The goals of the current study were to compare the pharmacokinetics of five oral CBD preparations over 4 h, to examine the relationship between body composition and CBD pharmacokinetics, and to explore the influence of acute CBD ingestion on heart rate variability. Our primary findings were: (1) compared with most of the other preparations, the preparation comprising 5% CBD concentration liquid (preparation 707; Table 2) evoked the fastest T_max, and the greatest C_max; (2) within each CBD preparation, there was considerable variability in the calculated pharmacokinetic parameters; some of the variability for some of the preparations could be explained by body size and composition; and, (3) CBD had only a modest effect on some of the parameters used to describe heart rate variability.

The high degree of variability in CBD absorption and the resulting pharmacokinetic parameters following CBD ingestion have been previously described [4,12,18,19,20]. Potential explanations for variable, and often poor, CBD absorption have pertained to properties of the CBD itself (e.g., poor water solubility) and also variability brought about by the significant first pass metabolism it must endure following oral ingestion. To counter these potential absorption hurdles, CBD preparations have been modified, with mixed success, in a variety of ways, including generation of synthetic CBD [20], creation of water-soluble CBD powders [12], development of self-emulsifying delivery systems [18,20], and encapsulation of CBD within gelatin matrix pellets [21] and liposomes [22]. One important consideration when evaluating CBD formulations is the pharmacokinetic goal and intended use of the CBD. For example, if the indication for the CBD is to treat acute pain, then a faster T_max and higher C_max may be desirable, and also may help to decrease the risk of overdose due to premature repeat self-administration. Alternatively, as a chronic treatment for anxiety, a larger AUC may be preferrable if a user follows a regular dosing schedule. The CBD preparations under investigation in the current study generated a wide range of values for pharmacokinetic parameters (Table 3). Preparation 707 appeared to be the superior preparation as, compared with most of the others, it generally evoked the fastest T_max, greatest C_max, and largest AUC. Perhaps more important than comparisons within the current study are comparisons of the preparations to others described within the literature. In this regard, a very thorough review of CBD pharmacokinetics was published in 2018 [19]. We have supplemented this published information to include data from the current study, and other data published since the release of the original review (Table 6). An important caveat to these comparisons is that the dose of CBD administered across the reviewed studies ranged between 5 and 6000 mg; the influence of CBD dose on pharmacokinetics, especially AUC, has been previously described [19,23], thus direct comparisons to appreciably smaller/larger doses are problematic. Further, these are informal and not definitive statistical/quantifiable comparisons. With these caveats in mind, preparation 707 from the current study appears to have the fastest T_max, but a smaller C_max when compared with the Self-Emulsifying Drug Delivery System, despite the latter comprising a slightly smaller dose (25 mg) [18]. The favorable CBD bioavailability of the Self-Emulsifying Drug Delivery System was attributed to augmented solubility within the gastrointestinal tract [18]. A similar rationale was employed during the development of preparation 707; some of the components of the preparation, such as gum arabic and medium-chain triglycerides (MCTs) have been shown to improve bioavailability of dietary supplements [24,25] and may have contributed to the superior performance in the current study, and its favorable comparison to the other published formulations.

Another important consideration for CBD use is terminal elimination half-life. In the context of pharmacokinetic research, undetectable baseline circulating CBD concentrations can be critical for valid derivation of pharmacokinetic parameters. The terminal elimination half-life of CBD administered to fasted humans varies greatly (between 6 and 32 h) [37,38] depending on mode of administration and CBD preparation. This variability is further illustrated by the K_e values (i.e., the rate of CBD removal from the body) presented in Table 3 and Table 6. In the current study, baseline (Time 0) concentrations for all CBD preparations, for all participants, were below the limit of quantitation. This provides support for our rationale for a minimum 72 h “washout” period between consecutive laboratory visits, although it should be noted that other studies have employed considerably longer duration (14 days) CBD abstention periods between repeated study visits [18].

An influence of body size and composition on CBD pharmacokinetics has been previously speculated [18] but to our knowledge is currently undocumented. In the current study we used DEXA to quantify body composition. Some of the inter-personal variability, for some of the preparations, could be explained by body size and composition as reflected by correlations between several of the DEXA-derived variables and CBD pharmacokinetic parameters. It is not uncommon for DEXA-derived variables to be interrelated (for example, high fat free mass is often associated with high body mass), thus we employed stepwise regression to further explore potential relations between body composition and CBD pharmacokinetics. With respect to our superior CBD preparation, preparation 707, fat free mass was a significant predictor of T_max (r = −0.60, p = 0.017).

