R16GM146679

Quantifying Effects of Comorbidities and Genetics on Cannabinoid Exposure in the Elderly - Project Summary/Abstract

Americans =65 years represent a growing segment of the US population who use cannabis for multiple ailments, increasing about two-fold from 2015 to 2018. Despite these trends, knowledge about how the aging process combined with comorbidities or genetic polymorphisms in drug metabolizing enzymes alter the safety of cannabis remains limited.

This knowledge gap is particularly worrisome given nearly all 50 states have passed some legislation allowing legal medical cannabis use and that the elderly are more vulnerable to adverse drug events.

The non-psychoactive cannabidiol (CBD) and psychoactive -9-tetrahydrocannabinol (THC) are the most extensively studied cannabinoids in cannabis. CBD has been the top-selling herbal supplement ingredient in the US natural channel since 2018. CBD received particular interest from the elderly suffering comorbidities who are poorly managed with current treatments.

CBD is eliminated from the body mainly by hepatic cytochrome P450 (CYP)-mediated metabolism (CYP2C19, CYP3A). Mean THC concentration in cannabis-related products was reported to increase 2-fold from 2008 to 2017. THC is eliminated mainly by hepatic CYP-mediated metabolism, primarily by CYP2C9, with a minor contribution by CYP3A.

Biotransformation activity generally tends to slow with age due to decreased blood flow and reduced liver mass. Both CYP2C19 and CYP2C9 harbor multiple reduced function genetic variants that could further reduce the safety of CBD and THC. Therefore, the elderly with hepatic impairment or carrying such genetic variants may be at heightened risk for adverse events from CBD and THC.

Collectively, there is an urgent and critical need to understand how comorbidities such as hepatic impairment, along with select CYP variants, affect CBD and THC disposition in the elderly. Because conducting clinical trials in the elderly can be challenging, model-based approaches such as physiologically-based pharmacokinetic (PBPK) modeling and simulation can be used to project systemic exposure to CBD and THC.

The objective of this project is to incorporate age-related physiological changes, hepatic impairment, and select CYP genetic variants, as well as oral or inhaled CBD- and THC-specific characteristics, into novel PBPK models to predict CBD and THC disposition in hepatic-impaired elderly patients (65-98 years) and assess the combined effects of age and genetic CYP polymorphisms on CBD and THC exposure.

We will (1) quantify the effects of age on oral and inhaled CBD and THC disposition and (2) develop PBPK models to predict both oral and inhaled CBD and THC exposure in elderly patients with hepatic impairment and (3) assess the impact of select CYP genetic variants on oral and inhaled CBD and THC exposure in the elderly.

Results from this project are expected to provide critical and timely data to inform consumers and healthcare professionals about the safety linked to CBD and THC use among the elderly with and without hepatic impairment or select CYP genetic variants. Importantly, results will lay the foundation for future benefit/risk assessment of the complex natural cannabinoid mixture (cannabis/marijuana/hemp) in this special population.

Research Foundation Of The City University Of New York

THE NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES (NIGMS) SUPPORTS BASIC RESEARCH THAT INCREASES OUR UNDERSTANDING OF BIOLOGICAL PROCESSES AND LAYS THE FOUNDATION FOR ADVANCES IN DISEASE DIAGNOSIS, TREATMENT, AND PREVENTION. NIGMS ALSO SUPPORTS RESEARCH IN SPECIFIC CLINICAL AREAS THAT AFFECT MULTIPLE ORGAN SYSTEMS: ANESTHESIOLOGY AND PERI-OPERATIVE PAIN, CLINICAL PHARMACOLOGY ?COMMON TO MULTIPLE DRUGS AND TREATMENTS, AND INJURY, CRITICAL ILLNESS, SEPSIS, AND WOUND HEALING.? NIGMS-FUNDED SCIENTISTS INVESTIGATE HOW LIVING SYSTEMS WORK AT A RANGE OF LEVELSFROM MOLECULES AND CELLS TO TISSUES AND ORGANSIN RESEARCH ORGANISMS, HUMANS, AND POPULATIONS. ADDITIONALLY, TO ENSURE THE VITALITY AND CONTINUED PRODUCTIVITY OF THE RESEARCH ENTERPRISE, NIGMS PROVIDES LEADERSHIP IN SUPPORTING THE TRAINING OF THE NEXT GENERATION OF SCIENTISTS, ENHANCING THE DIVERSITY OF THE SCIENTIFIC WORKFORCE, AND DEVELOPING RESEARCH CAPACITY THROUGHOUT THE COUNTRY.

93.859 - Biomedical Research and Research Training

National Institute of General Medical Sciences (NIGMS) [HHS - NIH]

HHS Office of the Assistant Secretary for Financial Resources (ASFR) [HHS]

Jamaica, New York 114510001 United States

Single Zip Code

Support for Research Excellence First Independent Research (SuRE-First) Award (R16 - Clinical Trial Not Allowed) (PAR-21-173)

Amendment Since initial award the End Date has been shortened from 06/30/26 to 02/28/26 and the total obligations have increased 306% from $195,750 to $794,611.