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problems with first pass effect in capsule administration of cbd

39. Deabold KA, Schwark WS, Wolf S, Wakshlag JJ. Single-dose pharmacokinetics and preliminary safety assessment with use of CBD-rich hemp neutraceutical in healthy dogs and cats. Animals. (2019) 9:832. doi: 10.3390/ani9100832

DH, SK-M, KM, and EM contributed to the conception and design of the study. EM, SK-M, and DS collected data and blood samples. JC provided behavior analysis software. EM performed sample and data analyses, statistical analysis, and wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

In contrast, CBD has been shown to reduce anxious behaviors in mouse, rat, and human models, but at this time there is little to no literature regarding its effect on canine behavior. In mouse and rat models, responses to threatening or unpleasant stimuli were assessed by several methods, including the elevated plus-maze, Vogel-conflict test, contextual fear conditioning, and elevated T maze (63–65). The use of these models has shown that intraperitoneal administration of CBD in doses ranging from 1 to 20 mg/kg produced anxiolytic effects with some responses being dose-dependent (18, 19). Though different models of anxiety were used in rodents, this may indicate that a higher dose is necessary to produce the desired behavioral changes associated with reduced stress and anxiety, particularly if dosed orally due to the considerable first-pass effect on CBD in the liver (24, 66). Future research should investigate the effect of higher dosage of CBD for dogs above the dose tested in this study. Another important consideration is the time of CBD administration prior to noise exposure. As previously mentioned, oral CBD has been shown to have a half-life of <4 h (16, 38, 39), but CBD treats in this experiment were dosed between 4 and 6 h of testing. Thus, it is possible that the dose used in this study would be sufficient to generate an anxiolytic effect if dosed closer to the fireworks test. Alternatively, CBD may need to be dosed for longer than 7 days in order to produce anxiolytic effects. Future investigation into these possibilities is warranted.

Conclusions

CBD tended to increase overall HR (Table 4; P = 0.093), and decreased LF regardless of time point (P = 0.011). All treatments reduced HF compared to control (P < 0.05). AVNN, SDNN, RMSSD, and pNN50 were unaltered by CBD and trazodone (P < 0.05). No HRV variables were affected by the CBD by time nor the trazodone by time interaction (P > 0.05). The CBD by trazodone by time interaction influenced the LF/HF ratio (P = 0.039). During the Pre-Noise time point, trazodone tended (P = 0.061) to increase the LF/HF ratio compared to control and increased the LF/HF ratio compared to the combination of CBD and trazodone (P = 0.038). During the Noise time point, the combination of CBD and trazodone tended (P = 0.083) to reduce the LF/HF ratio compared to control.

13. Tambaro S, Bortolato M. Cannabinoid-related agents in the treatment of anxiety disorders: current knowledge and future perspectives. Recent Pat. CND Drug Discov. (2012) 7:25–40. doi: 10.2174/157488912798842269

Citation: Morris EM, Kitts-Morgan SE, Spangler DM, McLeod KR, Costa JHC and Harmon DL (2020) The Impact of Feeding Cannabidiol (CBD) Containing Treats on Canine Response to a Noise-Induced Fear Response Test. Front. Vet. Sci. 7:569565. doi: 10.3389/fvets.2020.569565

19. Lee JC, Bertoglio LJ, Guimarães FS, Stevenson CW. Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders. Brit J Pharmacol. (2017) 174:3242–56. doi: 10.1111/bph.13724

Limitations of this review should be acknowledged. Different population types including healthy and patient populations and cannabis naïve or not were all grouped together which may impede generalizability. The proportions of men and women in each study were also not uniform, and it is still being elucidated whether men and women have distinct pharmacokinetic profiles with regards to cannabinoids (Fattore and Fratta, 2010). One study suggested that the PK of CBD was different in their female volunteers (Nadulski et al., 2005a). It should also be mentioned that CBD is currently not an approved product with a pharmacopeia entry so using different sources of CBD that are subject to different polymeric forms, different particle sizes, and different purities may also affect the PK profiles observed. It is important for future work that researchers record the source of the CBD material used so that results have the highest chance of being replicated. Despite a thorough search of the two databases chosen, the addition of more databases may have widened the search to increase the number of results and hence improve the reliability and validity of the findings. However, the review was carried out by two independent reviewers, and searches generated were analyzed separately and then compared.

Stott et al. reported an increase in CBD bioavailability under fed vs. fasted states in 12 men after a single 10 mg dose of CBD administered through an oromucosal spray which also contained THC (Stott et al., 2013a,b). Mean AUC and Cmax were 5- and 3-fold higher during fed conditions compared to fasted (AUC0−t 23.1 vs. 4.5; Cmax 3.7 vs. 1.2 ng/mL). Tmax was also delayed under the fed state (4.0 vs. 1.4 h).

Results: Of 792 articles retireved, 24 included pharmacokinetic parameters in humans. The half-life of cannabidiol was reported between 1.4 and 10.9 h after oromucosal spray, 2–5 days after chronic oral administration, 24 h after i.v., and 31 h after smoking. Bioavailability following smoking was 31% however no other studies attempted to report the absolute bioavailability of CBD following other routes in humans, despite i.v formulations being available. The area-under-the-curve and Cmax increase in dose-dependent manners and are reached quicker following smoking/inhalation compared to oral/oromucosal routes. Cmax is increased during fed states and in lipid formulations. Tmax is reached between 0 and 4 h.

Discussion

Only one study used intravenous administration of CBD and reported PK details, which could be a beneficial route of administration in some acute indications. Results from other routes such as rectal, transdermal, or intraperitoneal have also not been published in humans, although transdermal CBD gel and topical creams have been demonstrated to be successful in animal studies (Giacoppo et al., 2015; Hammell et al., 2016). Interestingly, intraperitoneal (i.p.) injection of CBD corresponded to higher plasma and brain concentrations than oral administration in mice, however in rats, similar concentrations were observed for both administration routes, and brain concentrations were in fact higher following oral compared to i.p. route (Deiana et al., 2012). No published data exists on the tissue distribution of CBD in humans. Although plasma levels of CBD do not show accumulation with repeated dosing, it is possible that there may be tissue accumulation.

In children, Devinsky et al. reported mean AUC as 70, 241, 722, and 963 h × ng/mL in groups receiving 2.5, 5, 10, and 20 mg/Kg/day of CBD in oral solution (Devinsky et al., 2018b).

Conclusions: This review highlights the paucity in data and some discrepancy in the pharmacokinetics of cannabidiol, despite its widespread use in humans. Analysis and understanding of properties such as bioavailability and half-life is critical to future therapeutic success, and robust data from a variety of formulations is required.

(A) Mean or median Tmax (h) and range against CBD dose (mg) (B) mean or median area under the curve (AUC0-t) (h × ng/mL) and SD against CBD dose (mg) and (C) plasma mean or median concentration max (Cmax; ng/mL) against CBD dose (mg). It was not possible to present error bars for Cmax as SD and SEM were both reported in the data. IV, intravenous; SD, standard deviation; SEM, standard error of the mean.