A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans

Abstract

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

Full text

ORIGINAL RESEARCH
published: 26 November 2018
doi: 10.3389/fphar.2018.01365
Frontiers in Pharmacology | www.frontiersin.org 1November 2018 | Volume 9 | Article 1365
Edited by:
Thomas Dorlo,
The Netherlands Cancer Institute
(NKI), Netherlands
Reviewed by:
Constantin Mircioiu,
Carol Davila University of Medicine
and Pharmacy, Romania
Pius Sedowhe Fasinu,
Campbell University, United States
*Correspondence:
Sophie A. Millar
stxsamil@nottingham.ac.uk
Specialty section:
This article was submitted to
Drug Metabolism and Transport,
a section of the journal
Frontiers in Pharmacology
Received: 19 September 2018
Accepted: 07 November 2018
Published: 26 November 2018
Citation:
Millar SA, Stone NL, Yates AS and
O’Sullivan SE (2018) A Systematic
Review on the Pharmacokinetics of
Cannabidiol in Humans.
Front. Pharmacol. 9:1365.
doi: 10.3389/fphar.2018.01365
A Systematic Review on the
Pharmacokinetics of Cannabidiol in
Humans
Sophie A. Millar 1
*, Nicole L. Stone 1, Andrew S. Yates2and Saoirse E. O’Sullivan 1
1Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Royal Derby
Hospital, Derby, United Kingdom, 2Artelo Biosciences, San Diego, CA, United States
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.
Methods: A systematic search of PubMed and EMBASE (including MEDLINE) was
conducted to retrieve all articles reporting pharmacokinetic data of CBD in humans.
Results: Of 792 articles retireved, 24 included pharmacokinetic parameters in
humans. The half-life of cannabidiol was reported between 1.4 and 10.9 h after
oromucosal spray, 2–5 days after chronic oral administration, 24 h after i.v., and 31 h
after smoking. Bioavailability following smoking was 31% however no other studies
attempted to report the absolute bioavailability of CBD following other routes in humans,
despite i.v formulations being available. The area-under-the-curve and Cmax increase
in dose-dependent manners and are reached quicker following smoking/inhalation
compared to oral/oromucosal routes. Cmax is increased during fed states and in lipid
formulations. Tmax is reached between 0 and 4 h.
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.
Keywords: pharmacokinetics, endocannabinoid system, bioavailability, CMAX, TMAX, half life, plasma clearance,
volume of distribution
INTRODUCTION
The Cannabis sativa plant contains more than a hundred phytocannabinoid compounds,
including the non-psychotomimetic compound cannabidiol (CBD) (Izzo et al., 2009).
CBD has attracted significant interest due to its anti-inflammatory, anti-oxidative and
anti-necrotic protective effects, as well as displaying a favorable safety and tolerability
profile in humans (Bergamaschi et al., 2011), making it a promising candidate in many
therapeutic avenues including epilepsy, Alzheimer’s disease, Parkinson’s disease, and
multiple sclerosis. GW pharmaceuticals have developed an oral solution of pure CBD
(Epidiolex R
) for the treatment of severe, orphan, early-onset, treatment-resistant epilepsy
syndromes, showing significant reductions in seizure frequency compared to placebo in
several trials (Devinsky et al., 2017, 2018a; Thiele et al., 2018). Epidiolex R
has recently

Millar et al. Pharmacokinetics of Cannabidiol in Humans
received US Food and Drug Administration (FDA) approval
(GW Pharmaceuticals, 2018). CBD is also being pursued in
clinical trials in Parkinson’s disease, Crohn’s disease, society
anxiety disorder, and schizophrenia (Crippa et al., 2011; Leweke
et al., 2012; Chagas et al., 2014; Naftali et al., 2017), showing
promise in these areas. Additionally, CBD is widely used as a
popular food supplement in a variety of formats for a range of
complaints. It is estimated that the CBD market will grow to
$2.1 billion in the US market in consumer sales by 2020 (Hemp
Business, 2017).
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.
