Psychedelic, empathogen, connectogen — how do we classify MDMA? 5 Questions for neuroscientist Matt Baggott
Baggott discusses how he thinks about describing and categorizing MDMA’s effects.
MDMA, also known as ecstacy, has been a hot topic this year. After Lykos Therapeutics submitted an application to the U.S. Food and Drug Administration to approve MDMA-assisted therapy as a treatment for PTSD, many expected it to be the first FDA-approved psychedelic. The FDA did not approve the drug, but many clinical trials are still underway on MDMA as a potential treatment for all kinds of conditions including depression, PTSD, OCD and eating disorders. But there remain basic unanswered questions about the drug, including how and why it works. There also been a decades-long discussion over how to categorize MDMA — researchers have suggested different names to describe its effects: an empathogen (a drug that promotes empathy), an entactogen (a drug that produces a “touching within”), or, as a recent paper argues, a connectogen (a drug that generates a feeling of connection).
To weigh in on this question, we spoke with neuroscientist Matthew Baggott. Over his decades-long career, Baggott has worked alongside pioneering psychedelics researchers including Alexander "Sasha" Shulgin, Harriet De Wit, and Fire and Earth Erowid. He also consulted for MAPS on their phase 2 MDMA trials. In 2020, Baggott founded Tactogen, a company that is studying, among other drugs, MDMA and the SSRI Citalopram to treat PTSD. The Microdose asked Baggott about how he thinks about describing and categorizing MDMA’s effects.
MDMA is a relatively new drug — how did people describe it when it was first discovered?
The first time that we know of a human experiencing an MDMA-like drug was when Gordon Alles took MDA in 1930. (Reporter’s note: MDA and MDMA are closely related drugs that have similar effects; MDA is often described as more potent.) He had just discovered the effects of amphetamines in the previous year, which he recognized as producing wellbeing. This was work he was doing when he was trying to identify treatments for allergies and congestion, so he wasn't inherently interested in these psychological effects — but when he took MDMA, the description that he gave is really curious: he completely failed to notice any of these social emotional effects. Similarly, after Sasha Shulgin took an 81 mg dose — which should have produced a noticeable effect — he described the effect as a light, alcohol-like intoxication. It wasn’t until his second dose a few days later, when he took 100 mg, that he began to appreciate how unusual the effects were. In subsequent experiences he started to use this term “window” to describe the feeling of having clarity, of being able to see inside himself without distortion or defensiveness. These were the effects that he thought would make it a better drug for assisting psychotherapy than previous known substances.
When the therapists started to study it, they did so very quietly. They started trying to articulate what they thought was unusual about it; there's some interesting quotes from that period about how these different therapists, mostly psychiatrists, understood the effects of MDMA. George Greer talked about how the usual feeling in the pit of the stomach that accompanies anxiety-provoking thoughts or perceptions was greatly reduced or absent — your response to things that would normally upset you seemed to be attenuated. Claudio Naranjo talked about a temporary anesthesia of the neurotic self. Phil Wolfson talked about a rapid and significant break with your defensive structures. There's something to these descriptions; it's a complicated matter, though. If we think about Sasha Shulgin and Gordon Alles not noticing these drug effects, that might tell us something about them. Just as first-time cannabis users often don’t think they are feeling any effects, it’s possible the same thing happens with MDMA because people haven't learned to identify them, or that some effects are like capabilities that need activating. For instance, if you have chronic inflammation that restricts the range of motion in your neck, and then you took something that was an effective antidepressant, you might suddenly have a much greater range of motion, but you wouldn't know it unless you actually tried to turn your head more than normal. (Reporter’s note: There is evidence that some antidepressants alleviate pain, including neck pain.)
What do we know about what distinguishes MDMA from other so-called psychedelics?
As scientists, we are really in the early days of understanding these components. There have only been six different entactogens that have been studied in formal modern experiments, and for most of the experiments, the people being studied knew what drug they were taking, and many had tried MDMA or related drugs before. They were going in with cultural expectations.
It's hard and perhaps impossible to escape from the fact that our experience has a specific social history. The philosopher of science Ian Hacking talks about looping effects: when people are categorized, by science or some other social process, the people who are categorized will change their behaviors as a result of being categorized, and that will produce changes in the category. I think there's something similar that happens with drugs; they are cultural artifacts that are used by certain groupings of people for specific purposes. The categories are real — like you may take MDMA and you feel increased capacity for introspection or intimacy — but that experience is also maintained and shaped by our own categories, and by the people who are taking these drugs, and by experts and institutions.
