Pharmacokinetics of Cannabidiol: A Systematic Review and Meta-Regression Analysis

Ehsan Moazen-Zadeh; Alexandra Chisholm; Keren Bachi; Yasmin L Hurd

doi:10.1089/can.2023.0025

. 2024 Aug 16;9(4):939–966. doi: 10.1089/can.2023.0025

Pharmacokinetics of Cannabidiol: A Systematic Review and Meta-Regression Analysis

Ehsan Moazen-Zadeh ^1,², Alexandra Chisholm ^1,^2,³, Keren Bachi ^1,^2,⁴, Yasmin L Hurd ^1,^2,^3,^*

PMCID: PMC11397906 PMID: 37643301

Abstract

Background:

In this review, we provide an updated assessment of available evidence on the pharmacokinetics (PK) of CBD and explore the impact of different factors on PK outcomes.

Materials and Methods:

This systematic review and meta-regression analysis was preregistered (PROSPERO: CRD42021269857). We systematically searched Medline, Embase, PsycInfo, and Web of Science Core Collection up to November 19, 2022. Trials of CBD in healthy adults were included if they reported at least one of the PK parameters of interest, including T_max, C_max, AUC_0–t, AUC_0–inf, and T_1/2, in serum or plasma. Studies of patient populations or CBD co-administration with other medications were excluded. The National Heart, Lung, and Blood Institute's Quality Assessment Tool for Before-After Studies with no Control Group was used. Random-effects multivariable meta-regression analysis was conducted.

Results:

A total of 112 trial arms from 39 studies were included; 26 trial arms had a “Good” quality, 70 “Fair,” and 16 “Poor.” Eight arms used inhalation CBD, 29 oromucosal, 73 oral, and 2 intravenous. CBD formulations could be categorized to nanotech (n=14), oil-based (n=21), alcohol-based (n=10), water-based (n=12), Sativex (n=17), and Epidiolex^® (n=22). For single-dose studies, CBD doses ranged between 2 and 100 mg in inhalation, 5–50 mg in oromucosal, and 0.42–6000 mg in oral administration. Sixty-six trial arms had only male participants or a higher number of male than female participants. The duration of the PK session was between 4 and 164 h. A higher CBD dose was associated with higher C_max, AUC_0–t, and AUC_0–inf. Compared with oral administration, oromucosal administration was associated with lower C_max, AUC_0–t, and AUC_0–inf. Fed status was associated with higher C_max and AUC_0–t when compared with the fasting status. A higher ratio of female participants was associated with lower T_max in oral administration and higher C_max.

Conclusion:

As expected, CBD dose, route of administration, and diet were major determinants of CBD PK with oral routes providing higher bioavailability and nanotechnology formulations a faster onset. Although CBD appeared to have a faster onset and longer duration in women, more studies are required to delineate the role of biological sex. Factors that influence CBD PK have implications for medication development and appropriate dosing in clinical practice.

Keywords: pharmacokinetics, CBD, cannabis, clinical trials, bioavailability

Introduction

CBD, a cannabinoid constituent of the cannabis plant, has exponentially gained attention in both research and clinical applications as a potential treatment of several neuropsychiatric and general medical conditions.¹ Epidiolex^® was the first FDA-approved plant-derived CBD medication. Today, many CBD-based formulations are in development aiming for FDA approval and numerous nonapproved CBD preparations are available over the counter often implying beneficial “medicinal” properties.² However, many questions raised by clinicians, researchers, and consumers of CBD products often relates to dosing and administration.

Pharmacokinetics (PK) is fundamental to medication development and guides appropriate dosing to achieve clinical effectiveness. Important factors normally considered for medication development include the route of administration and bioavailability. Keeping in line with the route of administration most preferred for medicinal purposes, the majority of CBD products currently available are for oral use. However, similar to other cannabinoids, CBD generally has poor bioavailability when consumed orally.³ That challenge has sparked a growth in the industry for the development of new nanotechnologies to improve bioavailability, thus increasing the diversity of formulations and delivery systems being used. There are now multiple CBD products being investigated in clinical studies with varying routes of administration, formulations, and administration conditions. Data generated from such studies should help to shed significant light on CBD PK parameters relevant to identifying those products potentially most suitable for subsequent trials regarding CBD's pharmacodynamic properties to alleviate specific clinical conditions.

However, one of the major challenges across studies and even in previous reviews has been the poor comparability of outcomes across different CBD PK studies owing to the different units and scales of reporting PK parameters, mainly geometric versus arithmetic scales.³ Although both scales have been commonly used in reporting PK data, they are not readily or precisely convertible, which contributes to confusion regarding PK outcomes. Of the scales, geometric method is preferred for reporting certain PK parameters owing to its greater robustness.⁴ No study has yet integrated the various CBD PK data on one scale.

In this review, we aimed to provide an updated systematic assessment of available evidence on the PK of CBD, covering recently published studies that were not included in previous reviews; provide comparable values of PK parameters from different studies on the same scale, and demonstrate patterns in outcomes based on the CBD dose and route of administration; and explore the simultaneous impact of different factors on PK outcomes using meta-regression models.

Materials and Methods

Protocol

This systematic review and meta-regression analysis was preregistered on PROSPERO (https://www.crd.york.ac.uk/prospero, ID: CRD42021269857) and conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines as much as it applied to pharmacokinetic studies.

Research objectives and outcomes

This review systematically assessed PK studies of CBD (pure CBD or in combination with THC) in healthy adults for both the quality of the studies and PK outcomes. The primary outcome was patterns of PK parameters of interest classified based on the route of entry and CBD dose to find potential meaningful patterns in outcomes that could help predict the PK of CBD relevant for clinical applications. The secondary outcome was the statistical significance level for each of the variables/factors that could potentially influence PK parameters, based on the available literature resulting from meta-regression models.

There were five PK parameters of interest:

(1)
T_max: time from CBD administration to the maximum concentration of CBD in plasma/serum,
(2)
C_max: maximum concentration of CBD in plasma/serum,
(3)
AUC_0–t: the area under the curve of serum/plasma concentrations plotted against time from CBD administration to a specific time point, usually the end of the PK session,
(4)
AUC_0–inf: the extrapolation of AUC_0–t to the infinity time point,
(5)
Half-life, T_1/2: the time needed for the concentration of the drug in the plasma to be reduced by 50%.

Potential variables of interest were the following: route of administration, CBD dose, CBD formulation, dietary (fasting/fed) status before CBD administration, abstinence from cannabis before CBD administration, sex, and duration of the PK session.^3,5,6

Inclusion/exclusion criteria

Trials of any design were considered for inclusion if conducted on healthy adults (age between 18–65 years) and reported at least one of the PK parameters of interest after CBD administration in serum or plasma. CBD could be administered in any form, through any entry route, in any formulation or product. Studies were excluded if there was a history of major psychiatric disorders or general medical conditions in the sample, or if CBD was co-administered with another medication.

Search strategy

We systematically searched Medline, Embase, PsycInfo, Web of Science Core Collection, LILACS, and OpenGrey from inception to September 19, 2021, and in the case of Google Scholar, for the first 200 citations, using the following search terms: [Title/abstract➔ (CBD OR cannabidiol OR Sativex OR Epidiolex)] AND [Title/abstract➔ (pharmacokinetic OR concentration OR serum OR plasma OR blood)]. The above search was systematically updated on November 19, 2022 to cover publications since 2021 to date. Search terms were in English, but no language or publication period restriction was applied. Appropriate special characters/suffixes were used to search for any extension of the above terms. After the systematic search and screening, previous reviews of PK studies on CBD were searched manually for relevant original studies in addition to the reference lists of original articles published in the past 5 years. Experts in the field were consulted to seek any missed literature that could be included.

Study selection and data extraction

Two doctorate-level authors were co-trained and calibrated for the screening and data extraction on a sample of CBD PK studies. Any discrepancy would be discussed and resolved between the two screeners and the senior author at each stage. Conference abstracts and thesis reports were also included if the minimum required data were reported. Title-abstract and full-text screening were carried out in parallel using EndNote v. 9 (Cleverbridge, Inc.). Data extraction was carried out by one of the two authors, and then all the data were checked against the original source for accuracy by the other author.

Microsoft Excel sheets with predefined columns were used for extracting data, including but not limited to full citation details, study design, participants' age/sex/health status, sample size and dropouts, cannabis use pattern and abstinence status, fast/fed status before CBD administration, CBD source/supplier, details of CBD formulation, route of administration, CBD dosing, duration of the study session, values of any reported PK parameter in their original format, any relevant considerations of statistical methods, and finally any other relevant methodological information. Published articles, supplementary material, and pharmaceutical providers' websites were all used to collect relevant information, and in some cases, authors were contacted to obtain further details.

CBD formulation determination

CBD formulations were determined using three primary factors. First, when a patent was held and the specific ingredients were not provided in the methodology section for each study, a CBD sample would be designated as its own formulation (i.e., Epidiolex or Sativex). Second, when a methodology section indicated that the solution used a specific technology type (e.g., nanoparticle), these solutions were determined to be their own formulation. Third, when a study provided specific ingredients in the methodology section, the main base of the solution was determined to categorize different CBD formulation types. For example, most formulations consist mainly of oil-based, ethanol-based, gelatin-based, or water-based solutions. All CBD solutions were categorized using these three factors.

Quality assessment

The two authors who carried out the screening and data extraction also conducted a parallel quality assessment of all the studies. Any differences in ratings would be discussed and resolved between the two screeners and the senior author. Given the lack of a widely accepted quality assessment tool for PK studies, the US National Heart, Lung, and Blood Institute Quality Assessment Tool for Before-After Studies with no Control Group was deemed the best choice.⁷ The tool consists of 12 items assessing different aspects of before-after studies, from the clarity of the study question to the very end analysis. Each item is rated as Yes, No, Cannot Determine (CD), or Not Reported (NR). Specifically for the sample size question (Q5), a sample of >19 was considered as “Yes,” <10 was considered “No,” and in between was rated as “CD.”⁸

The assessor assigned an overall rating to each study as Poor, Fair, or Good. Toward a more precise and replicable application of this tool for PK studies, the authors weighted some items and developed a stratification strategy for overall rating, which can be found in Section A in the Supplementary Data.

Narrative synthesis

Study characteristics were organized, summarized, and presented separately for each trial arm in Table 1 in the order of date of publication. Similarities and differences among trial arms were described, including characteristics of the population such as sex, cannabis use, study design, diet status, CBD formulations, CBD dose, and reported outcomes. Numerical values of PK parameters were given in Supplementary Table S1 and described in the Quantitative Synthesis section.

Table 1.