METHODS
Search Strategy
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, Cmax, plasma
concentrations, plasma levels, half-life, peak concentrations,
absorption, bioavailability, AUC, Tmax, Cmin , 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.
Eligibility Criteria
The titles and abstracts of retrieved studies were examined by
two independent researchers, and inappropriate articles were
rejected. Inclusion criteria were as follows: an original, peer-
reviewed paper that involved administration of CBD to humans,
and included at least one pharmacokinetic measurement as listed
in the search strategy.
Data Acquisition
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 Cmax (ng/mL) were
plotted against CBD dose (mg). Similarly, mean or median Tmax
and range, and mean or median area under the curve (AUC0−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).
Definitions of PK Parameters
Tmax: Time to the maximum measured plasma concentration.
Cmax: Maximum measured plasma concentration over the time
span specified.
t1/2: Final time taken for the plasma concentration to be reduced
by half.
AUC0−t: The area under the plasma concentration vs. time curve,
from time zero to “t.”
AUC0−inf: The area under the plasma concentration vs. time
curve from zero to t calculated as AUC0−tplus the extrapolated
amount from time t to infinity.
Kel: The first-order final elimination rate constant.
RESULTS
In total, 792 records were retrieved from the database searching,
24 of which met the eligibility criteria (Figure 1). Table 1
summarizes each included study. Routes of administration
included intravenous (i.v.) (n=1), oromucosal spray (n=21),
oral capsules (n=13), oral drops (n=2), oral solutions (n=1),
nebuliser (n=1), aerosol (n=1), vaporization (n=1),
and smoking (n=8). CBD was administered on its own in 9
publications, and in combination with THC or within a cannabis
extract in the remainder. One study was conducted in children
with Dravet syndrome, while the remainder were conducted in
healthy adult volunteers (Devinsky et al., 2018b). Overall, the
included studies were of good quality (Supplementary Table 1).
However, many studies had small sample sizes. Additionally,
not all studies included both males and females, and frequent
cannabis smokers were included in a number of studies. Thus,
interpretation and extrapolation of these results should be done
with caution.
Cmax, Tmax, and Area Under the Curve
Within the 25 included studies, Cmax was reported on 58
occasions (for example within different volunteer groups or doses
in a single study), Tmax on 56 occasions and area under the curve
(AUC0−t) on 45 occasions. These data from plasma/blood are
presented in Figures 2A–C. The AUC0−tand Cmax of CBD is
dose-dependent, and Tmax occurs between 0 and 5 h, but does
not appear to be dose-dependent.
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Millar et al. Pharmacokinetics of Cannabidiol in Humans
FIGURE 1 | Flow chart for study retrieval and selection.
Oromucosal Drops/Spray
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
Cmax between 2.5 and 3.3 ng/mL and mean Tmax between 1.64
and 4.2 h. Sublingual drops resulted in similar Cmax of 2.05
and 2.58 ng/mL and Tmax of 2.17 and 1.67 h, respectively. Other
oromucosal single dose studies reported Cmax and Tmax values
within similar ranges (Karschner et al., 2011; Atsmon et al.,
2017b).
Minimal evidence of plasma accumulation has been reported
by chronic dosing studies over 5–9 days (Sellers et al., 2013;
Stott et al., 2013a). Cmax appears to be dose-dependent. A dose
of 20 mg/day resulted in a mean Cmax of 1.5 ng/mL and mean
AUC0−tof 6.1 h ×ng/mL while 60 mg/day equated to a mean
Cmax of 4.8 ng/mL and AUC0−twas 38.9 h ×ng/mL (Sellers
et al., 2013). In another study, Cmax increased dose-dependently
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Millar et al. Pharmacokinetics of Cannabidiol in Humans
TABLE 1 | Human studies reporting pharmacokinetic (PK) parameters for cannabidiol (CBD).
