Among 71 older oral cannabis users, 86% had genetic variants in enzymes that metabolize THC and CBD—meaning most people process cannabinoids differently than the 'standard' pharmacology textbook suggests.
Medical cannabis prescribers, pharmacologists, clinical trial designers, and patients who have had inconsistent responses to cannabis products.
What the researchers found
Why do two people taking the same cannabis product at the same dose sometimes have dramatically different responses? This study points to genetics as a major factor.
The researchers reviewed charts of 71 patients who had both pharmacogenomic testing and reported oral cannabis use. The findings were striking: only 10 out of 71 patients (14%) had completely typical variants across all relevant metabolic enzymes. The vast majority had atypical variants in one or more of the CYP450 enzymes that process cannabinoids:
- 31 had atypical CYP2C9 variants (processes THC)
- 37 had atypical CYP2C19 variants (processes both THC and CBD)
- 6 had atypical CYP3A4 variants (processes both)
- 15 had atypical CYP3A5 variants (processes both)
Additionally, 5 patients were taking medications that could interact with THC metabolism, and 8 were taking medications that could interact with CBD metabolism.
This has enormous practical implications. A patient with reduced CYP2C9 function will process THC more slowly, potentially experiencing stronger and longer-lasting effects from the same dose. Conversely, someone with enhanced enzyme activity might barely feel a dose that's overwhelming for another person. Without pharmacogenomic information, cannabis dosing is essentially guesswork.
Why it matters
RTHC-00186 emphasized the importance of 'start low, go slow' CBD dosing for epilepsy, partly because of drug interactions. This study reveals that even without drug interactions, the majority of patients have genetic variants that alter cannabinoid metabolism. This means the same dose produces different blood levels in different people—which could explain why clinical trials show inconsistent results and why individual patients have such variable experiences.
The numbers in context
N = 71 oral cannabis users. Average age 68.5. Only 14% had typical variants in all enzymes. CYP2C9 atypical: 43.7%. CYP2C19 atypical: 52.1%. CYP3A4 atypical: 8.5%. CYP3A5 atypical: 21.1%. 5 patients on THC-interacting drugs. 8 on CBD-interacting drugs.
How the study worked
Retrospective chart review of 71 patients with prior pharmacogenomic testing who reported oral cannabis use. Average age 68.5, primarily white women. Genotyping of CYP2C9, CYP2C19, CYP3A4, and CYP3A5. Medication review for CYP450 interactions with THC and CBD.
Who was studied
N=71 patients aged 68.5 years on average, primarily white women, who reported oral cannabis use.
What this study cannot tell us
Retrospective, small sample (71 patients). Primarily white older women—allele frequencies vary across ethnic groups. No outcome data (were atypical metabolizers actually more or less responsive to cannabis?). Self-reported oral cannabis use. The study generates hypotheses about how genetic variants affect cannabis response but doesn't test those hypotheses clinically. Chart review can't capture all relevant medications or supplements.
How to read the evidence
Retrospective chart review generating pharmacogenomic hypotheses—valuable for framing the variability problem but not testing clinical outcomes.
When this study was published
Published in 2025 in the Journal of Cannabis Research, reflecting growing pharmacogenomic interest in cannabis medicine.
The bigger picture
This provides a pharmacogenomic lens for understanding variable cannabis response. RTHC-00214's geriatric cannabis clinic included medication review—this study shows why genetic review should be added. The variable drug response also helps explain mixed results in clinical trials: RTHC-00182 found CBD didn't help knee OA, and RTHC-00158 found no overall symptom benefit in cancer—but in both cases, individual patients may have had very different drug exposures despite identical doses.
Replication
Not stated in abstract.
Funding
Not reported in abstract.
Conflicts of interest
Not reported in abstract.
Questions still open
- Should pharmacogenomic testing be standard before prescribing medical cannabis? Could genotype-guided dosing improve outcomes in cannabis clinical trials? Do the same CYP variants that affect cannabis metabolism also predict side effects?
Read the original research
Hypothesized pharmacogenomic and medication influences on tetrahydrocannabinol and cannabidiol metabolism in a cohort of unselected oral cannabis users.
Journal of cannabis research, 7(1), 1
The Journal of Cannabis Research is a peer-reviewed journal focusing on cannabis science and its applications.
Citation
Wright, Jessica A; Huang, Linda; Katamesh, Basant E; Yadav, Siddhant; Singla, Abhinav; Vincent, Ann. (2025). Hypothesized pharmacogenomic and medication influences on tetrahydrocannabinol and cannabidiol metabolism in a cohort of unselected oral cannabis users.. Journal of cannabis research, 7(1), 1. https://doi.org/10.1186/s42238-024-00256-6
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