The Life-Changing Potential of Medical Psychedelics
John McCorvy, PhD, associate professor of cell biology, neurobiology and anatomy at the 星空无限传媒 (MCW), says psychedelics have the potential for life-changing effects as a medicine.
Dr. McCorvy describes himself as a chemical neuropsychopharmacologist – someone who uses chemistry and compounds to address problems in the brain and studies the effects of drugs on the mind. Many of the questions he seeks to answer relate to mental health, mental health disorders and neurological diseases, illnesses he believes psychedelics have the power to treat.
Psychedelics, like LSD (lysergic acid diethylamide), activate serotonin receptors, which in turn activate G protein signaling in brain neurons. What is less known is how psychedelics lead to long-lasting changes in behavior and thought processes and what specific receptor signaling pathway they use. Dr. McCorvy’s research, which began during his doctoral studies, explores these issues.
Using LSD for Medical Purposes
The 1943 discovery of LSD and its potent psychotropic effects led to a renewed focus on serotonin as an important component in mental health, ultimately resulting in the development of selective serotonin reuptake inhibitors (SSRIs).
SSRIs are first line therapies to treat a wide range of mental health disorders, including major depressive disorder, obsessive compulsive disorder and anxiety. However, SSRIs have limited efficacy for these disorders, take weeks to work, and have several side-effects, including withdrawal, Dr. McCorvy says, which makes the identification of other treatments crucial.
Research into the use of LSD and other psychedelics for medicinal purposes stopped in 1970, when the Drug Enforcement Agency classified them as scheduled narcotics. That research was revived in the 2000s, Dr. McCorvy says, but there were challenges. For instance, because LSD trips can last more than 10 hours, patients in these studies have to be observed over a long period of time, which can become cost prohibitive.
“As my PhD advisor would say, LSD is a different beast,” he says. “That's part of the reason why you don't see it being used in a lot of human clinical trials.”
Dr. McCorvy’s thesis addressed how LSD fits into a key serotonin receptor, 5-HT2A subtype, which is expressed on the cortex of the brain in areas involved in executive function and conscious awareness. His post-doctoral work led to the discovery that LSD has an extremely slow off-rate from the 5-HT2A receptor, a potential reason why LSD trips may last so long. This landmark research was published in the journal Cell.
Psychedelics as Promising Antidepressants
Using LSD and other psychedelics such as psilocybin, or magic mushrooms, to better understand and potentially treat humans is still the focus of Dr. McCorvy’s lab. His team works to answer questions including: Which psychedelic shows toxicity? Which can be beneficial? What is the level of activation of the 5-HT2A receptor or other receptor needed to treat a particular mental health condition? Can some of these compounds be used for other disorders?
Another challenge is avoiding side-effects, such as cardiovascular effects or mental health complications.
A recent study of Dr. McCorvy’s found that novel designer opioid drugs called nitazenes, which caused respiratory depression and death in Milwaukee during the pandemic, were more potent than fentanyl and caused longer lasting respiratory depression.
“If we hadn't uncovered those profiles, we wouldn't know that this is what you want to stay away from in terms of further drug development,” he says.
Still, he adds, it’s also important to learn as much as they can about the dangers of different compounds to better understand the science and propose solutions.
Dr. McCorvy’s team is currently working with companies to improve a specific psychedelic compound that's designed to treat major depressive disorder and lacks the side effects of the 5-HT2B activation that leads to cardiotoxic effects. As part of this research, his lab has created a workflow that predicts the psychedelic effects of a compound by examining its receptor signaling profile.
The findings from that study, which showed the potential to remove the psychedelic effects of the drugs but retain their longer-lasting antidepressant effects, were published in the journal in December 2023.
Changing the Nature of Psychedelic Use
Psychedelics have a long history of use across the world, including in ancient cultures for ceremonial and mind-opening purposes.
Fast forward to the 1960s, the era Dr. McCorvy’s parents grew up in, and the use of psychedelics as recreational drugs was rather common. Today, they are being looked at as medicines.
A key to continuing that momentum is harnessing the power of psychedelics as a rapid-acting antidepressant and continuing to better understand how they activate different receptors and interact with different biological targets.
“We have a whole freezer of compounds, and we are trying to understand what each one of them does,” Dr. McCorvy says.“A drug fits into your biology, your proteins, like a puzzle piece, so we need to understand all the edges and all the rounded ways that it can fit into your body to identify potential therapeutic candidates.”
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