Metabolomic profiling of cannabis use and cannabis intoxication in humans.
Francisco Madrid-Gambin, Noemí Haro, Natasha L Mason, Pablo Mallaroni, Eef L Theunissen, Stefan W Toennes, Oscar J Pozo, Johannes G Ramaekers
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology May 1, 2025 Peer reviewed DOI: 10.1038/s41386-025-02082-7 via PubMed
Summary
Blood metabolites differ between occasional and chronic cannabis users, both when sober and after acute THC intoxication. A set of 14 metabolites, mainly involved in endocannabinoid and amino acid metabolism, distinguished chronic from occasional users with 80% accuracy. During intoxication, occasional users showed attentional impairment and elevated subjective high, accompanied by increases in organic acids, β-hydroxybutyrate, and ceramides, while chronic users did not. Metabolomic profiling may help identify objective markers of cannabis impairment beyond mere drug presence.
Study at a glance
| Design | observational cohort |
|---|---|
| Sample size | 35 |
| Population | occasional and chronic cannabis users |
| Key finding | Metabolomic fingerprints distinguished chronic from occasional cannabis users at baseline and identified metabolic changes specific to acute cannabis intoxication and attentional impairment in occasional users. |
Abstract
Acute intoxication from Δ9-tetrahydrocannabinol (THC, the primary active ingredient of cannabis) can lead to neurocognitive impairment and interference with day-to-day operations, such as driving. Present evaluations of THC-induced impairment in legal settings rely on biological drug tests that solely establish cannabis use, rather than cannabis impairment. The current study evaluated the metabolome in blood collected from occasional and chronic cannabis users (N = 35) at baseline and following treatments with cannabis (300 μg/kg THC) and placebo, with the aim to identify unique metabolic alterations that are associated with acute cannabis intoxication and cannabis use frequency. Blood samples were collected at baseline and repeatedly during 70 min after treatment. Sustained attention performance and ratings of subjective high were taken twice within 40 min after treatment. Metabolomic fingerprints of occasional and chronic cannabis users were distinctly different at baseline, when both groups were not intoxicated. A total of 14 metabolites, mainly related to endocannabinoid and amino acid metabolism, were identified that distinguished chronic from occasional cannabis users and that yielded a discriminant analysis model with an 80% classification rate (95% CI: 61-91%). Distinct metabolomic fingerprints were found for occasional cannabis users who, in contrast to chronic cannabis users, showed attentional impairment and elevated ratings of subjective high during cannabis intoxication. These included increments in organic acids, β-hydroxybutyrate and second messenger ceramides. The current study demonstrates the feasibility of the metabolomics approach to identify metabolic changes that are specific to the neurocognitive state of cannabis intoxication and to the history of cannabis use.