References Total n, sex Administration Source CBD dose PlasmaaPK details Other
Tmax
(median,
range)bhrs
Cmax (mean,
SD)bng/mL
AUC0-t
(mean, SD)b
h×ng/mL
AUC0-inf
(mean,
SD) h ×
ng/mL
Kel (mean,
SD) 1/h
t1/2 (mean,
SD)bh
CL/F (mean,
SD) L/h
Mean (SD)
Ohlsson et al.,
1986
5, M, infrequent to
frequent cannabis
smokers
i.v. In lab 20 mg 686 (239) ng/ml min ×
10−3=16.67
(3.23)
24 (6) 74.4 (14.4) Distribution
volume:
32.7 (8.6)
l/kg.
‘’ Smoking In lab 19.2 ±0.3mg 110 (55) ng/ml min ×
10−3=4.85
(1.72)
31 (4) Estimated
systemic
availability
(%) from
smoking:
31 (13)
Consroe et al.,
1991
15, M/F Oral capsules NIDA 10 mg/kg/day
daily for 6
weeks
2–5 days
Guy and
Robson, 2004b
12, M/F Oromucosal spray
sublingual (CBD and
THC)
GW 10 mg 1.63 (SD
0.68)
2.5 (1.83) 6.81 (4.33) 7.12 (4.31) 1.44 (0.79)
Oromucosal spray
buccal (CBD and THC)
GW 10 mg 2.79 (SD
1.31)
3.02 (3.15) 6.4 (4.62) 6.8 (4.46) 1.81 (2.05)
Oromucosal spray
oro-pharyngeal (CBD
and THC)
GW 10 mg 2.04 (SD
1.13)
2.61 (1.91) 7.81 (5.13) 8.28 (5.32) 1.76 (0.8)
CBME oral capsule
(CBD and THC)
GW 10 mg 1.27 (SD
0.84)
2.47 (2.23)
5.76 (4.94)
6.03 (4.97) 1.09 (0.46)
Guy and
Robson, 2004a
24, M Oromucosal spray
sublingual (CBD and
THC)
GW 10 mg 4.22 3.33 11.34 11.97 1.81
Guy and Flint,
2004
6 M/F Nebuliser (CBD and
THC)
GW 20 mg 0.6 (0.08–1) 9.49 (8.01) 9.41 (10.8) 12.11
(10.83)
0.98 (0.58) 1.1 (0.97)
Aerosol (with THC) GW 20mg 2.35 (0.75–6) 2.6 (1.38) 5.43 (5.88) 13.53
(3.64)
0.43 (0.26) 2.4 (2.02)
Sublingual drops (CBD) GW 20 mg 2.17 (1–4) 2.05 (0.92) 2.60 (3.45)
Sublingual drops (CBD
and THC)
GW 20 mg 1.67 (1–3) 2.58 (0.68) 3.49 (2.65) 9.65 (4.02) 0.37 (0.114) 1.97 (0.62)
Nadulski et al.,
2005a
24, M/F Oral capsule (CBD and
THC)
Scherer
GmbH & Co.
KG,
Eberbach,
Germany
5.4mg once a
week for 3
weeks
Mean 0.99
(0.5–2)
0.93 (range
0–2.6)
Mean 4.35,
range
(2.7–5.6)
(Continued)
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TABLE 1 | Continued
References Total n, sex Administration Source CBD dose PlasmaaPK details Other
Tmax
(median,
range)bhrs
Cmax (mean,
SD)bng/mL
AUC0-t
(mean, SD)b
h×ng/mL
AUC0-inf
(mean,
SD) h ×
ng/mL
Kel (mean,
SD) 1/h
t1/2 (mean,
SD)bh
CL/F (mean,
SD) L/h
Mean (SD)
12, M/F Oral capsule (CBD and
THC) and breakfast
consumed 1 hour after
Scherer
GmbH & Co.
