Available via license: CC BY 4.0
Content may be subject to copyright.
ARTICLE OPEN
Does cannabidiol make cannabis safer? A randomised, double-
blind, cross-over trial of cannabis with four different CBD:THC
ratios
Amir Englund
1,2
✉, Dominic Oliver
2
, Edward Chesney
2
, Lucy Chester
2
, Jack Wilson
3
, Simina Sovi
2
, Andrea De Micheli
2
,
John Hodsoll
4
, Paolo Fusar-Poli
2,5
, John Strang
1,6
, Robin M. Murray
2
, Tom P. Freeman
7
and Philip McGuire
2
© The Author(s) 2022
As countries adopt more permissive cannabis policies, it is increasingly important to identify strategies that can reduce the
harmful effects of cannabis use. This study aimed to determine if increasing the CBD content of cannabis can reduce its harmful
effects. Forty-six healthy, infrequent cannabis users participated in a double-blind, within-subject, randomised trial of cannabis
preparations varying in CBD content. There was an initial baseline visit followed by four drug administration visits, in which
participants inhaled vaporised cannabis containing 10 mg THC and either 0 mg (0:1 CBD:THC), 10 mg (1:1), 20 mg (2:1), or 30 mg
(3:1) CBD, in a randomised, counter-balanced order. The primary outcome was change in delayed verbal recall on the Hopkins
Verbal Learning Task. Secondary outcomes included change in severity of psychotic symptoms (e.g., Positive and Negative
Syndrome Scale [PANSS] positive subscale), plus further cognitive, subjective, pleasurable, pharmacological and physiological
effects. Serial plasma concentrations of THC and CBD were measured. THC (0:1) was associated with impaired delayed verbal
recall (t(45) =3.399, d=0.50, p=0.001) and induced positive psychotic symptoms on the PANSS (t(45) =−4.709, d=0.69,
p=2.41 × 10
–5
). These effects were not significantly modulated by any dose of CBD. Furthermore, there was no evidence of CBD
modulating the effects of THC on other cognitive, psychotic, subjective, pleasurable, and physiological measures. There was a
dose-response relationship between CBD dose and plasma CBD concentration, with no effect on plasma THC concentrations. At
CBD:THC ratios most common in medicinal and recreational cannabis products, we found no evidence that CBD protects against
the acute adverse effects of cannabis. This should be considered in health policy and safety decisions about medicinal and
recreational cannabis.
Neuropsychopharmacology; https://doi.org/10.1038/s41386-022-01478-z
INTRODUCTION
Several countries and US states have decriminalised or legalised
cannabis use, and many permit the use of cannabis preparations
for medicinal purposes. Over a similar period, the potency of
cannabis, as indexed by its Δ9-tetrahydrocannabinol (THC)
content, has been progressively increasing [1]. THC can cause
acute impairments in memory and attention and psychotic
symptoms among infrequent users [2–4]. In the longer term,
using cannabis with a high THC content may increase the risk of
developing a psychotic disorder [5] and cannabis use disorder [6].
As well as THC, cannabis also contains cannabidiol (CBD), which
has very different effects. CBD does not impair cognitive
performance, and has antipsychotic properties [7]. Both frequent
and infrequent cannabis users who smoke varieties of cannabis
with a high CBD content have a lower risk of cognitive
impairments [8] and psychotic symptoms [9]. Some studies in
infrequent users have reported that pre-treatment with CBD
attenuates acute THC-induced memory impairments and psycho-
tic symptoms [10], but others, in more frequent users, have not
[11].
These findings suggest that cannabis with a relatively high
CBD:THC ratio may be less likely to have adverse effects than
cannabis with a low CBD:THC ratio. The present study sought to
investigate this by examining the acute effects of cannabis
containing four different CBD:THC ratios (0:1, 1:1, 2:1 and 3:1) on
cognitive performance and psychotic symptoms in healthy
volunteers. These ratios were selected to reflect the CBD:THC
ratios typically found in recreational cannabis, and in medicinal
cannabis products [1,12,13]. We tested the hypothesis that
administration of cannabis with higher CBD:THC ratios would be
associated with less memory impairment and fewer psychotic
symptoms.
Received: 23 June 2022 Revised: 5 October 2022 Accepted: 10 October 2022
1
National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 4 Windsor Walk, SE5 8AF London, UK.
2
Department of Psychosis Studies,
Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 16 De Crespigny Park, SE5 8AF London, UK.
3
The Matilda Centre for Research in Mental Health and
Substance Use, The University of Sydney, Level 6, Jane Foss Russell Building, G02, Sydney 2006 NSW, Australia.
4
Department of Biostatistics and Health Informatics, Institute of
Psychiatry, Psychology and Neuroscience, King’s College London, 16 De Crespigny Park, SE5 8AF London, UK.
5
Department of Brain and Behavioural Sciences, University of Pavia,
Pavia, Italy.
6
South London & Maudsley, NHS Foundation Trust, Maudsley Hospital, London, UK.
7
Department of Psychology, University of Bath, Claverton Down, Bath BA2 7AY,
UK. ✉email: Amir.englund@kcl.ac.uk
www.nature.com/npp
1234567890();,:
METHODS
The study was approved by the King’s College London Research Ethics
Committee (RESCMR-16/17-4163). All participants provided written
informed consent and the study was conducted in compliance with the
principles of Good Clinical Practice, the Declaration of Helsinki (1996). The
study was registered on Open Science Framework (https://osf.io/kt3f7) and
clinicaltrials.gov (NCT05170217).
