Pilot Study Shows First Molecular Link Behind Successful PTSD Treatment (2023)

May 22, 2023

According to the National Institute of Mental Health, by 2022, an estimated 3.6% of Americans will be affected by PTSD, including women (8%) and veterans (10% of men and 19% of women). women) who have higher prevalence figures. In fact, about 60 percent of men and 50 percent of women experience at least one major trauma in their lives, according to the National Center for PTSD.

"Trauma rates in children and adults are high all over the world, including in the United States," said Candace Lewis, an assistant professor in the ASU College of Life Sciences who is exploring the biological roots of trauma responses. people to trauma and stress. Pilot Study Shows First Molecular Link Behind Successful PTSD Treatment (1) Arizona State University College of Life Sciences researcher Candace Lewis (foreground) and her lab team explore the biological reasons why the psychedelic drug MDMA may play a role in the successful treatment of PTSD. Her lab includes (back row, left to right) neuroscience graduate student Allison Hays, BASIS Chandler High School senior Alyssa Ford, and psychology graduate student Taena Hanson. download full image

While most people can recover and return to their daily activities within a few weeks or months, for some, PTSD can lead to serious and debilitating mental health conditions that can take months or years of intervention and psychotherapy for people to go back to normal. .

The root of PTSD is trauma.

"Trauma comes in many forms, whether it's child abuse/neglect, poverty, race, fighting or domestic partner violence, many of us live with trauma," Lewis said. "For some, these experiences increase vulnerability to the development of maladaptive behaviors and cognitive patterns. Stress-related disorders, such as post-traumatic stress disorder, depression and anxiety, we can define as maladaptive behaviors."

PTSD is often triggered by a scary event experienced or witnessed. It can cause severe anxiety, flashbacks, or nightmares that last for months or years. For those who need medical intervention, the revolutionary treatment drug is 3,4-methylenedioxymethamphetamine, or ecstasy.

MDMA is not without controversy. It is currently an illegal drug commonly known as MDMA or Molly. It is associated with the all-night rave culture that began in the early 1990s. More recently, the topic entered the public zeitgeist in 2018, with Michael's #1 bestseller How to Change Your Mind: What that the new psychedelic science can teach us about consciousness, death, addiction, depression, and transcendence.

This book delves into the science of psychedelics and psychotherapy. And, after decades of anecdotal data about the success of mental health professionals, MDMA has received accelerated approval from the FDA, specifically for the treatment of PTSD.

For scientists like Lewis, it also opens up a new avenue of research to explore possible biological reasons why MDMA might play a role in the successful treatment of PTSD.

Lewis is trying to capture data on the link between behavior, mental health, and our biological responses to stress. To that end, she is studying in more detail how experience alters the molecular regulation of systems involved in stress and mental health.

Now, he's completed a pilot study showing the first molecular link behind the successful treatment of PTSD and new evidence that may explain what's behind its success.

behavior and biology

Lewis hopes to use his own family's experiences and the struggles of others as motivation to help revolutionize mental health treatment.

"I have witnessed serious mental health problems since I was a child," Lewis said. "The data shows that this is becoming more common."

It studies the molecular impact of our social environment, right down to the brain and behaviour, with the goal of enabling everyone to live healthier lives.

"We don't yet know what we don't know," Lewis said, "but your experiences have the power to change you at the molecular level, which changes downstream gene transcription, which changes the structure, function and behavior of the brain." .

An exciting new field that links experience with behavior and biology is that of epigenetics, which involves chemical modifiers that act like traffic signals to help change whether genes are turned on or off.

"Epigenome refers to this infinitely complex regulatory system over our genome," Lewis said. Research has shown that a person's experiences and exposures can change the way genes are expressed through epigenetics.

Before returning to ASU to join the faculty, Lewis completed his PhD work in Behavioral Neuroscience in the ASU Department of Psychology, inProfessor Foster Olive's LaboratoryHis doctoral research investigated how early experiences increase vulnerability to addiction. LuisSafeIn an animal model, epigenetic marks of stress experienced early in life increased drug intake. she can toorevokeEpigenetic marks in models that reduce drug use behavior.

So it was natural for Lewis to broaden his research and wonder if severe forms of PTSD might also be under epigenetic control.

Pilot Study Shows First Molecular Link Behind Successful PTSD Treatment (2)

The research team explores the molecular connections that underlie biology and behavior. Photo courtesy of Candice Lewis

downstream pilotage

Lewis relied on data from a large MDMA clinical trial conducted by researchers sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS). Lewis conducted a pilot epigenome study that examined a subset of 23 people for molecular clues to MDMA in the successful treatment of PTSD.