KG,
Eberbach,
Germany
5.4mg once a
week for 3
weeks
Mean 1.07
(0.5–2)
1.13 (range
0.39–1.9)
Mean 4.4
(range
2.5–5.3)
Nadulski et al.,
2005b
24, M/F Cannabis extract Sigma 5.4 mg Mean 1.0
(0.5–2.0)
0.95 (range
0.3–2.57)
Karschner et al.,
2011
9, M/F cannabis
smokers
Oromucosal spray
(Sativex: CBD and
THC)
GW 5 mg 3.6 (1.0–5.5) Mean (SE):
1.6 (0.4)
4.5 (SE 0.6)
15 mg 4.6 (1.2–5.6) Mean (SE):
6.7 (2.0)
18.1 (SE 3.6)
Schwope et al.,
2011
10, M/F, usual
infrequent
cannabis smokers
Cannabis cigarette NIDA 2 mg 0.25
(0.25–0.50 h)
whole
blood/plasma
Median
(range):
plasma 2
(<LOQ−3.4)
Eichler et al.,
2012
9, M Oral capsules (CBD
and THC)
Cannapharm
AG
Heated CBD
(27.8 mg
CBD: 0.8mg
CBDA)
0.83 (SD
0.17)
pmol/mL:
0.94 (0.22)
pmol h/moL
3.68 (1.34)
Unheated
14.8 mg
CBD:10.8 mg
CBDA)
1.17 (SD
0.39)
3.95 (0.92)
pmoL/mL
pmol h/mol
7.67 (2.06)
Lee et al., 2012 10, M/F, cannabis
smokers
Cannabis cigarette NIDA 2 mg Median 0.25
(oral fluid)
0.03 (oral
fluid)
Sellers et al.,
2013
60, M/F Oromucosal spray
(CBD and THC)
GW 20 mg, 5 days 1.4 (0, 8.45) 1.5 (0.78) 6.1 (5.76) 14.8 (7.87)
51, M/F 90 mg –
60 mg, 5 days
1.5 (0–6.45) 4.8 (3.4) 38.9 (33.75) 60.3
(37.71)
Stott et al.,
2013b
12, M Oromucosal spray
(CBD and THC)
GW 10 mg (fed
state)
4.00
(3.02–9.02);
3.66 (2.28) 23.13 (9.29) 20.21
(8.43)
0.155 (0.089) 5.49 (2.17) 533 (318)
Stott et al.,
2013a
24, M Oromucosal spray
(CBD and THC)
GW 5 mg single
dose
Mean 1.00
(0.75–1.50)
0.39 (0.08) 0.82 (0.33) 1.66 (0.51) 0.173 (0.084) 5.28 (3.28) 3,252 (1,002)
10 mg single
dose
Mean 1.39
(0.75–2.25)
1.15 (0.74) 4.53 (3.53) 5.64 (4.09) 0.148 (0.079) 6.39 (4.48) 2,546 (1,333)
20 mg single
dose
Mean 1.00
(0.75–1.75)
2.17 (1.23) 9.94 (9.02) 13.28
(12.86)
0.123 (0.097) 9.36 (6.81) 3,783 (4,299)
(Continued)
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TABLE 1 | Continued
References Total n, sex Administration Source CBD dose PlasmaaPK details Other
Tmax
(median,
range)bhrs
Cmax (mean,
SD)bng/mL
AUC0-t
(mean, SD)b
h×ng/mL
AUC0-inf
(mean,
SD) h ×
ng/mL
Kel (mean,
SD) 1/h
t1/2 (mean,
SD)bh
CL/F (mean,
SD) L/h
Mean (SD)
5 mg, 9 days Mean 1.64
(1.00–4.02)
0.49 (0.21) 2.52 (0.73)
10 mg, 9 days Mean 1.27
(0.75–2.52)
1.14 (0.86) 6.66 (3.10)
20 mg 9 days Mean 2.00
(1.02–6.00)
3.22 (1.90) 20.34 (7.29)
Stott et al.,
2013c
36, M Oromucosal spray
(CBD and THC)
GW 10 mg (3
groups)
1.00
(0.50–4.00);
1.38
(0.75–6.00);
1.15
(0.50–3.02)
1.03 (0.81);
0.66 (0.37);
0.63 (0.43)
3.23 (2.13);
1.82 (1.03);
1.83 (1.19)
5.10
(3.06);
3.54
(0.80);
3.00 (1.43)
0.148(0.108);
0.122 (0.111);
0.224 (0.158)
10.86(12.71);
7.81 (3.00);
5.22 (4.51)
2817 (1913);
2998 (896);
4,741 (3,835)
Varea/F (L):
28312
(19355);
31994
(12794);
26298
(14532)
15 mg 4.5 (1.2–5.6) Mean (SE):
