Retirada abrupta de canabidiol CBD - um estudo randomizado

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Epilepsy & Behavior 104 (2020) 106938
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Epilepsy & Behavior
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Abrupt withdrawal of cannabidiol (CBD): A randomized trial
Lesley Taylor a, Julie Crockett a, Bola Tayo a, Daniel Checketts a, Kenneth Sommerville b,⁎
a GW Research Ltd., Sovereign House, Vision Park, Histon, Cambridge CB24 9BZ, UK
b Greenwich Biosciences, Inc., 5750 Fleet Street, Suite 200, Carlsbad, CA 92008, USA
⁎ Corresponding author at: 5005 Lenoraway Drive, Rale
E-mail addresses: lesley@alchemymedicalwriting.com
JCrockett@gwpharm.com (J. Crockett), BTayo@gwpharm.c
Dchecketts@gwpharm.com (D. Checketts), kwsommervill
https://doi.org/10.1016/j.yebeh.2020.106938
1525-5050/© 2020 Elsevier Inc. All rights reserved.
a b s t r a c t
a r t i c l e i n f o
Article history:
Received 28 October 2019
Revised 23 December 2019
Accepted 17 January 2020
Available online xxxx
Rationale: The rationale of this study was to assess occurrence of withdrawal symptoms induced by abrupt ces-
sation of cannabidiol (CBD) after prolonged administration in healthy volunteers.
Methods: Thirty volunteerswere randomized to receive 750mgof a plant-derived pharmaceutical formulation of
highly purified CBD in oral solution (100 mg/mL; Epidiolex® in the United States and Epidyolex® in Europe)
twice daily (b.i.d.) for 4 weeks (Part 1) followed by 2 weeks of 750mg b.i.d. CBD (Part 2, Arm 1) or matched pla-
cebo (Part 2, Arm 2). All volunteers completed the CannabisWithdrawal Scale (CWS) and the 20-item Penn Phy-
sician Withdrawal Checklist (PWC-20) on days −1, 21, 28, 31, 35, 42, and at follow-up.
Results:Median CWSand PWC-20 scores slightly decreased fromPart 1 to Part 2.Median CWS scores ranged from
0.0 to 4.0 (out of a possible 190) in Arm 1 and 0.0 to 0.5 in Arm 2. Median PWC-20 scores were 0.0 (out of a pos-
sible 60) in both arms. Twenty-nine (97%) volunteers in Part 1 reported all-causality treatment-emergent ad-
verse events (AEs); the most commonly reported was diarrhea (63%). In Part 2, Arm 1, 6 (67%) volunteers
reported all-causality AEs; themost commonly reportedwas diarrhea (44%). In Part 2, Arm 2, 9 (75%) volunteers
reported all-causality AEs; themost commonly reportedwas headache (58%). Nine volunteerswithdrewbecause
of AEs in Part 1; 1withdrew in Part 2, Arm2, because of an AE that began in Part 1. Four severe AEswere reported
in Part 1; the remainder were mild or moderate. No serious AEs were reported.
Conclusion: In healthy volunteers, no evidence of withdrawal syndrome was found with abrupt discontinuation
of short-term treatment with CBD.
© 2020 Elsevier Inc. All rights reserved.
Keywords:
Cannabinoid
Cannabidiol
Drug withdrawal
Epilepsy
Seizure
1. Introduction
Highly purified cannabidiol (CBD) (approved as Epidiolex® in
United States and Epidyolex® in Europe) has demonstrated clinical effi-
cacy, with a well-characterized safety profile in patients with Lennox–
Gastaut syndrome (LGS) or Dravet syndrome (DS) in 4 randomized,
controlled trials [1–4]. Based on recent nonclinical scientific literature,
it is likely that the cumulative anticonvulsant effect is regulated via at
least 3 targets: modulation of intracellular Ca2+ via G protein-coupled
receptor 55, desensitization of transient receptor potential vanilloid
type 1 channels, and inhibition of adenosine reuptake [5–7]. Because
there is limited or no interaction with the cannabinoid receptors, CB1
and CB2, CBD is unlikely to cause euphoric effects linked to propensity
for abuse [8,9].
Cannabis withdrawal symptoms (Table 1, [10]) are thought to be
caused mainly by the activity of Δ9-tetrahydrocannabinol (THC) at the
CB1 receptor [11] rather than by CBD, which is not active at the CB1
igh, NC 27613, USA.
(L. Taylor),
om (B. Tayo),
e@gmail.com (K. Sommerville).
receptor [12]. In a nonclinical, nonprecipitated withdrawal test in juve-
nile and adult male and female rats, at oral (gavage) doses of up to
100 mg/kg CBD twice daily (b.i.d.) for 19 days with a single dose on
day 20, no clear withdrawal effects of CBD were observed. In contrast,
diazepam and morphine induced moderate and mild withdrawal, re-
spectively [13]. There is a lack of evidence regarding the consequences
of abrupt withdrawal from clinical CBD use. Given the clinical impor-
tance of understanding the potential for CBD withdrawal effects in pa-
tients, this trial investigated whether withdrawal symptoms like those
reported following cannabis withdrawal occurred in healthy volunteers
taking CBD.
