This trial in healthy subjects explored the effects of meal composition, whole milk, and alcohol on the PK of CBD and its major metabolites, 7‐OH‐CBD and 7‐COOH‐CBD.

4.1 CBD and metabolite PK

Time for CBD to reach maximum plasma concentration was unaffected by any test treatment; median t max was 3 to 5 hours in all treatment groups. This result is consistent with an earlier phase 1 trial in healthy subjects in which a single 1500‐mg dose of the same CBD formulation administered with a standardized high‐fat meal had no effect on t max .11

After a single 750‐mg CBD dose, all test treatments increased CBD exposure (AUC and C max ) compared with the fasted state. The largest increases occurred when CBD was administered following a high‐fat/calorie meal. An almost identical food effect was reported in the earlier phase 1 trial in healthy subjects when a 1500‐mg dose of the same CBD formulation was administered with a standardized high‐fat meal.11

In the current trial, similar but less notable effects on CBD exposure were seen with a low‐fat/calorie meal and whole milk. This is the first trial to explore the PK of CBD under these dietary conditions.

Administration of CBD with alcohol caused a modest increase in CBD exposure; none of the treatment ratios was >2.0. There are no previous studies investigating the effects of alcohol on CBD exposure, although evidence suggests that alcohol may increase19, 20 or have no effect21, 22 on Δ9‐tetrahydrocannabiniol absorption.

As 7‐OH‐CBD is an active metabolite and 7‐COOH‐CBD is highly abundant,11 understanding changes in the MR with reference to extrinsic factors such as food is important. Although most treatments also increased exposure to both CBD metabolites within this trial, increases in exposure were greatest for parent CBD, as supported by the MR AUC0‐t , MR AUC0‐∞ , and MR Cmax , which were all reduced compared to administration of CBD in the fasted condition. These findings suggest that metabolic transformation of CBD was not affected by different food types or milk. By contrast, exposure to 7‐COOH‐CBD in the alcohol group was considerably lower than in any other group, despite an increase in CBD exposure in this treatment group. The reason for decreased exposure 7‐COOH‐CBD relative to other test treatment conditions when CBD was given with alcohol is unknown, but may be due to inhibition of the biotransformation pathway leading to 7‐COOH‐CBD.

In terms of the effect of a high‐fat meal on the PK of the CBD metabolites, the current trial data are consistent with an earlier food effect trial in which concentrations of the same metabolites were measured.11

The high variability in the PK of CBD and its metabolites in this trial is common with other cannabinoids.11-14, 23, 24 During validation of the bioanalytical method to quantify CBD and metabolite plasma concentrations, recovery of CBD was low at 45.4%‐48.8%; however, recovery levels were consistent across the assay range and sufficient to achieve adequate method sensitivity.

Although this trial was designed to explore extreme scenarios in terms of food intake—strict overnight fasting conditions versus extreme dietary conditions—real‐life patients are likely to be taking food of various composition throughout the day and their prandial status may vary. Given that a significant food effect has been demonstrated for CBD, particularly with high‐fat meals, this extrinsic variable may be considered on a case by case basis in clinical practice to reduce variability in exposure to CBD and its metabolites.