cbd oralDecember 15, 2021
Aims: Despite reports that medical cannabis improves symptoms in Crohn’s disease [CD], controlled studies evaluating disease response are lacking. This study assessed the effect of cannabidiol [CBD]-rich cannabis oil for induction of remission in CD.
Results: The study included 56 patients, age 34.5 ± 11 years, men/women 30/26 [54/46%],30 in cannabis and 26 in placebo groups. CDAI at recruitment and after 8 weeks was 282 (interquartile range [IQR] 243-342) and 166 [IQR 82-226], and 264 [IQR 234-320] and 237 [IQR 121-271] [p <0.05] in the cannabis and placebo groups, respectively. Median quality of life [QOL] score improved from 74 for both groups at baseline to 91 [IQR 85-102] and 75 [IQR 69-88] after 8 weeks in the cannabis and placebo groups, respectively [p = 0.004]. SES-CD was 10 [IQR 7-14] and 11 [IQR7-14], and 7 [4-14] and 8 [IQR 4-12] [p = 0.75] before and after treatment, in the cannabis and placebo groups, respectively. Inflammatory markers (C-reactive protein [CRP], calprotectin) remained unchanged.
Methods: In a double-blind, randomised, placebo-controlled, single-centre trial, patients received orally either cannabis oil containing160/40 mg/ml cannabidiol/tetrahydrocannabinol [CBD/THC] or placebo for 8 weeks. Disease parameters, including the CD activity index [CDAI], and simple endoscopic score for CD [SES-CD], were assessed before and after treatment. In a subgroup of patients, blood samples were collected for CBD and THC plasma levels.
Conclusions: Eight weeks of CBD-rich cannabis treatment induced significant clinical and QOL improvement without significant changes in inflammatory parameters or endoscopic scores. The oral CBD-rich cannabis extract was well absorbed. Until further studies are available, cannabis treatment in Crohn’s disease should be used only in the context of clinical trials.
The highest plasma concentrations of CBD were reported by Ohlsson et al. following i.v. administration of 20 mg of deuterium-labeled CBD. Mean plasma CBD concentrations were reported at 686 ng/mL (3 min post-administration), which dropped to 48 ng/mL at 1 h.
A number of trials in humans were conducted by Guy and colleagues to explore administration route efficiency of sprays, an aerosol, and a nebuliser containing CBD or CBD and THC (CBD dose 10 or 20 mg) (Guy and Flint, 2004; Guy and Robson, 2004a,b). Oromucosal spray, either buccal, sublingual, or oropharyngeal administration, resulted in mean C max between 2.5 and 3.3 ng/mL and mean T max between 1.64 and 4.2 h. Sublingual drops resulted in similar C max of 2.05 and 2.58 ng/mL and T max of 2.17 and 1.67 h, respectively. Other oromucosal single dose studies reported C max and T max values within similar ranges (Karschner et al., 2011; Atsmon et al., 2017b).
Within the adult studies, inter- and intra-subject variability was observed in studies, and it remains to be seen whether i.v. and other routes of administration that by-pass initial metabolism will alleviate this issue. Interestingly, although each of the subject’s weight was taken into account, none of the studies addressed subject fat content as a factor in their exclusion criteria; as muscle can weigh more than the same proportion of fat. It is well-known that cannabinoids are highly lipophilic compounds and accumulate in fatty tissue which can then be released gradually (Gunasekaran et al., 2009). It may be of benefit in future study to either put in place more stringent exclusion criteria and measure subject fat content or assess the possible accumulation of CBD in fatty tissue. Differences in metabolism, distribution and accumulation in fat, and in biliary and renal elimination may be responsible for prolonged elimination half-life and variable pharmacokinetic outcomes. CBD use is widespread and has been recommended for use by the FDA in childhood-onset epilepsy. CBD also displays therapeutic promise in other disorders such as schizophrenia and post-traumatic stress disorder. If we are to understand the actions of CBD in those disorders and increase the success rate for treatment, these groups of patients and their distinct characteristics must be assessed as they may not be comparable to a healthy volunteer population.
(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.
Human studies reporting pharmacokinetic (PK) parameters for cannabidiol (CBD).
Controlled smoking and inhalation.