2. Methods
This randomized, double-blind trial, with a single-blind baseline as-
sessment, was conducted between 17 November 2015 and 05 February
2016 at the Pharmaceutical Research Associates Health Sciences
(PRAHS) - Early Development Services trial site in Groningen, the
Netherlands. All relevant trial-related documents, including the proto-
col, were reviewed and approved by an independent ethics committee,
the Foundation Evaluation of Ethics in Biomedical Research, Assen, the
Netherlands. The trial was performed in full conformity with the
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Table 1
Proposed cannabis withdrawal criteria [10].
Common symptoms
Anger or aggression
Decreased appetite or weight loss
Irritability
Nervousness/anxiety
Restlessness
Sleep difficulties, including strange dreams
Less common symptoms/equivocal symptoms
Chills
Depressed mood
Stomach pain
Shakiness
Sweating
2 L. Taylor et al. / Epilepsy & Behavior 104 (2020) 106938
Declaration of Helsinki [14], the International Conference on
Harmonisation guidelines for Good Clinical Practice [15], and all other
applicable regulations. All volunteers provided written informed con-
sent before trial participation.
2.1. Trial design
The primary objective of the trial was to assess the potential for
withdrawal symptoms after prolonged treatment with a pharmaceuti-
cal formulation of highly purified CBD derived from Cannabis sativa L.
plants in oral solution (100 mg/mL; Epidiolex® in the US; Epidyolex®
in Europe; GW Research Ltd. [GW], Cambridge, UK). The trial consisted
of 2 consecutive parts: In Part 1, 30 volunteers received b.i.d. doses of
750 mg CBD for 4 weeks in single-blinded fashion. In Part 2, all volun-
teers from Part 1 were randomized in double-blinded manner to con-
tinue to receive 750 mg CBD b.i.d. for another 2 weeks (Arm 1; n =
15) or to receive an equivalent volume of CBD-matched placebo b.i.d.
for 2 weeks after abrupt discontinuation of CBD (Arm 2; n = 15).
Randomization for Part 2 treatment assignments took place on day 1
of Part 1 of the trial. All volunteers were randomly assigned to a treat-
ment (750 mg CBD b.i.d. or an equivalent volume of CBD-matched
placebo) using block randomization (fixed block size = 15). Randomi-
zation codes were electronically generated by the Biostatistics Depart-
ment of PRAHS. The treatment assignment code list was available only
to the trial statistician and the clinical trials supplies operations group.
Individual envelopes containing the randomization code for each volun-
teer were sealed and kept in a medication storage room, which was
locked with restricted access. All volunteers were informed that they
were receiving “trial medication,” and the oral liquid formulation con-
taining CBD and placebo was indistinguishable in appearance and taste.
Volunteerswere admitted to the clinic on day−1 and stayed 1 night
before discharge. For the remainder of the trial, volunteers returned to
the trial site for weekly ambulatory visits on days 7, 14, 21, 28, 31, 35,
and 42. In addition, volunteers returned to the trial site for a follow-up
assessment 14 to 18days after the last blood sample was taken (days
56 to 60).
2.2. Trial population
Healthy male and female volunteers aged 18–45 years with a body
mass index (BMI) between 18 and 28 kg/m2 were eligible. Volunteers
were required to have no clinically significant medical history, no his-
tory of alcohol abuse or drug addiction, and normal physical examina-
tion, 12-lead electrocardiogram (ECG), vital signs, and clinical
laboratory findings, as judged by the principal investigator. Female vol-
unteers were nonpregnant and nonlactating at screening. Male and fe-
male volunteers agreed to use effective contraception and not to
donate sperm from first admission to the clinical research center until
90 days after the follow-up visit.
2.3. Withdrawal assessments
Any symptoms of withdrawal reactions were monitored using the
Cannabis Withdrawal Scale (CWS) questionnaire, which contains 19
questions selected to distinguish withdrawal symptoms from other
symptoms [16]. Each symptom is measured on a 0–10 numerical rating
scale (NRS) (0= not at all; 5 =moderately; 10 = extremely). The vol-
unteer was asked to indicate the extent to which each withdrawal
symptom was experienced in the last 24 h and to rate the negative im-
pact on normal daily activities (2 separate scoreswere recorded for each
item using the same 0–10 NRS). Scores were summed over the 19 items
for each measure. Possible scores range from 0 to 190, with higher
scores indicating a greater intensity of cannabis withdrawal symptoms
[16]. Thus, a reduction in score indicates an improvement inwithdrawal
symptoms. The CWS was administered by appropriately trained site
personnel on days −1, 21, 28, 31, 35, 42, and at follow-up. The ques-
tionnaire was completed 3 to 5 h after themorning dose on ambulatory
visits.
