The interest and growing demand worldwide for natural cannabidiol (CBD) due to its many health benefits is clear. To insure the beneficial effects of this botanical extract we explored how to optimize its oral bioavailability and pharmacokinetics.

CBD shows limited oral bioavailability due to its poor aqueous solubility and extensive first-pass metabolism [13,14,19,30,31]. To overcome these limitations a novel self-emulsifying drug delivery system (SEDDS) based on VESIsorb^® formulation technology (SEDDS-CBD) was developed. The data presented show that SEDDS-CBD provided improved bioavailability over MCT-CBD. A single oral dose of SEDDS-CBD resulted in a 2.85-/1.70-fold increase in AUC_0–8h/AUC_0–24h and a 4.4-fold increase in C_max compared to MCT-CBD.

Solubilization of CBD in the aqueous environment of the gastrointestinal (GI) tract is thought to be the main mechanism by which SEDDS-CBD is improving the oral bioavailability of CBD. The SEDDS-CBD mediated absorption pathway of CBD can be broken down as follows: (i) SEDDS-CBD spontaneously forms tiny droplets upon contact with the gastric or intestinal fluid. The formed droplets contain/solubilize the co-administered lipophilic CBD; (ii) after formation, the droplets diffuse across the aqueous lumen of GI-tract to the surface of the enterocyte; (iii) once at the surface of the enterocyte, single molecules of CBD dissociate from the droplets and are transferred to the enterocyte membrane (flip-flop) and further to the blood vessels.

In a recently performed systematic search of PubMed and EMBASE (including MEDLINE), with the aim to review and analyze all available pharmacokinetic data of CBD, it is illustrated that the pharmacokinetic profile of CBD is dependent on the route of application, dosage schedule (single, multiple dose), type of formulation system and diet (fasted vs. fed). Of 792 articles retrieved, 24 included pharmacokinetic parameters in humans and were summarized and compared [15]. The review article cites two studies using SEDDS as delivery system: the pro-nano-dispersion technology (PTL401, Atsmon et al. [22]) and the piperine-pro-nanolipospheres (PNL, Cherniakov et al. [23]), the latter combining the SEDDS formulation principle (solubilisation) with the absorption enhancer piperine. Piperine, naturally found in black pepper, has been shown to inhibit first pass metabolism mechanisms such as Cytochrome P450 family enzymes and the P-glycoprotein efflux pump [23]. Thus, the PNL formulation may increase the bioavailability of cannabinoids CBD and THC not only by increasing their solubility in the gastrointestinal tract, but also by inhibiting or reducing their first pass metabolism.

The AUC data of SEDDS-CBD compare favorable to both SEDDS formulations, PNL and PTL401. The AUC_0–24h value of SEDDS-CBD was 1.9- and 1.3-fold higher compared to PNL and PTL401, respectively (PNL: AUC_0–24h 6.9 ng/mL*h, 10 mg dose, fasted; PTL401: AUC_0–24h 9.85 ng/mL*h, 10 mg dose, fed; SEDDS-CBD: AUC_0–24h 13.1 ng/mL*h, 10 mg dose-adjusted, fasted).

Furthermore, the C_max values of SEDDS-CBD were 2.6- and 1.9-fold higher compared to PNL and PTL401, respectively (PNL: C_max 2.1 ng/mL, 10 mg dose, fasted; PTL401: C_max 2.9 ng/mL, 10 mg dose, fed; SEDDS-CBD: C_max 5.4 ng/mL, 10 mg dose-adjusted, fasted).

We are aware that inter-study comparisons have to be made with caution and therefore the following comments should be considered:

First, the CBD dose of the current study was 25 mg whereas the CBD dose administered by Cherniakov et al. (PNL) [23] and Atsmon et al. (PTL401) [22] was 10 mg. An approximately dose-proportional increase in AUC after the administration of single dose of 10 mg and 20 mg CBD has been shown by Stott et al. [32]. A saturation effect was observed at CBD doses of 400–800 mg [15]. Thus, the dose-adjusted comparison of the current test product with PNL and PTL401 is certainly reasonable.

Second, the current study and the study by Cherniakov et al. [23] were conducted under fasted conditions whereas the study by Atsmon et al. [22] was carried out under fed conditions. The relevance of these dietary conditions for CBD’s pharmacokinetics was recently demonstrated by Stott et al. who reported an increase in CBD bioavailability under fed vs. fasted states in 12 men after a single 10 mg dose of CBD administered as oromucosal spray (Sativex^®) [16]. Mean AUC and C_max were 4- and 3-fold higher during fed compared to fasted conditions (AUC_0–t, 20.2 vs. 4.5 ng/mL*h; C_max 3.7 vs. 1.2 ng/mL). Absorption was delayed in the fed state (T_max 4.0 vs. 1.4 h). A 4-fold increase of AUC levels has also been reported for Epidiolex^®, when administered with a high-fat/high-caloric meal [33]. Epidiolex^®, recently approved by the FDA for the treatment of rare childhood-onset epileptic seizures, is an oral oily solution. The formulation excipients include sesame oil, ethanol and flavours [33]. The possible impact of food on bioavailability of the current study product cannot be estimated from the study data and should be assessed in further studies to allow comparison to studies reporting CBD bioavailability under fed conditions.