Summary of Pharmacokinetic Studies of Cannabidiol

		M:F	Abstinence status before medication	Diet status	Study design	Route of administration	Technology/formulation	CBD dose, mg	Duration of the PK session	Reported PK parameters
Abbotts et al. (2022)¹²	Arm1	14 M	3 Days	Fast	Probably open-label, randomized, crossover (unclear washout)	Oral solution	Water-based	30, Single dose	6	T_max C_max AUC_0–t AUC_0–inf T_1/2 K_e V_d
	Arm2	14 M	3 Days	Fed	Probably single-blinded, randomized, crossover (unclear washout)	Oral solution	Water-based	30, Single dose	6	T_max C_max AUC_0–t AUC_0–inf T_1/2 K_e V_d
	Arm3	14 M	3 Days	Fast	Probably open-label, randomized, crossover (unclear washout)	Oral oil	Oil-based	30, Single dose	6	T_max C_max AUC_0–t AUC_0–inf T_1/2 K_e V_d
	Arm4	14 M	3 Days	Fast	Probably open-label, randomized, crossover (unclear washout)	Oral solution	Water-based	30, Single dose	6	T_max C_max AUC_0–t AUC_0–inf T_1/2 K_e V_d
	Arm5	14 M	3 Days	Fast	Probably open-label, randomized, crossover (unclear washout)	Oral solution	Water-based	30, Single dose	6	T_max C_max AUC_0–t AUC_0–inf T_1/2 K_e V_d
	Arm6	14 M	3 Days	Fast	Probably open-label, randomized, crossover (unclear washout)	Oral solution	Water-based	30, Single dose	6	T_max C_max AUC_0–t AUC_0–inf T_1/2 K_e V_d
Bergeria et al. (2022)¹³	Arm1a	3:3	Yes (urine negative)	Fed	Double-blind, double-dummy, randomized, crossover (washout 1 week)	Oral capsule	Water-based	100, Single dose	58	C_max T_max
	Arm1b	3:3	Yes (urine negative)	Fed	Double-blind, double-dummy, randomized, crossover (washout 1 week)	Oral solution	Epidiolex^® formulation	100, Single dose	58	C_max T_max
	Arm1c	3:3	Yes (urine negative)	Fed	Double-blind, double-dummy, randomized, crossover (washout 1 week)	Oral solution	Water-based	100, Single dose	58	C_max T_max
	Arm2	9:9	Yes (urine negative)	Fed	Double-blind, double-dummy, randomized, crossover (washout 1 week)	Inhalation/vaporization	N/A	100, Single dose	58	C_max T_max
	Arm3	9:9	Yes (urine negative)	Fed	Double-blind, double-dummy, randomized, crossover (washout 1 week)	Inhalation/vaporization	N/A	100, Single dose	58	C_max T_max
	Arm4	3:3	Yes (urine negative)	Fast	Double-blind, double-dummy, randomized, crossover (washout 1 week)	Oral solution	Water-based	100, Single dose	58	None
Berl et al. (2022)¹⁴	Arm1	8:8	30 Days	Fed	Triple-blind, randomized, parallel group	Oral solution	Nanotech	9.76, Single dose	48	T_max C_max AUC_0–t AUC_0–inf T_1/2 K_a t_lag λ_Z λ
Berl et al. (2022)¹⁴	Arm2	7:8	30 Days	Fed	Triple-blind, randomized, parallel group	Oral solution	Oil-based	9.92, Single dose	48	T_max C_max AUC_0–t AUC_0–inf T_1/2 K_a t_lag λ_Z λ
Busardò et al. (2021)¹⁵		12:2	5 Days	Fast	Open-label, nonrandomized, single arm	Inhalation/vaporization	N/A	8, Single dose	24	T_max C_max AUC_0–t T_1/2 Kel
Hosseini et al. (2021)¹⁶	Arm1	11:1	6 Months	Fast	Open-label, randomized, crossover (24 h washout)	Oromucosal/sublingual	Nanotech	25, Single dose	24	T_max C_max AUC_0–t AUC_0–inf CL/F
	Arm2	11:1	6 Months	Fast	Open-label, randomized, crossover (24 h washout)	Oromucosal/sublingual	Nanotech	50, Single dose	24	T_max C_max AUC_0–t AUC_0–inf CL/F
	Arm3	11:1	6 Months	Fast	Open-label, randomized, crossover (24 h washout)	Oral oil	Oil-based	50, Single dose	24	T_max C_max AUC_0–t AUC_0–inf CL/F
	Arm4	11:1	6 Months	Fast	Open-label, randomized, crossover (24 h washout)	Oromucosal spray	Sativex formulation	25, Single dose	24	T_max C_max AUC_0–t AUC_0–inf CL/F
	Arm5	3 Total	6 Months	Fast	Double-blind, randomized, placebo-controlled	Oromucosal/sublingual	Nanotech	50, Multiple dose	12	T_max C_max AUC_0–t T_1/2
Vitetta et al. (2021)¹⁷	Arm1	11 Total (25% male in the original sample)	Yes (urine negative)	Fast	Single-blind, randomized placebo-controlled	Oromucosal spray buccal	Nanotech	6, Single dose	12	T_max C_max AUC_0–t T_1/2 CL/F
Vitetta et al. (2021)¹⁷	Arm2	12 Total (25% male in the original sample)	Yes (urine negative)	Fast	Single-blind, randomized placebo-controlled	Oromucosal spray buccal	Nanotech	18, Multiple dose	12	T_max C_max AUC_0–t T_1/2 CL/F
Williams et al. (2021)¹⁸	Arm1	9:6	3 Days	Fast	Double-blind, randomized, crossover (72 h washout)	Oral solution	Oil-based	30, Single dose	4	T_max C_max AUC_0–t K_a
	Arm2	9:6	3 Days	Fast	Double-blind, randomized, crossover (72 h washout)	Oral solution	Water-based	30, Single dose	4	T_max C_max AUC_0–t K_a
	Arm3	9:6	3 Days	Fast	Double-blind, randomized, crossover (72 h washout)	Oral solution	Oil-based	30, Single dose	4	T_max C_max AUC_0–t AUC_0–inf T_1/2 Kel V_d K_a
	Arm4	9:6	3 Days	Fast	Double-blind, randomized, crossover (72 h washout)	Oral solution	Oil-based	30, Single dose	4	T_max C_max AUC_0–t AUC_0–inf T_1/2 Kel V_d K_a
	Arm5	9:6	3 Days	Fast	Double-blind, randomized, crossover (72 h washout)	Oral solution	Oil-based	30, Single dose	4	T_max C_max AUC_0–t AUC_0–inf T_1/2 Kel V_d K_a
Crockett et al. (2020)¹⁹	Arm1	12:17	1 Month	Fast	Open-label, randomized, crossover (14 days washout)	Oral solution	Epidiolex formulation	750, Single dose	96	T_max C_max AUC_0–t AUC_0–inf T_1/2 CL/F V/F
	Arm2	9:6	1 Month	Fed	Open-label, randomized, crossover (14 days washout)	Oral solution	Epidiolex formulation	750, Single dose	96	T_max C_max AUC_0–t AUC_0–inf T_1/2 CL/F V/F
	Arm3	3:11	1 Month	Fed	Open-label, randomized, crossover (14 days washout)	Oral solution	Epidiolex formulation	750, Single dose	96	T_max C_max AUC_0–t AUC_0–inf T_1/2 CL/F V/F
	Arm4	6:9	1 Month	Fed	Open-label, randomized, crossover (14 days washout)	Oral solution	Epidiolex formulation	750, Single dose	96	T_max C_max AUC_0–t AUC_0–inf T_1/2 CL/F V/F
	Arm5	6:9	1 Month	Fed	Open-label, randomized, crossover (14 days washout)	Oral solution	Epidiolex formulation	750, Single dose	96	T_max C_max AUC_0–t AUC_0–inf T_1/2 CL/F V/F
Hobbs et al. (2020)²⁰	Arm1	2:3	3 Days	Fast	Double-blind, randomized, parallel arm	Oral solution	Oil-based	30, Single dose	6	T_max C_max AUC_0–t AUC_0–inf T_1/2 Kel V_d K_a K_e
Hobbs et al. (2020)²⁰	Arm2	2:3	3 Days	Fast	Double-blind, randomized, parallel arm	Oral solution	Oil-based	30, Single dose	6	T_max C_max AUC_0–t AUC_0–inf T_1/2 Kel V_d K_a K_e
Izgelov et al. (2020)²¹	Arm1	12 M	30 Days	Fast	Blinded, randomized, crossover (3 weeks washout)	Oral capsule	Nanotech	90, Single dose	24	T_max C_max AUC_0–t AUC_0–inf Kel CL/F V/F
	Arm2	12 M	30 Days	Fast	Blinded, randomized, crossover (3 weeks washout)	Oral capsule	Oil-based	90, Single dose	24	T_max C_max AUC_0–t AUC_0–inf Kel CL/F V/F
	Arm3	12 M	30 Days	Fast	Blinded, randomized, crossover (3 weeks washout)	Oral capsule	Water-based	90, Single dose	24	T_max C_max AUC_0–t
Pérez-Acevedo et al. (2021)²²	Arm1	11:2	Yes (urine negative)	Fast	Open-label, nonrandomized, crossover (15 days washout)	Oral oil	Oil-based	0.9, Single dose	24	T_max C_max AUC_0–t T_1/2 Kel
Pérez-Acevedo et al. (2021)²²	Arm2	11:2	Yes (urine negative)	Fast	Open-label, nonrandomized, crossover (15 days washout)	Oral decoction	Water-based	0.7, Single dose	24	T_max C_max AUC_0–t T_1/2 Kel
Perkins et al. (2020)²³	Arm1	4:2	3 Months	Fed	Double-blind, randomized, placebo-controlled	Oral solution	Oil-based	5 mg/kg, Single dose	168	T_max C_max AUC_0–t AUC_0–inf T_1/2
	Arm2	5:1	3 Months	Fed	Double-blind, randomized, placebo-controlled	Oral solution	Oil-based	10 mg/kg, Single dose	168	T_max C_max AUC_0–t AUC_0–inf T_1/2
	Arm3	5:1	3 Months	Fed	Double-blind, randomized, placebo-controlled	Oral solution	Oil-based	20 mg/kg, Single dose	168	T_max C_max AUC_0–t AUC_0–inf T_1/2
Pichini et al. (2020)²⁴	Arm1	1 M	NR	NR	Open-label, nonrandomized, crossover (2 weeks washout)	Oral decoction	Water-based	0.42, Single dose	24	T_max C_max AUC_0–t T_1/2
Pichini et al. (2020)²⁴	Arm2	1 M	NR	NR	Open-label, non-randomized, crossover (2 weeks washout)	Oral oil	Oil-based	0.86, Single dose	24	T_max C_max AUC_0–t T_1/2
Tayo et al. (2020)²⁵		3:5	1 Month	Fed	Open-label, nonrandomized, parallel-group	Oral solution	Epidiolex formulation	200, Single dose	48	T_max C_max AUC_0–t AUC_0–inf T_1/2 CL/F V/F
Knaub et al. (2019)²⁶	Arm1	8:8	7 Days	Fast	Double-blind, randomized, crossover (14 days washout)	Oral capsule	Nanotech	25, Single dose	24	T_max C_max AUC_0–t
Knaub et al. (2019)²⁶	Arm2	8:8	7 Days	Fast	Double-blind, randomized, crossover (14 days washout)	Oral capsule	Oil-based	25, Single dose	24	T_max C_max AUC_0–t
Morrison et al. (2019)²⁷	Arm1	9 Total	3 Months	Fed	Open-label, nonrandomized, parallel arm	Oral solution	Epidiolex formulation	750, Multiple dose	12	T_max C_max AUC_0–t
	Arm2	8 Total	3 Months	Fed			Epidiolex formulation	750, Multiple dose	12	T_max C_max AUC_0–t
	Arm3	6 Total	3 Months	Fed	Open-label, nonrandomized, parallel arm	Oral solution	Epidiolex formulation	250, Multiple dose	12	T_max C_max AUC_0–t
	Arm4	4 Total
	Arm5	14 Total
	Arm6	9:6	3 Months	Fed	Open-label, nonrandomized, parallel arm	Oral solution	Epidiolex formulation	750, Multiple dose	12	T_max C_max AUC_0–t
	Arm7	8:4
	Arm8	9:5
Patrician et al. (2019)²⁸	Arm1	12 M	Yes (time NR)	Fed	Double-blind, placebo-controlled, crossover (6 days washout)	Oral capsule	Nanotech	45, Single dose	6	T_max C_max AUC_0–t
	Arm2	12 M	Yes (time NR)	Fed	Double-blind, placebo-controlled, crossover (6 days washout)	Oral capsule	Nanotech	90, Single dose	6	T_max C_max AUC_0–t
	Arm3	12 M	Yes (time NR)	Fed	Double-blind, placebo-controlled, crossover (6 days washout)	Oral capsule	Oil-based	45, Single dose	6	T_max C_max AUC_0–t
	Arm4	12 M	Yes (time NR)	Fed	Double-blind, placebo-controlled, crossover (6 days washout)	Oral capsule	Oil-based	90, Single dose	6	T_max C_max AUC_0–t
