A team of University of Arkansas for Medical Sciences (UAMS) researchers has received a federal grant to conduct the first comprehensive study of the dangers posed by synthetic marijuana products.
The $2.7 million grant from the National Institutes of Health (NIH) National Institute on Drug Abuse (NIDA) will enable a seven-member interdisciplinary research team to determine the toxicity of the man-made cannabinoids and inform policymakers as they consider regulating the products, which are intended to mimic the effects of marijuana.
“Synthetic cannabinoid products such as K2 and Spice are deceptively marketed as safe and legal alternatives to marijuana, but admissions to emergency rooms and calls to poison control centers suggest that they are certainly not safe,” said Paul Prather, Ph.D., the study’s principal investigator and professor in the UAMS College of Medicine Department of Pharmacology and Toxicology. “Users of these products are experiencing psychosis, seizures, heart attacks and even death.”
Since 2015, there have been 83 calls for synthetic cannabinoid exposures to the Arkansas Poison & Drug Information Center at UAMS. Synthetic cannabinoids are psychoactive chemicals often sprayed on plants that have been cut up to look like natural marijuana. They are also sold as powders, tablets and capsules.
Over the next five years, the UAMS team will explore why the synthetic compounds are more toxic than marijuana, even though both activate the same cannabinoid receptors in the brain. Researchers will study the effects of the man-made compounds on human cells in the lab, in mice, and in those who take synthetic cannabinoids and are admitted to the ER at UAMS and ERs in New York.
“When we test patients who have used synthetic cannabinoids, we can identify what specific compounds are being abused, the levels of compounds and their metabolites in patient samples, and we can link this information to the symptoms that brought them into the ER,” said co-investigator Laura James, M.D., a professor in the UAMS College of Medicine Department of Pediatrics, director of the UAMS Translational Research Institute, and Section Chief, Clinical Pharmacology and Toxicology at Arkansas Children’s Hospital. “The significance of this grant is that numerous experts are working across disciplines to produce findings that will directly improve human health and safety.”
“Our goal is to provide the public and scientific community definitive information that these compounds are not an alternate form of marijuana that’s safe,” Prather said. “This would give federal and state agencies grounds for further regulating these compounds.”
In addition, he said, the team’s findings could help lead to antidotes for people with synthetic cannabinoid toxicity.
The NIH/NIDA grant builds on the work of a one-year 2011 pilot study that was conducted by largely the same team and was funded by the Translational Research Institute. That study, led by James, resulted in development of a clinical test by co-investigator Jeffery H. Moran, Ph.D., to determine the presence and amount of the toxic synthetic compounds in a person’s body. Their findings also informed the work of the Arkansas Legislature, which in 2013 added new synthetic cannabinoid groups to the state’s list of controlled substances (Act 329).
As part of the new five-year study, Moran, assistant professor in the Department of Pharmacology and Toxicology and section director of Environmental Chemistry at the Arkansas Department of Health, will identify the synthetic cannabinoids in blood and urine samples obtained from ER patients.
Co-investigator Anna Radominska-Pandya, Ph.D., will determine what enzymes are metabolizing (inactivating) the synthetic cannabinoids.
“The knowledge gained from this work will help researchers predict whether certain populations are more likely to experience adverse effects from the drugs,” said Radominska-Pandya, a professor in the UAMS College of Medicine Departments of Biochemistry and Molecular Biology and Medicine.
Prather will focus on studying the synthetic compounds and metabolites identified from the urine of the ER patients. By analyzing cells expressing human cannabinoid receptors in his lab he will learn which specific synthetic compounds and metabolites bind to the brain’s cannabinoid receptors as well as other aspects of their activity. For example, he said the man-made compounds bind better to cannabinoid receptors and produce greater activity compared to natural marijuana’s main ingredient – tetrahydrocannabinol (THC). These differences in binding and activity may contribute to the synthetic compounds’ toxicity, but researchers don’t yet know the specific culprits.
“No one has ever looked at this,” Prather said. “To this point it’s just conjecture how these compounds and metabolites bind to and activate cannabinoid receptors.”
Prather’s findings will inform the work of co-investigator William Fantegrossi, Ph.D., who will take the compounds and metabolites that bind to the cannabinoid receptors and study their actions in mice.
“Our animal models should help clarify the toxicity associated with these compounds,” said Fantegrossi, associate professor in the Department of Pharmacology and Toxicology. “Right now when a synthetic cannabinoid user is admitted to the ER, we don’t know what component of the drug really contributed to their symptoms.”
Co-investigator Susan Abdel-Rahman, Pharm.D., professor of pediatrics at the University of Missouri, Kansas City, an expert in pharmacokinetics, will provide consultation to assist Fantegrossi and Moran with their experiments to determine how the synthetic cannabinoids are absorbed, distributed and eliminated in the body.
The research team will be alerted to any surges in synthetic cannabinoid use as well as new cannabinoids that require the team’s study by co-investigator Keith McCain, Pharm.D., associate professor in the UAMS College of Pharmacy and clinical toxicologist in the Arkansas Poison & Drug Information Center, who will be monitoring calls to the UAMS Center.