The mean half-life (t 1/2 ) of CBD was reported as 1.1 and 2.4 h following nebuliser and aerosol administration (20 mg) (Guy and Flint, 2004), 1.09 and 1.97 h following single oral administration (10 and 20 mg) (Guy and Flint, 2004; Guy and Robson, 2004b), 2.95 and 3.21 h following 10 mg oral lipid capsules (Atsmon et al., 2017a,b), between 1.44 and 10.86 h after oromucosal spray administration (5–20 mg) (Guy and Robson, 2004b; Sellers et al., 2013; Stott et al., 2013a,b; Atsmon et al., 2017b), 24 h after i.v. infusion, 31 h after smoking (Ohlsson et al., 1986), and 2–5 days after chronic oral administration (Consroe et al., 1991).
One hour after oral capsule administration containing 5.4 mg CBD in males and females, mean C max was reported as 0.93 ng/mL (higher for female participants than male) (Nadulski et al., 2005a). A subset ( n = 12) consumed a standard breakfast meal 1 h after the capsules, which slightly increased mean C max to 1.13 ng/mL. CBD remained detectable for 3–4 h after administration (Nadulski et al., 2005b).
Mean apparent volume of distribution (V/F [L]) was reported as 2,520 L following i.v. administration (Ohlsson et al., 1986). Following single acute doses through oromucosal spray administration, apparent volume of distribution was reported as 26,298, 31,994, and 28,312 L (Stott et al., 2013a).
C max : Maximum measured plasma concentration over the time span specified.
T max : Time to the maximum measured plasma concentration.
In conclusion, this review demonstrates the lack of research in this area, particularly in routes of administration other than oral. An absence of studies has led to failure in addressing the bioavailability of CBD despite intravenous formulations being available. This is of critical importance due to the popularity of CBD products and will help interpret other PK values. Standardized and robust formulations of CBD and their PK data are required for both genders, with consideration of other factors such as adiposity, genetic factors that might influence absorption and metabolism, and the effects of disease states.
From previous investigations including animal studies, the oral bioavailability of CBD has been shown to be very low (13–19%) (Mechoulam et al., 2002). It undergoes extensive first pass metabolism and its metabolites are mostly excreted via the kidneys (Huestis, 2007). Plasma and brain concentrations are dose-dependent in animals, and bioavailability is increased with various lipid formulations (Zgair et al., 2016). However, despite the breadth of use of CBD in humans, there is little data on its pharmacokinetics (PK). Analysis and understanding of the PK properties of CBD is critical to its future use as a therapeutic compound in a wide range of clinical settings, particularly regarding dosing regimens and routes of administration. Therefore, the aim of this systematic review was to collate and analyse all available CBD PK data recorded in humans and to highlight gaps in the literature.
The aim of this study was to review and analyse all available PK data on CBD in humans. Only 8 publications reported PK parameters after administering CBD on its own, and the others were in combination with THC/cannabis. Only 1 study reported the bioavailability of CBD in humans (31% following smoking). From the analysis of these papers, the following observations were made; peak plasma concentrations and area under the curve (AUC) are dose-dependent and show minimal accumulation; C max is increased and reached faster following i.v., smoking or inhalation; C max is increased and reached faster after oral administration in a fed state or in a pro-nanoliposphere formulation; T max does not appear to be dose-dependent; and half-life depends on dose and route of administration. Overall, considerable variation was observed between studies, although they were very heterogeneous, and further work is warranted.
Human studies administering CBD showed that the AUC 0−t and C max are dose-dependent, and T max mostly occurred between 1 and 4 h. Animal studies in piglets, mice, and rats also all demonstrate a dose-dependent relationship between CBD and both plasma and brain concentrations (Long et al., 2012; Hammell et al., 2016; Garberg et al., 2017), suggesting that human brain concentrations will also be dose-dependent. Ten publications in this review reported the half-life of CBD which ranged from 1 h to 5 days and varies depending on the dose and route of administration. Very limited data was available for detailed analysis on the elimination rate, apparent clearance or distribution of CBD in humans.
C max , T max , and area under the curve.
Background: Cannabidiol is being pursued as a therapeutic treatment for multiple conditions, usually by oral delivery. Animal studies suggest oral bioavailability is low, but literature in humans is not sufficient. The aim of this review was to collate published data in this area.