Design
This randomised, double-blind, four-arm, within-subjects study was
conducted at the NIHR Wellcome Trust Clinical Research Facility (CRF) at
King’s College Hospital, London, UK (randomisation and masking described
in Appendix pp2). Participants attended a baseline session, followed by
four experimental visits, with a minimum one-week wash-out period
between each experimental visit (average duration between experiments
was 24 days).
Participants
Forty-six healthy volunteers (age 21–50 years), who had used cannabis at
least once in the past, but had not used cannabis >1/week over the last
12 months, had never used synthetic cannabinoids, and did not have a
substance use disorder were recruited. Additional inclusion/exclusion
criteria are listed in Appendix pp2.
Procedure (Fig. 1)
At baseline, participants were assessed for study eligibility, and practiced
the inhalation procedure. At baseline and all experimental visits, urine drug
and pregnancy screen as well as alcohol and carbon monoxide breath tests
(<10 ppm CO to verify 12 h tobacco abstinence) were completed.
Participants were asked to avoid using cannabis and all other illicit drugs
during the entire course of the study, including the periods between
sessions.
Prior to each experimental visit participants had their usual breakfast
and amount of caffeine –caffeine was not allowed again until completion
of cognitive tests. An intravenous cannula was inserted before participants
were administered vaporised cannabis (detailed below). Fifteen minutes
after the completion of cannabis inhalation, participants completed a
battery of cognitive tasks (30–35 min). This was followed by assessments of
pleasurable responses to cannabis as well as a ‘hospital walk’(15 min), a
task previously been found to increase paranoia following THC [14]. In this
task, participants were given £2 to purchase an item of their choice from a
till operator in the hospital shop and to ask for a receipt before returning to
the CRF. The research team observed from a distance for safety purposes.
Participants were then given lunch and enough of a break to allow any
intoxicating effects to wear off. When participants felt that at least 90% of
the drug effect had subsided they completed the psychological
questionnaires (CAPE, PSI and SSPS, detailed below) and a semi-
structured clinical interview (PANSS-P, detailed below). This approach
allows the scales to capture all the symptoms which have occurred
throughout the experiment, as opposed to those that are evident at a
particular time point. We have previously found that assessing participants
after the maximal phase of acute intoxication has subsided increases the
likelihood of them disclosing delusional thoughts or suspiciousness
[10,15]. Participants were discharged after a field sobriety test, having
been informed of safety protocols, and provided with a 24 h emergency
number.
Study drug and administration
The study drug was provided in the form of granulated cannabis
inflorescence by Bedrocan BV (Netherlands) produced in accordance with
Good Manufacturing Practice and confirms to the European Medicines
Agency’s contaminant levels for products used in the respiratory tract.
Each cannabis dose consisted of 10 mg of THC (two standard THC units
[16]) and either 0 mg, 10 mg, 20 mg, or 30 mg of CBD. Participants were
given preparations with CBD:THC ratios of 0:1, 1:1, 2:1, and 3:1, in a random
order across visits. Bedrocan (22.6% THC, 0.1% CBD), Bedrolite (7.5% CBD,
0.3% THC) and Bedrocan placebo (<0.01% THC) were used to provide
cannabis containing THC, CBD and placebo, respectively. The placebo
cannabis was added to ensure that all preparations had the same weight
(see Appendix pp4).
Cannabis preparations were administered using a Volcano®Medic
Vaporiser (Storz-Bickel GmbH, Tüttlingen, Germany). Each preparation was
vaporised at 210 °C into a transparent polythene bag. This temperature has
been found to maximise cannabinoid delivery [17]. Once filled, the
transparent bag was encased with an opaque bag to ensure blinding (a
higher CBD:THC ratio produces a denser vapour). Inhalation was
standardised by asking participants to hold their breath for 8 s before
exhaling, with an 8 s break between inhalations (as described in [18]).
Participants were asked to inhale a comfortable amount of vapour on each
inhalation to minimise the risk of loss of study drug through coughing. The
procedure continued until the contents of two bags had been emptied –
all participants successfully inhaled the entire contents of both bags on all
visits. The inhalation duration of each visit was recorded, and the severity
of participant coughing was rated by the researchers using a visual
analogue scale. A cup of warm lemon and honey water was provided to
help with the abrasiveness of cannabis inhalation.
Blood collection and analysis
Venous blood samples were taken before drug administration, and at 0, 5,
15, and 90 min following the final exhalation, alongside blood pressure,
heart rate and temperature. The concentration of Δ9-THC, 11-OH-Δ9-
THC (OH-THC), 11-COOH-Δ9-THC (COOH-THC), CBD and 7-OH-CBD were
determined using high performance LC/MS at the Mass Spectrometry
Facility, KCL [19].
Cognitive tasks
Hopkins verbal learning task—Revised (HVLT-R) [20]. A researcher read out
a list of 12 words to the participant, who then repeated the list back. This
was repeated over three trials, with the total number of words recalled
indexing immediate recall. 20–25 min later participants were asked to
Fig. 1 Timeline of baseline and experimental sessions (baseline did not include bloods or return to sobriety).
A. Englund et al.
2
Neuropsychopharmacology
recall the words again, indexing delayed recall. The percentage of correctly
recalled words indexed retention. Recalled words that were related to the
words in the original list, but not part of it, were defined as intrusions.
Repetitions referred to the number of times a correctly recalled word was
repeated. A different word list was used on each study visit and the order
was randomised.