And there are other kinds of complexities in the science we do, too; we tend to make very focused measurements for something that we have come to expect will be a drug effect.
For MDMA, what measurements do we tend to focus on?
One example is that Harriet De Wit’s lab has done a couple of studies now on the experience of touch during MDMA. It is true that people anecdotally report changed experiences of touch, like receiving a massage, while on MDMA, but it's also the case that people report that smoking tobacco or cigarettes is profoundly more pleasurable on MDMA. But we as scientists might be more interested in the effects of touch, which means we focus on that, and we might end up kind of going down these roads that maybe don't necessarily get to the core phenomena.
What would be the right constructs to measure? One notable phenomenon is that people report positive social and emotional effects even if they are on MDMA alone. Some researchers have measured self-acceptance or self-compassion, which seems to increase. Others are trying to measure feelings of authenticity, where people feel like they can be themselves without having to really monitor or censor who they are.
As a society we aren't very good at talking about certain things, like self-acceptance, or feeling less neurotic, or the ability to consider things that would normally upset you without wanting to switch topics, or get up and distract yourself. That's a little more subtle than the kinds of things that we've traditionally measured in psychopharmacology. And those are differences that are hard to find on a pharmacological level.
How does one study this on a pharmacological level — and where does that leave us in terms of classifying MDMA as a drug?
While we like to think in terms of categories for clarity’s sake, drug categories are distinctions of convenience; we use them to emphasize specific features of the drug. A scientist may be less interested in categories and instead try to make continuous measures of phenomena. You can always create categories later. Say you've got a scale from 0 to 100 of how much love you feel, and you give someone MDMA and they say 100. Then you give someone amphetamine and they say 20, and you give them a placebo and they say 3. Then you can come up with some sort of dividing line between these different drugs, where something can be more of an MDMA like drug.
I did a study where I gave people MDA, which is the oldest known MDMA like drug, and compared it to an equimolar dose — a dose with the same number of molecules — of MDMA. What I found was that they were pretty similar in activating the sympathetic nervous system, and increasing heart rate and blood pressure. MDA produced more mystical experiences as well, whereas MDMA mostly didn't. In both cases, people reported positive social and emotional experiences that you might consider indicative of MDMA, though people on MDA were not as extroverted — possibly because they were more likely to be going through this powerful, mystical, emotional experience.
In this description, I've implicitly distinguished between mystical effects, physical effects, and other measures like extroversion, or having a friendly effect. MDMA is definitely very effective on that latter dimension — it can produce some difficult-to-describe social and emotional effects. But in other ways, it’s very much like any other stimulant, as is MDA, not just because it has all these physiological effects like increasing heart rate and blood pressure, but also because people experience euphoria and positive mood, which is very similar to effects from amphetamines. You can imagine this multidimensional space where you measure all these different types of phenomena and you might conclude MDMA is not very psychedelic. It's not a whole lot like LSD, but there is some overlap there. This rough way of looking at it is pretty similar to what you see in rodent training discrimination studies.
Tell me about that. How do you get rodents to distinguish between drugs?
We train a rat to distinguish between placebo and a standard dose of say, MDMA, through giving them treats if they press the right lever. Then we give them smaller or larger doses of the drug; you can see that you get this nice curve in their responses where they become more certain that they've been given MDMA with higher doses. After you've trained them, you can give rats a novel test drug and see if they think it's more like MDMA or more like the placebo. You can get really nice data showing that the rats think there are similarities between stimulants and MDMA or between psychedelics and MDMA.
And there's some asymmetries based on what you’ve experienced. Rats that have learned to distinguish MDMA from placebo will tend to think that classical psychedelics, like LSD, do feel a bit like MDMA. But rats trained to distinguish between a classical psychedelic like LSD and a placebo will tend to say that MDMA is really different. There's complexity here, and I think that supports us looking at this as a continuous measure rather than strict classifications.
One way to think about these results is that the experience of MDMA is a compound one. It's more like a musical chord than a single note; it's made up of a bunch of individual notes, and they have a higher volume and may be quieter, but you need a certain amount of volume for it to sound like MDMA.
This interview has been edited and condensed for clarity and length.
