Psychedelics & Empathy

In 1912, a German pharmaceutical company developed a new drug to help with dieting and blood clotting. They called it methylenedioxymethamphetamine, or MDMA for short. Things got interesting as more people consumed the drug. By the 1970s, some psychiatrists noticed that their patients who took this drug had better psychiatric outcomes, seemingly caused by a more open mindset. But in 1985, due to widespread concern about the adverse effects of mind-altering drugs, MDMA was placed on an emergency ban in the United States. Now, almost 40 years later, there has been a new surge of interest in MDMA for the exact reasons that doctors were interested in it in the 1970s. Can MDMA lead people to have a more open mindset?

MDMA, ecstasy, or “molly” is part of a unique class of drugs known as “empathogens,”. These drugs often cause people to feel a stronger sense of connection to one another - empathy. For this reason, many recreational users take MDMA at music festivals or parties, and it has been used in a therapeutic setting to foster trust between patient and therapist. Our research team wanted to study how exactly MDMA works to increase empathy-like behaviors. Because we wanted to look at which specific chemicals and cells were involved in this process, we needed to be able to manipulate the brain’s activity. This is quite challenging in humans, but relatively easy to do in mice. So, for this experiment we looked at how MDMA changes empathy in mice.  

  Many of the aspects of a psychedelic experience are deeply psychological and emotional, and animals (of course!) can’t tell us what they’re thinking or feeling. For this reason, we have to create tests that allow us to measure animal behavior as a stand-in for certain human emotions. So, we first had to figure out how mice showed empathy, and then create a test to measure that behavior. 

Typically we think of empathy as feeling someone else’s pain alongside them. For example, we may hear a friend telling a sad story and begin to feel a sense of sadness ourselves. We have taken on the burden of some of their pain. Empathy involves taking on another person’s feelings as your own and is integral to developing deep relationships. 

While much of human empathy is in response to emotional distress, both humans and mice show an empathy-like response to physical pain. Mice are social animals, and are housed together in tight-knit groups. Mice living together are known as “cagemates”. In this experiment, we looked at how one mouse, an “observer,” reacts when it sees one of its cagemates in pain. The mice in pain were referred to as “demonstrators,” because they were demonstrating pain behavior (such as limping and sensitivity). Before testing, we measured each animal’s pain tolerance through a test called the Von Frey test. Essentially, this involved poking the animal in the foot with fibers similar to the bristles of a broom. The fibers are pressed into the animal’s foot until the fiber bends slightly, and each fiber gets progressively thicker, meaning that as the test goes on more pressure is needed to bend the fiber. At a certain point, the animal will register the discomfort caused by the fiber and pull their foot away. This is how we measure their pain threshold. Interestingly, the Von Frey Test is not just used in mice – it’s also a way to measure a human’s pain tolerance if they have a condition that makes them more or less sensitive to pain.

  Unsurprisingly, the demonstrator mice are more sensitive to pain than the observer mice due to the injection they received in their paw. After measuring the baseline pain threshold of the demonstrators and observers, we then allow one demonstrator and one of its cagemate observers to interact for an hour. We put the two mice together in a clean cage, where they sniff each other and run around. After this interaction period, we do another test of pain tolerance. The demonstrators still show a low pain tolerance due to their inflamed feet. But, shockingly, after this interaction, the healthy observer mice are suddenly much more sensitive to pain, acting more like their demonstrator cagemates. This phenomenon, in which healthy mice will start to mimic pain behavior shown by their cagemates, is known as the “social transfer of pain”. This suggests that mice experience something like human empathy in that they sense and identify with another animal’s experience.

We next wanted to see if MDMA would intensify the social transfer of pain. Since MDMA is an empathy-enhancing drug, we thought this would be an exciting path for discovery. We found that male mice on MDMA only needed to interact with their demonstrator cagemate for 10 minutes in order for social transfer of pain to occur. This is 6 times faster than if they didn't receive MDMA! On top of that, the social transfer of pain lasted a full 24 hours!

Interestingly, we did not see this enhanced social transfer of pain in female mice given MDMA. We are not sure why this is the case, but it’s not unusual in behavioral neuroscience for there to be sex-differences. We decided to move forward testing only in the male mice, and hopefully circle back in a future experiment to further investigate why the female mice didn’t show an effect. 