6.7 (2.0)
Newmeyer et al.,
2014
24, M/F, frequent
or occasional
cannabis smokers
Cannabis cigarette
(frequent smokers)
NIDA 2 ±0.6 mg 0.5 (0.5–1) Median
(range): 14.8
(1.4–162)
Median
(range): 29
(4.7–211)
Cannabis cigarette
(occasional smokers)
2±0.6 mg 1 (0.5–2) Median
(range): 7
(1.9–111)
Median
(range): 11.6
(4.1–185)
Desrosiers et al.,
2014
21, M/F frequent
and occasional
smokers
Cannabis cigarette
(frequent smokers)
NIDA 2 mg 0.5 (0.0–1.1) 1.1 (0.0–1.6)
Cannabis cigarette
(occasional smokers)
2 mg 0 (0–500) 0 (0–1300)
Manini et al.,
2015
17, M/F Oral capsules
Co-administered with
i.v. fentanyl
GW 400 mg 3 and 1.5
(plasma) and
6 and 2 (urine)
Plasma:
181.2 (39.8)
and 114.2
(9.5); Urine:
4600 and
2900
704 (283) and
482 (314)
mcg*hr/dL
800 mg 3 and 4
(plasma) and
4 and 6 (urine)
Plasma: 221
(35.6) and
157.1 (49.0);
Urine: 3700
and 2800
867 (304) and
722 (443)
mcg*hr/dL
(Continued)
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TABLE 1 | Continued
References Total n, sex Administration Source CBD dose PlasmaaPK details Other
Tmax
(median,
range)bhrs
Cmax (mean,
SD)bng/mL
AUC0-t
(mean, SD)b
h×ng/mL
AUC0-inf
(mean,
SD) h ×
ng/mL
Kel (mean,
SD) 1/h
t1/2 (mean,
SD)bh
CL/F (mean,
SD) L/h
Mean (SD)
Haney et al.,
2016
8, M/F cannabis
smokers
Oral capsules STI
pharmaceuticals
800 mg Mean 3 (2–6) 77.9 (range
1.6–271.9)
Cherniakov
et al., 2017a
9, M Oral capsules with
piperine
pro-nanolipospeheres
(CBD and THC)
STI
pharmaceuticals
10 mg 1 (0.5–1.5) 2.1 (0.4) 6.9 (1.3)
Oromucosal spray
(CBD and THC;
Sativex®)
10 mg 3 (1–5) 0.5 (0.1) 3.1 (0.4)
Swortwood
et al., 2017
20, M/F Cannabis
smokers
Cannabis cigarettes –
frequent smokers
NIDA 1.5 mg Mean 0.29
(0.17–1.5)
(oral fluid)
93.3 (range
0.65–350)
(oral fluid)
Cannabis cigarettes –
occasional smokers
NIDA 1.5 mg Mean 0.17
(oral fluid)
55.9 (range
2.5–291) (oral
fluid)
Cannabis containing
brownie – frequent
smokers
NIDA 1.5 mg Mean 0.53
(0.17–1.5)
(oral fluid)
8.0 (range
0.48–26.3)
(oral fluid)
Cannabis containing
brownie – occasional
smokers
NIDA 1.5 mg Mean 0.47
(0.17–1.5)
(oral fluid)
5.9 (range
2.1–11.4)
(oral fluid)
Vaporization – frequent
smokers
Volcano®
Medic, Storz
& Bickel,
Tuttlingen,
Germany
1.5 mg Mean 0.29
(0.17–1.5)
(oral fluid)
76.3 (range
2.3–339) (oral
fluid)
Vaporization –
occasional smokers
Volcano®
Medic, Storz
& Bickel,
Tuttlingen,
Germany
1.5 mg Mean 0.17
(oral fluid)
28.2 (range
0.23–167)
(oral fluid)
Atsmon et al.,
2017b
15, M CBD extract >93% in a
PTL101 formulation
(oral gelatin matrix
pellet technology)
Sublingual/buccal
AiFame-AiLab
GmbH (CBD),
Gelpell AG
(capsules)
10 mg 3.0 (2.0–4.0) 3.22 (1.28) 9.64 (3.99) 10.31
(4.14)
2.95 (2.58)
100 mg 3.5 (1.5–5.0) 47.44 (20.14) 149.54
