more time in the social chamber of the three-chambered tank that we had built for them. This was exactly what happens when we do the same experiment in mice, for example. That was both a little bit exciting and surprising because octopuses aren’t normally social. It was amazing to us that MDMA could encourage social behaviors in an animal that doesn’t normally exhibit social behaviors at all, much less increase social behaviors. What it suggests is that the neural circuitry that enables social behavior exists in an octopus brain but then outside the reproductive period, when they would be socially tolerant, it just gets turned off. What MDMA is doing is releasing that circuitry to act the way that they would when they’re mating, for example.
RM: You also conducted research exposing mice to MDMA – what did you learn from these experiments?
GD: The mouse study had more novel mechanistic details. The way we started studying MDMA really was that firstly we had discovered a brand-new critical period in mouse behavior. Critical periods are familiar to most people because they are aware of the adage “you can’t teach an old dog new tricks”. Anybody who’s tried to learn a second language when they were an adult knows that it’s much harder to do. When you’re a child you pick up languages without even being aware of the effort of learning them but as an adult, when you try and learn a language it’s difficult. The reason for that is the brain is less able to learn information when it’s older than when it’s younger because it has less plasticity. Different parts of the brain have different windows of time when they are most plastic. Those different windows of time support learning and memory of different types of behaviors.
There’s a critical period for language and for vision. What we discovered is that there’s also a critical period for social behaviors and forming social attachments. We think that this critical period for social reward learning is the reason why, for example, kids are so much more susceptible to peer pressure and why they have 400 friends, and they’re always on their iPhones.
They’re insatiably social, whereas most adults relish their alone time and after a week of conferencing for example you need to have some quiet time when you’re not interacting quite so much. What we wondered is whether or not we could reopen that [social] critical period in adulthood. We thought this might be important in certain clinical situations where, for example, a person was socially injured during their childhood, which was leading to all kinds of maladaptive behaviors in adulthood: addiction or PTSD.
There are some theories out there that these are the consequence of social injury during earlier parts of life. If we could reopen that critical period and have them relearn those social interactions under optimized conditions, that might have some therapeutic value. When we were working on the critical period for social reward learning one of the mechanisms that we focused on was the developmental regulation of the receptor for [“love” hormone] oxytocin in a brain region called the nucleus accumbens. In mammals, the nucleus accumbens is one of those nodes of the brain that’s knowing for sex, drugs, and rock and roll and is the pleasure center of the brain. In previous work I had done when I was a post-doc, we had shown that oxytocin acting in that nucleus accumbens node of the reward circuit was really important for encoding the reward value of social interactions.
What we figured out in this more recent paper is that the oxytocin receptor protein that senses the oxytocin in the nucleus accumbens is developmentally downregulated. This downregulation of the receptor corresponds to the time in the animal’s life when social interactions behaviorally become less important for helping them learn new things. We had identified this mechanism, but we knew that targeting it to reopen the critical period would be difficult because despite what you may have heard about intranasal oxytocin, it actually doesn’t get into the brain when you squirt it up your nose.
But then we thought of this psychedelic drug, MDMA. Everybody knows when people take it at parties, they get extremely social and they want to hug everybody. They form these cuddle puddles! So wouldn’t it be cool if MDMA could somehow interact with our neural circuits to reopen the critical period? Basically, that’s what we found that it does. It causes the oxytocin synaptic plasticity mechanisms to come back online and make the adult brain socially plastic again, the way that it was when the animal was a juvenile. We think that this property of MDMA to reopen this critical period is going to be really useful in explaining why this drug works so well for treating things like PTSD. It also gives us some hints about where we might go next; understanding the mechanism helps us to build up other potential applications and figure out how else we might tweak this critical period for therapeutic benefit.
RM: So, should we be giving out MDMA at conferences?
GD: I don’t know about you, but for me, being a teenager was difficult. It’s not without an energetic cost to care what people think about you. I think the great thing about being an adult is not having to care quite so much. I find that to be quite nice. I think a lot of people have a first knee jerk reaction of “Great, I can make my brain young again! I want to make myself young in every way, why not my brain too?” I think that it’s adaptive to devote your emotional energies to other things as you mature, once your group membership is stabilized. If you have a problem that you’re trying to fix, then maybe you want to be able to selectively target this one critical period, open it, fix your problem and then have it closed back up again.
RM: Is there therapeutic potential for disorders with social deficits?
GD: I think that there are a lot of other diseases that we don’t necessarily think of as being social in their ideology but actually are. There’s a lot of evidence that people who become addicts have social injury in their past. A huge percentage of female heroin addicts have been sexually abused when they were children. For those types of illnesses where there is a social injury component, I think there’s an obvious potential therapeutic link.
Even if there is no social injury per se, I think that there is something useful about being able to reopen the social critical period. Being able to reopen the critical period and reform a therapeutic alliance with your therapist, for example, and being able to trust somebody and tell them everything that has been festering because it’s so horrifying you haven’t been able to look at it. I think that’s another way that we can think about how MDMA might be working therapeutically in the context of a critical period for social learning.
RM: These drugs are very heavily regulated in research. Is the regulation proportionate to the risk?
GD: Very soon, I suspect, the FDA will reconsider their scheduling of these drugs. MDMA and psilocybin are both what we call Schedule 1 drugs in the United States. Cocaine, for example, is Schedule 2 and the reason that they have decided to schedule them that way is because cocaine has some therapeutic uses, I believe in dentistry as a numbing agent. There’s no known therapeutic use for psychedelic drugs but given that the FDA has just given both the psychedelics MDMA and psilocybin breakthrough therapy status, which is encouraging clinical trials for these drugs, that rationale for making them Schedule 1 will go away.
The other rationale for making them Schedule 1 is that they are highly addictive. There is to my knowledge no evidence that these drugs are addictive at all. Most people who take psilocybin take it once and they need a rest, they’re not really interested in taking another dose for months. It doesn’t have a profile of a drug that is addictive in any way. I think both of those reasons mean that these drugs will be rescheduled shortly. I hope.
RM: What does Schedule 1 classification mean in terms of access to these drugs in research?
GD: It takes a long time to get a license. You need a separate license for Schedule 1 drugs. It’s different from the license that you need for Schedule 2 drugs. It took our lab roughly eight months or something to get the Schedule 1 license. The FDA has to send people out here and make sure the building is secure and we have the proper locks and safes and double locks and logs and that people who are using it are properly trained in how to handle it and dispose of it and log the amount that we use every time we use it.
It’s involved, and for a lot of science, before you can devote the resources to studying something you want to test it quickly. Just to do a quick pilot study and if it works then you can devote a full-time post-doc to it, put the resources in. When a drug is Schedule 1, and you don’t have a Schedule 1 license, doing that pilot experiment is not feasible.
A lot of crazy ideas just don’t get done because it’s not worth it to invest eight months of paperwork to test one crazy idea that probably won’t work anyway.
RM: They’re often the best ideas.
GD: I think so, yes. With our octopus MDMA idea, we would never have started with MDMA and an octopus if it hadn’t been for the fact that we were already licensed to use it in the PTSD and critical period for social behavior studies. I think a lot of science comes from those one-off, crazy, wouldn’t it be cool if, kind of experiments, that just don’t get done if you have to fill out too much paperwork.
Interviews have been edited for length and clarity