Third, the oromucosal spray Sativex^® was used as a reference product by Cherniakov et al. [23] and by Atsmon et al. [22]. As Sativex^® is classified as a pharmaceutical product additionally containing THC, the product could not be used as reference in the current study. Anyhow, the pharmacokinetic data of SEDDS-CBD compare favorable to Sativex^®, a solution of CBD/THC in ethanol/propylene glycol. The AUC_0–24h value of SEDDS-CBD was 4.2-fold higher compared to Cherniakov et al. (fasted) and 1.8-fold higher compared to Atsmon et al. (fed) (Sativex^®: AUC_0–24h 3.1 ng/mL*h, 10 mg dose, fasted; Sativex^®: AUC_0–24h 7.3 ng/mL*h, 10 mg dose, fed; SEDDS-CBD: AUC_0–24h 13.1 ng/mL*h, 10 mg dose-adjusted, fasted).

In the current study, absorption of CBD from SEDDS-CBD was substantially faster compared to the reference with 87.5% of subjects showing peak concentration within 1 h, whereas the median of T_max for the MCT-CBD was 3.0 h. A fast absorption of CBD is favorable in various conditions, especially in the therapeutic field. With respect to data presented in literature, T_max values for SEDDS-CBD and PNL were comparable (PNL: T_max 1.0 h vs. SEDDS-CBD: T_max 1.0 h) under fasted conditions. In contrast, PTL401 administered under fed conditions showed a slightly higher T_max value of 1.64 h [22]. Such a shift of T_max values was also reported by Stott et al. comparing the concentration time profile of Sativex^® under fasting and fed conditions [16]. T_max values were 1.4 h and 4.00 h for the fasted and fed state, respectively. The delayed absorption of CBD under fed conditions might be explained at least partially by the increased gastric transit time after consumption of meals with high fat content.

The pharmacokinetic endpoints were additionally investigated separately for women and men. Differences in AUC and C_max were observed between women and men after ingestion of MCT-CBD with a higher absorption in women compared with men. A weak correlation was seen in the current study between AUC_0-8h and body weight (r = −0.4260, p = 0.0999) after ingestion of MCT-CBD, but not with BMI. However, gender differences have been reported for all phases of compound disposition (absorption, distribution, metabolism, excretion) and may be due to molecular and physiological factors. The molecular factors include the metabolism rate of cytochrome P-450 (CYP) enzymes and relevant transporter systems [34,35,36]. Physiological factors comprise not only the lower body weight of females, but might be also ascribed to other intrinsic factors such as differences in distribution volume, higher percentage of body fat, lower glomerular filtration rate, slower gastric motility, or hormonal status of women [37,38,39,40]. Nadulski et al. also reported differences between men and women with significantly higher AUC and C_max values found for females as compared with males after oral application of THC or CBD [41] and thus confirmed the current findings. In this context, it is worth mentioning that the “one size fits all” dosage strategy often leads to higher exposures in women also for other substances [42].

Interestingly, the gender differences were much less pronounced for SEDDS-CBD. The correlation with body weight was overrode (r = −0.1457, p = 0.5903). SEDDS-CBD seems to overcome the physiologic responsible differences in women and men due to the enhanced delivery of cannabidiol. However, these observations are based so far on a very limited sample size of n = 8 and should be confirmed in further studies. Since these gender differences are important and the reasons/mechanisms behind this warrant further research to truly understand further.

With regards to study limitations, we like to address the high inter-individual variability of CBD bioavailability which accounted for 60.5% after MCT-CBD and 54.4% after SEDDS-CBD administration (based on AUC_0–24h). Such high inter-individual variability was already reported in previous literature [10,17,18,31]. Therefore, the study was performed in cross-over design to control for inter-individual variability. As study products were only provided once to subjects, intra-individual variability cannot be estimated from the data. Anyhow, the inter-individual differences should be taken into consideration in the clinical setting. The possible impact of food on bioavailability of SEDDS-CBD cannot be estimated from the study data and should possibly be assessed in further studies.

As data continue to emerge looking at the efficacy of CBD on various functional outcomes, achieving certain thresholds for plasma levels of CBD may be important. Although this study did not investigate efficacy, it is possible that a product’s efficacy or lack thereof, may be correlated with its ability to deliver sufficient CBD to the blood.