A prior high-fat meal increases plasma cannabidiol concentrations compared to an isoenergetic high-carbohydrate meal in healthy young participants: a randomised crossover study

Cannabidiol (CBD), a widely available nutritional supplement, has low oral bioavailability due to its lipophilicity and extensive first-pass metabolism (1) , which can be improved by consuming CBD with food (2,3) . Current recommendations to maximise bioavailability are to consume CBD with a high fat, high calorie meal, but it remains unclear whether fat or total energy content influences bioavailability (4) . Given the potential health implications of regularly consuming high-fat meals (5) , this study examined the effect of isoenergetic high- fat and high-carbohydrate meals on CBD bioavailability. Ten healthy adults (4 females, 27 ± 5 y; 73.17 ± 15.97 kg; body mass index 24.53 ± 2.75 kg/m 2 ) completed a screening visit and two experimental trials consuming, in randomised order, a high-fat (HiFAT; 800 kcal, 70% fat; 15% carbohydrate; 15% protein) or high- carbohydrate (HiCARB; 800 kcal, 15% fat; 70% carbohydrate; 15% protein) meal 30 minutes before ingesting 60 mg CBD isolate in 1 mL hemp oil. Venous blood samples were collected before, and for 7 hours after CBD ingestion (-0.5, 0, 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 6, 7 h), with a standard lunch meal (800 kcal) provided after the 4 h sample. Blood samples were analysed for concentrations of CBD and metabolites (6-OH-CBD, 7-OH-CBD and 7- COOH-CBD), glucose, creatinine, triglycerides, AST, ALT and ALP, with area under the max) calculated. Visual analogue scales responses (appetite, nausea, headache, and gastrointestinal discomfort) were measured hourly using 100-mm scales. Plasma CBD and metabolite concentrations increased after ingestion, with a time by trial interaction effect for plasma CBD concentration, and a greater total AUC for CBD in HiFAT (7595 ± 378 ng/ml·7.5 h vs 4780 ± 3171 378 ng/ml·7.5 h; P=0.002), although Cmax (HiFAT 67 ± 45 ng/mL; HiCARB 47 ± 35 ng/mL; P=0.070) and Tmax (P=0.068) were not different between trials. For the CBD metabolites, there were no differences for total AUC, Cmax or Tmax. Plasma glucose was greater in HiCARB vs HiFAT at 0 h (P=0.032) and greater in HiFAT vs HiCARB at 3, 4, 5 and 7 h ( P≤ 0.040), with no further trial by time interaction effects for blood-based or subjective outcomes. This study provides novel data supporting that a prior high-fat meal enhances CBD bioavailability more than an energy matched high-carbohydrate meal. Therefore, timing CBD ingestion after high-fat meals may be an advantageous strategy to maximise the efficacy of CBD supplementation. Future studies should seek to explore the dose- response relationship between meal fat content and CBD bioavailability to understand minimum meal fat content required to maximise bioavailability.