Symptoms of withdrawal reactions were also monitored using the
Penn Physician Withdrawal Checklist (PWC-20) [17], a 20-question,
physician-completed checklist designed to detect benzodiazepine-like
withdrawal symptoms. Each item is measured on a 0–3 NRS (0 = not
present; 1 = mild; 2 = moderate; 3 = severe). Scores on the PWC-20
range from 0 to 60, with higher scores indicating more severe with-
drawal symptoms [17]. Thus, a reduction in score indicates an improve-
ment in the severity of withdrawal symptoms. The physicianwas asked
to indicate whether the volunteer manifested or described any of the
symptoms listed. The PWC-20 was performed on days −1, 21, 28, 31,
35, 42, and at follow-up. The questionnaire was completed 3 to 5 h
after the morning dose on ambulatory visits.
2.4. Safety assessments
The safety and tolerability of CBD and the effect of CBD withdrawal
were evaluated by recording the incidence of treatment-emergent ad-
verse events (AEs) throughout the trial, clinical laboratory tests, vital
signs, 12-lead ECG, and physical examinations. In addition, the effect
of CBD and the effect of CBD withdrawal on sleep were evaluated by
sleep disruption 0–10NRS and Epworth Sleepiness Scale (ESS) [18]. Sui-
cidal thoughts and behaviors were evaluated by Columbia-Suicide Se-
verity Rating Scale (C-SSRS) [19], and level of depression was assessed
using the Hamilton Depression Rating Scale (HAM-D) [20].
2.5. Treatment compliance
Although there were no pharmacokinetic (PK)-related objectives,
blood samples (6 mL) were collected predose on day 1, and 4 to 5 h
after the morning dose on days 7, 14, 21, 28, 35, and 42. Cannabidiol
and THC plasma concentrations were assessed by LGC (Fordham, UK)
using validated bioanalytical methods to confirm treatment compliance
[21].
2.6. Statistical analysis
For this exploratory trial, no prospective calculations of statistical
powerweremade. The sample size was selected to provide information
on safety, tolerability, and withdrawal effects after multiple doses of
CBD. This trial had 1 analysis set, the safety set, defined as all volunteers
who received at least 1 dose of CBD or placebo. There were no plans for
formal hypothesis testing. Summary statistics were calculated by arm,
trial part, treatment (and time point, if applicable). Screening data
were pooled with data from all volunteers assigned to different arms
combined.
The CWS individual score, total individual score, and change from
baseline of the total score were listed, and the total score and change
from baseline were summarized descriptively. The total score for the
Table 2
Demographics and baseline characteristics.
Characteristic Part 1 Part 2
Arm 1 Arm 2
750 mg CBD b.i.d.
28 days
(N = 30)
750 mg CBD b.i.d.
14 days
(N = 9)
Placebo b.i.d.
14 days
(N = 12)
Sex, n (%)
Male 17 (56.7) 7 (77.8) 4 (33.3)
Female 13 (43.3) 2 (22.2) 8 (66.7)
Race, n (%)
White 27 (90.0) 8 (88.9) 10 (83.3)
Multiple: Asian and Caucasian 2 (6.7) 1 (11.1) 1 (8.3)
American Indian or Alaska Native 1 (3.3) 0 (0) 1 (8.3)
Mean (SD) age (years) 25.3 (6.7) 22.7 (2.0) 27.8 (8.2)
Mean (SD) BMI (kg/m2) 23.77 (2.23) 23.74 (2.71) 24.59 (2.13)
b.i.d., twice daily; BMI, body mass index; CBD; cannabidiol; SD, standard deviation.
3L. Taylor et al. / Epilepsy & Behavior 104 (2020) 106938
extent to which each withdrawal symptomwas experienced in the last
24 h and the negative impact on normal daily activities were analyzed
separately. Individual PWC-20 score, total individual score, and change
from baseline of the total score were listed, and the total score and
change from baseline were summarized descriptively.
All AEswere coded by SystemOrgan Class (SOC) and Preferred Term
(PT) using the Medical Dictionary for Regulatory Activities (MedDRA)
version 17.1. The incidence of all-causality AEs, any serious AEs, and dis-
continuations because of AEs were summarized by treatment group. All
laboratory datawere listed, and numeric hematology, biochemistry, and
coagulation data were summarized descriptively. Vital signs and ECG
data were listed and summarized descriptively.
On days −1, 1, 7, 14, 21, 28, 31, 35, and 42, sleep disruption 0–10
NRS, ESS, and HAM-D scores, total scores, and change from baseline of
the total score were listed and summarized descriptively by phase
(Part 1/Part 2) and treatment group (in Part 2). In general, for HAM-D,
question 17 (insight into own depressive illness) could not be scored
because the HAM-D questionnaire is not validated as a screening tool
in healthy volunteers. For this reason, question 17 was only scored if
the volunteer suffered from depression, otherwise a score of 0 was
added. In addition, the comment “Score must be greater than or equal
to 18 to continue in the trial” was not applicable to this trial. For the
C-SSRS, the frequencies of shifts between the categories of “yes,” “no,”
and “missing” were determined. SAS® version 9.4 (SAS Institute Inc.,
Cary, NC, US) was used for statistical analysis.