Taylor et al. (2019)²⁹		4:4	1 Month	Fed	Open-label, nonrandomized, parallel group	Oral solution	Epidiolex formulation	200, Single dose	48	T_max C_max AUC_0–t AUC_0–inf T_1/2 CL/F V/F
Atsmon et al. (2018a)³⁰		15 M	30 Days	Fed	Open-label, randomized, crossover (7 days washout)	Oral capsule	Nanotech	10, Single dose	24	T_max C_max AUC_0–t AUC_0–inf T_1/2 Kel
Atsmon et al. (2018b)³¹	Arm1	15 M	Yes (urine negative)	Fed	Open-label, randomized, crossover (7 days washout)	Oral capsule	Nanotech	10, Single dose	24	T_max C_max AUC_0–t AUC_0–inf T_1/2
	Arm2	15 M	Yes (urine negative)	Fed	Open-label, randomized, crossover (7 days washout)	Oral capsule	Nanotech	100, Single dose	24	T_max C_max AUC_0–t AUC_0–inf T_1/2
	Arm3	15 M	Yes (urine negative)	Fed	Open-label, randomized, crossover (7 days washout)	Oromucosal spray	Sativex formulation	10, Single dose	24	T_max C_max AUC_0–t AUC_0–inf T_1/2 Kel
Meyer et al. (2018)³²		8, Total	Yes (urine negative)	Fasted, irrelevant	Open-label, nonrandomized, single arm	IV	N/A	1.6, Single dose	58	T_max C_max AUC_0–t
Schoedel et al. (2018)³³	Arm1	38 Total (72.1% male in original sample)	>12 Days	Fast	Double-blind, randomized, placebo-controlled crossover (8 days washout)	Oral solution	Epidiolex formulation	750, Single dose	24	T_max C_max AUC_0–t AUC_0–inf
	Arm2	39 Total (72.1% male in original sample)	>12 Days	Fast	Double-blind, randomized, placebo-controlled crossover (8 days washout)	Oral solution	Epidiolex formulation	1500, Single dose	24	T_max C_max AUC_0–t AUC_0–inf
	Arm3	40 Total (72.1% male in original sample)	>12 Days	Fast	Double-blind, randomized, placebo-controlled crossover (8 days washout)	Oral solution	Epidiolex formulation	4500, Single dose	24	T_max C_max AUC_0–t AUC_0–inf
Taylor et al. (2018)³⁴	Arm1	1:5	1 Month	Fast	Double-blind, randomized, placebo-controlled	Oral solution	Epidiolex formulation	1500, Single dose	48	T_max C_max AUC_0–t AUC_0–inf T_1/2 CL/F V/F
	Arm2	3:3	1 Month	Fast	Double-blind, randomized, placebo-controlled	Oral solution	Epidiolex formulation	3000, Single dose	48	T_max C_max AUC_0–t AUC_0–inf T_1/2 CL/F V/F
	Arm3	0:6	1 Month	Fast	Double-blind, randomized, placebo-controlled	Oral solution	Epidiolex formulation	4500, Single dose	48	T_max C_max AUC_0–t AUC_0–inf T_1/2 CL/F V/F
	Arm4	2:4	1 Month	Fast	Double-blind, randomized, placebo-controlled	Oral solution	Epidiolex formulation	6000, Single dose	48	T_max C_max AUC_0–t AUC_0–inf T_1/2 CL/F V/F
	Arm5	2:7	1 Month	Fast	Double-blind, randomized, placebo-controlled	Oral solution	Epidiolex formulation	750, Single dose and multiple dose	12	T_max C_max AUC_0–t T_1/2
	Arm6	5:4	1 Month	Fast	Double-blind, randomized, placebo-controlled	Oral solution	Epidiolex formulation	1500, Single dose and multiple dose	12	T_max C_max AUC_0–t T_1/2
	Arm7	4:8	1 Month	Fast	Open-label, randomized, crossover (7 days washout)	Oral solution	Epidiolex formulation	1500, Single dose	48	T_max C_max AUC_0–t AUC_0–inf T_1/2 CL/F V/F
	Arm8	4:8	1 Month	Fed	Open-label, randomized, crossover (7 days washout)	Oral solution	Epidiolex formulation	1500, Single dose	48	T_max C_max AUC_0–t AUC_0–inf T_1/2 CL/F V/F
Cherniakov et al. (2017)³⁵	Arm1	9 M	28 Days	Fast	Open-label, randomized, crossover (21 days washout)	Oral capsule	Nanotech	10, Single dose	24	T_max C_max AUC_0–t Kel
Cherniakov et al. (2017)³⁵	Arm2	9 M	28 Days	Fast	Open-label, randomized, crossover (21 days washout)	Oromucosal spray	Sativex formulation	10, Single dose	24	T_max C_max AUC_0–t Kel
Haney et al. (2016)³⁶		8 Total	No (urine positive)	Fed	Probably open-label, nonrandomized, single arm	Oral capsule	NR	800, Single dose	6	T_max C_max
Desrosiers et al. (2014)³⁷	Arm1	10:4	No (urine positive)	NR_ irrelevant	Open-label, nonrandomized, parallel arm	Inhalation/smoking	N/A	2, Single dose	30	T_max C_max
Desrosiers et al. (2014)³⁷	Arm2	8:3	No (urine positive)	NR_irrelevant	Open-label, nonrandomized, parallel arm	Inhalation/smoking	N/A	2, Single dose	30	T_max C_max
Sellers et al. (2013)³⁸	Arm1	60 Total (64.2%:35.8%)	90 Days	Fast	Double-blind, randomized, placebo-controlled, parallel arm	Oromucosal spray	Sativex formulation	20, Multiple dose	24	T_max C_max AUC_0–t AUC_0–inf
Sellers et al. (2013)³⁸	Arm2	51 Total (64.2%:35.8%)	90 Days	Fast	Double-blind, randomized, placebo-controlled, parallel arm	Oromucosal spray	Sativex formulation	60–90, Multiple dose	24	T_max C_max AUC_0–t AUC_0–inf
Stott et al. (2013a)³⁹	Arm1	6 M	30 Days	Fast	Open-label, randomized, parallel arm	Oromucosal spray	Sativex formulation	5, Single dose	24	T_max C_max AUC_0–t AUC_0–inf T_1/2 Kel CL/F
	Arm3	6 M	30 Days	Fast	Open-label, randomized, parallel arm	Oromucosal spray	Sativex formulation	20, Single dose	24	T_max C_max AUC_0–t AUC_0–inf T_1/2 Kel CL/F
	Arm4	6 M	30 Days	Fast	Open-label, randomized, parallel arm	Oromucosal spray	Sativex formulation	5, Multiple dose	24	T_max C_max AUC_0–t
	Arm5	12 M	30 Days	Fast	Open-label, randomized, parallel arm	Oromucosal spray	Sativex formulation	10, Multiple dose	24	T_max C_max AUC_0–t
	Arm6	6 M	30 Days	Fast	Open-label, randomized, parallel arm	Oromucosal spray	Sativex formulation	20, Multiple dose	24	T_max C_max AUC_0–t
Stott et al. (2013b)⁴⁰	Arm1	12 M	30 Days	Fed	Open-label, probably nonrandomized, crossover (3 days washout)	Oromucosal spray	Sativex formulation	10, Single dose	24	T_max C_max AUC_0–t AUC_0–inf T_1/2 Kel CL/F
Stott et al. (2013b)⁴⁰	Arm2	12 M	30 Days	Fast	Open-label, probably nonrandomized, crossover (3 days washout)	Oromucosal spray	Sativex formulation	10, Single dose	24	T_max C_max AUC_0–t AUC_0–inf T_1/2 Kel CL/F
Stott et al. (2013c)⁴¹	Arm1	12 M	30 Days	NR	Open-label, randomized, intra-arm crossover (7 days washout)	Oromucosal spray	Sativex formulation	10, Single dose	24	T_max C_max AUC_0–t AUC_0–inf T_1/2 Kel CL/F V/F
	Arm2	12 M	30 Days	NR	Open-label, randomized, intra-arm crossover study (5 days washout)	Oromucosal spray	Sativex formulation	10, Single dose	24	T_max C_max AUC_0–t AUC_0–inf T_1/2 Kel CL/F V/F
	Arm3	12 M	30 Days	NR	Open-label, randomized, intra-arm crossover study (2 days washout)	Oromucosal spray	Sativex formulation	10, Single dose	24	T_max C_max AUC_0–t AUC_0–inf T_1/2 Kel CL/F V/F
Eichler et al. (2012)⁴²	Arm1	9 M	Yes (urine negative)	Fast	Double-blind, randomized, crossover (2 weeks washout)	Oral capsule	Alcohol-based	27.8, Single dose	24	T_max C_max AUC_0–t
Eichler et al. (2012)⁴²	Arm2	9 M	Yes (urine negative)	Fast	Double-blind, randomized, crossover (2 weeks washout)	Oral capsule	Alcohol-based	14.8, Single dose	24	T_max C_max AUC_0–t
Karschner et al. (2011)⁴³	Arm1	6:3	Yes (urine negative)	Fed	Double-blind, randomized, placebo-controlled, double dummy	Oromucosal spray	Sativex formulation	5, Single dose	10	T_max C_max AUC_0–t
Karschner et al. (2011)⁴³	Arm2	6:3	Yes (urine negative)	Fed	Double-blind, randomized, placebo-controlled, double dummy	Oromucosal spray	Sativex formulation	15, Single dose	10	T_max C_max AUC_0–t
Schwope et al. (2011)⁴⁴		9:1	No (urine positive)	NR_ irrelevant	Probably open-label, nonrandomized, single arm	Inhalation/smoking	N/A	2, Single dose	6	T_max C_max
Nadulski et al. (2005a)⁴⁵	Arm1	12:12	30 Days	Fast	Double-blind, randomized, placebocontrolled crossover (1 week washout)	Oral capsule	Oil-based	5.4, Single dose	24	T_max C_max AUC_0–t
Nadulski et al. (2005a)⁴⁵	Arm2	12 Total	30 Days	Fast	Open-label, nonrandomized, crossover (1 week washout)	Oral capsule	Oil-based	5.4, Single dose	24	T_max C_max AUC_0–t
Nadulski et al. (2005b)⁴⁶		24 Total	NR	Fast	Double-blind, probably randomized, placebo-controlled	Oral capsule	NR	5.4, Single dose	24	T_max C_max
Guy and Flint (2004)⁴⁷	Arm1	3:3	30 Days	Fast	Double-blind, placebo-controlled, crossover (6 days washout)	Oromucosal/sublingual	Alcohol-based	20, Single dose	12	T_max C_max AUC_0–t
	Arm2	3:3	30 Days	Fast	Open-label, crossover (6 days washout)	Inhalation/nebulizer	Oil-based	20, Single dose	12	T_max C_max AUC_0–t AUC_0–inf T_1/2 Kel
	Arm3	3:3	30 Days	Fast	Open-label, crossover (6 days washout)	Oromucosal/aerosol/sublingual	Alcohol-based	20, Single dose	12	T_max C_max AUC_0–t AUC_0–inf T_1/2 Kel
	Arm4	3:3	30 Days	Fast	Open-label, crossover (6 days washout)	Oromucosal/sublingual	Alcohol-based	20, Single dose	12	T_max C_max AUC_0–t AUC_0–inf T_1/2 Kel
Guy and Robson (2004a)⁴⁸		24 M	Yes (urine negative)	Fed	Double-blind, randomized placebo-controlled	Oromucosal spray sublingual	Alcohol-based	10, Single dose	24	T_max C_max AUC_0–t AUC_0–inf T_1/2
Guy and Robson (2004b)⁴⁹	Arm1	6:6	30 Days	Fast	Open-label, randomized, crossover (6 days washout)	Oromucosal spray sublingual	Alcohol-based	10, Single dose	12	T_max C_max AUC_0–t AUC_0–inf T_1/2
	Arm2	6:6	30 Days	Fast	Open-label, randomized, crossover (6 days washout)	Oromucosal spray buccal	Alcohol-based	10, Single dose	12	T_max C_max AUC_0–t AUC_0–inf T_1/2
	Arm3	6:6	30 Days	Fast	Open-label, randomized, crossover (6 days washout)	Oromucosal spray oro-pharyngeal	Alcohol-based	10, Single dose	12	T_max C_max AUC_0–t AUC_0–inf T_1/2
	Arm4	6:6	30 Days	Fast	Open-label, nonrandomized, crossover (6 days washout)	Oral capsule	Gelatin-based	10, Single dose	12	T_max C_max AUC_0–t AUC_0–inf T_1/2
Ohlsson et al. (1986)⁵⁰	Arm1	5 M	72 h	NR_irrelevant	Open-label, randomized, crossover (1 week washout)	IV	Alcohol-based	20, Single dose	72	T_max C_max AUC_0–t T_1/2 CL/F V_d
Ohlsson et al. (1986)⁵⁰	Arm2	5 M	72 h	NR_irrelevant	Open-label, randomized, crossover (1 week washout)	Inhalation/smoking	N/A	19.2, Single dose	72	T_max C_max AUC_0–t T_1/2