(34.34)
153.04
(34.7)
3.59 (0.26)
(Continued)
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TABLE 1 | Continued
References Total n, sex Administration Source CBD dose PlasmaaPK details Other
Tmax
(median,
range)bhrs
Cmax (mean,
SD)bng/mL
AUC0-t
(mean, SD)b
h×ng/mL
AUC0-inf
(mean,
SD) h ×
ng/mL
Kel (mean,
SD) 1/h
t1/2 (mean,
SD)bh
CL/F (mean,
SD) L/h
Mean (SD)
Oromucosal spray
(CBD and THC)
GW 10 mg 3.5 (1.0–5.0) 2.05 (1.1) 7.3 (2.86) 7.81 (2.81) 0.33 (0.09) 2.31 (0.72)
Atsmon et al.,
2017a
15, M CBD and THC in a
PTL401 capsule
(self-emulsifying oral
drug delivery system)
STI
pharmaceuticals
10 mg 1.25 (0.5–4.0) 2.94 (0.73) 9.85 (4.47) 10.52
(4.53)
0.29 (0.17) 3.21 (1.62)
Devinsky et al.,
2018b
34, children Oral solution GW 2.5 mg 70.23 (mean
from 3
groups)
5 mg/kg/day 241
10 mg/kg/day 722
20 mg/kg/day 963
a,bUnless otherwise stated. PK, pharmacokinetics; CBD, cannabidiol; THC, Tetrahydrocannabinol; M, male; F, female; AUC, area under the curve; Conc., concentration; GW, GW pharmaceuticals; NIDA, US national institute on drug
abuse; LOQ, limit of quantification; IV, intravenous; CBME, cannabis based medicine extract; Min(s), min(s).
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 AUC0−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. Tmax does not appear
to be dose-dependent, nor affected by acute or chronic dosing
schedules.
Stott et al. reported an increase in CBD bioavailability under
fed vs. fasted states in 12 men after a single 10 mg dose of CBD
administered through an oromucosal spray which also contained
THC (Stott et al., 2013a,b). Mean AUC and Cmax were 5- and 3-
fold higher during fed conditions compared to fasted (AUC0−t
23.1 vs. 4.5; Cmax 3.7 vs. 1.2 ng/mL). Tmax was also delayed under
the fed state (4.0 vs. 1.4 h).
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).
Oral Intake
Cmax and AUC following oral administration also appears to
be dose dependent. A dose of 10 mg CBD resulted in mean
Cmax of 2.47 ng/mL at 1.27 h, and a dose of 400 or 800 mg
co-administered with i.v. fentanyl (a highly potent opioid) to
examine its safety resulted in a mean Cmax of 181 ng/mL (at 3.0 h)
and 114 ng/mL (at 1.5 h) for 400 mg, and 221 ng/mL (at 3.0 h) and
157 ng/mL (at 4.0 h) for 800 mg, in 2 sessions, respectively (Guy
and Robson, 2004b; Manini et al., 2015). A dose of 800 mg oral
CBD in a study involving 8 male and female cannabis smokers,
reported a mean Cmax of 77.9 ng/mL and mean Tmax of 3.0 h
(Haney et al., 2016). Although, an increase in dose corresponds
with an increase in Cmax, the Cmax between the higher doses of
CBD does not greatly differ, suggesting a saturation effect (e.g.,
between 400 and 800 mg).
