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The Ecstasy and the Agony
SMHS researchers take on PTSD, anxiety, and depression through less conventional means
The headline was intended to be provocative: “The Promise of Ecstasy for PTSD.”
In a November 2017 op-ed, the New York Times reported on the FDA’s approval of a pair of final-stage clinical trials involving the use of the drug MDMA—commonly known as “ecstasy”—for the treatment of mental illness.
The move, which allows physicians and researchers more access to the “club drug” for studying the treatment of PTSD and other mental disorders, came six years after a seminal study found that ecstasy use reduced PTSD symptoms in patients nearly four times better than traditional antidepressants or psychotherapy alone.
“In a clinical setting—that sort of result is unheard of,” muses Keith Henry, PhD, of the 2010 paper that appeared in the Journal of Psychopharmacology . “We never see that sort of separation.”
Keith Henry, PhD, in his office at the UND School of Medicine & Health Sciences in Grand Forks.
An associate professor in the Department of Biomedical Sciences at UND’s School of Medicine and Health Sciences (SMHS), Henry himself has spent years studying how, where, and why a series of chemical compounds—antidepressants, amphetamines, and, yes, ecstasy—bind to the proteins in the brain that transport serotonin and dopamine back into the neuron after it has been released in response to stimuli. He considers the FDA’s ecstasy decision vital to advancing the pharmacological treatment of a variety of mental illnesses in America and around the globe.
“Because of how similar PTSD, anxiety, and depression are, it’s not unreasonable that researchers would begin to explore how ecstasy could be applied to the treatment of those disorders as well. Something that was taboo for decades has now seen a resurgence,” Henry says, noting that case reports indicate psychiatrists had administered ecstasy as an adjunct to psychotherapy long before the drug’s criminalization in 1985.
The Science of Addiction
Since most of the antidepressants on the market are selective serotonin re-uptake inhibitors (SSRIs), which increase serotonin levels in the brain, they produce many negative side effects in patients, including weight gain and the loss of affect or emotional “flatness.” Furthermore, such pharmaceuticals tend to help only about half of patients who take them.
But ecstasy is different.
“We already have drugs that block serotonin re-uptake,” Henry notes from his office on the second floor of the SMHS in Grand Forks. “What we’re looking to help develop are drugs that may not block these chemicals but instead modulate the serotonin slightly without blocking its activity entirely. That’d be a better outcome for the patient in that he or she is likely to experience fewer side effects, and perhaps better relief of symptoms.”
While the mechanism of addiction is complicated, generally speaking, drugs like methamphetamine tell neurons to release the chemicals in question (serotonin, dopamine) but reverse the transportation of those chemicals and even block their “re-uptake” by the brain, resulting in a huge, non-physiological release of chemicals that give the drug user a quick, strong sense of pleasure and contentedness.
Addictions to many of these compounds emerge because they activate the reward center of the brain to associate these feelings with this chemical mechanism. In time, the cells themselves begin to tolerate the influx of excess neurotransmitters and adapt their function in a way that soon expects the routine presence of these compounds. So it is that a body deprived of elevated levels of serotonin, for example, will come to suffer both physical and neurological symptoms associated with the drugs’ absence, including anxiety, insomnia, diarrhea, and widespread physical discomfort.
But, again, ecstasy—a type of amphetamine known as an entactogen—is different.
Although MDMA can be dangerous in large amounts or in combination with other pharmaceuticals, it is far less addictive than methamphetamine.
“There is a lot less happening in terms of neuronal loss and cognitive decline with MDMA relative to methamphetamine, especially in the clinical setting at small, therapeutic doses,” Henry summarizes. “Most importantly, MDMA doesn’t activate the brain’s reward pathway like methamphetamine does. And since we have evidence that serotonin and ecstasy bind to the cellular transporter differently, we’re now trying to leverage those differences to see if there is a path toward the development of new pharmaceuticals. This may have the potential to give people their lives back.”
Basic Science First
Before researchers doing this clinical translational science can wade into the development of a novel pharmaceutical that gives back lives, though, Henry and researchers like him have a lot of work to do.
Such work includes determining, primarily through cross-species studies, how adjustments in the same proteins in different species result in different physiological outcomes.
Referencing a study recently published by Henry and one of his colleagues at Purdue University, Henry notes that while the human serotonin transporter can transport ecstasy, the fruit fly serotonin transporter cannot. By studying the genetic differences between humans and fruit flies that generate such variances, researchers are investigating how they might develop compounds that take advantage of such molecular insights in order to block drugs like methamphetamine while sparing the normal function of these brain transporters.
“This helps us focus our efforts,” Henry says. “By changing one amino acid out of 630 we were able to reverse the biochemical properties of these transporters. That mutation we made affects ecstasy, but has no impact on serotonin. This could be a foundational observation in therapeutic development. But, what does that mean and what could it mean? Those are the types of questions we’re exploring.”
Noting that his team’s research on MDMA and serotonin is at a crossroads, Henry has been pleased to see both the medical community’s and patients’ change in perception of ecstasy from being a drug of abuse to being a potential breakthrough treatment for mental illness.
“This elevates our research,” Henry concludes with a smile. “It’s exciting to think that this research has the potential to make a major difference in the lives of millions of people suffering from these mental illnesses.”