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N/A, not applicable; NR, not reported; IV, intravenous; PK, pharmacokinetics.

Statistical analyses

To make between-study comparisons and meta-regression analysis feasible, the reported values for PK parameters went through two steps of conversion/estimation, using online calculators and SPSS v. 28 (IBM Statistics).

In the first step, values were converted into a unified form consisting of hours for T_max and T_1/2, ng/mL for C_max, h×ng/mL for AUC_0–t and AUC_0–inf. In the second step, we converted the values for T_max and T_1/2 into arithmetic mean (standard deviation [SD]) format and all the values for C_max, AUC_0–t, and AUC_0–inf in geometric mean (coefficient of variation [CV%]) format as the preferred method for reporting of PK parameters.⁴ This was carried out because C_max, AUC_0–t, and AUC_0–inf are usually highly variable and skewed, so a geometric scale is preferrable. In contrast, T_max and T_1/2 are less variable and an arithmetic scale is an acceptable method, which also would require less conversions in this review, thus allowing for higher accuracy. For the linear meta-regression analysis, confidence intervals were estimated and log-transformed for every parameter's values as necessary. Step 2 conversions are based on previously published methods and the latest guidelines,^9–11 summarized and simplified in the Section B in the Supplementary Data to help with utilization in other PK reviews and replicability of this work.

Missing data were addressed as follows: (1) if the mean or median was not reported for a specific PK parameter, it was considered missing and was not imputed; and (2) if no measure of distribution (e.g., SD or CV%) was reported for a PK parameter, but the mean or median was reported, the SD (for T_max and T_1/2) or CV% (for C_max, AUC_0–t, AUC_0–inf) was imputed using the largest SD or CV% value available for that parameter among all single-dose trial arms.

Comprehensive Meta-Analysis v. 3 (Biostat, Inc.) software was used for random-effects multivariable meta-regression analysis, with PK parameters as dependent outcomes and route of administration, CBD dose, diet status, CBD formulation, female ratio, and duration of PK session as independent predictors. Details of considerations for modeling are provided in the Section C in the Supplementary Data.

Overall, three groups of models were built for each PK parameter across single-dose trial arms: (1) models including all the three routes of CBD administration (inhalation, oromucosal, and oral); (2) models including only oromucosal and oral trial arms; and (3) models including only oral CBD trial arms. For sensitivity analysis, models were conducted once with all the single-dose trial arms irrespective of the quality rating and then a second time only including trial arms with a “Good” or “Fair” quality rating. For each model, the number of included arms was reported alongside the R-squared value to measure model fit, indicating the amount of variability in the data that the model could explain. For each variable in the model, the significance level (alpha=0.05) and the positive or negative sign of the regression coefficient were reported to indicate a positive or negative association, respectively. Because models were based on log-transformed data, the net regression coefficient values were not interpretable in terms of effect size, and thus only their positive/negative sign was reported.

Results

Study selection and overview

After processing all the retrieved records, 39 studies comprising 112 trial arms were included in the narrative synthesis,^12–50 out of which 34 studies comprising 87 arms were used for quantitative comparisons and regression analysis (Fig. 1). Of the 25 trial arms that were excluded from the analysis, but included in the narrative synthesis, 15 trial arms administered multiple doses of CBD (Table 1), 2 arms had only 1 participant,²⁴ 2 arms were intravenous administration of CBD,^32,50 PK values was not reported for 1 trial arm,¹³ and whole blood was used instead of plasma or serum for 5 trial arms.¹³

FIG. 1. — PRISMA flow diagram. PRISMA, preferred reporting items for systematic reviews and meta-analyses.

Quality assessment

Twenty-six trial arms were rated as “Good,” 70 as “Fair,” and 16 as “Poor” based on 12 criteria (Q1–Q12) (Table 2). Most studies clearly stated the study question (Q1), described eligibility criteria (Q2) and had a representative sample in terms of inclusion/exclusion criteria (Q3). At the same time, they mostly failed to report whether all the eligible potential participants were included (Q4), and most had either moderate or low sample sizes (Q5), which was an essential consideration for rating. The intervention was well described in most studies (Q6), and PK outcomes were well-defined and consistently assessed (Q7). The majority of trial arms were non–double blind (Q8). Subject loss at follow-up (Q9) was reported in most studies. Statistical methods primarily measured before-after changes (Q10), for multiple times (Q11), except in some cases where it was not clearly stated. All studies were conducted at the individual participant level with no group interventions applicable to any of the studies (Q12).

Table 2.

