Scientists have unearthed a promising new technique to counteract overdoses of fentanyl by employing altered cannabidiol (CBD) as a negative allosteric modulator at the opioid receptor binding location. Preliminary in vitro experiments indicate that this modified form of CBD effectively neutralizes the impact of fentanyl. Additional in vivo research is forthcoming to evaluate its capability to alleviate respiratory depression, a chief symptom of overdose.
Data from the Centers for Disease Control reveal that overdoses are responsible for the deaths of approximately 100,000 Americans each year. A significant portion of these fatalities are linked to the ingestion of synthetic opioids, notably fentanyl. Despite the increased availability of naloxone, currently the sole approved antidote for opioid overdoses, its efficacy against synthetic opioids like fentanyl is limited.
A team of researchers at Indiana University has pinpointed an alternative approach to mitigating the severe effects of fentanyl, an opioid that is 50 to 100 times more potent than morphine. Their findings, documented in the Journal of Medicinal Chemistry, may pave the way for novel overdose reversal mechanisms, either as standalone solutions or in conjunction with existing naloxone treatments.
Alex Straiker, the senior research scientist at the Gill Center for Biomolecular Science, remarked, “Synthetic opioids adhere strongly to opioid receptors. Naloxone has to vie with opioids for the identical binding site within the central nervous system to negate an overdose. During a fentanyl overdose, however, naloxone and fentanyl attach to disparate sites, eliminating any competition. We aimed to investigate whether a negative allosteric modulator could negate the effects of fentanyl.”
Straiker initiated an analysis of the influence of opioid receptors on a signaling molecule known as cAMP. He evaluated fifty chemically-related molecules to ascertain which exhibited the most potential as an effective negative allosteric modulator. The team identified that cannabidiol (CBD) could function as such a modulator at the binding site. During initial testing phases, they modified the chemical structure of CBD to enhance its efficacy. In vitro tests on blood and tissue samples confirmed that the modified CBD effectively neutralized the impacts of fentanyl.
“We’ve pinpointed structural elements that are crucial for achieving the desired antidotal effect,” stated Straiker. “Some of these compounds have proven far more potent than the original. We’ve collaborated with a third laboratory to model the binding site, which could assist in the identification of further compounds in future.”
The subsequent phase of research will involve in vivo experiments to determine whether the modified CBD can indeed reverse respiratory depression, the principal symptom of overdose.
Reference: “Structure–Activity Relationship Study of Cannabidiol-Based Analogs as Negative Allosteric Modulators of the μ-Opioid Receptor” by Taryn Bosquez-Berger, Jessica A. Gudorf, Charles P. Kuntz, Jacob A. Desmond, Jonathan P. Schlebach, Michael S. VanNieuwenhze, and Alex Straiker, published on 12 July 2023 in the Journal of Medicinal Chemistry. DOI: 10.1021/acs.jmedchem.3c00061
Additional contributors to the study include Taryn Bosquez-Berger, a Ph.D. candidate in Psychological and Brain Sciences at IU Bloomington, Jessica A. Gudorf, a graduate student in organic chemistry at IU Bloomington, Charles P. Kuntz, Jonathan P. Schlebach, an assistant professor of chemistry at IU Bloomington, and Michael S. VanNieuwenhze, the Standiford H. Cox Professor of chemistry at IU Bloomington.
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Frequently Asked Questions (FAQs) about Fentanyl Overdose Reversal
What is the new method for reversing fentanyl overdoses?
The new method involves using modified cannabidiol (CBD) as a negative allosteric modulator at the opioid receptor binding site. Preliminary in vitro tests indicate that this modified CBD can effectively neutralize the impact of fentanyl.
Who conducted the research on this new method?
The research was conducted by a team at Indiana University, led by Alex Straiker, the senior research scientist at the Gill Center for Biomolecular Science.
What is the significance of this new method compared to existing treatments like naloxone?
Naloxone, the current antidote for opioid overdoses, is less effective against fentanyl-class synthetic opioids. The new method offers an alternative approach that could either work as a standalone solution or in conjunction with naloxone to more effectively reverse fentanyl overdoses.
What are the next steps in the research?
The next phase will involve in vivo testing to evaluate the modified CBD’s ability to alleviate respiratory depression, the principal symptom of an opioid overdose.
How was the research published?
The research findings were documented in the Journal of Medicinal Chemistry, in an article published on 12 July 2023.
How many Americans die annually from overdoses, and how is fentanyl involved?
According to the Centers for Disease Control, approximately 100,000 Americans die from overdoses each year. A significant portion of these fatalities are attributed to the ingestion of synthetic opioids like fentanyl.
What other compounds were studied for their potential as a negative allosteric modulator?
Fifty structurally related molecules were tested chemically to identify which showed the most promise as an effective negative allosteric modulator.
Who were the additional contributors to the study?
Additional contributors include Taryn Bosquez-Berger, a Ph.D. candidate in Psychological and Brain Sciences at IU Bloomington, Jessica A. Gudorf, a graduate student in organic chemistry at IU Bloomington, Charles P. Kuntz, Jonathan P. Schlebach, an assistant professor of chemistry at IU Bloomington, and Michael S. VanNieuwenhze, the Standiford H. Cox Professor of chemistry at IU Bloomington.
More about Fentanyl Overdose Reversal
- Journal of Medicinal Chemistry Article – Link to the full research article titled “Structure–Activity Relationship Study of Cannabidiol-Based Analogs as Negative Allosteric Modulators of the μ