Flow chart for study retrieval and selection.
AUC 0−t : The area under the plasma concentration vs. time curve, from time zero to “t.”
The included articles were analyzed, and the following data extracted: sample size, gender, administration route of CBD, source of CBD, dose of CBD, and any pharmacokinetic details. Where available, plasma mean or median C max (ng/mL) were plotted against CBD dose (mg). Similarly, mean or median T max and range, and mean or median area under the curve (AUC 0−t ) and SD were plotted against CBD dose (mg). The source/supplier of the CBD was also recorded. No further statistical analysis was possible due to sparsity of data and heterogeneity of populations used. All studies were assessed for quality using an amended version of the National Institute for Health (NIH), National Heart, Lung and Blood Institute, Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group (National Institute for Health, 2014). A sample size of ≤ 10 was considered poor, between 11 and 19 was considered fair, and ≥20 was considered good (Ogungbenro et al., 2006).
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).
The systematic review was carried out in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (Moher et al., 2009). A systematic search of PubMed and EMBASE (including MEDLINE) was conducted to retrieve all articles reporting pharmacokinetic data of CBD in humans. Search terms included: CBD, cannabidiol, Epidiolex, pharmacokinetics, C max , plasma concentrations, plasma levels, half-life, peak concentrations, absorption, bioavailability, AUC, T max , C min , and apparent volume of distribution. No restrictions were applied to type of study, publication year, or language. The searches were carried out by 14 March 2018 by two independent researchers.
Only one study in this review was conducted in children ( n = 34) (Devinsky et al., 2018b). Children (4–10 years) with Dravet syndrome were administered an oral solution of CBD and AUC was reported to increase dose-dependently. It is important to emphasize the statement that children are not small adults, and there are many differences in their pharmacokinetic and pharmacodynamic profiles. Absorption, excretion, metabolism, and plasma protein binding are generally reduced in children compared to adults, and apparent volume of distribution is generally increased (Fernandez et al., 2011). These parameters need to be explored fully for CBD in order to understand and advise dose adjustments.
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.
K el : The first-order final elimination rate constant.
Within the 25 included studies, C max was reported on 58 occasions (for example within different volunteer groups or doses in a single study), T max on 56 occasions and area under the curve (AUC 0−t ) on 45 occasions. These data from plasma/blood are presented in Figures 2A–C . The AUC 0−t and C max of CBD is dose-dependent, and T max occurs between 0 and 5 h, but does not appear to be dose-dependent.
Minimal evidence of plasma accumulation has been reported by chronic dosing studies over 5–9 days (Sellers et al., 2013; Stott et al., 2013a). C max appears to be dose-dependent. A dose of 20 mg/day resulted in a mean C max of 1.5 ng/mL and mean AUC 0−t of 6.1 h × ng/mL while 60 mg/day equated to a mean C max of 4.8 ng/mL and AUC 0−t was 38.9 h × ng/mL (Sellers et al., 2013). In another study, C max increased dose-dependently from 0.4 to 1.2 and 2.2 ng/mL following 5, 10, and 20 mg single doses, respectively, and from 0.5 to 1.1 and 3.2 ng/mL, respectively following chronic dosing over 9 consecutive days (Stott et al., 2013a). There was a significant increase in time-dependent exposure during the chronic treatment. Mean AUC 0−t for the single doses were 0.8, 4.5, 9.9, and 2.5, 6.7, and 20.3 for the chronic dosing schedule, respectively. T max does not appear to be dose-dependent, nor affected by acute or chronic dosing schedules.
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.
Plasma levels of CBD were increased when CBD was administered with food or in a fed state, or when a meal is consumed post-administration. Oral capsules with piperine pro-nanolipospheres also increased AUC and C max . This is also demonstrated in animal studies; co-administration of lipids with oral CBD increased systemic availability by almost 3-fold in rats (Zgair et al., 2016) and a pro-nanoliposphere formulation increased oral bioavailability by about 6-fold (Cherniakov et al., 2017b). As CBD is a highly lipophilic molecule, it is logical that CBD may dissolve in the fat content of food, increasing its solubility, and absorption and therefore bioavailability as demonstrated by numerous pharmacological drugs (Winter et al., 2013). Thus, it may be advisable to administer CBD orally in a fed state to allow for optimal absorption.