Forward and reverse digit span. Digit span is a measure of verbal working
memory and attention, involving the recall of sequences of numbers with
increasing length (WAIS-III). Beginning with three digits on forward and
two digits on reverse, the task ceased when the participant failed two
consecutive attempts at a number sequence.
Spatial N-back [21]. Participants responded to a visual stimulus appearing
in one of eight locations, with task demand varied across 0-back, 1-back,
and 2-back conditions. Participants were required to indicate (by pressing
a Yes or No button) whether the stimulus appeared at the 12 o’clock
position (0-back), the same position as the previous visual stimulus (1-
back), or the same position as the visual stimulus two previous (2-back).
Psychological measures
Positive and negative syndrome scale—positive subscale (PANSS-P)
[22]. The PANSS-P is an investigator-rated semi-structured interview,
which assesses positive psychotic symptoms (delusions, conceptual
disorganisation, hallucinations, hyperactivity, grandiosity, suspiciousness,
and hostility). Information from this assessment was supplemented by the
researcher’s observations of, and interactions with the participant, while
they were intoxicated.
State social paranoia scale (SSPS) [23]. The SSPS was used to assess
persecutory thoughts.
Community assessment of Psychic Experiences—state (CAPE-state) [24]. The
CAPE-state is a self-rated scale and was used to assess psychotic-like
experiences.
Psychotomimetic states inventory (PSI) [25]. The PSI questionnaire was
used to assess psychotic-like experiences following the use of
cannabis use.
Visual analogue scales (VAS). VAS were used to measure subjective effects
along a continuum. Participants marked on a 100 mm horizontal line to
indicate the level of a given feeling at that moment (0mm ‘Not at all’to
100 mm ‘Extremely’). The feeling states included: ‘feel drug effect’,‘like drug
effect’,‘want more drug’,‘mentally impaired’,‘dry mouth’,‘enhanced sound
perception’,‘enhanced colour perception’,‘want food’,‘want alcohol’,‘high’,
‘calm and relaxed’,‘tired’,‘anxious’,‘paranoid’,‘stoned’, and ‘pleasure’.VAS
were administered 5 times over the course of the experimental session: pre-
drug, 10 min post-drug, after cognitive assessment, after the hospital walk,
and finally before discharge. In order to explore drug effects over time, area
under the curve (AUC) analyses we included as well as peak effects.
Pleasurable responses. Pleasurable effects of cannabis were assessed by
the participant rating their enjoyment of a piece of either milk (Marabou)
or dark (Lindt 70%) chocolate, and a self-selected piece of music, on a
visual analogue scale (VAS), ranging from −5to+5 on a 100 mm line. The
centre of the line (indicated by 0) indicates that the chocolate and music is
enjoyed as much as it was at baseline. A negative score indicates that they
were enjoyed less compared to baseline, while a positive score indicates
that they were more enjoyable.
Statistical analysis
According to our power calculation, at 80% power and Bonferroni adjusted
alpha <0.008, a sample size of n=45 will give a target ES of d=0.5 as a
minimum difference of interest for any of the 6 comparisons. The full
power calculation for the study is presented in Appendix pp3.
The effect of THC was determined by comparing outcome scores from
the baseline visit with those following administration with THC alone (0:1)
using paired t-tests. For the primary analysis, we used linear mixed models
to assess the effect of varying the CBD:THC ratio on delayed recall on the
HVLT-R. The four CBD:THC ratios (0:1, 1:1, 2:1, 3:1) were included as a fixed
effect, with participant as a random effect to account for the dependency
between repeated measures. All 6 contrasts were of interest (0:1 vs 1:1, 0:1
vs 2:1, 0:1 vs 3:1, 1:1 vs 2:1, 1:1 vs 3:1, 2:1 vs 3:1) and alpha was set
according to the results of our power calculation at p< 0.008 with the
expectation that modulatory effects of CBD could emerge in any one of
these comparisons. The same analysis was used for secondary pharma-
cokinetic, cognitive, psychological, pleasurable, and physiological out-
comes. To account for any potential order effects, sensitivity analyses were
conducted adding visit into the model as a fixed effect.
For pharmacokinetics, VAS scores and physiological outcomes, both
peak effects (0 min for pharmacokinetic and physiological outcomes) and
area under the curve (AUC) were investigated. For the AUC analyses, values
were baseline corrected before using the spline method using the
bayestestR package (version 0.7.5.1) [26]. Potential differences in VAS
scores for ‘feel paranoid’between the ‘post-cognition’and ‘post-walk’
timepoints were assessed using paired t-tests to assess the effect of the
walk on paranoia.
The relationships between both inhalation time and coughing with peak
plasma THC and CBD, in addition with their respective AUCs, were assessed
using Pearson’s correlation coefficients.
We additionally categorised clinically significant psychotic-like reactions
as increases in PANSS scores from baseline of ≥3 points, as in previous
studies due to floor effects [27,28]. Similarly, we categorised any increase
in SSPS score from baseline. The difference in the frequency of these
reactions across CBD:THC ratios was analysed using Pearson’s Chi-
square test.
Multiple imputation chain equations (MICE) were used to impute
missing values in pharmacokinetic, cognitive, pleasurable, and physiolo-
gical outcomes using the mice package (version 3.13.0) [29], following no
detection of deviation from missing completely at random (MCAR) based
on Little’s MCAR test.
All analyses were conducted using R version 3.5.3. lme4 (version 1.1-26)
[30] was used to fit the linear mixed effects models and estimated marginal
mean (EMM) contrasts were calculated using the emmeans package
(version 1.5.2-1) [31].