3. Results
3.1. Volunteer demographics
Table 2 presents a summary of the demographic and baseline char-
acteristics. A total of 30 volunteers were enrolled into Part 1 of the
trial. Seventeen (57%) volunteers were male, and the majority (27
[90%]) were White; 2 (7%) were Asian and Caucasian, and 1 (3%) was
American Indian or Alaska Native. The mean (standard deviation [SD])
age was 25.3 (6.7) years, and mean (SD) BMI was 23.8 (2.2) kg/m2. A
total of 21 volunteers that completed Part 1 entered Part 2 of the trial;
9 had been randomized to receive CBD (Arm 1) and 12 to receive pla-
cebo (Arm 2). In Part 2, there were 11 (52%) males (7 in the CBD
group and 4 in the placebo group). Most (18 [86%]) volunteers were
White; 2 (10%) volunteers (1 each in the CBD and placebo groups)
were Asian and Caucasian, and 1 (3%) volunteer in the placebo group
was American Indian or Alaska Native.
3.2. Volunteer disposition
Patients were enrolled from November 17, 2015 through December
8, 2015, and follow-up continued through February 5, 2016. Thirty
volunteers were enrolled into Part 1, during which all volunteers were
to receive 750 mg CBD b.i.d. for 4 weeks. During Part 1, 9 (30%) volun-
teers were withdrawn. During Part 1, volunteers were randomized
into1 of 2 arms for Part 2 (hence, the 21 volunteers remaining in Part
1 entered Part 2). Volunteers in Arm 1 continued to take 750 mg CBD
b.i.d., and volunteers in Arm 2 took an equivalent volume of CBD-
matched placebo after CBD was abruptly discontinued. On the first
day of Part 2 (Day 29), 1 (7%) volunteer was withdrawn from Arm 2.
All withdrawals in Parts 1 and 2 were due to AEs. Of the 30 volunteers
randomized, 20 (66.7%) volunteers completed the trial. Fig. 1 details
the disposition of volunteers in the trial.
3.3. Withdrawal evaluation
Volunteers were asked to record CWS scores for 2 categories: 1) the
extent towhich each of the 19withdrawal symptomswere experienced
in the last 24 h and 2) the negative impact each of the 19 withdrawal
symptoms had on normal daily activities. The sum of the response
scores for all 19 symptoms was recorded for each volunteer, and the
mean of these total scores (out of a possible 190) was calculated for
each category for volunteers who completed Part 1 (all CBD, n = 23)
and Part 2 (Arm 1 [CBD], n = 9; Arm 2 [placebo], n = 12).
All mean total scores for each category were consistently low
throughout the trial and remained close to the predose scores. On day
28, the mean total CWS score (out of a possible 190) after 4 weeks
(28 days) of taking 750 mg CBD b.i.d. was 9.3 (range: 0–45) for experi-
ence of withdrawal symptoms in the last 24 h and 5.8 (range: 0–41) for
the negative impact of the symptoms on normal daily activity. During
Part 2, in both the CBD and placebo groups, mean CWS scores recorded
on days 31, 35, and 42 decreased from the baseline reported at day 28.
This applied to both experience of withdrawal symptoms in the last
24 h and negative impact of the symptoms on normal daily activity.
Fig. 3A and B shows the change from baseline of mean (±SD) total
CWS scores during Part 2 for the last 24 h and negative daily impact, re-
spectively. Median change from baseline during Part 2 for the experi-
ence of withdrawal symptoms in last 24 h score ranged from 0.0 to
−2.0 for Arm 1 (CBD) and −1.0 to −2.5 for Arm 2 (placebo). For the
negative daily impact score, the median change from baseline was
0.0 at all time points.
For the PWC-20, mean scores were consistently low throughout the
trial and remained close to predose scores. On day 28, the mean total
PWC-20 score (out of a possible 60) after 4 weeks (28 days) of taking
750 mg CBD b.i.d. was 1.4 (range: 0–5). Median scores were 0.0
throughout Part 2 for both Arm 1 (CBD) and Arm 2 (placebo). During
Part 2, mean PWC-20 scores recorded on days 31, 35, and 42 decreased
from the baseline reported at day 28 in both Arm 1 (CBD) and Arm 2
(placebo). Fig. 3C shows the change from baseline in mean (±SD)
PWC-20 scores during Part 2 of the trial.
Fig. 1. Disposition of trial volunteers.