Another colleague, Rachel Yehuda, of the Icahn School of Medicine at Mount Sinai, recently reported positive results from a phase 3 clinical trial showing that ecstasy-assisted therapy was more effective than placebo in patients with severe PTSD.

Lewis and his research team identified epigenetic changes in three key genes before and after treatment with MDMA and placebo. All three genes are known to be involved in the way humans respond to environmental disturbances through the stress response. They are an important component of the homeostatic response of the hypothalamic-pituitary-adrenal (HPA) axis, a complex but powerful neuroendocrine mechanism that mediates the effects of stressors.

"The epigenome refers to an infinitely complex regulatory system of the genome," Lewis said. "However, DNA methylation, the most studied epigenetic mechanism, is the covalent addition of methyl (CH3) groups to CpG sites."

CpG sites refer to two of the four chemical/letter abbreviations that make up the rungs of the iconic model of DNA's double helix ladder: A, G, C, or T nucleotides that make up the genetic code.

"A CpG site is a cytosine upstream of a guanine," Lewis said. "CpG sites tend to cluster in promoter regions of genes that must be available for transcription and subsequent translation into protein products. These methyl groups are just a physical block to gene transcription."

A CpG site acts like a red traffic light, telling the genome to stop producing its protein products, or in this case, to turn off key genes involved in the stress response.

This study evaluated the DNA methylation levels of the 259 annotated CpG sites in three HPA axis genes (CRHR1, FKBP5, and NR3C1). Importantly, methylation changes occurred only in the group that significantly predicted symptom reduction at 37 of the 259 CpG sites tested. In addition, the ecstasy-treated group showed more methylation changes at one site in the NR3C1 gene compared to the placebo group.

"It goes back to the point of our CpG field course," Lewis said. "We evaluated CpG sites throughout the gene body, rather than focusing only on promoter regions. Although little is known about the functional impact of CpG methylation outside of the promoter, it may still be an important factor in trauma and response to treatment. The effect we found in NR3C1 was not surprising. If there were a famous gene, it would be this glucocorticoid receptor."

"Changes in glucocorticoid receptor gene expression caused by early life trauma were the first epigenetic discovery that really started the field. Now, studies have shown that epigenetic regulation of many genes is associated with impaired mental health," Lewis said. "Those who experienced trauma were more likely to have different glucocorticoid receptor expression and a different cortisol profile than those who did not."

Next step

The results of this study suggest that treatment-related improvements in PTSD symptoms may be related to changes in DNA methylation in HPA axis genes, changes that may be greater in patients receiving adjuvant MDMA therapy.

"The results of this study are exciting and similar to those of another PTSD psychotherapy study," said Yehuda, director of clinical trials. "More research is needed to fully examine how this new approach relates to epigenetic changes. United to promote lasting change.”

Lewis is now turning to expanding and refining his pilot findings.

"Our ASU BEAR (Brain, Epigenetics, and Altered States Research) lab is interested in measuring epigenetic biomarkers to understand treatment response to various treatment options, including psilocybin, ketamine and, of course, MDMA in a larger sample size," Lewis said. "We also hope that it will encourage others to start looking at biomarkers."

Along with collaborators at ASU and other local institutes, Lewis is leading the formation of a clinical and research group focused on psychedelic-assisted therapies called Translational Research in Psychedelics (TRiP).

talk about it

Lewis emphasized that a better understanding of the biology behind MDMA treatment will further improve psychotherapy, as well as the time and experience required to recover from severe traumatic experiences.

"What I hope to convey as a take-home message is that therapy needs to stand out...Some patients need help breaking down the walls and cognitive barriers built around their traumatic experiences. For many traumatized people, therapy may of conversation does not penetrate deep enough to effect real change. If a person is unable to talk to a therapist about their trauma and is (is) struggling with mental health symptoms, MDMA-assisted treatment may be a treatment option more effective for them.

"The psychopharmacological effects of MDMA are actually quite extraordinary: reduced anxiety, strong positive effects, increased insight, racing thinking and euphoria, and an increased feeling of trust and connection. It is in this state that patients find the ability to resolve the problems they need, it's an intense experience, it's an intense therapy.

Lewis' ultimate goal is to subvert psychotherapy by asking, "If trauma is shaping epigenetics leading to increased symptoms, what therapeutic experiences are shaping epigenetics in ways that reduce symptoms?"

"People are suffering, right? There is a reason they have maladaptive behaviors and cognitive distortions. How can we help them? Surely we can do better than the current model of chronic drug treatment. I wonder, what do we need to cure? I am I'm a neuroscientist, so I stick to the data. I think the whole outcome is biology, and experience shapes biology. We know we have traumatic experiences, and I'm looking for experiences that heal. We really need them."

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