RESULTS
Participants and demographics
80 potential participants were screened from which 64 were
randomised and 46 completed the study (Fig. 2) between
Fig. 2 Study flow diagram.
A. Englund et al.
3
Neuropsychopharmacology
November 2017 and June 2019. Of the 18 randomised participants
who were later excluded (one excluded at completion, two
following the second visit, and the remaining did not complete
their first visit), 12 dropped out due to unpleasant drug effects,
one due to a positive drug screen, one due to an absence of
subjective and objective THC effects, and four for reasons
unrelated to study procedures. Of the participants who dropped
out on their first visit significantly more dropped out after
receiving 3:1, although there was no statistical difference between
number of sessions stratified by visit and CBD:THC ratio
(Appendix pp5). Demographics for participants who completed
the study compared with those who dropped out are presented in
Table 1. All analyses were restricted to data from subjects (n=46)
with complete datasets.
Pharmacokinetics
There were no significant differences in either peak plasma THC,
OH-THC or COOH-THC, or their respective AUCs between the
CBD:THC ratios (p>0.008, Fig. 3A, Appendix pp6–12). In contrast,
there was a significant, dose-dependent increase in peak plasma
CBD, and in plasma CBD AUC, as CBD:THC ratio increased (p<0.001,
Fig. 3B, Appendix pp6–12). Peak plasma 7-OH-CBD was higher for
the 3:1 ratio compared to 0:1 (EMM difference =2.686, 95%CI:
1.888, 3.483, p=1.25 × 10
−9
) and 1:1 (EMM difference =2.206, 95%
CI: 1.551, 2.861, p=0.002), with AUC higher for 2:1 compared to 0:1
(EMM difference =4.676, 95% CI: 3.287, 6.064, p=0.003) and for 3:1
compared to 0:1 EMM difference =8.898, 95%CI: 6.256, 11.540,
p=1.71 × 10
−9
) and 1:1 (EMM difference =6.843, 95% CI: 4.811,
8.875, p=3.57 × 10
−6
). Logarithmic concentrations of THC and CBD
over time, with intercept and slope across ratios are presented in
Appendix pp13–14.
Cognitive effects
Hopkins verbal learning task. When the 0:1 condition (THC only)
was compared to baseline, there were impairments in both
immediate (t(45) =5.580, d=0.82, p=1.31 × 10
−6
) and delayed
recall (t(45) =3.399, d=0.50, p=0.001), and higher rates of
intrusion in both conditions (t(45) =−3.824, d=0.56,
p=4.02 × 10
−4
; t(45) =−3.322, d=0.49, p=0.002). However,
there were no significant differences on any measure of
performance between the different CBD:THC ratios (p> 0.008,
Fig. 4A, B, Appendix pp15–23).
Digit span. There was significant impairment in the 0:1 condition
compared to baseline in forward digit span (t(45) =3.309,
d=0.49, p=0.002), but not for reverse digit span (t(45) =2.361,
d=0.35, p=0.023). There were no significant differences in either
Table 1. Demographics and cannabis use at baseline.
Completers
(n=46)
Drop-outs
(n=17)
Sex; N(%)
Male 25 (54.3) 6 (35.3)
Female 21 (45.7) 11 (64.7)
Age; Mean (SD) 26.62 (4.94) 25.88 (4.41)
Ethnicity; N(%)
White 31 (67.4) 12 (70.6)
Asian 11 (23.9) 1 (5.9)
Mixed 3 (6.5) 4 (23.5)
Black 1 (2.2) 0 (0)
Education; N(%)
A Levels 9 (19.6) 2 (11.8)
Vocational 0 (0) 1 (5.9)
University/Professional
qualification (degree+)
18 (39.1) 11 (64.7)
Postgraduate degree 19 (41.3) 3 (17.6)
Weight (kg); Mean (SD) 70.68 (11.3) 66.14 (1.97)
BMI (kg/m
2
); Mean (SD) 23.72 (2.57) 22.62 (1.97)
Body Fat (%)- Male;
Mean (SD)
15.56 (5.50) 11.76 (3.67)
Body Fat (%)- Female;
Mean (SD)
25.50 (6.33) 24.47 (3.27)
Age of first cannabis use;
Mean (SD)
17.67 (2.46) 16.71 (2.02)
Years of cannabis use;
Median (IQR)
5.50 (6.5) 5.00 (3.00)
Cannabis use occasions in
last year; Median (IQR)
5.00 (6.00) 3.00 (7.00)
Fig. 3 Blood plasma THC and CBD concentrations over time and
across CBD:THC ratio. Plasma concentrations of ATHC, BCBD at
each time point, stratified by CBD:THC ratio. Circles show individual
data points, diamonds show mean values and boxplots show
median and interquartile range. CBD:THC ratios 0:1 (orange) 1:1
(green); 2:1 (pink); 3:1 (blue).
A. Englund et al.
4
Neuropsychopharmacology
forward or reverse digit span between the CBD:THC ratios
(p> 0.008, Appendix pp16–20).
Spatial N-Back. There were no significant differences between
baseline and 0:1, or between CBD:THC ratios (p> 0.008,
Appendix pp16–21).
Psychological effects
PANSS positive subscale. There was a significant increase in
PANSS positive score between baseline and 0:1 (t(45) =−4.709,
d=0.69, p=2.41 × 10
−5
). 24 participants (52.2%) had an increase
of 3 points on the PANSS on at least one visit across 47 visits
(25.5%) with a PANSS response (n=12 (26.1%) in the 0:1
condition, n=10 (21.7%) in the 1:1 condition, n=15 (32.6%) in
the 2:1 condition, n=10 (21.7%) in 3:1 condition). There were no
significant differences in PANSS positive scores (p> 0.008, Fig. 4C,
Appendix pp25–26) or PANSS response (X
2
(3, n=46) =2.202,
d=0.44, p=0.532) between CBD:THC ratios.