4 L. Taylor et al. / Epilepsy & Behavior 104 (2020) 106938
3.4. Treatment compliance
Individual plasma concentrations of CBD were measured to assess
compliance, and geometric mean plasma concentration-time profiles
are presented in Fig. 2. When volunteers in Arm 2 began receiving pla-
cebo in place of CBD, mean plasma concentrations of CBD decreased
steadily and had fallen to nearly predose levels by the end of treatment
on day 42. In Arm 1 (continuation of CBD dosing), plasma concentra-
tions of CBD remained high.
Intervolunteer variability was high, with mean CBD plasma concen-
trations ranging from 17.4 to 1264 ng/mLwhen volunteers were taking
CBD. The concentration-time profiles of the major metabolites of CBD
Fig. 2.Geometricmean (±SD) plasma concentration-time profiles for CBD throughout the trial
Arm 1 or 2. Arm 1: 750mg cannabidiol b.i.d., 14 days, n= 9; Arm 2: Placebo b.i.d., 14 days, n=
blind phase of the trial. bIn Part 2, Arm 1, the spike in plasma concentration on day 42 was due
showed a similar pattern (data not shown). Δ9-Tetrahydrocannabinol
was detected only at trace levels, with themean plasma THC concentra-
tion on day 42 reaching 0.402 ng/mL (range: 0.130–0.952 ng/mL) in
Arm 1 (CBD).
3.5. Safety
In Part 1 of the trial (CBD only), most (29 [97%]) volunteers experi-
enced AEs. Of these, 4 (13%) volunteers reported severe AEs, and 6
(20%) volunteers reported moderate AEs. The majority of AEs were
mild. In Part 2 of the trial, 6 (67%) volunteers in Arm 1 (CBD) and 9
(75%) in Arm 2 (placebo) experienced AEs. With the exception of an
, startingwith Part 1 (n=21) between days 7 and 28, then transitioning to randomization,
12 (except n=11 on day 31). aDotted verticle line represents the beginning of the double-
to individual variability.
Fig. 3. Change frombaseline inmean (±SD) CannabisWithdrawal Scale total scores during Part 2 of the trial for A) the extent towhich the 19withdrawal symptomswere experienced in
the last 24 h and B) the negative impact each of the 19 withdrawal symptoms had on normal daily activities. C) Change from baseline in mean (±SD) Penn Physician Withdrawal Scale
total scores during Part 2 of the trial. For both the CWS and PWC-20, a negative value indicates an improvement. Arm 1: 750 mg cannabidiol b.i.d., 14 days, n = 9; Arm 2: Placebo b.i.d.,
14 days, n = 12 (except n = 11 on day 31). aBaseline = day 28.
5L. Taylor et al. / Epilepsy & Behavior 104 (2020) 106938
increased incidence of headaches in Arm 2 (7 [58%] in Arm 2 vs. 2 [22%]
in Arm 1), all of which were mild in intensity, the types of AEs experi-
enced were comparable between Arm 1 and Arm 2, showing no clear
withdrawal syndrome. Therewere no serious AEs or pregnancies during
the trial. Table 3 presents a summary of all-causality AEs reported by N1
volunteer in at least 1 treatment group during the trial.
In Part 1 (750 mg b.i.d. CBD for 4 weeks), 29 (97%) volunteers re-
ported AEs, of which diarrhea (63%), headache (50%), abdominal pain
Table 3
All-causality AEs experienced by N1 volunteer in any treatment group (safety set).
Part 1 Part 2
Arm 1 Arm 2
750 mg CBD b.i.d.
28 days
(N = 30)
750 mg CBD b.i.d.
14 days
(N = 9)
Placebo b.i.d.
14 days
(N = 12)
Volunteer experiencing any AE, n (%) 29 (96.7) 6 (66.7) 9 (75.0)
Mild AEs 19 (63.6) 6 (66.7) 9 (75.0)
Moderate AEs 6 (20.0) 0 0
Severe AEs 4 (13.3) 0 0
SAEs 0 0 0
Discontinued treatment because of AE, n (%) 9 (30.0) 0 1 (8.3)
SOC
PT
Gastrointestinal disorders, n (%)
Diarrhea 19 (63.3) 4 (44.4) 2 (16.7)
Abdominal pain 14 (46.7) 0 1 (8.3)
Nausea 13 (43.3) 2 (22.2) 0
Dyspepsia 4 (13.3) 0 0
Dry mouth 2 (6.7) 0 0
Epigastric discomfort 2 (6.7) 0 0
Gastrointestinal sounds abnormal 2 (6.7) 0 0
Regurgitation 2 (6.7) 0 0
Nervous system disorders, n (%)
Headache 15 (50.0) 2 (22.2) 7 (58.3)
Somnolence 7 (23.3) 1 (11.1) 0
Dizziness 7 (23.3) 0 0
Disturbance in attention 2 (6.7) 0 0
Dizziness postural 2 (6.7) 0 0
General disorders & administration site conditions, n (%)
Fatigue 10 (33.3) 0 0
Influenza-like illness 2 (6.7) 0 1 (8.3)
Asthenia 2 (6.7) 0 0
Chest discomfort 2 (6.7) 0 0
Chest pain 2 (6.7) 0 0
Pyrexia 2 (6.7) 0 0
Skin and subcutaneous tissue disorders, n (%)
Rash 7 (23.3) 0 0
Musculoskeletal and connective tissue disorders, n (%)
Myalgia 3 (10.0) 0 2 (16.7)
Arthralgia 2 (6.7) 0 0
Psychiatric disorders, n (%)
Nightmare 2 (6.7) 0 1 (8.3)
Insomnia 2 (6.7) 0 0
Respiratory, thoracic, and mediastinal disorders, n (%)
Oropharyngeal pain 1 (3.3) 0 2 (16.7)
Metabolism and nutrition disorders, n (%)
Decreased appetite 2 (6.7) 0 0
Blood and lymphatic system disorders, n (%)
Eosinophilia 3 (10.0) 0 0
Hepatobiliary disorders, n (%)
Drug-induced liver injury 2 (6.7) 0 0
AEs, adverse events; b.i.d., twice daily; CBD, cannabidiol; PT, Preferred Term; SOC, System Organ Class.