Quality Assessment of Pharmacokinetic Studies of Cannabidiol

		Q1	Q2	Q3	Q4	Q5	Q6	Q7	Q8	Q9	Q10	Q11	Q12	Overall
Abbotts et al. (2022)¹²	Arm1	Yes	Yes	Yes	Yes	CD	Yes	Yes	NR	Yes	Yes	Yes	N/A	Fair
	Arm2	Yes	Yes	Yes	Yes	CD	Yes	Yes	NR	Yes	Yes	Yes	N/A	Fair
	Arm3	Yes	Yes	Yes	Yes	CD	Yes	Yes	NR	Yes	Yes	Yes	N/A	Fair
	Arm4	Yes	Yes	Yes	Yes	CD	Yes	Yes	NR	Yes	Yes	Yes	N/A	Fair
	Arm5	Yes	Yes	Yes	Yes	CD	Yes	Yes	NR	Yes	Yes	Yes	N/A	Fair
	Arm6	Yes	Yes	Yes	Yes	CD	Yes	Yes	NR	Yes	Yes	Yes	N/A	Fair
Bergeria et al. (2022)¹³	Arm1a	Yes	Yes	Yes	NR	No	Yes	Yes	Yes	NR	Yes	Yes	N/A	Fair
	Arm1b	Yes	Yes	Yes	NR	No	Yes	Yes	Yes	NR	Yes	Yes	N/A	Fair
	Arm1c	Yes	Yes	Yes	NR	No	Yes	Yes	Yes	NR	Yes	Yes	N/A	Fair
	Arm2	Yes	Yes	Yes	NR	CD	Yes	Yes	Yes	NR	Yes	Yes	N/A	Fair
	Arm3	Yes	Yes	Yes	NR	CD	Yes	Yes	Yes	NR	Yes	Yes	N/A	Fair
	Arm4	Yes	Yes	Yes	NR	No	Yes	Yes	Yes	NR	Yes	Yes	N/A	Fair
Berl et al. (2022)¹⁴	Arm1	Yes	Yes	Yes	Yes	CD	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Fair
Berl et al. (2022)¹⁴	Arm2	Yes	Yes	Yes	Yes	CD	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Fair
Busardò et al. (2021)¹⁵		Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
Hosseini et al. (2021)¹⁶	Arm1	Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
	Arm2	Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
	Arm3	Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
	Arm4	Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
	Arm5	Yes	Yes	Yes	NR	No	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Fair
Vitetta et al. (2021)¹⁷	Arm1	Yes	Yes	Yes	Yes	CD	Yes	Yes	No	Yes	Yes	Yes	N/A	Good
Vitetta et al. (2021)¹⁷	Arm2	Yes	Yes	Yes	Yes	CD	Yes	Yes	No	Yes	Yes	Yes	N/A	Good
Williams et al. (2021)¹⁸	Arm1	Yes	Yes	Yes	Yes	CD	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
	Arm2	Yes	Yes	Yes	Yes	CD	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
	Arm3	Yes	Yes	Yes	Yes	CD	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
	Arm4	Yes	Yes	Yes	Yes	CD	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
	Arm5	Yes	Yes	Yes	Yes	CD	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
Crockett et al. (2020)¹⁹	Arm1	Yes	Yes	Yes	NR	Yes	Yes	Yes	No	Yes	Yes	Yes	N/A	Good
	Arm2	Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
	Arm3	Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
	Arm4	Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
	Arm5	Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
Hobbs et al. (2020)²⁰	Arm1	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Fair
Hobbs et al. (2020)²⁰	Arm2	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Fair
Izgelov et al. (2020)²¹	Arm1	Yes	Yes	Yes	NR	CD	Yes	Yes	Yes	NR	Yes	Yes	N/A	Fair
	Arm2	Yes	Yes	Yes	NR	CD	Yes	Yes	Yes	NR	Yes	Yes	N/A	Fair
	Arm3	Yes	Yes	Yes	NR	CD	Yes	Yes	Yes	NR	Yes	Yes	N/A	Fair
Pérez-Acevedo et al. (2021)²²	Arm1	Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
Pérez-Acevedo et al. (2021)²²	Arm2	Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
Perkins et al. (2020)²³	Arm1	Yes	Yes	Yes	NR	No	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Fair
	Arm2	Yes	Yes	Yes	NR	No	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Fair
	Arm3	Yes	Yes	Yes	NR	No	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Fair
Pichini et al. (2020)²⁴	Arm1	Yes	No	CD	No	No	Yes	Yes	NR	N/A	Yes	Yes	N/A	Poor
Pichini et al. (2020)²⁴	Arm2	Yes	No	CD	No	No	Yes	Yes	NR	N/A	Yes	Yes	N/A	Poor
Tayo et al. (2020)²⁵		Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
Knaub et al. (2019)²⁶	Arm1	Yes	Yes	Yes	Yes	CD	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
Knaub et al. (2019)²⁶	Arm2	Yes	Yes	Yes	Yes	CD	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
Morrison et al. (2019)²⁷	Arm1	Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	CD	NR	N/A	Poor
	Arm2	Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	CD	NR	N/A	Poor
	Arm3	Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	CD	NR	N/A	Poor
	Arm4	Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	CD	NR	N/A	Poor
	Arm5	Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	CD	NR	N/A	Poor
	Arm6	Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	CD	NR	N/A	Poor
	Arm7	Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	CD	NR	N/A	Poor
	Arm8	Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	CD	NR	N/A	Poor
Patrician et al. (2019)²⁸	Arm1	Yes	Yes	Yes	NR	CD	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
	Arm2	Yes	Yes	Yes	NR	CD	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
	Arm3	Yes	Yes	Yes	NR	CD	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
	Arm4	Yes	Yes	Yes	NR	CD	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
Taylor et al. (2019)²⁹		Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
Atsmon et al. (2018a)³⁰		Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
Atsmon et al. (2018b)³¹	Arm1	Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
	Arm2	Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
	Arm3	Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
Meyer et al. (2018)³²		Yes	Yes	Yes	NR	No	Yes	Yes	No	No	Yes	Yes	N/A	Poor
Schoedel et al. (2018)³³	Arm1	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
	Arm2	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
	Arm3	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
Taylor et al. (2018)³⁴	Arm1	Yes	Yes	Yes	NR	No	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Fair
	Arm2	Yes	Yes	Yes	NR	No	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Fair
	Arm3	Yes	Yes	Yes	NR	No	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Fair
	Arm4	Yes	Yes	Yes	NR	No	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Fair
	Arm5	Yes	Yes	Yes	NR	No	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Fair
	Arm6	Yes	Yes	Yes	NR	No	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Fair
	Arm7	Yes	Yes	Yes	NR	CD	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
	Arm8	Yes	Yes	Yes	NR	CD	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
Cherniakov et al. (2017)³⁵	Arm1	Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	CD	Yes	N/A	Poor
Cherniakov et al. (2017)³⁵	Arm2	Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	CD	Yes	N/A	Poor
Haney et al. (2016)³⁶		Yes	Yes	Yes	NR	No	Yes	Yes	Yes	No	NR	Yes	N/A	Poor
Desrosiers et al. (2014)³⁷	Arm1	Yes	Yes	Yes	NR	CD	Yes	Yes	NR	NR	Yes	Yes	N/A	Fair
Desrosiers et al. (2014)³⁷	Arm2	Yes	Yes	Yes	NR	CD	Yes	Yes	NR	NR	Yes	Yes	N/A	Fair
Sellers et al. (2013)³⁸	Arm1	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
Sellers et al. (2013)³⁸	Arm2	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	Yes	N/A	Good
Stott et al. (2013a)³⁹	Arm1	Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
	Arm3	Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
	Arm4	Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
	Arm5	Yes	Yes	Yes	NR	CD	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
	Arm6	Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
Stott et al. (2013b)⁴⁰	Arm1	Yes	Yes	Yes	NR	CD	Yes	Yes	No	NR	Yes	Yes	N/A	Fair
Stott et al. (2013b)⁴⁰	Arm2	Yes	Yes	Yes	NR	CD	Yes	Yes	No	NR	Yes	Yes	N/A	Fair
Stott et al. (2013c)⁴¹	Arm1	Yes	Yes	Yes	NR	CD	Yes	Yes	No	NR	Yes	Yes	N/A	Fair
	Arm2	Yes	Yes	Yes	NR	CD	Yes	Yes	No	NR	Yes	Yes	N/A	Fair
	Arm3	Yes	Yes	Yes	NR	CD	Yes	Yes	No	NR	Yes	Yes	N/A	Fair
Eichler et al. (2012)⁴²	Arm1	Yes	Yes	Yes	NR	CD	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
Eichler et al. (2012)⁴²	Arm2	Yes	Yes	Yes	NR	CD	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
Karschner et al. (2011)⁴³	Arm1	Yes	Yes	Yes	NR	No	Yes	Yes	Yes	NR	Yes	Yes	N/A	Fair
Karschner et al. (2011)⁴³	Arm2	Yes	Yes	Yes	NR	No	Yes	Yes	Yes	NR	Yes	Yes	N/A	Fair
Schwope et al. (2011)⁴⁴		Yes	Yes	Yes	NR	CD	Yes	Yes	No	NR	Yes	Yes	N/A	Fair
Nadulski et al. (2005a)⁴⁵	Arm1	Yes	Yes	Yes	NR	Yes	Yes	Yes	Yes	NR	Yes	Yes	N/A	Good
Nadulski et al. (2005a)⁴⁵	Arm2	Yes	Yes	Yes	NR	CD	Yes	Yes	No	NR	Yes	Yes	N/A	Fair
Nadulski et al. (2005b)⁴⁶		Yes	Yes	Yes	NR	Yes	Yes	Yes	Yes	NR	Yes	Yes	N/A	Good
Guy and Flint (2004)⁴⁷	Arm1	Yes	Yes	Yes	NR	No	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Fair
	Arm2	Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
	Arm3	Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
	Arm4	Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
Guy and Robson (2004a)⁴⁸		Yes	Yes	Yes	NR	Yes	Yes	Yes	Yes	Yes	Yes	Yes	N/A	Good
Guy and Robson (2004b)⁴⁹	Arm1	Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
	Arm2	Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
	Arm3	Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
	Arm4	Yes	Yes	Yes	NR	No	Yes	Yes	No	Yes	Yes	Yes	N/A	Fair
Ohlsson et al. (1986)⁵⁰	Arm1	Yes	Yes	Yes	NR	No	Yes	Yes	No	NR	Yes	Yes	N/A	Poor
Ohlsson et al. (1986)⁵⁰	Arm2	Yes	Yes	Yes	NR	No	Yes	Yes	No	NR	Yes	Yes	N/A	Poor

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Q1: Was the study question or objective clearly stated? Q2: Were eligibility/selection criteria for the study population prespecified and clearly described? Q3: Were the participants in the study representative of those who would be eligible for the test/service/intervention in the general or clinical population of interest? Q4: Were all eligible participants that met the prespecified entry criteria enrolled? Q5: Was the sample size sufficiently large to provide confidence in the findings? Q6: Was the test/service/intervention clearly described and delivered consistently across the study population? Q7: Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed consistently across all study participants? Q8: Were the people assessing the outcomes blinded to the participants' exposures/interventions? Q9: Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted for in the analysis? Q10: Did the statistical methods examine changes in outcome measures from before to after the intervention? Were statistical tests done that provided p-values for the pre-to-post changes? Q11: Were outcome measures of interest taken multiple times before the intervention and multiple times after the intervention (i.e., did they use an interrupted time-series design)? Q12: If the intervention was conducted at a group level (a whole hospital, a community, etc.) did the statistical analysis take into account the use of individual-level data to determine effects at the group level?

CD, cannot determine.

Narrative synthesis

Thirty studies had more than one treatment arm, of which 22 studies, comprising 69 arms, had crossover designs with washout periods ranging between 24 h and 21 days (Table 1). Seventeen studies, comprising 42 arms, had at least one double-blind arm. Sixty-six trial arms had either only male participants or a higher number of males than females, while the sex ratio was either equal to one or favored females in 36 arms. Participants' sex was not clearly reported for 10 arms. Participants were abstinent from cannabis before study initiation in 105 arms and had fasted before CBD administration in 63 arms. Eight arms used inhalation as the route of administration, 29 oromucosal, 73 oral, and 2 intravenous. A variety of formulations were used consisting of nanotech (n=14), oil-based (n=21), alcohol-based (n=10), and water-based (n=12), alongside Sativex (n=17) and Epidiolex (n=22) formulations. For single-dose studies, CBD doses ranged between 2–100 mg in inhalation, 5–50 mg in oromucosal, and 0.42–6000 mg in oral administration (Table 1). The duration of the PK session was between 4–164 h. All trial arms reported T_max and C_max except one that did not report any values, 96 reported AUC_0–t, 59 reported AUC_0–inf, and 60 reported T_1/2. Only 22 treatment arms from 4 studies reported C_max and AUC in geometric scale (Supplementary Table S1 and Showcase in the Supplementary Data). At least one PK parameter from each and all treatment arms needed to go through second step conversions to geometric values to conform to the reporting format in Supplementary Table S1.

Quantitative synthesis

Reported PK values

Given the large variability of the doses studied, Table 3 provides a summary of the PK parameters for doses consisting of more than two trials. Supplementary Table S1 presents the PK parameters from all single-dose trial arms. Figure 2 demonstrates the PK parameters in order of increasing CBD dose for all the trial arms. Supplementary Figure S1 is a magnified version of Figure 2 for CBD doses ≤100 mg. Among single-dose trial arms, the arithmetic mean T_max ranged between 0.00 and 0.60 h for inhalation, 1.00–5.01 h for oromucosal, and 0.59–10.45 h for oral administration (Supplementary Table S1 and Fig. 2). Geometric mean C_max ranged between 0.42 and 120.77 ng/mL for inhalation, 0.38–12.90 ng/mL for oromucosal, and 0.22–1628 ng/mL for oral administration.

