Transdermal delivery of cannabinoids may provide advantages over other more traditional routes of administration. Cannabis smoking rapidly yields very high concentrations of cannabinoids in the bloodstream, but comes with risks associated with toxicity, exposure to carcinogenic byproducts, and respiratory conditions, as well as loss of activity through combustion (inactive and degraded cannabinoids due to excess heat) [1, 8–11]. When consumed orally, cannabinoids undergo first-pass metabolism, resulting in reductions in bioavailability and other unwanted effects associated with liver metabolizing enzymes, most notably, the cytochrome P450 system [12]. THC metabolism via cytochrome P450 (CYP450) produces a greater accumulation of 11-hydroxytetrahydrocannabinol, a potent, longer-lasting psychoactive metabolite that that may go beyond the desired effects of a novice or medical consumer [12]. Furthermore, CBD metabolism by CYP450 is associated with potentially dangerous drug–drug interactions that may be minimized when CBD is delivered through the skin, owing to delayed cannabinoid accumulation [13]. This can be particularly important in the treatment of chronic conditions over long periods of time or where a treatment regimen involves significant quantities of CBD as it relates to the patient’s body weight, for example in pediatrics. It is suggested that by avoiding first-pass metabolism and applying cannabinoids to the skin, psychotropic impacts may be reduced, and more constant cannabinoid plasma levels can be achieved [3, 4]. A challenge with transdermal delivery is that cannabinoids are hydrophobic molecules, preventing them from easily diffusing through the aqueous layer of the skin [5]. In general, cannabinoids are molecules that have low transdermal uptake, build up in a reservoir in the stratum corneum, and thought not to reach the blood [6]. Using emulsion technology containing penetrating agents, basement membrane disruptors, and vasodilators, Gefion GT4 technology targets hydrophilic and lipophilic structures to open channels and transport cannabinoids deep into the dermis layer of the skin, while vasodilators dilate the capillary bed to increase fluid dynamic flow to deliver cannabinoids into the blood stream [7].

To our knowledge, this is the first PK study that has demonstrated the ability of CBD and THC to successfully enter systemic circulation via transdermal administration in humans. Importantly, the successful delivery of cannabinoids via Gefion GT4 technology was safe and well tolerated by all participants. There were no clinically significant changes in clinical chemistry or hematology, or any related AEs in the 7-day monitoring period following dosing. This study represents an important step in understanding cannabinoid PKs, opening the door for novel cannabinoid delivery systems, and therapeutic interventions. Previous in vitro studies investigating cannabinoid permeability in human skin found that CBD had an approximately 10 × higher permeability than THC [14, 15], aligning with research that determined that CBD is relatively less lipophilic than its psychoactive counterpart [15]. These findings are consistent with the greater AUC and C_max found with CBD in the current study, although to a lesser degree than what has been previously reported [15]. This preliminary data suggests that to deliver equal doses of CBD and THC via the skin, a greater dose of THC may be required. In the current study, T_max for CBD and THC occurred later in the blood sampling period compared to what is expected from other routes of administration. Previous literature has demonstrated that T_max for CBD and THC in inhaled and orally consumed forms occurred within only a few minutes to approximately 4 h post-dose [16–18]. Inhalation provides a faster T_max because of avoidance of the gastrointestinal tract and first-pass metabolism [5, 19]. Given the challenges of transdermal delivery of cannabinoids (hydrophobic molecules required to pass through aqueous layers of the skin) and preclinical research demonstrating a T_max of up to 38 h post-dose [20], it is not surprising that delayed absorption and a longer T_max for CBD and THC was found in this study. Furthermore, transdermal delivery of CBD and THC appeared to result in a smaller C_max than has been found for inhaled and orally consumed cannabis. When occasional cannabis consumers were given a maximal 50.6 mg dose of THC via smoked, vaporized, and ingested routes of administration, C_max was found to be 52, 48, and 10 ng/mL, respectively [19]. In another study of occasional users, administration of only 1.35 mg of CBD in a liquid extract capsule resulted in a C_max of 0.93 ng/mL [21]. Comparatively, in the current study topical application of 100 mg of CBD and THC resulted in a C_max of 576.52 pg/mL (0.576 ng/mL) and 346.57 pg/mL (0.346 ng/mL), respectively. The C_max of cannabinoids delivered transdermally appear to be lower than that of inhaled or oral routes of administration, despite a higher delivered dose. However, the results of this study need to be considered in the context of large interindividual variation and a blood sampling period that was not sufficient to capture the full descending arm of the PK curve.