6 L. Taylor et al. / Epilepsy & Behavior 104 (2020) 106938
(47%), nausea (43%), and fatigue (33%) were the most common. In Part
2, 6 (67%) volunteers reported all-causality AEs in Arm 1 (CBD) and 9
(75%) volunteers in Arm 2 (placebo). The most common all-causality
AEs in Arm 1 were diarrhea, reported by 4 (44%) volunteers, nausea,
and headache, both reported by 2 (22%) volunteers. In Arm 2, headache
was themostcommon all-causality AE, reported by 7 (58%) volunteers.
Nine (30%) volunteers discontinued CBD in Part 1 because of AEs,
and 1 volunteer discontinued placebo on the first day of Part 2 because
of an AE that began in Part 1. A summary of AEs leading to discontinua-
tion of CBD or placebo and withdrawal from the trial is provided in
Table 4.
Two volunteers werewithdrawn for potential drug-induced liver in-
jury (DILI), with raised transaminases and associated signs and symp-
toms. One had a moderate AE of DILI and a severe AE of eosinophilia
on day 28 accompanied by headache, as well as mild chest pain on
day 29 andmild chest discomfort on day 30. The secondvolunteer expe-
rienced a moderate AE of DILI on day 21, accompanied by mild AEs of
epigastric discomfort, regurgitation, and esophageal discomfort. No
elevated bilirubin levels were detected in either volunteer, and there-
fore, the cases did not fulfill Hy's Law for DILI. Both volunteers recovered
from these AEs after withdrawal of CBD. In addition to the 2 volunteers
whowere withdrawn, 12 volunteers' transaminase levels increased but
remained within the predefined toxicity limits and b3 × upper limit of
normal. None of these were reported as AEs.
Seven volunteers were withdrawn from Part 1 because of rashes; 2
rashes were severe, and 5 were moderate. All 7 (23%) rashes were gen-
eralized. One (3%) additional volunteer developed a mild rash during
Part 1 butwasnotwithdrawn; the volunteer completed the trial. All vol-
unteers with rashes completely recovered; none of the rashes were re-
ported in association with any documented systemic illness, and none
had mucosal involvement.
One volunteer developed a severe AE of muscle injury on day 21,
sustained while not admitted to the trial site. Clinical laboratory results
reported raised creatine kinase and liver transaminases, compatible
with trauma noted on the volunteer's ankle. The volunteer was with-
drawn on the first day of Part 2, Arm 2 of the trial.
Table 4
Volunteers discontinuing treatment because of AEs.
SOC
PT
Part 1 Part 2
750 mg CBD b.i.d.
28 days
(N = 30)
750 mg CBD b.i.d.
14 days
(N = 9)
Placebo b.i.d.
14 days
(N = 12)
Injury, poisoning, and procedural complications, n (%) 0 0 1 (8.3)
Muscle injury 0 0 1a (8.3)
Skin and subcutaneous tissue disorders, n (%) 7 (23.3) 0 0
Generalized skin rash 6 (20.0) 0 0
Rash pruritic 1 (3.3) 0 0
Hepatobiliary disorders, n (%) 2 (6.7) 0 0
Drug-induced liver injury 2 (6.7)b 0 0
Blood and lymphatic system disorders, n (%) 1 (3.3) 0 0
Eosinophilia 1b (6.7) 0 0
b.i.d., twice daily; CBD, cannabidiol; PT, Preferred Term; SOC, System Organ Class.
a Not treatment-related.
b One volunteer discontinued treatment because of eosinophilia and drug-induced liver injury, therefore, has been counted once for total number of volunteers inwhich the treatment
was discontinued.
