Story by Lauren Ketwitz, Photos and Video by Tyler Chilton, Graphic by Isabel Stellato for UNC Media Hub
CHAPEL HILL, North Carolina — Dr. Bryan Roth found himself dealing with the complexities of the psyche when he was 5 or 6 years old: his mother suffered her first episode of schizophrenia.
The impact of that experience has shaped Roth’s life.
“In junior high I decided I wanted to be a psychiatrist, and by high school I was reading the collective works of Sigmund Freud,” Roth said. “It wasn’t until college that I heard about brain receptors, and they fascinated me.”
Roth followed his fascination with receptors — the protein in a cell that a drug binds with – to build a career. Now a pharmacologist at the UNC-Chapel Hill, Roth is researching the use of psychedelics to treat mental illness.
To be clear, the lab isn’t dosing people with magic mushrooms or LSD. It focuses on understanding the mechanics of drugs and receptors at a molecular level.
In late 2020, Roth and his lab received a $27 million grant from the Defense Advanced Research Projects Agency as part of the Focused Pharma program, which aims to develop a new class of psychotherapeutic drugs for treating a range of neuropsychiatric conditions. In addition, the psychedelic drug market holds the potential to generate more than $6.7 billion by 2027, according to an article from Cision PR Newswire.
For the last few decades, Roth’s research has centered on mapping and understanding receptors in the brain. Of particular interest is the 5-HT2A serotonin receptor, which is responsible for the regulation of mood, memory and cognition, and learning.
Finding compounds that attach to this serotonin receptor is a key step in creating safer drugs that provide relief from symptoms associated with anxiety, depression, addiction and PTSD. In a 2016 clinical trial, LSD therapy suggested significant improvements of psychological well being.
So far, the most promising aspect of psychedelic therapy is the prolonged duration of the relief.
“In numerous trials, psychedelic therapy has proven to positively alter one’s state of mind for months at a time,” said Walter Dunn, an assistant clinical professor at the Semel Institute for Neuroscience and Human Behavior at UCLA. “Hopefully a drug will be discovered that, when paired with a psychedelic therapy program, would only need to be taken a few times a year.”
On average, a trip associated with LSD and psilocybin, the magic in magic mushrooms, can last anywhere from eight to 20 hours. The experience is influenced by factors such as the user’s state of mind, surroundings, intentions and dosage. As a result, not all trips end well.
The negative stigma surrounding the use of psychedelics for scientific progress stems from those bad trips. Psychedelics are not legal in the United States, therefore it’s easy for someone to take a drug thinking it’s one thing, and it ends up being another.
In addition, the downward spiral of a trip only requires one trigger, which could be anything from overstimulation of sounds and smells to a pesky intrusive thought. Bad trips are often nerve-wracking or even terrifying. Although some trips result in life-altering states of mind, the molecular makeup of psychedelics aren’t too far off from compounds humans already produce.
“Many psychedelic compounds mimic those found naturally in our bodies,” said Ryan Gumpper, a postdoctoral researcher in the Roth lab. “We’re working on creating drugs that will only bind to certain receptors, similar to how a serotonin molecule would, therefore producing similar effects.”
The Roth lab hopes to discover a compound that elicits therapeutic effects without the patient having a psychedelic experience.
“Some evidence shows that a dissociation exists between the hallucinogenic and the therapeutic effects,” said Jeffery DiBerto, a UNC graduate student working with Roth in the lab. “In theory, we could find a molecular structure that is almost exactly like LSD, but without the components that trigger a trip.
For now, a hallucinogenic trip remains part of the experience for patients.
Recently, the Roth lab made a discovery that was years in the making: they solved the structure of an LSD molecule actively bound to the 5-HT2A receptor. Now, they have a model of the molecule and the receptor to reference when testing the fit of other drugs.
LSD and psilocybin are classified as Schedule 1 drugs under the Controlled Substances Act. They are believed to have a high potential for abuse while also failing to serve any medical purpose in the United States. As clinical trials begin to reemerge after the drugs’ criminalization in 1968 and 1970, scientists have started down a path that could reverse that ruling.
Because psychedelics remain illegal, the most common treatment for mental illnesses are SSRIs, or selective serotonin reuptake inhibitors. These drugs limit the reabsorption of the serotonin hormone, one of the main hormones associated with feelings of happiness. While successful in some cases, their side effects pose a number of shortcomings like insomnia, decreased libido and weight loss and gain.
In contrast, the positive effects of psilocybin can outweigh the negative. When properly dosed in a clinical setting, the drug has shown to have an almost euphoric effect on the mind. Anxiety is relieved, prolonged stress levels decrease, and overall mental health improves and stabilizes.
These results offer significant potential to the power of psychedelics in a medical setting. However, bigger sharks have begun circling the waters as this new type of therapy inches closer to an FDA approval.
Enter Big Pharma, a term which refers to the large pharmaceutical companies that hold a near-monopoly over the distribution and pricing of drugs and medical devices.
“One reason Big Pharma hasn’t stepped into this equation yet is the lack of a guaranteed way to make money fast,” Dunn said. “The FDA could make therapists complete psychedelic-specific training, which puts a stressor on when this treatment can become widely available.”
Drug prices and increased requirements for therapists could result in a shortage of both the drug and the psychotherapy needed to produce lasting effects on a patient. Although the next scientific breakthrough may be right around the corner, integration into the public might be farther down the road than anticipated.
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