SSPS. There were no significant differences in SSPS scores
between baseline and 0:1, between CBD:THC ratios
(t(45) =−1.096, d=0.16, p=0.279, Appendix pp24–27), or SSPS
response between CBD:THC ratios (X
2
(3, n=46) =5.4474,
d=0.73, p=0.142).
CAPE. There was a significant increase in total CAPE score
between baseline and 0:1 (t(45) =−4.088, d=0.60, p=0.0002)
but not between CBD:THC ratios (p> 0.008, Appendix pp24–26).
PSI. There was a significant increase in total PSI score between
baseline and 0:1 (t(39) =−7.461, d=1.18, p=5.025 × 10
−9
) but
not between CBD:THC ratios (p> 0.008, Appendix pp24–27).
VAS. There were no significant differences in subjective effects
between CBD:THC ratios in terms of either VAS AUC or peak VAS
ratings (p> 0.008, Appendix pp28–42). There were no significant
correlations between VAS measures of feeling high (either peak or
AUC) with plasma THC or CBD (either peak or AUC) (p > 0.008,
Appendix pp51–52).
Pleasurable responses. All CBD:THC ratios increased scores for
both chocolate and music compared to baseline, but there were
no significant differences between the CBD:THC ratios (p> 0.008,
Appendix pp43–45).
Physiological effects
Blood pressure. There were no significant differences in systolic
(t(44) =−1.19, d=0.18, p=0.240) or diastolic blood pressure
between baseline and the 0:1 condition (t(44) =0.312, d=0.05,
p=0.756). There were no significant differences between
CBD:THC ratios in peak systolic, diastolic blood pressure or AUC
(p> 0.008, Appendix pp46-49).
Heart rate. There was a significant increase in heart rate in the 0:1
condition compared to baseline (t(44) =−9.35, d=1.39, p=5.06 ×
10
−12
).There were no significant differences between CBD:THC
ratios in peak heart rate or AUC (p> 0.008, Appendix pp46–49).
Fig. 4 Immediate and delayed verbal recall, and psychotic symptoms across CBD:THC ratios compared to baseline. A HVLT-R Immediate
recall (number of words recalled across three encoding trials) BHVLT-R Delayed recall (number of words recalled from encoding phase).
CPANSS positive subscale symptom score. Circles show individual data points, diamonds show mean values, boxplots show median and
interquartile range, and half violin plots show distribution of participant scores. Baseline (B; grey), CBD:THC ratios 0:1 (orange) 1:1 (green); 2:1
(pink); 3:1 (blue).
A. Englund et al.
5
Neuropsychopharmacology
Body temperature. There were no significant differences in body
temperature between any of the conditions (Appendix pp46–50).
Inhalation and coughing. There was evidence of greater CBD:THC
ratios increasing inhalation time and coughing in a dose
responsive manner (Appendix pp46–50). Greater inhalation time
was correlated with lower peak and AUC concentrations of
cannabinoids at higher CBD:THC ratios (Appendix pp51–52).
Order and sex effects. Adding order to the models did not have
any impact on the significance or direction of pharmacokinetic,
cognitive, psychological, subjective, pleasurable, or physiological
effects. Restricting the analysis of the primary outcome to visit 1
found no differences across conditions, suggesting no evidence
for significant practice or fatigue effects (Appendix pp53). There
were no additional significant differences when analysis was
stratified by sex on any measure (Appendix pp54–90).
DISCUSSION
Our main finding is that the co-administration of CBD with THC
had no effect on the induction of either cognitive impairments or
psychotic symptoms following cannabis use. Similarly, CBD did not
influence the subjective (as measured by VAS) or the pleasurable
effects (music and chocolate) of THC. This was true across the
range of CBD:THC dose ratios that are typically present in both
recreational and medicinal cannabis [13]. Because we detected
robust effects of THC on cognitive performance and psychotic
symptoms and studied a relatively large number of subjects (given
the within-subject design), it is unlikely that the absence of a
modulatory effect of CBD was due to a lack of statistical power.
Furthermore, THC failed to show a significant effect on reverse
digit span, spatial N-back, SSPS, blood pressure and body
temperature.
Using a within-subjects design minimised the potentially
confounding effects of inter-individual differences in responses
to THC and CBD [32], while confounding effects of previous
cannabis use and of placebo responses were reduced by ensuring
that the participants were infrequent users and were blind to the
content of the preparations. Some participants dropped out of the
study because they could not tolerate the symptomatic effects of
THC, raising the possibility that those who completed it may have
been less sensitive to these effects. However, among those who
completed the study, THC induced significant changes on three
independent psychopathological instruments, as well as signifi-
cant impairments in memory and attention. Furthermore, there
was a significantly greater number of participants who dropped
out on their first visit when administered the 3:1 ratio. However, as
we did not observe a dose response, we find it unlikely that there
was a specific CBD effect on drop-outs. Previous studies have
found that females experience similar subjective effects of
cannabis to males at lower doses of THC, suggesting a greater
sensitivity towards cannabinoids [33]. However, in the present
study, we found no additional differences when stratifying
analyses by sex on any measure, across all CBD:THC ratios—
suggesting that females and males respond the same to cannabis
when administered the same dose. However, our study was not
powered to explore sex differences and further studies with larger
male and female subgroups may be needed to clarify if such
differences exist.