7L. Taylor et al. / Epilepsy & Behavior 104 (2020) 106938
Treatment-emergent increases in eosinophil levels occurred in 8
volunteers after ~2–4 weeks exposure to CBD, then reduced to normal
levels as the trial progressed. These increases were reported as AEs in
3 volunteers. None of the increases were defined by the investigator
as clinically significant, and 5 of the 8 volunteers went on to complete
the trial. As mentioned above, 1 volunteer was withdrawn on day 28
for theAEs of severe eosinophilia and raised transaminases, and another
volunteer was withdrawn on day 11 for a rash. In addition to the with-
drawn volunteer, 5 of the volunteers with eosinophilia also had raised
transaminases; none of these 5 met the criteria for potential DILI or
Hy's Law, and all 5 completed the trial with no associated pathology.
There were no clinically significant other laboratory parameters,
vital sign, bodyweight, or ECGfindings. One volunteer reported palpita-
tions, classified as a mild AE; however, all ECG parameters were within
normal ranges and the palpitations resolved.
The scores for sleep disruption 0–10 NRS and the ESS were low in
both trial arms (data not shown), suggestingminimum sleep disruption
and daytime sleepiness whether volunteers continued CBD or abruptly
stopped taking CBD and took placebo for Part 2. At all points and in both
trial arms, HAM-D scoreswerewell below 7, given as the threshold for a
normal score [22]. There was no evidence of increased suicidal behavior
or suicidal ideation; all volunteers in both arms answered “no” to all
questions on the C-SSRS at all points measured.
4. Discussion
This trial was designed to evaluate whether CBD produced any signs
or symptoms of withdrawal after abrupt discontinuation in healthy vol-
unteers. The 750mgCBDb.i.d. dose administered equates to a therapeu-
tic dosage of approximately 20 mg/kg/day for a 75-kg adult for the
treatment of epilepsy. Volunteers were dosed for 4 weeks, ensuring
steady-state before splitting into 2 groups.
In Part 2, 2 withdrawal scales, the CWS and PWC-20, were adminis-
tered at 3, 7, and 14 days after abrupt CBD cessation (or continuation) to
capture any withdrawal symptoms or signs, since CBD has a half-life of
around 60 h [21], and the withdrawal effects of cannabis peak between
days 2 to 6 [16]. No evidence for withdrawal symptoms was found on
either withdrawal scale. Cannabis Withdrawal Scale scores were low
throughout the trial, withmean scores for both the last 24 h and for neg-
ative daily impact lower in both arms during the withdrawal phase
(Part 2) than when all volunteers were taking CBD (Part 1); scores
were also lower in Arm 2 (placebo) compared with in Arm 1 (CBD).
Functional impairment scores following cannabis withdrawal tend to
be fairly mild, with the highest median score (out of a possible 190) of
24 (no relapse) to 60 (relapse) recorded in highly dependent cannabis
users and lower (between 8 [relapse] to 12.5 [no relapse]) in volunteers
clinically defined as less dependent [23]. In the present trial, themedian
total functional impairment score was 0.5 in the placebo group (Arm
2) 1 week after abrupt cessation of CBD, which corroborates the finding
that withdrawal symptoms were not experienced by volunteers in this
trial.
Scores on the PWC-20 were low throughout the trial, with mean
scores in Arm 2 (placebo) lower than those in Arm 1 (CBD) and also
lower than in Part 1 (before CBD discontinuation). The PK data support
these findings by demonstrating there was adequate CBD exposure in
the groups during Part 1 of the trial and then low levels of CBD in the
placebo group in Part 2.
Cannabidiol wasmoderatelywell-tolerated at a dose of 750mgb.i.d.
There was a high incidence of AEs in this trial; the majority of which
were mild (64% in Part 1 and 100% in Part 2). The most common AEs
reported in Part 1 (i.e., diarrhea, abdominal pain, nausea, and head-
ache) are similar to reports of other trials of CBD [1–4,24]. No notable
differences in the type or severity of AEs were observed between the
2 arms during Part 2, except for an increased incidence of headache
in the placebo group. Of note, all cases of headache in the placebo
group were reported between 6 and 16 days after CBD was abruptly
stopped, so it is likely that the symptoms occurred after the 2- to 6-
day period where cannabis withdrawal syndrome is normally ob-
served. When assessing AEs as symptoms indicative of a potential
withdrawal syndrome in cannabinoids, the presence of 4 or more
of the common or less common symptoms listed in Table 1 should
be considered when diagnosing a cannabis withdrawal [10]. There-
fore, an AE such as headache in isolation of other symptoms associ-
ated with withdrawal syndrome is unlikely to be indicative of
withdrawal or dependence. In addition, in Part 1 of the study, CBD
dosing was stable, and the incidence of headaches was 50%, suggest-
ing that headache was a common symptom in the trial and was not
related to CBD withdrawal.
