A THC Genetic Study Found Metabolite Differences Without Higher Parent THC

A genetic association with a THC metabolite did not translate into a demonstrated increase in parent THC in a forensic sample study. That distinction matters when a metabolism finding is used to explain an individual blood concentration.

Case samples were not controlled doses

Researchers combined CYP2C9 and CYP2C19 genotyping with plasma cannabinoid results from 66 men recruited through driving-aptitude assessments after cannabis-related cases. The study measured THC, 11-hydroxy-THC and THC-COOH.

Amounts consumed and precise consumption times were not controlled. The investigators expected inhalation to be common, but this was not a trial assigning everyone the same inhaled dose. Plasma results also should not be treated as numerically identical to whole-blood measurements.

The positive and null findings involved different analytes

Carriers of CYP2C9*3 had lower THC-COOH concentrations than the wild-type comparison, with a reported p value of 0.001. The lower THC-COOH observation for CYP2C9*2 did not reach the conventional significance threshold (p = 0.068). Parent-THC and 11-hydroxy-THC comparisons did not show significant differences.

THC/THC-COOH ratios were higher in variant-carrier comparisons. A ratio can increase because its denominator is lower; that does not require a demonstrated increase in its numerator. Treating the ratio result as proof that variant carriers had higher THC would misstate this dataset.

Genotype did not supply a reconstruction formula

The sample contained no CYP2C9*3/*3 homozygotes, and several genotype groups were very small. CYP2C19 comparisons did not show significant cannabinoid differences. These null findings should be retained alongside the metabolite association rather than replaced by a broad claim about every slow metabolizer.

Unknown dose and timing, selected case recruitment and genotype-group sizes limit causal interpretation. The results support examining metabolism as one contributor to variability. They do not validate a genotype-based calculation of dose, last-use time or impairment, nor establish that a particular person’s THC result was elevated because of a genetic variant.

Related: interpreting THC concentrations separately from impairment.

Primary research

Toxicogenetic analysis of Δ9-THC-metabolizing enzymes. DOI: 10.1007/s00414-020-02380-3.