Including an additional placebo arm might have made it easier
to establish the effects of THC. However, the focus of the study
was to compare cannabis with different CBD:THC ratios, rather
than to examine the effects of THC alone. The latter have been
described in previous studies, and the cognitive and psychological
effects of THC that we observed relative to baseline were in line
with those reported relative to placebo in infrequent users [2,3].
Serial measurements of the plasma concentrations of CBD, THC
and their metabolites indicated that the findings were not
attributable to pharmacokinetic effects. However, longer inhala-
tion time was associated with decreased peak and AUC plasma
CBD and THC, although only within higher CBD:THC ratios.
Our findings are consistent with previous reports that co-
administration of CBD with THC did not alter the effects of THC on
memory, psychotic symptoms [11], performance on a reward task
(in frequent users) [18], or driving (in infrequent users) [34].
Studies that examined the impact of pre-treatment with CBD on
the effects of THC have had more mixed results. Pre-treatment
with oral CBD did not alter the effect of THC on attention and
processing speed in infrequent users [35], and did not change the
subjective effects of inhaled THC in frequent cannabis users [36].
In contrast, two studies in infrequent users reported that
administration of CBD prior to intravenous THC attenuated the
induction of psychotic symptoms and memory impairments
[27,37]. The latter studies used relatively large doses of CBD
(5 mg i.v. and 600 mg orally, respectively), raising the possibility
that we might have seen similar effects if we had used cannabis
with higher CBD:THC ratios than those usually present in
recreational and medicinal cannabis. However, higher CBD:THC
ratios may be impractical when inhaled as a previous study found
participants were only able to inhale 62.5% of the high-CBD
condition (50:1 CBD:THC ratio; 400 mg CBD, 8 mg THC) [38].
There are other mechanisms by which cannabis with higher
CBD:THC ratios may be less harmful to users. The cannabis plant
produces both THC and CBD (in their acid forms) from a precursor
named cannabigerolic acid [39], which implies that a plant with a
higher CBD:THC ratio will produce less THC than a THC-dominant
one. The purported reduced risk from using high CBD varieties
(cognitive impairment and psychosis) may thus not be an effect of
the high CBD content, but due to the relatively low THC content.
This issue could be addressed in studies with a similar design to
the present one, but with experimental manipulation of the dose
of THC, rather than of CBD. Lastly, the present study found that
CBD did not acutely protect against the effects of THC - future
studies should explore if the presence of CBD in cannabis may
protect against the long-term harms of cannabis use.
CONCLUSIONS
At the doses typically present in recreational and medicinal
cannabis, we found no evidence of CBD reducing the acute
adverse effects of THC on cognition and mental health. Similarly,
there was no evidence that it altered the subjective or pleasurable
effects of THC. These results suggest that the CBD content in
cannabis may not be a critical consideration in decisions about its
regulation or the definition of a standard THC unit [16,40]. The
data are also relevant to the safety of licensed medicines that
contain THC and CBD, as they suggest that the presence of CBD
may not reduce the risk of adverse effects from the THC they
contain. Cannabis users may reduce harms when using a higher
CBD:THC ratio, due to the reduced THC exposure rather than the
presence of CBD. Further studies are needed to determine if
cannabis with even higher ratios of CBD:THC may protect against
its adverse effects.
REFERENCES
1. Freeman TP, Craft S, Wilson J, Stylianou S, ElSohly M, Di Forti M, et al. Changes in
delta‐9‐tetrahydrocannabinol (THC) and cannabidiol (CBD) concentrations in
cannabis over time: systematic review and meta‐analysis. Addiction.
2021;116:1000–10.
2. D’Souza DC, Perry E, MacDougall L, Ammerman Y, Cooper T, Wu Y, et al. The psy-
chotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy indivi-
duals: implications for psychosis. Neuropsychopharmacology. 2004;29:1558–72.
3. Morrison PD, Zois V, McKeown DA, Lee TD, Holt DW, Powell JF, et al. The acute
effects of synthetic intravenous Delta9-tetrahydrocannabinol on psychosis, mood
and cognitive functioning. Psychol Med. 2009;39:1607–16.
A. Englund et al.
6
Neuropsychopharmacology
4. Kleinloog D, Liem-Moolenaar M, Jacobs G, Klaassen E, de Kam M, Hijman R, et al.
Does olanzapine inhibit the psychomimetic effects of Δ
9
-tetrahydrocannabinol? J
Psychopharmacol. 2012;26:1307–16.
5. Di Forti M, Quattrone D, Freeman TP, Tripoli G, Gayer-Anderson C, Quigley H, et al.
The contribution of cannabis use to variation in the incidence of psychotic disorder
across Europe: the EUGEI case-control study. Lancet Psychiatry. 2019;6:427–36.
6. Freeman TP, Winstock AR. Examining the profile of high-potency cannabis and its
association with severity of cannabis dependence. Psychol Med. 2015;45:3181–9.
7. McGuire P, Robson P, Cubala WJ, Vasile D, Morrison PD, Barron R, et al. Canna-
bidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter random ized
controlled trial. Am J Psychiatry. 2018;175:225–31.
8. Morgan CJA, Schafer G, Freeman TP, Curran HV. Impact of cannabidiol on the
acute memory and psychotomimetic effects of smoked cannabis: naturalistic
study: naturalistic study [corrected]. Br J Psychiatry. 2010;197:285–90.
