Randomized single-dose crossover comparative bioavailability study of two novel oral cannabidiol (CBD) formulations in healthy volunteers under fed conditions, compared to a standard CBD isolate capsule.

BACKGROUND

This study aimed to compare the pharmacokinetics and relative bioavailability of two novel cannabidiol (CBD) formulations including bioavailability-enhanced capsule (CBDNEXT Supra capsule) and a bioavailability-enhanced liquid (CBDNEXT Supra liquid)- against a standard high-purity CBD isolate capsule in healthy volunteers under fed (low-fat) conditions.

METHODS

A single-dose, open-label, randomized, three-period, three-sequence crossover trial was conducted in 12 healthy male volunteers (18-50 years). Of the 12 enrolled subjects, 9 completed all three treatment periods per protocol. Each received 40 mg of CBD as one of three formulations: Test-1 (enhanced CBD capsule), Test-2 (enhanced CBD liquid), or Reference (unformulated CBD isolate capsule with microcrystalline cellulose only as excipient), with a washout of 14 days between treatments. All doses were administered 30 min after a standardized low-fat (~ 300-350 kcal, < 10 g fat) breakfast to minimize the impact of dietary fat on CBD absorption. Blood samples were collected up to 72 h post-dose for plasma CBD and 7-hydroxy-CBD analysis by a validated LC-MS/MS method (LLOQ 0.1 ng/mL). Pharmacokinetic (PK) parameters (C_max, tmax, AUC_0-72, and t_1/2) were determined by non-compartmental analysis. Safety was assessed by adverse events (AEs), vital signs, and laboratory tests (including liver enzymes). Plasma cortisol was measured pre-dose and at 2-, 4-, and 8-hours post-dose as an exploratory pharmacodynamic marker.

RESULTS

Nine subjects completed all treatments (three withdrew: two for positive drug screens and one for an intercurrent moderate infection). Mean plasma CBD concentration-time profiles for the three formulations demonstrated markedly different absorption kinetics. The enhanced capsule achieved the highest peak CBD concentration (C_max 14.1 ng/mL) and exposure (AUC_0-72 38.0 h·ng/mL), compared to the enhanced liquid (C_max 6.2 ng/mL, AUC_0-72 20.2 h·ng/mL) and the reference capsule (C_max 2.4 ng/mL, AUC_0-72 11.7 h·ng/mL). The time to peak concentration (tmax) was shortest for the liquid (median ~ 1.0 h), followed by the capsule (2.0 h), and longest for the reference (6.0 h). Inter-individual variability in C_max and AUC was substantially lower for both novel formulations (coefficients of variation ~ 27-44%) than for the reference (> 90%). Statistical analysis confirmed that both the enhanced capsule and liquid produced significantly greater C_max and AUC_0-72 than the reference (geometric mean C_max ratios ~ 566% and ~ 248%, AUC_0-72 ratios ~ 328% and ~ 166%, respectively; 90% confidence intervals did not include 100%). The 7-hydroxy-CBD metabolite reached much lower plasma levels than parent CBD for all treatments (C_max 0.4-1.8 ng/mL, ~ 5-13% of parent C_max), with a slightly delayed tmax (~ 2-6 h) and similar elimination half-life. No serious AEs occurred. The only treatment-related AE was mild-to-moderate transient headache in four subjects (1 on capsule, 2 on liquid, 1 on reference), all resolved without intervention. No clinically significant changes in liver function tests or other laboratory values were observed. Plasma cortisol levels remained within normal ranges after all treatments, with a decline over 8 h consistent with the normal diurnal rhythm and no significant differences between formulations.

CONCLUSIONS

Both novel formulations markedly improved CBD oral bioavailability under low-fat fed conditions relative to an unformulated CBD isolate capsule. The enhanced capsule in particular achieved a ~ 5.7-fold higher C_max and ~ 3.3-fold higher AUC than the reference, while the enhanced liquid was absorbed ~ 2.5-fold faster. Variability was reduced with the new formulations, and both were well tolerated at the 40 mg dose. These results indicate that the surfactant/acid formulation technology effectively enhances CBD absorption even with a low-fat meal, potentially obviating the need for high-fat co-administration. Further clinical studies (including in female subjects and at steady state) are warranted to confirm these pharmacokinetic advantages in broader populations.

TRIAL REGISTRATION

Not prospectively registered (pilot pharmacokinetic study without therapeutic intent, thus not subject to mandatory registration).