  After finding that MDMA enhances the social transfer of pain in mice, we then wanted to figure out what part of the brain was responsible for this. Past research by our lab and other researchers showed that a brain area called the nucleus accumbens was involved in the social transfer of pain and was also heavily impacted by MDMA. The nucleus accumbens plays a key role in pleasure, motivation, addiction, and pain. For this reason, we decided to inject MDMA only into the nucleus accumbens of mice. We found that the mice showed the same enhanced social transfer of pain when MDMA was placed directly into the nucleus accumbens.. Because of this, we were able to conclude that MDMA’s activity in the nucleus accumbens is what allowed it to increase the empathy-like behavior. This was exciting, because it was the first time that we were able to trace MDMA’s empathy-enforcing effects to a specific brain area. For a long time, we knew that MDMA worked in the nucleus accumbens, but now we were able to prove that the drug’s activity in this brain area was directly responsible for the increased feelings of connectedness and sociability that many human users have reported feeling after taking the drug.

  So, we had figured out a few pieces of the puzzle. We knew that MDMA increased empathy in humans and that it did the same in mice. We also showed that this increase in empathy was due to something that MDMA was doing in the nucleus accumbens. But how was MDMA acting on the nucleus accumbens to make this happen? 

To figure this out, we had to think about the specific way that MDMA worked. MDMA increases three different chemicals in the brain: norepinephrine, dopamine, and serotonin. Norepinephrine (NE) is mainly involved in stress or fight-or-flight reactions, so it seemed like an unlikely candidate for increasing empathy. We thought that dopamine (DA) might be our culprit, since it is known to be involved with learning, mood, memory, and motivation. However, past research showed that dopamine was not involved in the social transfer of pain. Because of this, we honed in on our third potential chemical of interest: serotonin.

Serotonin is often thought of as the “feel good” neurotransmitter because it majorly impacts mood. More recently, serotonin has become well known for its role in everything from blood clotting to digestion to sleep. In our case, we decided to test whether serotonin’s activity in the nucleus accumbens could explain the increased empathy behavior seen with MDMA. 

To do this, we used a process called “optogenetics”. This process allows us to use specially-bred mice (that’s the “genetics” part) whose neurons are sensitive to light (that’s the “opto” part). We can insert a tiny laser into specific parts of the mouse’s brain, then use that laser to turn neurons “on” or “off.” In our case, we used mice whose serotonin neurons were light-sensitive, and inserted our laser into the nucleus accumbens. This allowed us to specifically turn on or off the serotonin neurons in the nucleus accumbens. We used the light to turn the serotonin neurons in nucleus accumbens “on” in the observer’s brain during the interaction with the pain-demonstrator. In doing this, we saw the same effect as when MDMA was infused into the nucleus accumbens. We had the last piece of the puzzle! Serotonin activity in the nucleus accumbens was responsible for the increased empathy-like behavior caused by MDMA.

     In sum, we were able to show that MDMA enhances the social transfer of pain, an important measure of empathy in mice, and that this enhancement is due to serotonin acting on the nucleus accumbens. As interest grows in the potential therapeutic uses of psychedelics, this result will enhance our understanding of how MDMA works and encourage continuing research in the uses for empathogens. 

It’s important to know how a drug works in the brain for several reasons. First, it allows us to make better informed decisions about what kind of people might be eligible to take this drug. If someone is already taking a number of drugs that increase their serotonin levels, for example, it’s best to avoid prescribing them drugs that will further increase their serotonin as too much of this chemical can be harmful. Also, if we understand how a drug works, we can use this information to create other, more precise drugs. Now that we have a better understanding of where in the brain this drug acts to enhance empathy, we can create other drugs that are specially created to harness this therapeutic property. There is an increased interest in creating psychedelic drugs that are altered to avoid potentially harmful side effects, and this research could contribute to that work. As psychedelics gain traction as therapeutic treatments for conditions like depression and PTSD, understanding how MDMA works will allow us to broaden the number of people eligible to receive this treatment. That being said, it’s important to remember that all drugs need to be treated with caution. Hopefully, after many more years of research, we’ll be able to use these findings to create better medicine and therapy for people struggling with psychiatric illnesses. 

Written By: Kendall Raymond

Academic Editor: Neuroscientist

Non-Academic Reviewer: Small-business Owner

Original Paper

• Title: MDMA enhances empathy-like behaviors in mice via 5-HT release in the nucleus accumbens

• Authors: Ben Rein, Kendall Raymond, Cali Boustani, Sabrena Tuy, Jie Zhang, Robyn St. Laurent, Matthew Pomrense, Parnaz Boroon, Boris Heifets, Monique Smith, Robert Malenka

• Journal: Science Advances

• Date Published: 24 April 2024

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