Table 3.

Pharmacokinetic Parameters of Cannabidiol in Single-Dose Studies in Accordance with Increasing Cannabidiol Dose

	CBD dose	T_max, arithmetic			C_max, geometric			AUC_0–t, geometric			AUC_0–inf, geometric			T_1/2, arithmetic
	CBD dose	Mean	Lower ^a	Upper ^a	Mean	Lower	Upper	Mean	Lower	Upper	Mean	Lower	Upper	Mean	Lower	Upper
Oromucosal formulations
Cherniakov (2017) 2	10	3	1.96	4.04	0.43	0.28	0.66	2.89	2.17	3.85
Stott (2013c) 3	10	1.46	0.97	1.95	0.52	0.35	0.77	1.53	1.05	2.24	2.71	2.03	3.61	5.22	2.35	8.09
Stott (2013c) 2	10	2.38	1.36	3.40	0.58	0.41	0.8	1.58	1.13	2.21	3.45	3	3.98	7.81	5.90	9.72
Stott (2013c) 1	10	1.63	0.95	2.31	0.81	0.52	1.26	2.7	1.84	3.95	4.37	3.08	6.22	10.86	2.78	18.94
Stott (2013b) 2	10	1.45	1.16	1.74	0.97	0.67	1.41	3.57	2.31	5.54	4.57	3.02	6.9	6.39	3.54	9.24
Atsmon (2018b) 3	10	3.18	2.55	3.81	1.81	1.37	2.39	6.8	5.51	8.38	7.35	6.06	8.92	2.31	1.91	2.71
Guy and Robson (2004b) 1	10	1.63	1.20	2.06	2.02	1.33	3.06	5.75	3.97	8.32	6.09	4.27	8.69	1.44	0.94	1.94
Guy and Robson (2004b) 2	10	2.79	1.96	3.62	2.09	1.21	3.61	5.19	3.44	7.83	5.69	3.89	8.32	1.81	0.51	3.11
Guy and Robson (2004b) 3	10	2.04	1.32	2.76	2.11	1.39	3.19	6.53	4.46	9.55	6.97	4.8	10.12	1.76	1.25	2.27
Guy and Robson (2004a)	10	4.22	2.44	6.00	2.21	1.51	3.24	6.83	4.46	10.45	8.29	5.78	11.91	1.81	0.76	2.86
Stott (2013b) 1	10	5.01	3.84	6.18	3.11	2.16	4.47	18.65	14.46	24.06	21.46	16.79	27.44	5.49	4.11	6.87
Range		1.46–5.01	0.95–3.84	1.74–6.18	0.43–3.11	0.28–2.16	0.66–4.47	1.53–18.65	1.05–14.46	2.21–24.06	2.71–21.46	2.03–16.79	3.61–27.44	1.44–10.86	0.51–5.90	1.94–19.94
Guy and Flint (2004) 1	20	2.17	1.14	3.20	1.87	1.19	2.93	1.57	0.54	4.51
Stott (2013a) 3	20	1	0.58	1.42	1.89	1.09	3.29	7.36	3.26	16.61	9.54	4.06	22.4	9.36	2.21	16.51
Guy and Flint (2004) 3	20	2.35	0.12	4.58	2.3	1.36	3.87	3.68	1.46	9.29	13.07	9.9	17.24	2.4	0.28	4.52
Guy and Flint (2004) 4	20	1.67	0.81	2.53	2.5	1.9	3.28	2.78	1.37	5.64	8.91	5.85	13.56	1.97	1.32	2.62
Range		1–2.35	0.12–1.14	1.42–4.58	1.87–2.5	1.09–1.9	2.93–3.87	1.57–7.36	0.54–3.26	4.51–16.61	8.91–13.07	4.06–9.9	13.56–22.4	1.97–9.36	0.28–2.21	2.62–16.51
Oral formulations
Cherniakov (2017) 1	10	1	0.74	1.26	1.82	1.21	2.74	6.01	4.01	9.00
Guy and Robson (2004b) 4	10	1.27	0.74	1.80	1.83	1.12	2.99	4.37	2.73	7.01	4.65	2.95	7.35	1.09	0.80	1.38
Atsmon (2018a)	10	1.64	0.99	2.29	2.85	2.49	3.27	8.97	7.06	11.4	9.66	7.69	12.14	3.21	2.31	4.11
Atsmon (2018b) 1	10	3.1	2.85	3.35	2.99	2.42	3.7	8.91	7.15	11.1	9.57	7.72	11.85	2.95	1.52	4.38
Range		1–3.1	0.74–2.85	1.26–3.35	1.82–2.99	1.12–2.49	2.74–3.7	4.37–8.97	2.73–7.15	7.01–11.4	4.65–9.66	2.95–7.72	7.35–12.14	1.09–3.21	0.80–2.31	1.38–4.38
Abbotts (2022) 6	30	2.16	1.16	3.16	0.2219	0.107	0.4601	0.4727	0.2435	0.9179				7.38	0	26.05
Hobbs (2020) 2	30	1.5	0	3.36	0.43	0.14	1.33	54.48	15.59	190.35	68.24	23.55	197.69	2.3	0	6.21
Abbotts (2022) 3	30	1.94	1.13	2.75	0.4642	0.3634	0.593	0.948	0.7113	1.2634				4.68	1.75	7.61
Williams (2021) 2	30	3.39	3.03	3.75	0.72	0.39	1.31	1.47	0.87	2.48
Abbotts (2022) 1	30	0.64	0.40	0.88	1.3828	0.9092	2.1031	2.548	1.8574	3.4953	4.0519	0.011	1491.9221	2.22	1.95	2.49
Abbotts (2022) 5	30	0.86	0.63	1.09	1.6279	1.0399	2.5482	2.8186	1.9374	4.1006	5.2783	2.6764	10.4098	2.34	1.26	3.42
Williams (2021) 1	30	3.29	2.95	3.63	1.67	1.11	2.52	3.5	2.33	5.25
Hobbs (2020) 1	30	0.9	0	2.02	1.87	0.61	5.76	245.62	70.3	858.2	329.82	113.85	955.53	2.54	0	6.85
Williams (2021) 4	30	1.53	0.97	2.09	2.18	1.45	3.3	5.12	3.58	7.34	7.72	5.2	11.46	5.18	1.26	9.10
Abbotts (2022) 4	30	0.59	0.46	0.72	2.5665	1.7999	3.6598	3.8146	2.7132	5.3631	5.5323	3.1207	9.8074	2.85	1.61	4.09
Abbotts (2022) 2	30	1.89	1.21	2.57	2.6463	2.067	3.388	6.1004	4.8302	7.7046				4.14	0	8.84
Williams (2021) 3	30	1.28	0.94	1.62	3.21	2.51	4.1	6.98	5.37	9.08	11.87	8.76	16.1	2.2	1.57	2.83
Williams (2021) 5	30	0.7	0.57	0.83	4.79	3.53	6.49	7.73	5.62	10.63	9.52	7.22	12.54	1.42	1.13	1.71
Range		0.59–3.39	0–3.03	0.72–3.75	0.22–4.79	0.107–3.53	0.46–6.49	0.47–245.62	0.24–70.3	0.92–858.2	4.05–329.82	0.01–113.85	10.41–1491.92	1.42–7.38	0–1.95	1.71–26.05
Izgelov (2020) 3	90	10.45	5.96	14.94	0.6	0.37	0.97	6.4	4.19	9.78
Izgelov (2020) 2	90	4.38	3.12	5.64	12.52	9.28	16.91	60.76	46.92	78.68	65.73	51.21	84.36
Izgelov (2020) 1	90	2.13	1.64	2.62	16.1	11.93	21.74	58.51	48.69	70.3	63.42	53.01	75.88
Patrician (2019) 4	90	2.05	1.62	2.48	50.15	38.6	65.17	6563.29	5084.58	8472.05
Patrician (2019) 2	90	1.83	1.40	2.26	68.76	50.3	93.98	9390.94	6663.48	13234.79
Range		1.83–10.45	1.40–5.96	2.26–14.94	0.6–68.76	0.37–50.3	0.97–93.98	6.4–9390.94	4.19–6663.48	9.78–13234.79	63.42–65.73	51.21–53.01	75.88–84.36
Bergeria (2022) 1c	100	3.20	1.96	4.44	1.9941	0.8399	4.7344
Bergeria (2022) 1a	100	2.50	1.26	3.74	12.1901	4.8913	30.3802
Bergeria(2022) 1b	100	3.30	1.64	4.96	17.9012	10.3651	30.9167
Atsmon (2018b) 2	100	3.38	2.82	3.94	43.67	34.85	54.71	145.75	128.55	165.24	149.25	131.85	168.96	3.59	3.45	3.73
Range		2.50–3.38	1.26–2.82	3.74–4.96	1.99–43.67	0.84–34.85	4.73–54.71
Tayo (2020)	200	2.5	2.21	2.79	137.49	93.4	202.38	457.64	398.3	525.83	493.22	434.13	560.35	11.2	6.78	15.62
Taylor (2019)	200	2.78	1.75	3.81	148	90.09	243.13	449	259.17	777.87	474	273.11	822.67	8.58	3.67	13.49
Range		2.5–2.78	1.75–2.21	2.79–3.81	137.49–148	90.09–93.4	202.38–243.13	449–457.64	259.17–398.3	525.83–777.87	474–493.22	273.11–434.13	560.35–822.67	8.58–11.2	3.67–6.78	13.49–15.62
Crockett (2020) 1	750	3.75	3.47	4.03	187	155.16	225.38	1077	901.06	1287.29	1190	997.86	1419.14	39.7	34.27	45.13
Taylor (2018) 5	750	4.38	3.73	5.03	290.8	163.88	516.01	1070	641.7	1784.17
Schoedel (2018) 1	750	5.16	4.70	5.62	304.62	263.25	352.5	1407.75	1198.66	1653.31	1525.18	1318.03	1764.9
Crockett (2020) 5	750	5.76	4.64	6.88	354	260.51	481.05	1676	1237.73	2269.46	1782	1323.65	2399.07	34	29.78	38.22
Crockett (2020) 4	750	5.88	4.21	7.55	527	403.42	688.44	2450	1983.19	3026.69	2588	2084.54	3213.06	36.5	32.17	40.83
Crockett (2020) 3	750	5.26	3.90	6.62	722	572.7	910.22	3202	2623.11	3908.64	3394	2789.24	4129.89	39.4	33.88	44.92
Crockett (2020) 2	750	3.38	2.66	4.10	1050	786.26	1402.2	4584	3563.92	5896.06	4870	3806.16	6231.19	41.3	37.50	45.10
Range		3.38–5.88	2.66–4.70	4.03–7.55	187–1050	155.16–786.26	225.38–1402.2	1070–4584	641.7–3563.92	1287.29–5896.06	1190–4870	997.86–3806.16	1419.14–6231.19	34–41.3	29.78–37.50	38.22–45.13
Taylor (2018) 1	1500	4	3.17	4.83	292.4	132.16	646.95	1517	734.68	3132.35	1618	804.95	3252.28	14.43	8.96	19.90
Taylor (2018) 7	1500	3.63	3.13	4.13	335.4	213.31	527.38	1987	1443.87	2734.44	2198	1644.02	2938.65	30.33	24.84	35.82
Taylor (2018) 6	1500	4.38	3.73	5.03	361.8	185.85	704.35	1444	756.56	2756.07
Schoedel (2018) 2	1500	5.89	5.51	6.27	439.96	363.05	533.17	2169.62	1767.64	2663.01	2285.08	1889.86	2762.95
Taylor (2018) 8	1500	3.13	2.45	3.81	1628	1196.87	2214.42	8347	6760.99	10305.05	8669	7030.04	10690.06	24.4	21.92	26.88
Range		3.13–5.89	3.13–5.51	3.81–6.27	292.4–1628	132.16–1196.87	527.38–2214.42	1444–2169.62	734.68–6760.99	2663.01–10305.05	1618–8669	804.95–7030.04	2762.95–10690.06	14.43–30.33	8.96–24.84	19.90–35.82
Schoedel (2018) 3	4500	5.62	4.87	6.37	283.2	211.95	378.39	1576.25	1186.4	2094.2	1586.63	1206.29	2086.9
Taylor (2018) 3	4500	5	5.00	5.00	722.1	430.97	1209.88	3215	1952.97	5292.58	3426	2118.62	5540.15	16.61	13.35	19.87
Range		5–5.62	4.87–5	5–6.37	283.2–722.1	211.95–430.97	378.39–1209.88	1576.25–3215	1186.4–1952.97	2094.2–5292.58	1586.63–3426	1206.29–2118.62	2086.9–5540.15