One hour after oral capsule administration containing 5.4 mg
CBD in males and females, mean Cmax 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
Cmax to 1.13 ng/mL. CBD remained detectable for 3–4 h after
administration (Nadulski et al., 2005b).
Cherniakov et al. examined the pharmacokinetic differences
between an oromucosal spray and an oral capsule with piperine
pro-nanolipospheres (PNL) (both 10 mg CBD) in 9 men. The
piperine-PNL oral formulation had a 4-fold increase in Cmax
(2.1 ng/mL vs. 0.5 ng/mL), and a 2.2-fold increase in AUC0−t
(6.9 vs. 3.1 h ×ng/mL), while Tmax was decreased (1.0 vs. 3.0 h)
compared to the oromucosal spray (Cherniakov et al., 2017a).
This group further developed self-emulsifying formulations and
reported again an increased bioavailability and increased Cmax
within a shorter time compared to a reference spray (Atsmon
et al., 2017a,b).
Intravenous Administration
The highest plasma concentrations of CBD were reported
by Ohlsson et al. following i.v. administration of 20 mg of
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Millar et al. Pharmacokinetics of Cannabidiol in Humans
FIGURE 2 | (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.
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.
Controlled Smoking and Inhalation
After smoking a cigarette containing 19.2 mg of deuterium-
labeled CBD, highest plasma concentrations were reported as
110 ng/mL, 3 min post dose, which dropped to 10.2 ng/ml 1 h
later (Ohlsson et al., 1986). Average bioavailability by the smoked
route was 31% (Ohlsson et al., 1986). A nebuliser resulted in
a Cmax of 9.49 ng/mL which occurred at 0.6 h, whereas aerosol
administration produced Cmax (2.6 ng/mL) at 2.35 h (Guy and
Flint, 2004). In 10 male and female usual, infrequent cannabis
smokers, Cmax was 2.0 ng/mL at 0.25 h after smoking a cigarette
containing 2 mg of CBD (Schwope et al., 2011). CBD was
detected in 60% of whole blood samples and in 80% of plasma
samples at observed Cmax, and no longer detected after 1.0 h.
A study in 14 male and female cannabis smokers reported
15.4% detection in frequent smokers with no CBD detected in
occasional smokers in whole blood analysis (Desrosiers et al.,
2014). In plasma however, there was a 53.8 and 9.1% detection
in the frequent and occasional groups, with corresponding Cmax
of 1.1 ng/mL in the frequent group, and below limits of detection
in the occasional group.
Half-Life
The mean half-life (t1/2) 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).
Elimination Rate
Mean elimination rate constant (Kel [1/h]) has been reported as
0.148 in fasted state, and 0.155 in fed state after 10 mg CBD was
administered in an oromucosal spray also containing THC (Stott
et al., 2013a,b). After single doses of 5 and 20 mg CBD, mean
Kel (1/h) was reported as 0.173 and 0.123 (Stott et al., 2013a).
Following 20 mg CBD administration through a nebuliser and
pressurized aerosol, mean Kel was reported as 0.98 and 0.43,
respectively, while 20 mg CBD administered as sublingual drops
was reported as 0.37 (Guy and Flint, 2004).
Plasma Clearance
Plasma apparent clearance, CL/F (L/h) has been reported to range
from 2,546 to 4,741 in a fasted stated following 10 mg CBD
administered via oromucosal spray (Stott et al., 2013a,c). This
value decreases to 533 following the same concentration in a fed
state (Stott et al., 2013b). A plasma apparent clearance of 3,252
and 3,783 was reported following 5 and 20 mg single doses of
CBD via oromucosal spray (Stott et al., 2013a). Ohlsson et al.
reported plasma apparent clearance as 74.4 L/h following i.v.
injection (Ohlsson et al., 1986).
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Millar et al. Pharmacokinetics of Cannabidiol in Humans
Volume of Distribution
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).