Somewhat counter-intuitively, the association was negative, implying that a larger fat free mass was associated with a faster T_max. In light of the positive association between fat free mass and total blood volume [5,6], it may seem unlikely that peak concentration is reached earlier in adults with greater blood volumes. Circulating concentrations of all substances, including endogenous hormones and active ingredients in dietary supplements, are determined by a combination of rate of entry and rate of clearance from the blood. The shorter time to peak concentration in adults with greater fat free mass may reflect a greater rate of clearance by metabolically active and relatively well-perfused tissues (such as skeletal muscle). Noteworthy, fat free mass did not predict C_max or AUC for preparation 707. Alternatively, body mass index was positively associated with T_max for preparation 178 (r = 0.63, p = 0.016). The preparation 178 T_max was among the slowest of the compared preparations (approximately 3.5 hours); it is feasible that for preparations absorbed more slowly (i.e., slower rate of entry into the blood), body size (and presumably blood volume) may contribute to time to peak circulating concentration. From a broader perspective, CBD bioavailability may be determined not only by preparation/formulation, but perhaps also by body size and composition. The implication is that future dosing guidelines may better serve users of CBD when additional consideration is given to expected rates of CBD absorption based on preparation/formulation characteristics (e.g., presence/absence of ingredients used to promote solubility), requirements of intended use (e.g., acute needs from a single dose vs. chronic repeated dosing), and the body size and composition of the user. Dosing guidelines should be a focus of future research as we are unable to make definitive recommendations based on our current data.

An additional goal of the current study was to explore the influence of acute CBD ingestion on heart rate variability, the inconsistencies in the periods of time separating consecutive cardiac cycles. It is an important predictor of future cardiac events [14,15] and, in some instances, longevity [16]. While there are many methods and different parameters used to quantify heart rate variability, generally speaking, greater variability is considered desirable. To our knowledge, this is the first exploration of a potential influence of acute CBD on heart rate variability in adult humans. Only one previous study has examined the short-term influence of CBD (administered as a hemp oil extract) on heart rate variability [17] but the experimental design did not include an acute measurement. Other studies have compared heart rate variability in users and non-users of Cannabis sativa L. (i.e., CBD plus Δ⁹-Tetrahydrocannabinol and other potentially active ingredients), thus making assertions as to the independent influence of CBD difficult [39]. In the current study, acute CBD ingestion decreased heart rate, peak frequency of the high frequency band, and Poincaré plot standard deviation along the line of identity, and increased R-to-R interval and Poincaré plot standard deviation perpendicular to the line of identity (Table 4). Poincaré plots are a useful tool in the heart rate variability analysis arsenal; they are often able to recognize patterns and rhythms in the R-to-R interval data that are sometimes overlooked using spectral analysis [40,41]. From an interpretation perspective, the standard deviation perpendicular to the line of identity reflects short-term heart rate variability and is thought to be regulated by parasympathetic (vagal) input, while the standard deviation along the line of identity reflects total heart rate variability and is determined by a combination of sympathetic and parasympathetic input [40]. When considered together, the ratio of these two variables (i.e., the SD2/SD1 ratio; Table 4) represents sympathovagal balance. In light of the opposing direction of change in these Poincaré plot data, in addition to the small magnitude of change in the other heart rate variability parameters, it appears likely that acute CBD evokes only a modest, and physiologically irrelevant effect on heart rate variability, at least when studied at rest. In the short-term study [17], neither 3 nor 6 weeks of daily CBD ingestion influenced heart rate variability measured at rest or during mental stress activities. One important point worthy of emphasis in the current study—our primary focus was the pharmacokinetics of the different CBD preparations and the potential interaction with body size and composition. Accordingly, we did not include a placebo-control within our experimental design. Thus, any conclusions with respect to our exploration of the acute influence of CBD on heart rate variability must be considered with caution. For example, it is plausible that CBD does not exert any acute influence on heart rate variability and we are simply reporting on the influence of 60 min of semi-recumbent rest.

CBD may or may not have appreciable, and potentially favorable effects on physiological function. Conflicting empirical evidence describing the response to CBD can be partially explained by considerable inconsistencies in its bioavailability. In the current study we identified a CBD preparation that compared well with other preparations described in the literature [19], and with the other preparations incorporated within our design. Further, we demonstrate that some of the pharmacokinetic parameters of this superior preparation were influenced by body size and composition. These findings highlight the need to optimize CBD preparations and personalized dosing strategies in order to confirm/refute the physiological relevance of CBD as a potential therapeutic. Finally, we document, for the first time, a modest effect of acute CBD on selected parameters of resting heart rate variability in healthy adults, alleviating any potential concerns that CBD may unfavorably impact autonomic regulation of heart rate.