Objective Identification of Cannabis Use Levels in Clinical Populations Is Critical for Detecting Pharmacological Outcomes

Weize Huang, Lindsay C. Czuba, Jennifer A. Manuzak, Jeffrey N. Martin, Peter W. Hunt, Nichole R. Klatt, Nina Isoherranen

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Introduction: Cannabis is widely used for recreational and medical purposes, but its therapeutic efficacy remains unresolved for many applications as data from retrospective studies show dramatic discrepancy. We hypothesized that false self-reporting of cannabis use and lack of differentiation of heavy users from light or occasional users contribute to the conflicting outcomes. Objective: The goal of this study was to develop an objective biomarker of cannabis use and test how application of such biomarker impacts clinical study outcomes and dose-response measures. Methods and Analysis: Population pharmacokinetic (PK) models of (-)-trans-Δ9-tetrahydrocannabinol (THC) and its metabolites 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (11-COOH-THC) were developed based on published studies reporting cannabinoid disposition in individual subjects following intravenous administration or smoking of cannabis. Plasma 11-COOH-THC concentration distributions in different cannabis user groups smoking cannabis were generated via Monte Carlo simulations, and plasma concentration cutoff values of 11-COOH-THC were developed to differentiate light and heavy daily cannabis users in clinical studies. The developed cutoff value was then applied to a retrospective study that assessed the impact of cannabis use on T cell activation in subjects with HIV who self-reported as either nonuser or daily user of cannabis. Results: The developed population PK models established plasma 11-COOH-THC concentration of 73.1 μg/L as a cutoff value to identify heavy daily users, with a positive predictive value of 80% in a mixed population of equal proportions of once daily and three times a day users. The stratification allowed detection of changes in T cell activation in heavy users which was not detected based on self-reporting or detectability of plasma cannabinoids. A proof-of-concept power analysis demonstrated that implementation of such cutoff value greatly increases study power and sensitivity to detect pharmacological effects of cannabis use. Conclusions: This study shows that the use of plasma 11-COOH-THC concentration cutoff value as an objective measure to classify cannabis use in target populations is critical for study sensitivity and specificity and provides much needed clarity for addressing dose-response relationships and therapeutic effects of cannabis.

Original languageEnglish (US)
Pages (from-to)852-864
Number of pages13
JournalCannabis and Cannabinoid Research
Volume7
Issue number6
DOIs
StatePublished - Dec 1 2022

Bibliographical note

Funding Information:
This work was supported by grants from the National Institutes of Health: National Institutes of Drug Abuse grant DP1DA037979-01 to N.R.K. and P01DA032507 to N.I., and National Institute of Allergy and Infectious Diseases grant P30AI027763 to J.N.M. and K01OD024876 to J.A.M.

Publisher Copyright:
Copyright © 2022, Mary Ann Liebert, Inc.

Keywords

  • 11-COOH-THC
  • Monte Carlo simulation
  • THC
  • cannabis user classification
  • pharmacokinetic modeling
  • receiver operating characteristic curve

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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