The oral bioavailability of cannabinoids presents a well-documented challenge due to their lipophilic nature, limited gastrointestinal absorption, and extensive first-pass metabolism (Agurell et al. 1981; Gaston and Friedman 2017). Overcoming these obstacles is crucial to achieving desired therapeutic responses via oral delivery. Various advanced formulation strategies have been explored in the past to enhance the oral bioavailability of poorly water-soluble drug candidates, with several self-emulsifying formulations already on the market (Salawi 2022). Among these, certain formulations have previously demonstrated the potential to enhance the oral bioavailability of cannabinoids (Atsmon et al. 2018; Knaub et al. 2019; Cherniakov et al. 2017a, 2017b).

This study aimed to evaluate the pharmacokinetics and relative bioavailability of cannabinoids and their metabolites—specifically THC, 11-OH-THC, CBD, and 7-OH-CBD—administered via THC/CBD-SE Powder compared to a standard oil-based formulation. This novel SNEDDS-based powder achieves complete emulsification, ensuring stability, solubility, and consistent bioavailability.

The results confirmed that THC/CBD-SE Powder significantly enhanced the relative bioavailability of all tested cannabinoids compared to the oil-based formulation. Higher Cmax values and shorter Tmax times were observed for THC, CBD, and their active metabolites, indicating faster and more efficient absorption. Specifically, the relative bioavailability increased by 2.9-fold for THC, 2.5-fold for 11-OH-THC, 2.3-fold for CBD, and 3.2-fold for 7-OH-CBD. These improvements highlight the formulation’s ability to rapidly deliver active compounds into the bloodstream, potentially resulting in quicker therapeutic effects.

These outcomes are consistent with prior research on emulsion-based cannabinoid delivery systems. For instance, Berl et al. (2022) reported enhanced Cmax and faster Tmax with liquid emulsions compared to medium-chain triglyceride formulations. Similarly, Cherniakov et al. (2017a, 2017b) found that a capsule-based THC-CBD-piperine-pro-nanolipospheres delivery system resulted in a four-fold increase in Cmax and a 2.2-fold increase in AUC compared to Sativex^®, an oromucosal spray. Additionally, Atsmon et al. (2018) demonstrated that an oral THC and CBD formulation via a self-emulsifying drug delivery system provided higher plasma Cmax and relative bioavailability compared to Sativex^®. The consistency of these results supports the effectiveness of SNEDDS for cannabinoid delivery, underscoring its potential as a robust alternative to conventional cannabinoid delivery methods.

Interestingly, multiple peaks were observed in the concentration-time profiles, particularly for CBD at 4 h and THC at 8 h. These delayed secondary increases in systemic concentrations may be partly attributed to the lipophilic nature of cannabinoids, which enables their uptake into tissues such as adipose and subsequent redistribution into the plasma over time. This mechanism is consistent with prior observations and could also explain the smaller secondary fluctuations seen in the oil formulation (Huestis 2007). However, in the SNEDDS powder group, these multiphasic profiles were more pronounced. First, the rapid onset of absorption with the SNEDDS powder likely engages multiple absorption sites along the gastrointestinal tract, contributing to a more complex absorption profile. Second, the increased surface area of the self-emulsified nano-droplets may facilitate prolonged or sequential absorption across different intestinal segments, further accentuating the appearance of secondary peaks. Together, these mechanisms may help explain the appearance of multiphasic concentration-time profiles following oral cannabinoid administration, although further investigation would be needed to confirm their relative contributions.

The clinical implications of our findings are substantial. The enhanced relative bioavailability and faster onset of action provided by THC/CBD-SE Powder may support more efficient and timely therapeutic effects. This is particularly valuable in clinical settings where rapid relief is required, such as pain management or seizure control. While inhalation methods are known for their rapid absorption and almost immediate effects, they can also cause adverse effects, including respiratory issues and potential long-term lung damage (Tan and Sin 2018; Kaplan 2021; Tetrault et al. 2007; MacCallum and Russo 2018; Gracie and Hancox 2021; Tashkin 2013). THC/CBD-SE Powder, in contrast, provides a non-invasive oral alternative that delivers rapid systemic absorption without the risks associated with pulmonary route of administration. Furthermore, the enhanced relative bioavailability observed with THC/CBD-SE Powder suggests that therapeutic plasma concentrations may be achieved with smaller doses compared to conventional oil formulations. While this could potentially reduce the total amount of active compound administered and lower the risk of dose-dependent adverse effects, further studies are needed to confirm whether this translates to improved safety outcomes, particularly in vulnerable populations.

Despite these promising results, the study has limitations. The small sample size of 14 healthy participants limits the generalizability of the findings, and substantial inter-individual variability in pharmacokinetic parameters remains a challenge. This variability, frequently reported in cannabinoid studies (Atsmon et al. 2018; Knaub et al. 2019; Karschner et al. 2011; Huestis 2007), was partially mitigated by the crossover design, which controls for inter-individual differences. However, intra-individual variability could not be assessed due to the single administration of each formulation. These factors should be considered when applying these results in clinical practice, and further studies with larger, more diverse populations are needed to validate these findings.

In conclusion, THC/CBD-SE Powder significantly enhances the relative bioavailability and pharmacokinetic profile of cannabinoids compared to a standard oil-based formulation. The study results demonstrate that this technology provides a more efficient delivery method, leading to faster and more effective therapeutic outcomes. Its ability to deliver rapid therapeutic effects while reducing the risk of adverse outcomes positions it as a promising option for both acute and chronic conditions. Further research is warranted to validate its long-term safety and efficacy and to explore its potential in diverse patient populations. These findings provide a strong foundation for the development of THC/CBD-SE Powder as an effective and reliable cannabinoid delivery system.