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Numbers next each reference is in accordance with the trial arm number in Table 1, for example, Abbotts (2022) 3 means Abbotts et al. (2022) study, trial arm number 3.

^{^a}

CI 95% reported as lower limit and upper limit.

CI, confidence interval.

FIG. 2. — Pharmacokinetic parameters of single dose CBD studies in increasing order of CBD dose.

Geometric mean AUC_0–t ranged between 6.18 and 76.77 h×ng/mL for inhalation, 0.69–61.64 h×ng/mL for oromucosal, and 0.47–9390.94 h×ng/mL for oral administration. The geometric mean AUC_0–inf was 9.03 for the only inhalation study that reported this parameter, ranging between 1.59 and 70.98 h×ng/mL for oromucosal and 3.32–8669 h×ng/mL for oral administration. The arithmetic mean T_1/2 ranged between 1.10 and 31.00 h for inhalation, 1.44–10.86 h for oromucosal, and 1.09–70.3 h for oral administration.

Meta-regression analysis

Overall, of a total number of 87 trial arms that were included in analysis, 84 were used in regression models for T_max, 81 for C_max, 78 for AUC_0–t, and 51 for AUC_0–inf, and 53 for T_1/2. The amount of variability in the data that the models could explain (R²) ranged between 0 and 83% for T_max, indicating a very low to high model fit, 41–49% for C_max, indicating a moderate fit, 44–52% for AUC_0–t indicating a moderate fit, 35–70% for AUC_0–inf indicating a low to high fit, and 84–87% for T_1/2 indicating a high fit. Removing the “Poor” quality trial arms from the models did not result in a noticeable change in model fit or a change in the significance of variables.

Higher CBD dose was consistently associated with higher C_max, AUC_0–t, and AUC_0–inf across all models (Table 4, Fig. 2, and Supplementary Fig. S1). Compared with oral administration as a reference, inhalation was associated with lower T_max in a poorly fitted model (Table 4, Model Nos. 1 and 2), but did not show any significant difference for C_max (Model Nos. 7 and 8), AUC_0–t (Model Nos. 13 and 14), or AUC_0–inf (Model No. 19). In addition, compared with oral administration as a reference, oromucosal administration was associated with lower C_max (Model Nos. 7–10), AUC_0–t (Model Nos. 13–16), and AUC_0–inf (Model Nos. 19, 20), but there was no significant difference for T_max (Model Nos. 1–4). Compared with the Epidiolex formulation as a reference, nanotech, and oil-based formulations were associated with a lower T_max (Model Nos. 5 and 6).

Table 4.

Meta-Regression Models of Pharmacokinetic Parameters in Single-Dose Cannabidiol Studies

Parameter	Model No.	Route of administration	Number of arms	Model fit R ²	CBD dose	Route ^a		Formulation ^a		Diet: fed ^a	Female ^b /total ratio	Duration
Parameter	Model No.	Route of administration	Number of arms	Model fit R ²	CBD dose	Inhalation	Oromucosal	Nanotech	Oil-based	Diet: fed ^a	Female ^b /total ratio	Duration
T_max	1	All routes	84	0		(−) <0.001	(−) 0.960				(+) 0.213
	2	All routes—fair/good	81	0		(−) <0.001	(−) 0.856				(+) 0.294
	3	Oral and oromucosal	75	0.35			(+) 0.843			(+) 0.088	(+) 0.158
	4	Oral and oromucosal—fair/good	73	0.35			(+) 0.962			(+) 0.097	(+) 0.177
	5	Oral	48	0.83				(−) <0.001	(−) <0.001	(+) 0.51	(−) 0.006
	6	Oral—fair/good	47	0.83				(−) <0.001	(−) <0.001	(+) 0.717	(−) 0.004
C_max	7	All routes	81	0.41	(+) <0.001	(−) 0.973	(−) 0.009				(+) 0.022
	8	All routes—fair/good	78	0.41	(+) <0.001	(−) 0.417	(−) 0.013				(+) 0.018
	9	Oral and oromucosal	72	0.49	(+) <0.001		(−) 0.037			(+) <0.001	(+) 0.006
	10	Oral and oromucosal—fair/good	70	0.48	(+) <0.001		(−) 0.049			(+) <0.001	(+) 0.008
	11	Oral	53	0.48	(+) <0.001					(+) <0.001	(+) 0.010
	12	Oral—fair/good	52	0.47	(+) <0.001					(+) <0.001	(+) 0.011
AUC_0–t	13	All routes	78	0.44	(+) <0.001	(−) 0.747	(−) <0.003				(+) 0.583	(+) 0.001
	14	All routes—fair/good	75	0.44	(+) 0.001	(−) 0.887	(−) <0.004				(+) 0.723	(+) 0.001
	15	Oral and oromucosal	72	0.52	(+) <0.001		(−) <0.010			(+) <0.001	(+) 0.302	(+) 0.094
	16	Oral and oromucosal—fair/good	70	0.51	(+) <0.001		(−) <0.012			(+) <0.001	(+) 0.348	(+) 0.094
	17	Oral	53	0.49	(+) <0.001					(+) <0.001	(+) 0.128	(+) 0.510
	18	Oral—fair/good	52	0.49	(+) <0.001					(+) <0.001	(+) 0.143	(+) 0.505
AUC_0–inf	19	All routes—fair/good	51	0.36	(+) 0.001	(−) 0.463	(−) 0.025				(+) 0.201	(+) <0.001
	20	Oral and oromucosal—fair/good	47	0.35	(+) 0.001		(−) 0.054			(−) 0.600	(+) 0.350	(+) <0.001
	21	Oral—fair/good	33	0.70	(+) 0.002					(−) 0.531	(+) 0.341	(+) 0.001
T_1/2	22	All routes	53	0.84							(+) 0.493	(+) <0.001
	23	All routes—fair/good	52	0.86							(+) 0.277	(+) <0.001
	24	Oral and oromucosal—fair/good	50	0.86							(+) 0.230	(+) <0.001
	25	Oral—fair/good	35	0.87							(+) 0.005	(+) <0.001

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This table does not include regression coefficients because they were in log scale and not interpretable in terms of effect size. Hereby only the sig of regression coefficients, that is, negative or positive, and statistical significance level are reported.

^{^a}

Reference group for route of administration was “oral,” for CBD formulation was “Epidiolex,” and for diet was “fast” status.

^{^b}

The number of female participants was divided by the total participants, and the result ratio was a number between 0 and 1, which was included in the model.

Fed status was associated with higher C_max (Model Nos. 9–12) and AUC_0–t values for both oromucosal and oral administration models (Model Nos. 15–18) compared with the fasting status. No significant association of fed status was observed with either T_max (Model Nos. 3–6) or AUC_0–inf (Model Nos. 20 and 21). A higher ratio of female participants in the sample was associated with lower T_max (Model Nos. 5 and 6) and higher T_1/2 (Model No. 25) only among oral administration arms. A higher ratio of female participants was also associated with higher C_max (Model Nos. 9–12) in all models. There was no significant association of female/total ratio with AUC_0–t (Model Nos. 13–18) or AUC_0–inf (Model Nos. 19–21). Finally, longer study duration was associated with higher AUC_0–t only in the regression models that included all routes of administration (Model Nos. 13 and 14), and higher AUC_0–inf and T_1/2 in all the regression models (Model Nos. 19–25).

Discussion

In this review, we aimed to provide an updated systematic assessment of available evidence on the PK of CBD, provide comparable PK parameters from different studies on the same scale, and explore the impact of different relevant factors on PK outcomes. There was considerable heterogeneity in the available PK data for CBD both in terms of the study conducted and reported outcomes. Nevertheless, despite the heterogeneity and quality aspects, several meaningful patterns emerged for factors expected to influence the pharmacokinetic outcomes of CBD including the route of administration, dose, formulation, diet status, sex ratio, and study duration.

For the parameters related to bioavailability, that is, C_max, AUC_0–t, AUC_0–inf, it appeared that inhalation and oral administration had comparable outcomes. However, oromucosal administration consistently resulted in a lower bioavailability than oral administration, which is in line with a previous systematic review³ and some of the within-study comparisons using a similar dose for both routes of administration.^31,35 There are though other within-study comparisons indicating that bioavailability was comparable between oral and oromucosal administration,¹⁶ or that oral administration resulted in lower bioavailability.⁴⁹ Different CBD formulations for oral and oromucosal administration, as well as the possibility of swallowing the oromucosally administered CBD leading to oral absorption, could potentially explain in part these within-study inconsistencies.

However, owing to the low CBD doses used particularly in oromucosal trial arms, comparability is limited and reliable interpretation warrants additional studies. Regarding rate of absorption, as would be expected, inhalation resulted in the lower T_max/faster absorption compared with oral administration. There was a lack of significant difference between oromucosal and oral administration regarding absorption rate, which is in line with a previous systematic review³ as well as some of the direct within-study comparisons.^16,31,35

Given the general low bioavailability of oral administration of cannabinoids, recent years have seen an increase in CBD nanoformulations in the hope of increasing absorption and bioavailability through the oral and oromucosal administration routes. In the regression models for T_max, model fit was noticeably improved by accounting for formulation. Nanotech and oil-based formulations were associated with lower T_max than the Epidiolex formulation indicating that they would have a faster onset of action. To our knowledge, there has been no published direct side-by-side comparison of Epidiolex with nanotech or oil-based formulations. In this review, owing to the methodological considerations that are discussed in the Statistical analyses section and Supplementary Methods in the Supplementary Data, only certain formulations could be included in the regression models for T_max. Therefore, we could not explore other formulations or other PK parameters, thus limiting interpretation of different formulations on their comparable bioavailability for CBD.