9. Morgan CJA, Curran HV. Effects of cannabidiol on schizophrenia-like symptoms in
people who use cannabis. Br J Psychiatry. 2008;192:306–7.
10. Englund A, Morrison PD, Nottage J, Hague D, Kane F, Bonaccorso S, et al. Can-
nabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent
memory impairment. J Psychopharmacol. 2013;27:19–27.
11. Morgan CJA, Freeman TP, Hindocha C, Schafer G, Gardner C, Curran HV. Indivi-
dual and combined effects of acute delta-9-tetrahydrocannabinol and cannabi-
diol on psychotomimetic symptoms and memory function. Transl Psychiatry.
2018;8:181.
12. Davenport S. Price and product variation in Washington’s recreational cannabis
market. Int J Drug Policy. 2021;91:102547.
13. Pennypacker SD, Cunnane K, Cash MC, Romero-Sandoval EA. Potency and ther-
apeutic THC and CBD ratios: U.S. Cannabis markets overshoot. Front Pharm.
2022;13:1–9.
14. Freeman D, Dunn G, Murray RM, Evans N, Lister R, Antley A, et al. How cannabis
causes paranoia: using the intravenous administration of Δ9-Tetra-
hydrocannabinol (THC) to identify key cognitive mechanisms leading to paranoia.
Schizophr Bull. 2015;41:391–9.
15. Englund A, Atakan Z, Kralj A, Tunstall N, Murray R, Morrison P. The effect of five
day dosing with THCV on THC-induced cognitive, psychological and physiolo-
gical effects in healthy male human volunteers: A placebo-controlled, double-
blind, crossover pilot trial. J Psychopharmacol. 2016. 17 November 2016. https://
doi.org/10.1177/0269881115615104.
16. Freeman TP, Lorenzetti V. A standard THC unit for reporting of health research on
cannabis and cannabinoids. Lancet Psychiatry. 2021. 8 October 2021. https://
doi.org/10.1016/S2215-0366(21)00355-2.
17. Hazekamp A, Ruhaak R, Zuurman L, van Gerven J, Verpoorte R. Evaluation of a
vaporizing device (Volcano®) for the pulmonary administration of tetra-
hydrocannabinol. J Pharm Sci. 2006;95:1308–17.
18. Lawn W, Freeman TP, Pope RA, Joye A, Harvey L, Hindocha C, et al. Acute and
chronic effects of cannabinoids on effort-related decision-making and reward
learning: an evaluation of the cannabis ‘amotivational’hypotheses. Psycho-
pharmacol (Berl). 2016;233:3537–52.
19. Desrosiers NA, Himes SK, Scheidweiler KB, Concheiro-Guisan M, Gorelick DA,
Huestis MA. Phase I and II cannabinoid disposition in blood and plasma of
occasional and frequent smokers following controlled smoked cannabis. Clin
Chem. 2014;60:631–43.
20. Brandt J. The hopkins verbal learning test: Development of a new memory test
with six equivalent forms. Clin Neuropsychol. 1991;5:125–42.
21. Freeman TP, Morgan CJA, Vaughn-Jones J, Hussain N, Karimi K, Curran HV.
Cognitive and subjective effects of mephedrone and factors influencing use of a
‘new legal high’. Addiction 2012;107:792–800.
22. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS)
for schizophrenia. Schizophr Bull. 1987;13:261–76.
23. Freeman D, Pugh K, Green C, Valmaggia L, Dunn G, Garety P. A measure of state
persecutory ideation for experimental studies. J Nerv Ment Dis. 2007;195:781–4.
24. Stefanis NC, Hanssen M, Smirnis NK, Avramopoulos DA, Evdokimidis IK, Stefanis
CN, et al. Evidence that three dimensions of psychosis have a distribution in the
general population. Psychol Med. 2002;32:347–58.
25. Mason OJ, Morgan CJM, Stefanovic A, Curran HV. The psychotomimetic states
inventory (PSI): measuring psychotic-type experiences from ketamine and can-
nabis. Schizophr Res. 2008;103:138–42.
26. Makowski D, Ben-Shachar M, Lüdecke D. bayestestR: Describing Effects and their
Uncertainty, Existence and Significance within the Bayesian Framework. J Open
Source Softw. 2019;4:1541.
27. Englund A, Morrison PD, Nottage J, Hague D, Kane F, Bonaccorso S, et al. Can-
nabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent
memory impairment. J Psychopharmacol. 2013;27:19–27.
28. D’Souza DC, Abi-Saab WM, Madonick S, Forselius-Bielen K, Doersch A, Braley G,
et al. Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for
cognition, psychosis, and addiction. Biol Psychiatry. 2005;57:594–608.
29. van Buuren S, Groothuis-Oudshoorn K. Multivariate imputation by chained
equations in R. J Stat Softw. 2011;45:1–67.
30. Bates D, Mächler M, Bolker BM, Walker SC. Fitting linear mixed-effects models
using lme4. J Stat Softw. 2015;67:1–48.
31. Lenth R emmeans: Estimated Marginal Means, aka Least-Squares Means. Russell
Lenth; 2020.
32. Atakan Z. Cannabis, a complex plant: different compounds and different effects
on individuals. Ther Adv Psychopharmacol. 2012;2:241–54.
33. Matheson J, Sproule B, Di Ciano P, Fares A, Le Foll B, Mann RE, et al. Sex differ-
ences in the acute effects of smoked cannabis: evidence from a human labora-
tory study of young adults. Psychopharmacol (Berl). 2020;237:305–16.