Two volunteers were withdrawn for potential DILI, with raised
transaminases and associated signs and symptoms: eosinophilia,
fatigue, and nausea in 1 volunteer andabdominal pain and pyrexia in
the other volunteer. However, neither case showed an elevation of bili-
rubin or international normalized ratio and thus did not fulfill Hy's Law
for DILI. Seven volunteers were withdrawn because of the AE of rash
during Part 1 of the trial, all of which were generalized and occurred
6–12 days following first exposure to CBD.
For patients with Dravet or Lennox–Gastaut syndromes, the
Epidiolex prescribing information recommends a starting dosage of
5 mg/kg/day (much lower than in the current trial) with an increase
of 5mg/kg/day eachweek [25]. Themore rapid titration scheduled in
the current study may account for the higher dropout rate observed
in Part 1 and for the number of AEs reported.
The AE profile, together with the lack of clinically significant safety
findings for vital signs, ECG, body weight, sleep, suicidal behavior, or
8 L. Taylor et al. / Epilepsy & Behavior 104 (2020) 106938
depressive symptoms, corroborates the finding of an absence of with-
drawal effects when short-term treatment with CBD in healthy volun-
teers is abruptly discontinued and suggests that CBD has little or no
propensity to be physically addictive.
The CBD concentrations showed high variability but the aver-
ages for the treatment groups showed low to absent concentra-
tions in the placebo group and high concentrations in the group
that continued on CBD. The concentrations are generally consistent
with what is expected from the trial design and support the conclu-
sions of the trial.
The present trial had a number of strengths. The dosage of CBD ad-
ministered was considered therapeutic for epilepsy and long enough
to attain a potential physical dependence if possible; the PK profile
was measured to confirm both adequate exposure and withdrawal
from CBD. In addition, the withdrawal portion of the trial (Part 2) was
double-blind and placebo-controlled.
The limitations of the trial included the dropout rate, which limited
the number of volunteers assessed for symptoms of withdrawal in the
discontinuation phase. In addition, the possibility of withdrawal symp-
toms at supratherapeutic doses was not studied. However, a human
abuse liability trial examining a single 4500-mg supratherapeutic dose
found little evidence of abuse potential [9]. A further limitation was
that the participants were healthy volunteers and did not have epilepsy.
These results could be applied to an epilepsy population as it is unlikely
that patients with epilepsy would yield different outcomes; however,
there is always the potential for seizure exacerbation with rapid with-
drawal of an antiseizure medication. An additional limitation of the
trial is that dosing was for only one month and withdrawal symptoms
over longer periods were not investigated.
5. Conclusion
There was no evidence of a withdrawal syndrome with CBD admin-
istered at a therapeutic dose. Cannabis Withdrawal Scale and PWC-20
scores were low throughout the trial, with no increases after the abrupt
discontinuation of CBD.
Funding
This trial was sponsored by GW Pharmaceuticals (Cambridge, UK).
Author contributions
L. Taylor: data interpretation during trial reporting; co-authored and
reviewed the manuscript.
J. Crockett: significant contribution to data interpretation; authored
full first draft of manuscript and reviewed manuscript.
D. Checketts: data interpretation during trial reporting; reviewed
the manuscript.
B. Tayo: trial design, data interpretation, manuscript review, and
medical monitoring during the trial.
K. Sommerville: trial design, data interpretation, manuscript review,
and monitoring during the trial.
All authors provided final approval of the version to be published.
Declaration of competing interest
All authors met the International Committee of Medical Journal
Editors authorship criteria. Neither honoraria nor payments were made
for authorship. Lesley Taylor was an employee of GW Research Ltd. at
the time the work was completed. Julie Crockett is an employee of
GW Research Ltd. and has share options in the company. Bola Tayo is
an employee of GW Research Ltd. and owns shares in the company.
Daniel Checketts is an employee of GW Research Ltd. Kenneth
Sommerville was an employee of Greenwich Biosciences, Inc. at the
time the work was completed.
Acknowledgments
The authors would like to thank the trial participants, their families,
and the trial site that participated in this trial, as well as Sue Ditton, BSc,
of GW Research Ltd. for her contributions as the clinical trial manager.
Statistical analysis conducted by PRAHS Biostatistic department: Biosta-
tistics Department, PRA-Health Sciences, Stationsweg 163, 9471 GP
Zuidlaren, The Netherlands.
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	Abrupt withdrawal of cannabidiol (CBD): A randomized trial
	1. Introduction
	2. Methods
	2.1. Trial design
	2.2. Trial population
	2.3. Withdrawal assessments
	2.4. Safety assessments
	2.5. Treatment compliance
	2.6. Statistical analysis
	3. Results
	3.1. Volunteer demographics
	3.2. Volunteer disposition
	3.3. Withdrawal evaluation
	3.4. Treatment compliance
	3.5. Safety
	4. Discussion
	5. Conclusion
	Funding
	Author contributions
	Declaration of competing interest
	Acknowledgments
	References