As expected, higher CBD dose was consistently associated with higher bioavailability in all the models for C_max, AUC_0–t, and AUC_0–inf. The information provided in Table 3 and Figure 2 serve as a useful reference to help predict CBD dose to reach a certain serum level and potential clinical effect for specific conditions. Although various CBD formulations have been used in lower doses, all the studies with a CBD dose of >100 mg were only conducted with Epidiolex. As such, there is still a lack of PK information about CBD doses expected to be more aligned with a “medicinal” range.

Food consumption can influence bioavailability of many medications, especially lipophilic compounds like CBD through increased transit time and lymphatic absorption in the intestines. We observed that fed condition was associated with a higher bioavailability of CBD, but had no significant impact in the time to reach maximum serum concentrations, compared with the fasted status. Specifically, we observed a higher C_max and AUC_0–t across all the models for fed condition compared with fasted status, which is in line with within-study direct comparisons.^12,19,34,40 The lack of a significant effect of diet status on T_max, is in line with two multiple-arm comprehensive studies,^19,34 but inconsistent with two other studies where T_max was considerably longer in the fed group.^12,40

Although we would expect a significant effect of diet on AUC_0–inf, both theoretically and based on within-study comparisons,^19,34,40 we did not detect such an effect in our models. This could in part be attributed to the lower number of studies that reported AUC_0–inf and thus lower power of these models.

The importance of sex for drug bioavailability and clearance could also have significant implications, including a probably lower required dose of CBD in women to reach a certain blood level and clinical effect. There are noted sex differences in CYP450 family of enzymes that contribute to the metabolism of CBD.⁵¹ In addition, the literature suggests slower clearance in women compared with men.^52,53 We observed that for the PK studies in which sex ratio was reported, a higher female ratio was associated with a faster absorption and higher maximum concentrations through oral administration, evident with lower T_max and higher C_max, respectively. These findings are consistent with direct within-study CBD PK comparisons showing higher C_max and lower T_max in female participants compared with male participants.^26,45

A recent PK study with very low doses of CBD reported no effect for sex on T_max, but female sex was associated with significantly higher C_max and AUC_0–t.¹⁴ A higher C_max and lower T_1/2 with oral administration would mathematically be expected to be associated with a higher AUC_0–t and AUC_0–inf and also in line with direct within-study sex comparisons.^14,26,45 However, this relationship was not evident in our analysis perhaps owing to the few studies conducted with women. Well-powered studies with clinically relevant higher doses in men and women are still needed.

As expected, duration of PK session was a determinant of overall bioavailability and clearance of CBD with implications for designing future studies. A longer duration of PK session was associated with a higher AUC_0–inf in all models, and a higher AUC_0–t in models that included data from all routes of administration of CBD. A higher duration of the PK session was also consistently associated with a longer T_1/2 across all models. In line with this later finding, the literature suggests that cannabinoids in humans may need extended durations to adequately determine cannabinoid half-lives, given that the terminal half-life of cannabinoids is longer than the initial half-life.⁶ Indeed, half-lives of >60 h were reported for Epidiolex with a PK duration of 168 h.²³

A number of limitations should be considered in interpreting the results. For example, certain study characteristics could limit cross-study comparisons, including different reporting scales, potential variations in the equipment and methods used for CBD quantification by different laboratories, and heterogeneity of the study conditions. There was also a lack of detail regarding some formulations, particularly for commercialized products. In addition, the presence of other cannabinoids in the preparations is an important consideration; whereas to the best of the authors' knowledge, there are no human PK study to date that has systematically compared CBD bioavailability with and without THC, hypothetically the presence of THC could influence CBD PK at the level of shared metabolic pathways. Such a pharmacokinetic interaction is supported by a study of CBD oil in cats that demonstrated increased serum CBD levels in the presence of THC⁵⁴ and a recent study in humans where THC serum levels were increased in the presence of CBD.⁵⁵ In addition, cannabidiolic acid in some of the preparations could readily convert to CBD in the human body and alter pharmacokinetic outcomes. Unfortunately, given the variability in formulations, presence of cannabinoids other than THC in many of the preparations, and lack of any direct evidence from well-controlled human studies on how THC may influence CBD PK, we did not include THC dose in our analyses. Another factor for consideration is the washout period among the crossover studies. Of the studies included in our analysis, Hosseini et al.¹⁶ reported the shortest washout of 24 h that would not be expected to provide sufficient time for the cannabinoid to be fully cleared. Although CBD T_1/2 is >24 h, Hossieni et al.¹⁶ demonstrated a considerably low serum CBD concentration at 24 h compared with peak concentrations, and excluding this study from the meta-regression analysis did not change our findings. As such, this study was included in final analysis.

There were also certain limitations related to the methods of this review. Comprehensive quality assessment of PK studies requires a specifically designed assessment tool beyond the ones used for general before-after studies. Although there have been efforts to introduce such quality assessment tools,⁵⁶ there is still no commonly accepted one available. In addition to the items covered by the NIHLB tool, preregistration of study protocol as a clinical trial, the potential effect of other constituents of the administered product on the PK outcomes, sufficient length of study, accounting for the potential effect of important covariates like sex and body mass, would be important considerations. In regard to the statistical methods, the log-transformed regression coefficients could not be interpreted in terms of effect size, limiting our prediction of each factor's impact on PK parameters. Finally, we did not include the PK outcomes of CBD metabolites reported by some of the included studies since the CBD metabolism is affected by multiple factors thus requiring a focused and extensive exploration that was outside the scope of this review. Understanding the PK of CBD metabolites can provide further insights into the CBD half/life and sex differences.

Conclusion

We provided an updated overview of the current status of evidence of PK of CBD. In exploring how different factors potentially influenced the PK outcomes of CBD, consuming food while taking CBD, female sex, and oral administration were associated with higher bioavailability. Recommendations for future research would mainly concern conducting original systematic studies to elucidate the impact of biological sex and different formulations in single studies with multiple arms. It would also be beneficial for future studies to examine clinically relevant doses of CBD, for example, >200 mg, given the increasing number of such preparations on the market and their potential application in clinical practice. Finally, reporting PK parameters in both arithmetic and geometric scales would help improve comparisons across studies and would also enhance knowledge aggregation and replicability.

Abbreviations Used

CBD: cannabidiol
CD: cannot determine
CI: confidence interval
CV: coefficient of variation
NR: not reported
PK: pharmacokinetics
SD: standard deviation
THC: tetrahydrocannabinol

Authors' Contributions

E.M.-Z., K.B., Y.L.H.: conceptualization; E.M.-Z. and A.C.: methodology, data extraction, and quality assessments; E.M.-Z.: narrative and quantitative synthesis, and original article draft preparation; and A.C., K.B., and Y.L.H. edited the article. All authors have read and agreed to the final version of the article.

Author Disclosure Statement

Authors have no conflicts or competing interests to disclose.

Funding Information

Authors were supported by National Institutes of Health NIDA UG3DA050323 and K23-DA045928.

Supplementary Material

Supplementary Data

can.2023.0025_suppl_data.pdf^{(604.4KB, pdf)}

Supplementary Table S1

can.2023.0025_suppl_tables1.pdf^{(627.4KB, pdf)}

Supplementary Figure S1

can.2023.0025_suppl_figure1.pdf^{(173.5KB, pdf)}

Cite this article as: Moazen-Zadeh E, Chisholm A, Bachi K, Hurd YL (2023) Pharmacokinetics of cannabidiol: a systematic review and meta-regression analysis, Cannabis and Cannabinoid Research X:X, 1–28, DOI: 10.1089/can.2023.0025.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Data

can.2023.0025_suppl_data.pdf^{(604.4KB, pdf)}

Supplementary Table S1

can.2023.0025_suppl_tables1.pdf^{(627.4KB, pdf)}

Supplementary Figure S1

can.2023.0025_suppl_figure1.pdf^{(173.5KB, pdf)}

[B1] 1. VanDolah HJ, Bauer BA, Mauck KF. Clinicians' Guide to Cannabidiol and Hemp Oils. Mayo Clin Proc 2019;94(9):1840–1851. [DOI] [PubMed] [Google Scholar]

[B2] 2. WHO Expert Committee on Drug Dependence. Cannabidiol (CBD) Critical Review Report. Fortieth Meeting, Geneva, June 4–7, 2018. [Google Scholar]

[B3] 3. Millar SA, Stone NL, Yates AS, et al. A systematic review on the pharmacokinetics of cannabidiol in humans. Front Pharmacol 2018;9:1365. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B4] 4. Julious SA, Debarnot CA. Why are pharmacokinetic data summarized by arithmetic means? J Biopharm Stat 2000;10(1):55–71. [DOI] [PubMed] [Google Scholar]

[B5] 5. Lucas CJ, Galettis P, Schneider J. The pharmacokinetics and the pharmacodynamics of cannabinoids. Br J Clin Pharmacol 2018;84(11):2477–2482. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B6] 6. Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers 2007;4(8):1770. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B7] 7. National Heart, Lung, and Blood Institute. Study Quality Assessment Tools: For Observational Cohort and Cross-Sectional Studies, for Before-After (Pre-Post) Studies with No Control Group, for Case-Control Studies. Maryland, USA Im Internet (Stand: 1001 2019); 2019. Available from: www nhlbi nih gov/health-topics/study-quality-assessment-tools [Last accessed: September 21, 2022].

[B8] 8. Aarons L, Ogungbenro K. Optimal design of pharmacokinetic studies. Basic Clin Pharmacol Toxicol 2010;106(3):250–255. [DOI] [PubMed] [Google Scholar]

[B9] 9. Wan X, Wang W, Liu J, et al. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014;14(1):1–13. [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Pharmacokinetics of Cannabidiol: A Systematic Review and Meta-Regression Analysis

Ehsan Moazen-Zadeh

Alexandra Chisholm

Keren Bachi

Yasmin L Hurd

Abstract

Background:

Materials and Methods:

Results:

Conclusion:

Introduction

Materials and Methods

Protocol

Research objectives and outcomes

Inclusion/exclusion criteria

Search strategy

Study selection and data extraction

CBD formulation determination

Quality assessment

Narrative synthesis

Table 1.

Statistical analyses

Results

Study selection and overview

FIG. 1.

Quality assessment

Table 2.

Narrative synthesis

Quantitative synthesis

Reported PK values

Table 3.

FIG. 2.

Meta-regression analysis

Table 4.

Discussion

Conclusion

Abbreviations Used

Authors' Contributions

Author Disclosure Statement

Funding Information

Supplementary Material

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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