For both CBD and THC, there was large interindividual variation across all PK parameters except for t_1/2 and λ, suggesting that once successfully in the blood stream, the cannabinoids were removed from systemic circulation at similar rates between participants. However, the magnitude and rate at which cannabinoids were able to diffuse through the skin appeared to be highly dependent on the individual participant.

Several reasons may explain the variability found between individual participants in this study. Transdermal drug distribution tends to present in more erratic patterns with less symmetrical bell-shaped curves [22] due to biological differences that affect the structure and integrity of the skin, leading to variation in the quantity absorbed [23–25]. The quality of an individual’s skin may be influenced by gender, ethnicity, metabolism, and perhaps most notably, age [23]. As humans get older, the epidermis and dermis layers of the skin begin to thin, and there are critical changes in  keratinocytes, melanocytes, type-3 collagen fibers, and Langerhans cells [26]. Changes to aging skin has contributed to significant reductions in skin permeability and drug absorption [23]. However, those that are more lipophilic, such as testosterone and estradiol, were less impacted by aging skin [27]. Considering that participants in the current study ranged in age from 27 to 57 years, the integrity and quality of skin of individual participants may have contributed to large interindividual variation in cannabinoid absorption. Further adding to the large variation may have been differences between males and females, which made up an equal 50% of the enrolled study population. Men typically have larger keratinocytes [28] and sweat and sebaceous glands [29], and a lower skin pH than females [30], which could result in varying levels of transdermal permeation [23]. Although most studies have not demonstrated any significant differences between males and females in transdermal drug delivery, this previous research should not be generalized to cannabinoids without further investigation. Cannabinoids are highly lipophilic molecules that are readily absorbed into fatty tissues [5, 31] and contain unique molecular structures. Although BMI is a poor predictor of body fat [32], there was a range between 20.6 and 29.1 kg/m² in study participants, suggesting there may have been large variations in body fat percentage. Depending on the amount of body fat, particularly subcutaneous deposits at the application site, body fat may have contributed to the variation in PK parameters since this adipose layer can sequester CBD and THC molecules. This also could account for the PK penetration differential between CBD and THC as THC is substantially more lipophilic.

The findings of this study must be considered in the context of certain limitations. The study design was chosen to provide adequate information on the transdermal delivery of cannabinoids in humans. As this is the first study to demonstrate the PKs of CBD and THC following transdermal application, the length required for blood sampling was unclear. The preliminary results clearly demonstrate that the 12-h sampling period was not sufficient to capture a full PK curve, owing to the delayed rate at which cannabinoids entered the blood stream. Health Canada guidance on the conduct of bioequivalence studies recommends that to accurately estimate PK parameters, a minimum of three timepoints should be collected on the descending arm of the PK curve [33]. In total, 61% (8/13) of participants in the PP population had a T_max of 12 h, indicating that their true T_max may have been 12 h, or any number of hours after that final timepoint. Furthermore, only one participant had their concentration of THC drop to pre-dose levels by the end of blood sampling. In the same vein, the true C_max and AUC for both CBD and THC may have been larger than reported in the current study. Although there was less variability in t_1/2 and λ among participants, a complete representation of elimination is not possible without a longer sampling period. Furthermore, this study enrolled a relatively small sample size. The findings of this study will need to be confirmed with a larger double-blind, randomized, placebo-controlled PK trial that utilizes a longer blood sampling period, of at least 48–72 h. Future studies should evaluate differences in transdermal cannabinoid PK profile based on sex, age, and BMI, as well as cannabis use history. Emerging evidence has demonstrated that cannabinoid PKs differ based on years of recreational use, with those reporting more years of use having a greater AUC and C_max, and longer t_1/2 for major cannabinoids and analytes [34].

The successful delivery of CBD and THC to the blood stream highlights the advantages of transdermal cannabinoid delivery. Although more research is needed, more constant and lower plasma cannabinoid concentrations without concerns of psychoactive effects may be beneficial for certain therapeutic indications and individual lifestyles [3]. The results from the psychoactive assessment suggest that the concentration of THC that reached the brain was not sufficient to produce a feeling of being “high.” In the case of using cannabinoid therapy in the treatment of vulnerable populations, the lower concentration of delivered THC could be viewed as a safety mechanism to prevent psychoactive effects. However, the psychoactive effects of transdermally delivered THC should be explored in isolation from CBD. CBD acts as a negative allosteric modulator to THC and may have diminished the psychoactive effects reported in this trial [35]. Based on the extended delivery of CBD and/or THC demonstrated in this study, the GT4 transdermal delivery system may be more applicable for the treatment of chronic compared with acute conditions that require a more rapid C_max for symptom relief.