34. Arkell TR, Lintzeris N, Kevin RC, Ramaekers JG, Vandrey R, Irwin C, et al. Canna-
bidiol (CBD) content in vaporized cannabis does not prevent tetra-
hydrocannabinol (THC)-induced impairment of driving and cognition.
Psychopharmacol (Berl). 2019;236:2713–24.
35. WoelflT, Rohleder C, Mueller JK, Lange B, Reuter A, Schmidt AM, et al. Effects of
cannabidiol and Delta-9-Tetrahydrocannabinol on emotion, cognition, and
attention: a double-blind, placebo-controlled, randomized experimental trial in
healthy volunteers. Front Psychiatry. 2020;11:1–11.
36. Haney M, Malcolm RJ, Babalonis S, Nuzzo PA, Cooper ZD, Bedi G, et al. Oral
cannabidiol does not alter the subjective, reinforcing or cardiovascular effects of
smoked cannabis. Neuropsychopharmacology. 2015;41:1974–82.
37. Bhattacharyya S, Morrison PD, Fusar-Poli P, Martin-S antos R, Borgwardt S, Winton-
Brown T, et al. Opposite effects of Δ-9-Tetrahydrocannabinol and cannabidiol on
human brain function and psychopathology. Neuropsychopharmacology.
2010;35:764–74.
38. Solowij N, Broyd S, marie Greenwood L, van Hell H, Martelozzo D, Rueb K, et al. A
randomised controlled trial of vaporised Δ9 -tetrahydrocannabinol and canna-
bidiol alone and in combination in frequent and infrequent cannabis users: acute
intoxication effects. Eur Arch Psychiatry Clin Neurosci. 2019;269:17–35.
39. Clarke R, Watson D. Cannabis and Natural Cannabis Medicines. In: ElSohly MA,
editor. Marijuana and the Cannabinoids, Totowa, New Jersey: Humana Press Inc.;
2007. p. 1–15.
40. Freeman TP, Lorenzetti V ‘Standard THC Units’: a proposal to standardise dose
across all cannabis products and methods of administration. Addiction. 2019.
October 2019. https://doi.org/10.1111/add.14842.
ACKNOWLEDGEMENTS
We would like to wholeheartedly thank all the participants who took part in this
study, both the ones who completed as well as the ones who withdrew. We thank
George Brown, John Villajin, Louisa Green, Asha Mathews, Chifundo Stubbs, Olabisi
Awogbemila, Noah Yogo, Elka Giemza, Stephanie David, Adebukola Shopade, and
Herman Rocha of the NIHR Wellcome Trust Clinical Research Facility for supporting
this study. We also thank Storz-Bickel GmbH for generously providing us with the
cannabis vaporisers and related equipment for this study. We would like to thank
Bedrocan BV for their support and advice in supplying the study drug, as well as the
Maudsley Pharmacy for their support in receiving, storing, preparing, and dispensing
of the study drug. We thank GW Pharmaceuticals for kindly providing us with
reference standards for plasma analysis of cannabinoid metabolites, and thanks as
well to the Mass Spectrometry Facility at King’s for analysing the samples. We would
like to thank the following physicians who assisted us with medical screening of
participants: Giulia Spada, Victoria Rodriguez, Graham Blackman, Robert McCutcheon,
Matthew Nour, and Marco Colizzi. As well as a special thanks to Cathy Davies for
helping in the early stages of the study.
AUTHOR CONTRIBUTIONS
AE, TF, RM and PMG conceptualised and designed the study, as well as provided
continuous review and oversight of the running of the study along with PFP and JS.
AE, DO, EC, LC, JW, SS and ADM recruited participants, collected, and interpreted
data. JH set up the randomisation algorithm and contributed to the power analysis
and statistical analysis plan. All authors participated in the writing and editing of this
manuscript and approved the final submitted version. The corresponding authors
had final responsibility for the decision to submit for publication.
FUNDING
This study was fully funded by a Research Grant from the Medical Research Council
UK (MR/P006841/1). The funder had no involvement in the design, data collection,
analysis, interpretation, write up or the decision of where to publish. AE, LC, JH, RMM,
and JS are part-funded or supported by the National Institute for Health Research
(NIHR) Maudsley Biomedical Research Centre at South London and Maudsle y NHS
Foundation Trust and King’s College London. The views expressed are those of the
A. Englund et al.
7
Neuropsychopharmacology
author(s) and not necessarily those of the NHS, the NIHR or the Department of Health
and Social Care.
COMPETING INTERESTS
AE has received speakers’honoraria from GW Pharmaceuticals. RMM has received
speakers’honoraria from Lundbeck, Sunovian, Otsuka, and Janssen. JS has
undertaken research supported financially by various pharmaceutical companies,
but this has not involved studies of cannabis or cannabis-related products. All
remaining authors report no conflicting interests.
ADDITIONAL INFORMATION
Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s41386-022-01478-z.
Correspondence and requests for materials should be addressed to Amir Englund .
Reprints and permission information is available at http://www.nature.com/
reprints
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims
in published maps and institutional affiliations.
Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons licence, and indicate if changes were made. The images or other third party
material in this article are included in the article’s Creative Commons licence, unless
indicated otherwise in a credit line to the material. If material is not included in the
article’s Creative Commons licence and your intended use is not permitted by statutor y
regulation or exceeds the permitted use, you will need to obtain permission directly
from the copyright holder. To view a copy of this licence, visit http://
creativecommons.org/licenses/by/4.0/.
© The Author(s) 2022
A. Englund et al.
8
Neuropsychopharmacology