DISCUSSION
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; Cmax is increased and reached faster following i.v.,
smoking or inhalation; Cmax is increased and reached faster after
oral administration in a fed state or in a pro-nanoliposphere
formulation; Tmax 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 AUC0−t
and Cmax are dose-dependent, and Tmax 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.
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 Cmax. 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.
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.
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.
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 systematic review in 2014 concluded that CBD generally
has a low risk of clinically significant drug-interactions (Stout
and Cimino, 2014). A few studies in the current review
included examination of drug-drug interactions with CBD.
GW Pharmaceuticals performed a clinical trial investigating the
pharmacokinetic interaction between CBD/THC spray (sativex)
and rifampicin (cytochrome P450 inducer), ketoconazole, and
omeprazole (cytochrome P450 inhibitors) (Stott et al., 2013c).
Authors concluded overall that CBD in combination with the
drugs were well-tolerated, but consideration should be noted
when co-administering with other drugs using the CYP3A4
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Millar et al. Pharmacokinetics of Cannabidiol in Humans
pathway. Caution is also advised with concomitant use of CBD
and substrates of UDP-glucuronosyltransferases UGT1A9 and
UGT2B7, and other drugs metabolized by the CYP2C19 enzyme
(Al Saabi et al., 2013; Jiang et al., 2013). Manini et al. co-
administered CBD with i.v. fentanyl (a high potency opioid)
which was reported as safe and well-tolerated (Manini et al.,
2015). In a number of trials with CBD in children with severe
epilepsy, clobazam concentrations increased when CBD was co-
administered and dosage of clobazam had to be reduced in some
patients in one study (Geffrey et al., 2015; Devinsky et al., 2018b).
Gaston and colleagues performed a safety study in adults and
children in which CBD was administered with commonly-used
anti-epileptic drugs (AEDs) (Gaston et al., 2017). Most changes in
AED concentrations were within acceptable ranges but abnormal
liver function tests were reported in those taking valproate and
authors emphasized the importance of continued monitoring of
AED concentrations and liver function during treatment with
CBD.
Limitations of this review should be acknowledged. Different
population types including healthy and patient populations and
cannabis naïve or not were all grouped together which may
impede generalizability. The proportions of men and women in
each study were also not uniform, and it is still being elucidated
whether men and women have distinct pharmacokinetic profiles
with regards to cannabinoids (Fattore and Fratta, 2010). One
study suggested that the PK of CBD was different in their
female volunteers (Nadulski et al., 2005a). It should also be
mentioned that CBD is currently not an approved product with
a pharmacopeia entry so using different sources of CBD that are
subject to different polymeric forms, different particle sizes, and
different purities may also affect the PK profiles observed. It is
important for future work that researchers record the source of
the CBD material used so that results have the highest chance of
being replicated. Despite a thorough search of the two databases
chosen, the addition of more databases may have widened the
search to increase the number of results and hence improve the
reliability and validity of the findings. However, the review was
carried out by two independent reviewers, and searches generated
were analyzed separately and then compared.
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.
AUTHOR CONTRIBUTIONS
SM, SO, and AY: substantial contributions to the conception
or design of the work. SM: writing of the manuscript. SM and
NS: database searching and data extraction. All authors: the
analysis and interpretation of data for the work; drafting the
work or revising it critically for important intellectual content;
final approval of the version to be published; agreement to be
accountable for all aspects of the work in ensuring that questions
related to the accuracy or integrity of any part of the work are
appropriately investigated and resolved.
FUNDING
This work was supported by the Biotechnology and Biological
Sciences Research Council [Grant number BB/M008770/1].
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/fphar.
2018.01365/full#supplementary-material
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Conflict of Interest Statement: AY was employed by company Artelo Biosciences.
The remaining authors declare that the research was conducted in the absence of
any commercial or financial relationships that could be construed as a potential
conflict of interest.
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Frontiers in Pharmacology | www.frontiersin.org 13 November 2018 | Volume 9 | Article 1365