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How Molly Works in the Brain

10 March 2015 Written by 
From Scientific American By Anne Skomorowsky: On a Saturday night last month, 12 students at Wesleyan University in Connecticut were poisoned by “Molly,” a hallucinogenic drug they had taken to enhance a campus party. Ambulances and helicopters transported the stricken to nearby hospitals, some in critical condition. Molly—the street name for the amphetamine MDMA—can cause extremely high fevers, liver failure, muscle breakdown, and cardiac arrest.

Given the risks associated with Molly, why would anybody take it? The obvious answer—to get high—is only partly true. Like many drugs of abuse, Molly causes euphoria. But Molly is remarkable for its “prosocial” effects. Molly makes users feel friendly, loving, and strongly connected to one another. Molly is most commonly used in settings where communion with others is highly valued, such as raves, music festivals, and college parties.  Recently, psychiatrists have taken an interest in its potential to enhance psychotherapy; this has led to new research into the mechanisms by which MDMA makes people feel closer.

It appears that MDMA works by shifting the user’s attention towards positive experiences while minimizing the impact of negative feelings. To investigate this, a 2012 study by Cedric Hysek and colleagues used the Reading the Mind in the Eyes Test (RMET), which was developed to evaluate people with autism. In the RMET, participants are shown 36 pictures of the eye region of faces. Their task is to describe what the person in the picture is feeling.

Volunteers taking MDMA, under carefully controlled conditions, improved in their recognition of positive emotions; but their performance in recognizing negative emotions declined. In other words, they incorrectly attributed positive or neutral feelings to images that were actually negative in emotional tone. They mistook negative and threat-related images for friendly ones.

Two 2014 studies have borne this out. Kirkpatrick and colleagues used the Morphed Facial Expression Task (mFER), which uses standardized faces, morphed in 10 percent increments from neutral to emotional. The authors found that MDMA reduced the subjects’ accuracy in identifying angry and fearful faces but did not affect identification of happy faces, leading them to conclude that “The drug’s prosocial behavioral effects might be partially explained by a decreased capacity to perceive negative emotional states in others.”

The second study focused on social rejection, using a game called “Cyberball,” which was developed as a model for ostracism. In Cyberball, participants play virtual catch with two computer-simulated characters who can either toss the ball to the subject or to each other. If the subject receives more throws, he is meant to feel accepted. The fewer throws he receives, the more rejected he feels. Frye and colleagues hypothesized that rejection during Cyberball would have a negative impact on mood, while pretreatment with MDMA would reduce this effect.

The researchers found that MDMA users rated themselves highly both on “feeling high” in general and on feeling “loving” in particular. Subjects on MDMA accurately perceived acceptance in the Cyberball game, but they were much less bothered by rejection; in fact, rejected MDMA users believed they had received many more throws than they actually had. Like the authors of the previous study, these researchers concluded that MDMA’s prosocial effects are less based on positive bias than they are on impaired recognition of rejection. The user feels more positive and “loving” because she can’t accurately process hostility.

Supporting these studies are functional MRI experiments demonstrating that MDMA activates the ventral striatum, a structure involved in reward expectation, while decreasing the response to angry faces in the amygdala, which processes frightening stimuli.

How do neuroscientists explain these effects? Many different neurotransmitters have been invoked. MDMA’s effects on serotonin, a key player in all hallucinogenic drugs, accounts for its users’ increased sensitivity to music and appreciation of light shows, reflecting the drug’s popularity at raves. Its stimulation of norepinephrine and dopamine release may explain the euphoria and increased energy users experience, and increased cortisol levels are implicated in decreasing fatigue. The prosocial effects—the desire to socialize and bond with others— have been linked, though controversially, to MDMA’s effects on brain concentrations of the hormone oxytocin. Oxytocin is a hormone known to be important for human mating and bonding. Oxytocin release during breast-feeding is thought to strengthen the bond between mother and infant. Animal studies show that oxytocin administration in rats increases “adjacent lying”—ie, cuddling.

Another study by Kirkpatrick’s group looked at the effect of MDMA on oxytocin levels. They believed that MDMA would increase blood levels of oxytocin. Participants took different doses of MDMA and on other occasions, different doses of intranasal oxytocin. As expected, both inhaled oxytocin and MDMA increased blood oxytocin levels in a dose-dependent manner—meaning that the more of each substance ingested, the more oxytocin was found in the blood. While the researchers found that MDMA did indeed increase oxytocin levels, they showed that oxytocin alone—given in its inhaled formulation, without MDMA—did not produce prosocial effects. MDMA users rated themselves highly as “playful”, “friendly”, and “loving”, while the oxytocin group did not. While oxytocin’s role in mammalian social interaction is undisputed, the above study, and other recent work, casts doubt on the role that increases in oxytocin levels have to do with Molly’s popularity as a party drug.

While drug companies race to develop products which might take advantage of oxytocin’s beneficial effects—for example, as treatments for autistic disorders and depression—psychiatrists continue to look to MDMA as an adjunct to psychotherapy. MDMA was first used by the US military in interrogation enhancement studies in the 1950s. During the 1970s, it had a brief period of therapeutic use in psychiatry, but in1985, the DEA ruled it had high abuse potential and no approved medical use, making it illegal to possess. Thus, psychiatric research has been difficult to conduct.

Recently, however, MDMA’s capacity to mitigate negative perceptions while enhancing openness has led it to be reconsidered for psychotherapy in general and treatment of post-traumatic stress disorder in particular. The cornerstone of PTSD therapy is exposure and desensitization. The traumatized patient needs to encounter distressing memories until they gradually lose their power. Naturally this is very disturbing to most patients. It is hoped that MDMA might make bad memories less vivid, while increasing feelings of safety and trust.

A study conducted by London-based neurologists addresses this possibility through functional MRI responses to best and worst autobiographical memories. Participants were asked to provide six of their worst memories and six of their favorites, and were trained to recall them during the fMRI procedure. After taking MDMA, users rated their favorite memories as more vivid and emotionally intense, while their worst memories felt less negative. fMRI images supported these results, showing differential activation and attenuation in areas of the brain associated with positive and negative memories.

Relevant to MDMA’s potential as a treatment for PTSD, one subject stated: “When I reached back for the bad memories they did not seem as bad; in fact, I saw them as fatalistic necessities for the occurrence of later good events.”

Tragically for the students at Wesleyan, they may have gotten a “bad batch” of Molly.  The dose may have been too high, or the pills may have been adulterated with caffeine or other amphetamine-like substances. One testing service recently reported that only 39 percent of the pills they tested were pure MDMA, and half actually contained no MDMA. What any particular batch of Molly really contains is anyone’s guess. Here’s hoping we find a less toxic way to love one another.

Are you a scientist who specializes in neuroscience, cognitive science, or psychology? And have you read a recent peer-reviewed paper that you would like to write about? Please send suggestions to Mind Matters editor Gareth Cook. Gareth, a Pulitzer prize-winning journalist, is the series editor of Best American Infographics and can be reached at garethideas AT gmail.com or Twitter @garethideas.

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